HIV/AIDS Guidelines

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1 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019 Visit the AIDS info website to access the most up-to-date guideline. Register for e-mail notification of guideline updates at https://aidsinfo.nih.gov/e-news. Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

2 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Developed by the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents – A Working Group of the Office of AIDS Research Advisory Council (OARAC) How to Cite the Adult and Adolescent Guidelines: Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. Department of Health and Human Services. Available at http://www.aidsinfo.nih.gov/ContentFiles/ AdultandAdolescentGL.pdf . Accessed [insert date] [insert page number, table number, etc. if applicable] It is emphasized that concepts relevant to HIV management evolve rapidly. The Panel has a mechanism to update recommenda- tions on a regular basis, and the most recent information is available on the AIDS info ). Web site ( http://aidsinfo.nih.gov Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

3 What’s New in the Guidelines? (Last updated October 25, 2018; last reviewed October 25, 2018) Resistance Testing New information has been added regarding the use of HIV-1 proviral DNA genotypic resistance tests to identify drug resistance mutations, especially in the setting of low-level viremia or when plasma HIV RNA is below the limit of detection. The section now includes a discussion on the benefits and limitations of these tests. Co-Receptor Tropism Testing For patients who have undetectable HIV RNA, the Panel now recommends using a proviral DNA tropism assay to assess co-receptor usage before maraviroc is initiated as part of a new regimen. Dolutegravir and Association with Neural Tube Defects Preliminary data from Botswana suggest that there is an increased risk of neural tube defects in infants born to women who were receiving dolutegravir (DTG) at the time of conception. In response to these preliminary data, several sections in the Adult and Adolescent Guidelines have been updated to provide guidance for clinicians who are considering the use of DTG or other integrase strand transfer inhibitors (INSTIs) in individuals who are pregnant, or in those of childbearing potential who plan to get pregnant or who are sexually active and not using effective contraception. The sections that have been updated with this new information include: • What to Start • Virologic Failure (formerly Regimen Switching in • Optimizing Antiretroviral Therapy in the Setting of Viral Suppression the Setting of V irologic Suppression) Acute and Recent (Early) HIV-1 Infection • • Adolescents and Young Adults with HIV • Women with HIV What to Start The following changes have been made to the recommendations for initial antiretroviral (ARV) regimens: • Bictegravir/Tenofovir Alafenamide/Emtricitabine (BIC/TAF/FTC): BIC is a new INSTI that is approved by the Food and Drug Administration (FDA) as part of a single-tablet regimen (STR) that also includes TAF and FTC. This regimen is now classified as a Recommended Initial Regimen for Most People with HIV. • Elvitegravir/Cobicistat/Emtricitabine with T enofovir Alafenamide or Tenofovir Disoproxil Fumarate (EVG/c/FTC/TAF or EVG/c/FTC/TDF): These regimens have been moved to the category of Recommended Initial Regimens in Certain Clinical Situations. This change was made because these combinations include cobicistat, a pharmaco-enhancer that inhibits cytochrome P450 3A4 and increases the likelihood of drug-drug interactions. EVG also has a lower barrier to resistance than DTG and BIC. DOR, a new non-nucleoside reverse transcriptase inhibitor , was recently approved Doravirine (DOR): • by the FDA and is available as a single-drug tablet and as part of an STR that also includes TDF i Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

4 and lamivudine (3TC). DOR/TDF/3TC and DOR plus TAF/FTC have been added to the category of Recommended Initial Regimens in Certain Clinical Situations. • Dolutegravir plus Lamivudine (DTG plus 3TC): This two-drug regimen is now one of the regimens to consider when abacavir, TAF, or TDF cannot be used or are not optimal. • new table, Table 6b, has been added to provide guidance to clinicians who are considering the use of A DTG or other INSTIs in those who are pregnant and in those of childbearing potential. • Several new tables (T ables 8a–8d) have been added to the sections for the individual drug classes. These tables compare the characteristics of the different drugs within the classes. • Updates have been made throughout the section with new safety and clinical trial data. Virologic Failure • This section was updated to include newly reported data and new language on recently published clinical trial data for first-line ARV treatment failure. • The Panel notes that, in some persons with multidrug-resistant HIV, DTG may be the only treatment Accordingly, the language on the use of DTG in those of option, or one of few treatment options. childbearing potential has been updated. The section now emphasizes that clinicians and patients should discuss the risk of neural tube defects if pregnancy occurs while the patient is taking DTG, as well as the risk of persistent viremia in the patient and the risk of HIV transmission to the fetus if pregnancy occurs while the patient is not on effective ARV therapy. The decision of whether to initiate or continue DTG should be made after carefully considering these risks. • Ibalizumab (IBA), a CD4 post-attachment inhibitor, was recently approved for use in persons with . A review of the results of a clinical trial on IBA use in this setting has been multidrug-resistant HIV added to the section. Optimizing Antiretroviral Therapy in the Setting of Viral Suppression • The title of this section has been changed from Regimen Switching in the Setting of Virologic Suppression to Optimizing Antiretroviral Therapy in the Setting of Viral Suppression to better reflect the rationale for regimen changes in this setting. • The Panel emphasizes the importance of reviewing all available resistance test results when constructing a new regimen. -1 proviral DNA genotypic resistance testing in detecting archived drug resistance The role of HIV • mutations in the setting of viral suppression is discussed. • The Panel recommends performing pregnancy testing for those of childbearing potential before a regimen switch and provides recommendations for INSTI use in these patients. • Clinical trial data on the use of several ARV combinations in switch studies are updated and discussed in this section. Exposure-Response Relationship and Therapeutic Drug Monitoring Section • This section has been removed from the guidelines. The subsection regarding the role of therapeutic drug monitoring in managing drug-drug interactions has • been moved to the Drug-Drug Interactions section of the guidelines. ii Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

5 Additional Updates Various tables in the guidelines have been updated with new data, as well as information related to BIC and DOR. • Hepatitis C Virus/HIV Coinfection • Adverse Effects of Antiretroviral Agents • Monthly Average Prices of Commonly Used Antiretroviral Drugs • Drug-Drug Interactions Appendix B Tables: Characteristics of Antiretroviral Drugs and Antiretroviral Dosing Recommendations • in Patients with Renal and Hepatic Insufficiency iii Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

6 Table of Contents What’s New in the Guidelines ... i ... Panel Roster viii Financial Disclosure ... x ... A-1 Introduction Table 1. Outline of the Guidelines Development Process ... A-2 Table 2. Rating Scheme for Recommendations A-3 ... Baseline Evaluation ... B-1 Laboratory Testing ... C-1 Laboratory Testing for Initial Assessment and Monitoring of Patients with HIV Receiving ... C-1 Antiretroviral Therapy Table 3. Laboratory Testing Schedule for Monitoring Patients with HIV Before and After Initiation of Antiretroviral Therapy ... C-2 C-7 -1 RNA (Viral Load) and CD4 Count Monitoring ... Plasma HIV Table 4. Recommendations on the Indications and Frequency of Viral Load and CD4 Count Monitoring ... C-10 Testing ... C-13 Drug-Resistance Table 5. Recommendations for Using Drug-Resistance Assays ... C-18 Tropism Assays ... C-23 Co-Receptor C-27 HLA-B*5701 Screening ... Treatment Goals ... D-1 ... E-1 Initiation of Antiretroviral Therapy What to Start ... F-1 Table 6a. Recommended Antiretroviral Regimens for Initial Therapy F-5 ... Table 6b. Considerations Before Initiating Dolutegravir and Other Integrase Strand Transfer Inhibitors as Initial Therapy ... F-6 Table 7. Antiretroviral Regimen Considerations as Initial Therapy based on Specific Clinical Scenarios F-9 ... Table 8a. Characteristics of Dual-Nucleoside Reverse Transcriptase Inhibitor Options Recommended for Antiretroviral Therapy-Naive Patients ... F-13 Table 8b. Characteristics of Integrase Strand Transfer Inhibitors That Are Recommended for Antiretroviral Therapy-Naive Patients ... F-19 T able 8c. Characteristics of Non-Nucleoside Reverse Transcriptase Inhibitors that are ... F-26 Recommended for Antiretroviral Therapy-Naive Patients T able 8d. Characteristics of Protease Inhibitor Options that are Recommended for F-32 ... Antiretroviral Therapy-Naive Patients iv Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

7 Table 9. Advantages and Disadvantages of Antiretroviral Components Recommended as Initial Antir ... etroviral Therapy F-38 ... etroviral Components or Regimens Not Recommended as Initial Therapy Table 10. Antir F-42 What Not to Use ... G-1 ... H-1 Management of the Treatment-Experienced Patient ... H-1 Virologic Failure Table 11. Antiretroviral Options for Patients with Virologic Failure ... H-10 CD4 Cell Recovery and Poor Inflammation Despite Viral Suppression ... H-17 Persistent Optimizing Antiretroviral Therapy in the Setting of ... H-22 Virologic Suppression Agents ...H-31 Exposure-Response Relationship and Therapeutic Drug Monitoring (TDM) for Antiretroviral Discontinuation or Interruption of Antiretroviral Therapy ... H-33 ... I-1 Considerations for Antiretroviral Use in Special Patient Populations ... I-1 Acute and Recent (Early) HIV Infection Table 12. Identifying, Diagnosing, and Treating Acute and Recent HIV-1 Infection ... I-5 Adults with HIV ... Adolescents and Young I-8 HIV and People Who Use Illicit Drugs ... I-16 Women with HIV I-20 ... ... HIV-2 Infection I-29 ... I-34 HIV and the Older Patient ... J-1 Considerations for Antiretroviral Use in Patients with Coinfections ... J-1 Hepatitis B/HIV Coinfection Hepatitis C/HIV Coinfection J-6 ... Table 13. Concomitant Use of Selected Antiretroviral Drugs and Hepatitis C Virus Direct-Acting Antiviral Drugs for Treatment of HCV in Adults with HIV J-9 ... ... Tuberculosis/HIV Coinfection J-14 Limitations to Treatment Safety and Efficacy ... K-1 Adherence to the Continuum of Care ... K-1 Table 14. Strategies to Improve Linkage to Care, Retention in Care, Adherence to Appointments, and Adherence to Antiretroviral Therapy K-7 ... of Antiretroviral Agents Adverse Effects ... K-14 Table 15. Common and/or Severe Adverse Effects Associated with Antiretroviral Therapy ... K-15 Table 16. Antiretroviral Therapy-Associated Adverse Events That Can Be Managed with Substitution of Alternative Antiretroviral Agent K-21 ... ... K-25 Cost Considerations and Antiretroviral Therapy Table 1 7 . Monthly Average Prices of Commonly Used Antiretroviral Drugs ...K-27 Drug-Drug Interactions ... L-1 ... L-3 Table 18. Mechanisms of Antiretroviral-Associated Drug Interactions v Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

8 Table 19a. Drug Interactions between Protease Inhibitors and Other Drugs ... L-5 Table 19b. Drug Interactions between Non-Nucleoside Reverse Transcriptase Inhibitors and ... L-24 Other Drugs Table 19c. Drug Interactions between Nucleoside Reverse Transcriptase Inhibitors and Other Drugs (Including Antiretroviral Agents) ... L-34 Table 19d. Drug Interactions Between Integrase Strand Transfer Inhibitors and Other Drugs ...L-37 Table 19e. Drug Interactions between CCR5 Antagonist (Maraviroc) and Other Drugs L-52 (including Antiretroviral Agents) ... Table 20a. Interactions between Non-Nucleoside Reverse Transcriptase Inhibitors and Protease Inhibitors ... L-55 Table 20b. Interactions between Integrase Strand Transfer Inhibitors and Non-Nucleoside Reverse Transcriptase Inhibitors or Protease Inhibitors ... L-57 Conclusion M-1 ... N-1 Appendix A: Key to Acronyms ... ... Appendix B: Drug Characteristics Tables O-1 Appendix B, Table 1. Characteristics of Nucleoside Reverse Transcriptase Inhibitors ... O-1 Appendix B, Table 2. Characteristics of Non-Nucleoside Reverse Transcriptase Inhibitors ... O-6 Appendix B, Table 3. Characteristics of Protease Inhibitors ... O-9 Appendix B, Table 4. Characteristics of Integrase Inhibitors ... O-15 Appendix B, Table 5. Characteristics of Fusion Inhibitor ... O-17 Appendix B, Table 6. Characteristics of CCR5 Antagonist O-17 ... Appendix B, T able 7. Characteristics of CD4 Post-Attachment Inhibitor O-18 ... Appendix B, Table 8. Antiretroviral Dosing Recommendations in Patients with Renal or ... O-18 Hepatic Insufficiency List of Tables Table 1. Outline of the Guidelines Development Process ... A-2 ... A-3 Table 2. Rating Scheme for Recommendations Table 3. Laboratory Testing Schedule for Monitoring Patients with HIV Before and After ... C-2 Initiation of Antiretroviral Therapy Table 4. Recommendations on the Indications and Frequency of Viral Load and ... C-10 CD4 Count Monitoring ... C-18 Table 5. Recommendations for Using Drug-Resistance Assays Table 6a. Recommended Antiretroviral Regimens for Initial Therapy ... F-5 T able 6b. Considerations Before Initiating Dolutegravir and Other Integrase Strand Transfer Inhibitors as Initial Therapy ... F-6 Specific 7. Antiretroviral Considerations as Initial Therapy based on Regimen Table F-9 Clinical Scenarios ... Table 8a. Characteristics of Dual-Nucleoside Reverse Transcriptase Inhibitor Options F-13 ... Recommended for Antiretroviral Therapy-Naive Patients vi Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

9 Table 8b. Characteristics of Integrase Strand Transfer Inhibitors That Are Recommended for ... Antiretroviral Therapy-Naive Patients F-19 able 8c. Characteristics of Non-Nucleoside Reverse Transcriptase Inhibitors that are T ... F-26 Recommended for Antiretroviral Therapy-Naive Patients able 8d. Characteristics of Protease Inhibitor Options that are Recommended for T Antiretroviral Therapy-Naive Patients ... F-32 T able 9. Advantages and Disadvantages of Antiretroviral Components Recommended as ... Initial Antiretroviral Therapy F-38 T ... F-42 able 10. Antiretroviral Components or Regimens Not Recommended as Initial Therapy Table 11. Antiretroviral Options for Patients with Virologic Failure ... H-10 T able 12. Identifying, Diagnosing, and Treating Acute and Recent HIV-1 Infection ... I-5 Table 13. Concomitant Use of Selected Antiretroviral Drugs and Hepatitis C Virus Direct-Acting Antiviral Drugs for Treatment of HCV in Adults with HIV ... J-9 Table 14. Strategies to Improve Linkage to Care, Retention in Care, Adherence to Appointments, and Adherence to Antiretroviral Therapy ... K-7 Table 15. Common and/or Severe Adverse Effects Associated with Antiretroviral Therapy K-15 ... Table 16. Antiretroviral Therapy-Associated Adverse Events That Can Be Managed with Substitution of Alternative Antiretroviral Agent ... K-21 T ... able 17. Monthly Average Prices of Commonly Used Antiretroviral Drugs K-27 Table 18. Mechanisms of Antiretroviral-Associated Drug Interactions... L-3 Table 19a. Drug Interactions Between Protease Inhibitors and Other Drugs ... L-5 Table 19b. Drug Interactions between Non-Nucleoside Reverse Transcriptase Inhibitors and Other Drugs ... L-24 Table 19c. Drug Interactions between Nucleoside Reverse Transcriptase Inhibitors and Other Drugs (Including Antiretroviral Agents) ... L-34 Table 19d. Drug Interactions between Integrase Inhibitors and Other Drugs ... L-37 Table 19e. Drug Interactions between CCR5 Antagonist (Maraviroc) and Other Drugs (Including Antiretroviral Agents) ... L-52 Table 20a. Interactions between Non-Nucleoside Reverse Transcriptase Inhibitors and Protease Inhibitors ... L-55 T able 20b. Interactions between Integrase Strand Transfer Inhibitors and Non-Nucleoside Reverse ... L-57 Transcriptase Inhibitors or Protease Inhibitors vii Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

10 HHS Panel on Antiretroviral Guidelines for Adults and Adolescents (Last updated October 25, 2018; last reviewed Panel Members and Consultants October 25, 2018) These Guidelines were developed by the Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents (a working group of the Office of AIDS Research Advisory Council). Panel Co-Chairs Roy M. Gulick Weill Cornell Medicine, New York, NY H. Clifford Lane National Institutes of Health, Bethesda, MD Executive Secretary Alice K. Pau National Institutes of Health, Bethesda, MD Scientific Members Judith Aberg Icahn School of Medicine at Mount Sinai, New Y ork, NY Adaora Adimora University of North Carolina School of Medicine, Chapel Hill, NC Allison Agwu Johns Hopkins University, Baltimore, MD Alpert School of Medicine, Brown University, Providence, RI Curt Beckwith University of T exas Southwestern & VA North Texas Health Care System, Dallas, TX Roger Bedimo R. Douglas Bruce Cornell Scott Hill Health Center, New Haven, CT Tucson, AZ J. Kevin Carmichael El Rio Community Health Center, Geetanjali Chander Johns Hopkins University School of Medicine, Baltimore, MD Alpert School of Medicine, Brown University, Providence, RI Susan Cu-Uvin Eric Daar Medical Center, Torrance, CA Harbor-UCLA Rajesh Gandhi Massachusetts General Hospital & Harvard Medical School, Boston, MA Stephen J. Gange Johns Hopkins University, Baltimore, MD Denver Public Health & University of Colorado, Denver, CO Edward Gardner Thomas Giordano Baylor College of Medicine & Michael E. DeBakey V A Medical Center Houston, TX David Glidden University of California San Francisco, San Francisco, CA Peter Hunt University of California San Francisco, San Francisco, CA University of Colorado School of Medicine, Aurora, CO Steven Johnson Rami Kantor Alpert School of Medicine, Brown University, Providence, RI Albert Einstein College of Medicine & Montefiore Medical Center, Bronx, NY Marla J. Keller Michael Kozal Yale School of Medicine & VA Connecticut Healthcare System, New Haven, CT Emory University, Jeffrey Lennox Atlanta, GA Duke University, Durham, NC Susanna Naggie onia Poteat T University of North Carolina School of Medicine, Chapel Hill, NC York, NY Asa Radix Callen-Lorde Community Health Center, New James Raper AL University of Alabama at Birmingham, Birmingham, Daniel Reirden University of Colorado & Children’s Hospital, Colorado, Aurora, CO Kimberly Scarsi University of Nebraska Medical Center, Omaha, NE viii viii Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

11 Serena Spudich ale School of Medicine, New Haven, CT Y University of Nebraska Medical Center , Omaha, NE Susan Swindells University of Pennsylvania, Philadelphia, P A Pablo Tebas AIDS Research Consortium of Atlanta, Atlanta, GA Melanie Thompson Phyllis Tien University of California San Francisco, San Francisco, CA Rochelle Walensky Massachusetts General Hospital & Harvard Medical School, Boston, MA Community Members Los Angeles Women’s HIV/AIDS Task Force, Los Angeles, CA Danielle Campbell Project Inform, Pasadena, CA David Evans T im Horn National Alliance of State and Territorial AIDS Directors, Washington, DC Andy Kaytes AIDS Treatment Activists Coalition, San Diego, CA Steven Vargas Association for the Advancement of Mexican Americans, Houston, TX Members Representing Department of Health and Human Services Agencies John T. Brooks Atlanta, GA Centers for Disease Control and Prevention, Laura Cheever Administration, Rockville, MD Health Resources and Services National Institutes of Health, Bethesda, MD Henry Masur V irginia Sheikh Administration, Silver Spring, MD Food and Drug Kimberly Struble Food and Drug Administration, Silver Spring, MD Non-Voting Observers Nahida Chakhtoura National Institutes of Health, Bethesda, MD Rohan Hazra National Institutes of Health, Bethesda, MD Leidos Biomedical Research, Inc., in support of National Institute of Aller gy and Safia Kuriakose Infectious Diseases, National Institutes of Health, Frederick, MD Pharmacology Consultants Sarita Boyd Food and Drug Administration, Silver Spring, MD Lauren Cirrincione , Omaha, NE University of Nebraska Medical Center Safia Kuriakose gy and Aller Leidos Biomedical Research, Inc., in support of National Institute of Infectious Diseases, National Institutes of Health, Frederick, MD ix Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

12 Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents Financial Disclosure (Reporting Period: February 2018 to February 2019) (page 1 of 2) Panel Member Company (Relationship) Status Judith Aberg M • Frontier Biotechnologies (Research Support) • Gilead (Research Support) • Janssen (Advisory Board) • Merck (Advisory Board) • ViiV (Advisory Board, Research Support) M • Gilead (Consultant, Research Support) Adaora Adimora • Merck (Advisory Board) • ViiV (Consultant) Allison Agwu M • Gilead (Advisory Board) • Merck (Advisory Board) Curt Beckwith M • Gilead (Research Support) Roger Bedimo • Merck (Advisory Board, Research Support) M • Napo Pharmaceuticals (Consultant) • ViiV (Advisory Board, Research Support) John T. Brooks M None R. Douglas Bruce M None Danielle Campbell M • Gilead (Advisory Board) Geetanjali Chander M None Laura Cheever M None M Susan Cu-Uvin None Eric Daar M • Gilead (Consultant, Research Support) • Merck (Research Support) • ViiV (Research Support) M • Gilead (Travel Support) David Evans • Merck (Travel Support) • ViiV (Travel Support) M • Gilead (Advisory Board) Rajesh Gandhi • Merck (Advisory Board M None Stephen J. Gange Edward Gardner M None Thomas Giordano M None David Glidden M • Gilead (Advisory Board) Roy M. Gulick None C Tim Horn M None Peter Hunt M • Gilead (Honoraria, Research Support) • Janssen (Honoraria) • ViiV (Consultant) Steven Johnson M None Rami Kantor M None Andy Kaytes M • ViiV (Travel Support) • CytoDyn (Advisory Board, Honoraria) Marla J. Keller None M Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV x Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

13 Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents Financial Disclosure (Reporting Period: February 2018 to February 2019) (page 2 of 2) Panel Member Company (Relationship) Status Michael Kozal M • Gilead* • ViiV* Yale University receives grant support from these companies for studies where * Dr. Kozal served or serves as PI. Dr. Kozal is an employee of the federal government and does not receive any financial support from these grants. H. Clifford Lane C None Jeffrey Lennox M • Gilead (Advisory Board) • ViiV (Research Support) M None Henry Masur Susanna Naggie M • AbbVie (Research Support) • BioMarin (Advisory Board) • Bristol-Myers Squibb (Event Adjudication Committee) • Gilead (Research Support) • Tacere Therapeutics (Research Support) • Vir Biotechnology (Advisory Board) Alice K. Pau ES None Tonia Poteat M • Gilead (Advisory Board, Research Support) • ViiV (Research Support) M None Asa Radix James Raper None M Daniel Reirden M None Kimberly Scarsi M None Virginia Sheikh M None Serena Spudich M None Kimberly Struble M None Susan Swindells M • ViiV (Research Support) Pablo Tebas M • Gilead (Research Support, Consultant) • Inovio Pharmaceuticals (Research Support) • Janssen (Research Support) • Merck (Research Support, Consultant) • ViiV (Research Support, Consultant) Melanie Thompson M • Bristol-Myers Squibb (Research Support) • CytoDyn, Inc. (Research Support) • Frontier Biotechnologies (Research Support) • Gilead (Research Support) • GlaxoSmithKline (Research Support) • Merck, Sharpe, Dohme, Inc. (Research Support) • ViiV (Research Support) Phyllis Tien M • Merck (Research Support) • Theratechnologies (Research Support) M • ViiV (Honoraria) Steven Vargas None M Rochelle Walensky C = Co-Chair; ES = Executive Secretary; M = Member; PI = Principal Investigator Key to Acronyms: Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV xi Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

14 Introduction (Last updated January 28, 2016; last reviewed January 28, 2016) Antiretroviral therapy (ART) for the treatment of HIV infection has improved steadily since the advent of potent combination therapy in 1996. ART has dramatically reduced HIV-associated morbidity and mortality and has transformed HIV infection into a manageable chronic condition. In addition, ART is highly 1 effective at preventing HIV transmission. However, only 55% of people with HIV in the United States 2 have suppressed viral loads, mostly resulting from undiagnosed HIV infection and failure to link or retain diagnosed patients in care. The Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents (the Panel) is a working group of the Office of AIDS Research Advisory Council (OARAC). The primary goal of the Panel is to provide HIV care practitioners with recommendations based on current knowledge of antiretroviral drugs (ARVs) used to treat adults and adolescents with HIV in the United States. The Panel reviews new evidence and updates recommendations when needed. These guidelines include recommendations on baseline laboratory evaluations, treatment goals, benefits of ART and considerations when initiating therapy, choice of the initial regimen for ART-naive patients, ARV drugs or combinations to avoid, management of treatment failure, management of adverse effects and drug interactions, and special ART-related considerations in specific patient populations. This Panel works closely with the HHS Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children to provide recommendations for adolescents at different stages of growth and development. Recommendations for ART regimens in these guidelines are most appropriate for postpubertal adolescents (i.e., sexual maturity rating ). [SMR] IV and V Clinicians should follow recommendations in the Pediatric Guidelines when initiating ART in adolescents at 3 SMR III or lower. For recommendations related to pre- (PrEP) and post- (PEP) HIV exposure prophylaxis for people who do not have HIV, clinicians should consult recommendations from the Centers for Disease 4 Control and Prevention (CDC). These guidelines represent current knowledge regarding the use of ARVs. Because the science of HIV evolves rapidly, the availability of new agents and new clinical data may change therapeutic options and preferences. Information included in these guidelines may not always be consistent with approved labeling for the particular drugs or indications, and the use of the terms “safe” and “effective” may not be synonymous with the Food and Drug Administration (FDA)-defined legal standards for drug approval. The Panel frequently updates the guidelines (current and archived versions of the guidelines are available on the AIDS info website at http://www.aidsinfo.nih.gov ). However, the guidelines cannot always be updated apace with the rapid evolution of new data and cannot offer guidance on care for all patients. Patient management decisions should be based on clinical judgement and attention to unique patient circumstances. The Panel recognizes the importance of clinical research in generating evidence to address unanswered questions related to the optimal safety and efficacy of ART, and encourages both the development of protocols and patient participation in well-designed, Institutional Review Board (IRB)-approved clinical trials. A-1 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

15 Guidelines Development Process Table 1. Outline of the Guidelines Development Process Comment Topic Provide guidance to HIV care practitioners on the optimal use of antiretroviral agents (ARVs) for the Goal of the guidelines treatment of HIV in adults and adolescents in the United States. Panel members The Panel is composed of approximately 45 voting members who have expertise in HIV care and research, and includes at least one representative from each of the following U.S. Department of Health and Human Services (HHS) agencies: Centers for Disease Control and Prevention (CDC), Food and Drug Administration (FDA), Health Resource Services Administration (HRSA), and National Institutes of Health (NIH). Approximately two-thirds of the Panel members are nongovernmental scientific members. The Panel also includes four to five community members with knowledge in HIV treatment and care. The U.S. government representatives are appointed by their respective agencies; other Panel members are selected after an open announcement to call for nominations. Each member serves on the Panel for a 4 year term with an option for reappointment for an additional term. See the Panel Roster for a list of current Panel members. Financial disclosure , reporting any association All members of the Panel submit a written financial disclosure annually with manufacturers of ARV drugs or diagnostics used for management of HIV infections. A list of the latest disclosures is available on the AIDS info website ( http://aidsinfo.nih.gov/contentfiles/AA_ FinancialDisclosures.pdf ). Users of the guidelines HIV treatment providers Developer Panel on Antiretroviral Guidelines for Adults and Adolescents—a working group of the Office of AIDS Research Advisory Council (OARAC) Funding source Office of AIDS Research, NIH Evidence collection The recommendations in the guidelines are based on studies published in peer reviewed journals. On some occasions, particularly when new information may affect patient safety, unpublished data presented at major conferences or prepared by the FDA and/or manufacturers as warnings to the public may be used as evidence to revise the guidelines. Recommendation grading Table 2 As described in Method of synthesizing data Each section of the guidelines is assigned to a working group of Panel members with expertise in the section’s area of interest. The working groups synthesize available data and propose recommendations to the Panel. The Panel discusses all proposals during monthly teleconferences. Recommendations endorsed by the Panel are included in the guidelines. These guidelines focus on antiretroviral therapy (ART) use for adults and adolescents with HIV. For Other guidelines more detailed discussion on the use of ART for children and prepubertal adolescents (SMR I – III), clinicians should refer to the Pediatric ARV Guidelines. These guidelines also include a brief discussion on the management of women of reproductive age and pregnant women. Update plan The Panel meets monthly by teleconference to review data that may warrant modification of the guidelines. Updates may be prompted by new drug approvals (or new indications, dosing formulations, or frequency of dosing), new safety or efficacy data, or other information that may have an impact on the clinical care of patients. In the event of new data of clinical importance, the Panel may post an interim announcement with recommendations on the AIDS info website until the guidelines can be updated with the appropriate changes. Updated guidelines are available on the AIDS info website ( http://www.aidsinfo. nih.gov ). Public comments A 2-week public comment period follows release of the updated guidelines on the AIDS info website. The Panel reviews comments received to determine whether additional revisions to the guidelines are [email protected] indicated. The public may also submit comments to the Panel at any time at . gov A-2 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

16 Basis for Recommendations Recommendations in these guidelines are based upon scientific evidence and expert opinion. Each , B , or C ) that represents the strength of the recommendation and recommended statement includes a letter ( A I II , or III ) that represents the quality of the evidence that supports the recommendation a Roman numeral ( , (see Table 2). Table 2. Rating Scheme for Recommendations Quality of Evidence for Recommendation Strength of Recommendation i A: One or more randomized trials with clinical outcomes and/or I: Strong recommendation for the statement validated laboratory endpoints B: Moderate recommendation for the statement One or more well-designed, non-randomized trials or II: Optional recommendation for the statement C: observational cohort studies with long-term clinical outcomes Expert opinion III: HIV Expertise in Clinical Care Several studies have demonstrated that overall outcomes in patients with HIV are better when care is 5-9 delivered by clinicians with HIV expertise (e.g., care for a larger panel of patients), reflecting the complexity of HIV transmission and its treatment. Appropriate training, continuing education, and clinical experience are all components of optimal care. Providers who do not have this requisite training and experience should consult HIV experts when needed. References 1. YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med . Cohen MS, Chen Aug 11 2011;365(6):493-505. Available at https://www.ncbi.nlm.nih.gov/pubmed/21767103 . Centers for Disease Control and Prevention. Monitoring selected national HIV 2. prevention and care objectives by using HIV surveillance data—United States and 6 dependent areas, 2014. HIV Surveillance Supplemental Report. 2016;21(No. https://www.cdc.gov/hiv/pdf/library/reports/surveillance/cdc-hiv-surveillance-supplemental-report- 4). Available at . vol-21-4.pdf Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children. Guidelines for the use of 3. antiretroviral agents in pediatric HIV infection. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/ pediatricguidelines.pdf . 4. Centers for Disease Control and Prevention; US Public Health Service. (2014). Pre-exposure prophylaxis for the prevention of HIV ttp://www. infection in the United States States—2014: a clinical practice guideline. Available at: h . Accessed [November 2, 2015]. cdc.gov/hiv/pdf/PrEPguidelines2014.pdf Kitahata MM, Van Rompaey SE, Shields AW. Physician experience in the care of HIV-infected persons is associated 5. . Jun 1 2000;24(2):106-114. Available at J Acquir Immune Defic Syndr with earlier adoption of new antiretroviral therapy. https://www.ncbi.nlm.nih.gov/pubmed/10935685 . Wilson IB, McInnes K, et al. Physician specialization and the quality of care for human immunodeficiency 6. Landon BE, Arch Intern Med . May 23 2005;165(10):1133-1139. Available at virus infection. https://www.ncbi.nlm.nih.gov/ . pubmed/15911726 Kitahata MM, 7. Van Rompaey SE, Dillingham PW, et al. Primary care delivery is associated with greater physician experience and improved survival among persons with AIDS. . Feb 2003;18(2):95-103. Available at J Gen Intern Med https://www.ncbi.nlm.nih.gov/pubmed/12542583 . , Yip B, et al. Highly active antiretroviral therapy: physician experience and enhanced adherence to Delgado J, Heath KV 8. . https://www.ncbi.nlm.nih.gov/pubmed/14640395 . Oct 2003;8(5):471-478. Available at Antivir Ther prescription refill. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV A-3 Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

17 The HIV Workforce in New York State: Does Patient Volume Correlate with 9. O’Neill M, Karelas GD, Feller DJ, et al. http://www.ncbi.nlm.nih.gov/pubmed/26423383 . . Dec 15 2015;61(12):1871-1877. Available at Quality? Clin Infect Dis A-4 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

18 Baseline Evaluation (Last updated May 1, 2014; last reviewed May 1, 2014) Every patient with HIV entering into care should have a complete medical history, physical examination, and laboratory evaluation and should be counseled regarding the implications of HIV infection. The goals of the initial evaluation are to confirm the diagnosis of HIV infection, obtain appropriate baseline historical and laboratory data, ensure patient understanding about HIV infection and its transmission, and to initiate care as 1 recommended in HIV primary care guidelines and guidelines for prevention and treatment of HIV-associated 2 opportunistic infections. The initial evaluation also should include discussion on the benefits of antiretroviral therapy (ART) for the patient’s health and to prevent HIV transmission. Baseline information then can be used to define management goals and plans. In the case of previously treated patients who present for an initial evaluation with a new health care provider, it is critical to obtain a complete antiretroviral (ARV) history (including drug resistance testing results, if available), preferably through the review of past medical records. Newly diagnosed patients should also be asked about any prior use of ARV agents for prevention of HIV infection. The following laboratory tests performed during initial patient visits can be used to stage HIV disease and to assist in the selection of ARV drug regimens: • antibody testing (if prior documentation is not available or if HIV RNA is below the assay’s limit of HIV detection) (AI) ; • CD4 T lymphocyte cell count (CD4 count) (AI) ; • Plasma HIV RNA (viral load) (AI) ; • Complete blood count, chemistry profile, transaminase levels, blood urea nitrogen (BUN), and creatinine, urinalysis, and serologies for hepatitis A, B, and C viruses ; (AIII) Fasting blood glucose and serum lipids ; and • (AIII) . For patients who have HIV RNA levels <500 to 1,000 copies/mL, Genotypic resistance testing • (AII) viral amplification for resistance testing may not always be successful (BII) . In addition, other tests (including screening tests for sexually transmitted infections and tests for determining the risk of opportunistic infections and need for prophylaxis) should be performed as recommended in HIV 1,2 primary care and opportunistic infections guidelines. Patients living with HIV infection often must cope with many social, psychiatric, and medical issues that are best addressed through a patient-centered, multi-disciplinary approach to the disease. The baseline evaluation should include an evaluation of the patient’s readiness for ART, including an assessment of high-risk behaviors, substance abuse, social support, mental illness, comorbidities, economic factors (e.g., unstable housing), medical insurance status and adequacy of coverage, and other factors that are known to impair adherence to ART and increase the risk of HIV transmission. Once evaluated, these factors should be managed accordingly. The baseline evaluation should also include a discussion of risk reduction and disclosure to sexual and/or needle-sharing partners, especially with untreated patients who are still at high risk of HIV transmission. Education about HIV risk behaviors and effective strategies to prevent HIV transmission should be provided at each patient visit. References 1. Aberg JA, Kaplan JE, Libman H, et al. Primary care guidelines for the management of persons infected with human HIV Med immunodeficiency virus: 2009 update by the icine Association of the Infectious Diseases Society of America. B-1 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

19 Clin Infect Dis . Sep 1 2009;49(5):651-681. Available at https://www.ncbi.nlm.nih.gov/pubmed/19640227 . 2. Panel on Opportunistic Infections in HIV -Infected Adults and Adolescents. Guidelines for the Prevention and Treatment https://aidsinfo.nih.gov/ of Opportunistic Infections in HIV-Infected Adults and Adolescents. 2017. Available at guidelines/html/4/adult-and-adolescent-oi-prevention-and-treatment-guidelines/0 . B-2 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

20 Laboratory Testing Laboratory Testing for Initial Assessment and Monitoring of Patients with HIV Receiving Antiretroviral Therapy (Last updated October 25, 2018; last reviewed October 25, 2018) Several laboratory tests are important for initial evaluation of patients with HIV upon entry into care, and some tests should be performed before and after initiation or modification of antiretroviral therapy (AR T) to assess the virologic and immunologic efficacy of ART and to monitor for laboratory abnormalities that may be associated with antiretroviral (ARV) drugs. Table 3 outlines the Panel on Antiretroviral Guidelines for Adults and Adolescents (the Panel)’s recommendations on the frequency of testing. As noted in the table, some tests may be repeated more frequently if clinically indicated. Two surrogate markers are routinely used to monitor patients with HIV: CD4 T lymphocyte (CD4) cell count to assess immune function, and plasma HIV RNA (viral load) to assess level of HIV viremia. Resistance testing should be used to guide selection of an ARV regimen. A viral tropism assay should be performed before initiation of a CCR5 antagonist or at the time of virologic failure that occurs while a patient is receiving a CCR5 antagonist. HLA-B*5701 testing should be performed before initiation of abacavir (ABC). Patients should be screened for hepatitis B and hepatitis C virus infection before initiating ART and, if indicated, periodically after ART initiation, as treatment of these coinfections may affect the choice of ART. The rationale for and utility of some of these laboratory tests are discussed in the corresponding sections of the Guidelines. C-1 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

21 a Table 3. Laboratory Testing Schedule for Monitoring Patients with HIV Before and After Initiation of Antiretroviral Therapy (page 1 of 3) Timepoint or Frequency of Testing 2 to 8 Weeks ART Laboratory Test After ART Every 3 to 6 Entry into Clinically If ART Initiation is Treatment b or Every 12 Months Every 6 Months Initiation c Initiation or Months Care Delayed Indicated Failure Modification Modification HIV Serology √ If HIV diagnosis has not been confirmed CD4 Count √ √ √ √ √ √ √ During first 2 years After 2 Years on ART Every 3–6 months of ART, or if viremia with Consistently develops while Suppressed Viral patient is on ART, Load: or if CD4 count is CD4 Count 300–500 3 <300 cells/mm 3 : cells/mm • Every 12 months CD4 Count >500 cells/ 3 mm : CD4 monitoring is • optional. e d e iral Load √ √ √ HIV V √ √ Repeat testing is √ √ optional. f f Resistance √ √ √ √ √ Testing √ HLA-B*5701 Testing If considering ABC C-2 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

22 a Table 3. Laboratory Testing Schedule for Monitoring Patients with HIV Before and After Initiation of Antiretroviral Therapy (page 2 of 3) Timepoint or Frequency of Testing 2 to 8 Weeks ART Laboratory Test After ART Every 3 to 6 Entry into If ART Initiation is Clinically Treatment b or Every 6 Months Every 12 Months Initiation c Initiation or Months Care Indicated Delayed Failure Modification Modification √ √ √ Tropism Testing If considering If considering a CCR5 a CCR5 antagonist antagonist, or for patients experiencing virologic failure on a CCR5 antagonist- based regimen Hepatitis B √ √ √ √ Serology May repeat Including May repeat if patient is (HBsAb, HBsAg, if patient is prior to nonimmune and does g,h,i HBcAb total) nonimmune starting HCV not have chronic HBV h and does not DAA (see infection have chronic HCV/HIV h ) HBV infection Coinfection Hepatitis C √ √ √ Screening Repeat HCV screening k (HCV antibody or, for at-risk patients if indicated, HCV j RNA) Basic √ √ √ √ √ √ l,m Chemistry Every 6–12 months √ √ √ ALT, AST, Total √ √ √ Bilirubin Every 6–12 months √ √ CBC with √ √ √ √ √ Differential If on ZDV or if CD4 If on ZDV Every 3–6 months testing is done C-3 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

23 a Table 3. Laboratory Testing Schedule for Monitoring Patients with HIV Before and After Initiation of Antiretroviral Therapy (page 3 of 3) Timepoint or Frequency of Testing 2 to 8 Weeks ART Laboratory Test After ART Every 3 to 6 Entry into If ART Initiation is Clinically Treatment b or Every 12 Months Every 6 Months Initiation c Initiation or Months Care Delayed Indicated Failure Modification Modification √ Fasting Lipid √ √ √ √ √ n Profile If normal at If normal at last If abnormal measurement baseline, annually at last measurement √ √ √ √ Fasting Glucose √ √ or Hemoglobin If normal at If abnormal at last If normal at last A1C baseline, annually measurement measurement m,o Urinalysis √ √ √ √ √ l If on TAF or TDF p Pregnancy Test √ √ √ a This table pertains to laboratory tests done to select an ARV regimen and monitor for treatment responses or ART toxicities. Please refer to the HIV Primary Care Guidelines for guidance on other 1 laboratory tests generally recommended for primary health care maintenance of HIV patients. b If ART initiation occurs soon after HIV diagnosis and entry into care, repeat baseline laboratory testing is not necessary. c AR T is indicated for all individuals with HIV and should be started as soon as possible. However, if ART initiation is delayed, patients should be retained in care, with periodic monitoring as noted above. d If HIV RNA is detectable at 2 to 8 weeks, repeat testing every 4 to 8 weeks until viral load is suppressed to <200 copies/mL. Thereafter, repeat testing every 3 to 6 months. e In patients on ART, viral load typically is measured every 3 to 4 months. However, for adherent patients with consistently suppressed viral load and stable immunologic status for more than 2 years, monitoring can be extended to 6-month intervals. f Based on current rates of transmitted drug resistance to dif ferent ARV medications, standard genotypic drug-resistance testing in ARV-naive persons should focus on testing for mutations in the reverse transcriptase and protease genes. If transmitted INSTI resistance is a concern, providers should also test for resistance mutations to this class of drugs. In ART-naive patients who do not immediately begin ART, repeat testing before initiation of ART is optional if resistance testing was performed at entry into care. In patients with virologic suppression who are switching therapy because of toxicity or for convenience, viral amplification will not be possible; therefore, resistance testing should not be performed. Results from prior resistance testing can be helpful in constructing a new regimen. g If patient has HBV infection (as determined by a positive HBsAg or HBV DNA test result), TDF or TAF plus either FTC or 3TC should be used as part of the ARV regimen to treat both HBV and HIV infections. h If HBsAg, HBsAb, and HBcAb test results are negative, hepatitis B va c cine series should be administered. Refer to the HIV Primary Care Guidelines and the Adult and Adolescent Opportunistic 1,2 Infections Guidelines for detailed recommendations. i Most patients with isolated HBcAb have resolved HBV infection with loss of HBsAb. Consider performing an HBV viral load for confirmation. If the HBV viral load is positive, the patient may be acutely infected (and will usually display other signs of acute hepatitis) or chronically infected. If negative, the patient should be vaccinated. Refer to the HIV Primary Care Guidelines and the Adult C-4 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

24 1,2 and Adolescent Opportunistic Infections Guidelines for more detailed recommendations. j The HCV antibody test may not be adequate for screening in the setting of recent HCV infection (defined as acquisition within the past 6 months), or advanced immunodeficiency (CD4 3 count <100 cells/mm ). HCV RNA screening is indicated in persons who have been successfully treated for HCV or who spontaneously cleared prior infection. HCV antibody-negative patients with elevated ALT may need HCV RNA testing. k Injection drug users, persons with a history of incarceration, men with HIV who have unprotected sex with men, and persons with percutaneous/parenteral exposure to blood in unregulated settings are at risk of HCV infection. l , Cl, BUN, creatinine, glucose (preferably fasting), and creatinine-based estimated glomerular filtration rate. Serum phosphorus should be monitored in patients with Serum Na, K, HCO 3 3 chronic kidney disease who are on TAF- or TDF-containing regimens. m Consult the Guidelines for the Management of Chronic Kidney Diseas e in HIV -Infected Patients: Recommendations of the HIV Medicine Association of the Infectious Diseases Society 3 of America for recommendations on managing patients with renal disease. More frequent monitoring may be indicated for patients with evidence of kidney disease (e.g., proteinuria, decreased glomerular dysfunction) or increased risk of renal insufficiency (e.g., patients with diabetes, hypertension). n 4 Consult the National Lipid Association’s recommendations for management of patients with dyslipidemia. o Urine glucose and protein should be assessed before initiating T AF- or TDF-containing regimens and monitored during treatment with these regimens. p This applies to people of childbearing potential. Key to Acronyms: 3TC = lamivudine; ABC = abacavir; ALT = alanine aminotransferase; ART = antiretroviral therapy; ARV = antiretroviral; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CBC = complete blood count; CD4 = CD4 T lymphocyte; Cl = chloride; DAA = direct-acting antiviral; FTC = emtricitabine; HBcAb = hepatitis B core antibody; HBsAb = hepatitis B surface antibody; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCO = bicarbonate; HCV = hepatitis C virus; INSTI = integrase strand transfer inhibitor; K = 3 potassium; Na = sodium; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; ZDV = zidovudine C-5 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

25 References Aber g JA, Gallant JE, Ghanem KG, Emmanuel P, Zingman BS, Horberg MA. Primary care guidelines for the 1. management of persons infected with HIV: 2013 update by the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis . 2014;58(1):e1-34. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24235263 . 2. Panel on Opportunistic Infections in HIV -Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. 2018. Available at . http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf Lucas GM, Ross MJ, Stock PG, et al. Clinical practice guideline for the management of chronic kidney disease in 3. patients infected with HIV : 2014 update by the HIV Medicine Association of the Infectious Diseases Society of America. . 2014;59(9):e96-138. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25234519 Clin Infect Dis . Jacobson TA, Ito MK, Maki KC, et al. National Lipid Association recommendations for patient-centered management 4. http://www.ncbi.nlm.nih.gov/ of dyslipidemia: part 1--full report. J Clin Lipidol . 2015;9(2):129-169. Available at: . pubmed/25911072 C-6 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

26 Plasma HIV-1 RNA (Viral Load) and CD4 Count Monitoring (Last updated May 1, 2014; last reviewed May 1, 2014) RNA HIV (viral load) and CD4 T lymphocyte (CD4) cell count are the two surrogate markers of antiretroviral treatment (ART) responses and HIV disease progression that have been used for decades to infection. manage and monitor HIV Viral load is a marker of response to AR T. A s pre-ART viral load level and the magnitude of patient’ viral load decline after initiation of ART provide prognostic information about the probability of disease 1 progression. The key goal of ART is to achieve and maintain durable viral suppression. Thus, the most initiation of AR T. important use of the viral load is to monitor the effectiveness of therapy after before initiation of AR T. The CD4 cell count provides Measurement of CD4 count is particularly useful . The measurement is critical in establishing information on the overall immune function of a person with HIV thresholds for the initiation and discontinuation of opportunistic infection (OI) prophylaxis and in assessing the urgency to initiate AR T. The management of patients with HIV has changed substantially with the availability of newer, more potent, and less toxic antiretroviral (ARV) agents. In the United States, ART is now recommended for all patients Initiation of Antiretroviral Therapy ). In the with HIV regardless of their viral load or CD4 count (AI) (see past, clinical practice, which was supported by treatment guidelines, was generally to monitor both CD4 T, cell count and viral load concurrently. However, because most patients with HIV in care now receive AR . The roles and usefulness of these two tests in clinical the rationale for frequent CD4 monitoring is weaker practice are discussed in the following sections. Plasma HIV-1 RNA (Viral Load) Monitoring Viral load is the most important indicator of initial and sustained response to ART (AI) and should be (AIII) (AIII) , at initiation of therapy , and on a regular measured in all patients with HIV at entry into care basis thereafter. For those patients who choose to delay therap y, repeat viral load testing while not on ART (CIII) is optional . Pre-treatment viral load level is also an important factor in the selection of an initial ARV regimen because several currently approved ARV drugs or regimens have been associated with poorer responses in patients with high baseline viral load (see What to Start ). Commercially available HIV-1 RNA assays do not detect HIV-2 viral load. For further discussion on HIV-2 RNA monitoring in patients with HIV-2 Infection . HIV-1/HIV-2 coinfection or HIV-2 mono-infection, see Several systematic reviews of data from clinical trials involving thousands of participants have established that decreases in viral load following initiation of ART are associated with reduced risk of progression to 1-3 4 AIDS or death. The Thus, viral load testing is an established surrogate marker for treatment response. minimal change in viral load considered to be statistically signi ficant (2 standard deviations) is a three- fold change (equivalent to a 0.5 log copies/mL change). Optimal viral suppression is defined generally 10 RNA <20 to 75 copies/mL, depending on the as a viral load persistently below the level of detection (HIV assay used). However, isolated blips (viral loads transiently detectable at low levels, typically HIV RNA <400 copies/mL) are not uncommon in successfully treated patients and are not predictive of virologic 5 failure. Furthermore, the data on the association between persistently low level but quantifiable viremia (HIV RNA <200 copies/mL) and virologic failure is conflicting. One recent study showed an increased risk 6-9 of subsequent failure at this level of viremia; however, the association was not observed in other studies. These guidelines and the AIDS Clinical Trials Group (ACTG) now define virologic failure as a confirmed viral load >200 copies/mL—a threshold that eliminates most cases of apparent viremia caused by viral load 10 blips or assay variability (see Virologic Failure and Suboptimal Immunologic Response ). Individuals who are adherent to their ARV regimens and do not harbor resistance mutations to the component drugs can generally achieve viral suppression 8 to 24 weeks after ART initiation; rarely, in some patients it C-7 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

27 may take longer. Recommendations on the frequency of viral load monitoring are summarized below: • initiation of ART or modification of therapy because of virologic failure. Plasma viral load After should be measured before initiation of ART and within 2 to 4 weeks but no later than 8 weeks after treatment initiation or modification . The purpose of the measurements is to confirm an adequate (AIII) initial virologic response to ART, indicating appropriate regimen selection and patient adherence to therapy. Repeat viral load measurement should be performed at 4- to 8-week intervals until the level falls (BIII) . below the assay’s limit of detection • In vir ologically suppressed patients in whom ART was modified because of drug toxicity or for regimen simplification. Viral load measurement should be performed within 4 to 8 weeks after changing therapy (AIII) . The purpose of viral load monitoring at this point is to confirm the effectiveness of the new regimen. • In patients on a stable, suppr essive ARV regimen. Viral load should be repeated every 3 to 4 months (AIII) or as clinically indicated to confirm continuous viral suppression. Clinicians may extend the interval to 6 months for adherent patients whose viral load has been suppressed for more than 2 years and whose clinical and immunologic status is stable (AIII) . In patients with suboptimal r • esponse. The frequency of viral load monitoring will depend on clinical circumstances, such as adherence and availability of further treatment options. In addition to viral load monitoring, a number of additional factors, such as patient adherence to prescribed medications, suboptimal drug exposure, or drug interactions, should be assessed. Patients who fail to achieve viral suppression should undergo resistance testing to aid in the selection of an alternative regimen (see Drug- sections). Resistance Testing and Virologic Failure and Suboptimal Immunologic Repsonse CD4 Count Monitoring The CD4 count is the most important laboratory indicator of immune function in patients with HIV. It is also the strongest predictor of subsequent disease progression and survival according to findings from clinical 11,12 trials and cohort studies. CD4 counts are highly variable; a significant change (2 standard deviations) between 2 tests is approximately a 30% change in the absolute count, or an increase or decrease in CD4 percentage by 3 percentage points. Monitoring of lymphocyte subsets other than CD4 (e.g., CD8, CD19) has not proven clinically useful and is more expensive than monitoring CD4 count alone; therefore, it is not routinely recommended (BIII) . Use of CD4 Count for Initial Assessment CD4 count should be measured in all patients at entry into care (AI) . It is the key factor in determining the 13 need to initiate OI prophylaxis (see the Adult Opportunistic Infection Guidelines ) and the urgency to initiate (AI) ART (see the section of these guidelines). Although most OIs occur in Initiating Antiretroviral Therapy 14 3 patients with CD4 counts <200 cells/mm , some OIs can occur in patients with higher CD4 counts. Use of CD4 Count for Monitoring Therapeutic Response The CD4 count is used to assess a patient’s immunologic response to ART. It is also used to determine 13 whether prophylaxis for OIs can be discontinued (see the Adult Opportunistic Infection Guidelines ). For most patients on therapy, an adequate response is defined as an increase in CD4 count in the range of 50 to 3 150 cells/mm during the first year of ART, generally with an accelerated response in the first 3 months of 3 treatment. Subsequent increases average approximately 50 to 100 cells/mm per year until a steady state level 18 15 16,17 is reached. Patients who initiate therapy with a low CD4 count may have a blunted or at an older age increase in their counts despite virologic suppression. C-8 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

28 Frequency of CD4 Count Monitoring ART is now recommended for all patients with HIV. In patients who remain untreated for whatever reason, CD4 counts should be monitored every 3 to 6 months to assess the urgency of ART initiation and the need for OI prophylaxis . (AIII) A repeat CD4 count 3 months after ART initiation will provide information regarding the magnitude of immune reconstitution (AIII) . This repeat measurement is most important in patients who initiate ART with more advanced disease and require OI prophylaxis or treatment. In these patients, the magnitude and duration of CD4 count increase can be used to determine whether to discontinue OI prophylaxis and/or treatment as 13 recommended in the guidelines for treatment and prophylaxis of opportunistic infections. In this setting, and in the first 2 years following ART initiation, CD4 count can be monitored at 3- to 6- month intervals (BII) . The CD4 count response to ART varies widely, but a poor CD4 response in a patient with viral suppression is rarely an indication for modifying an ARV regimen. In patients with consistently suppressed viral loads who have already experienced ART-related immune reconstitution, the CD4 count provides limited information. Frequent testing is unnecessary because the results rarely lead to a change in clinical management. One 3 retrospective study found that declines in CD4 count to <200 cells/mm are rare in patients with viral 3 19 suppression and CD4 counts >300 cells/mm Similarly, the ARTEMIS trial found that CD4 monitoring . 3 had no clinical benefit in patients who had suppressed viral loads and CD4 counts >200 cells/mm after 48 20 weeks of therapy. Furthermore, the risk of Pneumocystis jirovecii pneumonia is extremely low in patients 21 3 on suppressive ART who have CD4 counts between 100 and 200 cells/mm Although uncommon, CD4 . count declines can occur in a small percentage of virologically suppressed patients and may be associated 22 with adverse clinical outcomes such as cardiovascular disease, malignancy, and death. An analysis of costs associated with CD4 monitoring in the United States estimated that reducing CD4 monitoring in treated 23 patients from every 6 months to every 12 months could result in annual savings of approximately $10 million. For the patient on a suppressive regimen whose CD4 count has consistently ranged between 300 and 500 3 cells/mm (BII) for at least 2 years, the Panel recommends CD4 monitoring on an annual basis . Continued CD4 monitoring for virologically suppressed patients whose CD4 counts have been consistently >500 cells/ 3 mm for at least 2 years may be considered optional (CIII) . The CD4 count should be monitored more frequently, as clinically indicated, when there are changes in a patient’s clinical status that may decrease CD4 count and thus prompt OI prophylaxis. Examples of such changes include the appearance of new HIV- associated clinical symptoms or initiation of treatment known to reduce CD4 cell count (e.g., interferon, (AIII) . In patients who fail to maintain viral suppression chronic corticosteroids, or antineoplastic agents) while on ART, the Panel recommends CD4 count monitoring every 3 to 6 months (AIII) (see Virologic Failure and Suboptimal Immunologic Response ). Factors that Affect Absolute CD4 Count The absolute CD4 count is a calculated value based on the total white blood cell (WBC) count and the percentages of total and CD4 T lymphocytes. This absolute number may fluctuate in individuals or may be influenced by factors that may affect the total WBC count and lymphocyte percentages, such as use of bone 24,25 marrow-suppressive medications or the presence of acute infections. Splenectomy or coinfection with 26 human T-lymphotropic virus type I (HTLV-1) may cause misleadingly elevated CD4 counts. Alpha-interferon 27 may reduce the absolute CD4 count without changing the CD4 percentage. In all these settings, CD4 percentage remains stable and may be a more appropriate parameter to assess a patient’s immune function. C-9 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

29 a Table 4. Recommendations on the Indications and Frequency of Viral Load and CD4 Count Monitoring CD4 Count Monitoring Clinical Scenario Viral Load Monitoring At entry into care (AIII) Before initiating ART At entry into care (AI) b If ART initiation is deferred, repeat before If ART is deferred, every 3 to 6 months (AIII) initiating ART . (AIII) In patients not initiating ART, repeat testing is . (CIII) optional After initiating ART Preferably within 2 to 4 weeks (and no later than 3 months after initiation of ART (AIII) (AIII) 8 weeks) after initiation of ART ; thereafter, every 4 to 8 weeks until viral load is suppressed (BIII) . 4 to 8 weeks after modification of ART to confirm Monitor according to prior CD4 count and After modifying ART because of drug . effectiveness of new regimen (AIII) toxicities or for regimen simplification in duration on ART, as outlined below. a patient with viral suppression After modifying ART because of (AI) Every 3 to 6 months Preferably within 2 to 4 weeks (and no later than ; thereafter, 8 weeks) after modification virologic failure (AIII) every 4 to 8 weeks until viral load is suppressed . If viral suppression is not possible, repeat (BIII) viral load every 3 months or more frequently if (AIII) indicated . a Every 3 to 4 months (AIII) Every 3 to 6 months During the first 2 years of ART (BII) After 2 years of ART (VL consistently (BII) Every 12 months suppressed, CD4 consistently 300-500 3 cells/mm ) Can extend to every 6 months for patients with consistent viral suppression for ≥2 years . (AIII) After 2 years of ART (VL consistently (CIII) Optional suppressed, CD4 consistently >500 3 cells/mm ) While on ART with detectable viremia Every 3 to 6 months Every 3 months (AIII) (AIII) or more frequently if (VL repeatedly >200 copies/mL) Virologic Failure ). clinically indicated (see (AIII) Change in clinical status (e.g., new Perform CD4 count and repeat as Every 3 months c clinically indicated HIV clinical symptom or initiation (AIII) of interferon, chronic systemic corticosteroids, or antineoplastic therapy) a Monitoring of lymphocyte subsets other than CD4 (e.g., CD8, CD19) has not proven clinically useful, adds to costs, and is not routinely recommended (BIII) . b 3 Some experts may repeat CD4 count every 3 months in patients with low baseline CD4 count (<200–300 cells/mm ) before ART but 3 every 6 months in those who initiated ART at higher CD4 cell count (e.g., >300 cells/mm ). c The following are examples of clinically indicated scenarios: changes in a patient’ s clinical status that may decrease CD4 count and thus prompt initiation of prophylaxis for opportunistic infections (OI), such as new HIV-associated symptoms, or initiation of treatment with medications which are known to reduce CD4 cell count. References 1. Murray JS, Elashof f MR, Iacono-Connors LC, Cvetkovich TA, Struble KA. The use of plasma HIV RNA as a study endpoint in efficacy trials of antiretroviral drugs. AIDS . May 7 1999;13(7):797-804. Available at https://www.ncbi.nlm. nih.gov/pubmed/10357378 . 2. AC, Coombs RW, et al. Use of changes in plasma levels of human immunodeficiency virus type 1 Marschner IC, Collier RNA to assess the clinical benefit of antiretroviral therapy. J Infect Dis . Jan 1998;177(1):40-47. Available at https://www. . ncbi.nlm.nih.gov/pubmed/9419168 C-10 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

30 3. , Jacqmin-Gadda H, et al. Clinical progression of HIV-1 infection according to the viral response Thiebaut R, Morlat P en Aquitaine (GECSA). AIDS during the first year of antiretroviral treatment. Groupe d’Epidemiologie du SIDA . May 26 . https://www.ncbi.nlm.nih.gov/pubmed/10853978 2000;14(8):971-978. Available at Human immunodeficiency virus type 1 RNA level and CD4 count as prognostic markers and surrogate end points: a 4. meta-analysis. HIV . Aug 10 2000;16(12):1123- Surrogate Marker Collaborative Group. AIDS Res Hum Retroviruses http://www.ncbi.nlm.nih.gov/pubmed/10954887 . 1133. Available at 5. Havlir DV, Bassett R, Levitan D, et al. Prevalence and predictive value of intermittent viremia with combination hiv JAMA . Jul 11 2001;286(2):171-179. Available at https://www.ncbi.nlm.nih.gov/pubmed/11448280 . . therapy , Roquebert B, Benard A, et al. Human immunodeficiency virus type 1 (HIV-1) plasma load discrepancies 6. Damond F between the Roche COBAS AMPLICOR HIV-1 MONITOR Version 1.5 and the Roche COBAS AmpliPrep/COBAS TaqMan HIV-1 assays. . Oct 2007;45(10):3436-3438. Available at https://www.ncbi.nlm.nih.gov/ J Clin Microbiol pubmed/17715371 . 7. Tsukada K, Honda H, et al. Detection of HIV type 1 load by the Roche Cobas TaqMan assay in patients Gatanaga H, with viral loads previously undetectable by the Roche Cobas Amplicor Monitor. . Jan 15 2009;48(2):260- Clin Infect Dis https://www.ncbi.nlm.nih.gov/pubmed/19113986 262. Available at . W illig JH, Nevin CR, Raper JL, et al. Cost ramifications of increased reporting of detectable plasma HIV -1 RNA levels 8. J Acquir Immune Defic Syndr . Aug by the Roche COBAS AmpliPrep/COBAS TaqMan HIV-1 version 1.0 viral load test. 1 2010;54(4):442-444. Available at https://www.ncbi.nlm.nih.gov/pubmed/20611035 . 9. Laprise C, de Pokomandy A, Baril JG, Dufresne S, Trottier H. Virologic failure following persistent low-level viremia in a cohort of HIV-positive patients: results from 12 years of observation. . Nov 2013;57(10):1489-1496. Clin Infect Dis Available at http://www.ncbi.nlm.nih.gov/pubmed/23946221 . Virologic failure endpoint definition in clinical trials: Is using HIV-1 RNA 10. Ribaudo H, Lennox J, Currier J, al e. threshold <200 copies/mL better than <50 copies/mL? An analysis of ACTG studies. 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montreal, Canada. 11. , Munoz A, Giorgi JV, et al. Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 Mellors JW Ann Intern Med infection. https://www.ncbi.nlm.nih.gov/pubmed/9182471 . Jun 15 1997;126(12):946-954. Available at . 12. Egger M, May M, Chene G, et al. Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a . Jul 13 2002;360(9327):119-129. Available at http://www.ncbi.nlm. collaborative analysis of prospective studies. Lancet . nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12126821 13. -Infected Adults and Adolescents. Guidelines for the prevention and treatment Panel on Opportunistic Infections in HIV of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease icine Association of the Infectious Diseases Control and Prevention, the National Institutes of Health, and the HIV Med Society of America. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf . Accessed January 6, 2014. 14. A, Furrer HJ, Miro JM, et al. The incidence of AIDS-defining illnesses at a current CD4 count >/= 200 cells/ Mocroft muL in the post-combination antiretroviral therapy era. . Oct 2013;57(7):1038-1047. Available at http:// Clin Infect Dis . www.ncbi.nlm.nih.gov/pubmed/23921881 15. Kaufmann GR, Perrin L, Pantaleo G, et al. CD4 T-lymphocyte recovery in individuals with advanced HIV-1 infection receiving potent antiretroviral therapy for 4 years: the Swiss HIV Cohort Study. . Oct 13 Arch Intern Med 2003;163(18):2187-2195. Available at https://www.ncbi.nlm.nih.gov/pubmed/14557216 . 16. Moore RD, Keruly JC. CD4+ cell count 6 years after commencement of highly active antiretroviral therapy in persons Available at https://www.ncbi.nlm.nih. Clin Infect Dis with sustained virologic suppression. . Feb 1 2007;44(3):441-446. gov/pubmed/17205456 . 17. ., Armon C, Chmiel JS, et al. CD4 cell count at initiation of ART, long-term likelihood of achieving CD4 Palella FJ, Jr >750 cells/mm3 and mortality risk. J Antimicrob Chemother . Sep 2016;71(9):2654-2662. Available at https://www.ncbi. nlm.nih.gov/pubmed/27330061 . 18. f KN, Justice AC, Gange SJ, et al. Virologic and immunologic response to HAART, by age and regimen class. Althof . Oct 23 2010;24(16):2469-2479. Available at http://www.ncbi.nlm.nih.gov/pubmed/20829678 . AIDS fman HJ, et al. Is frequent CD4+ T-lymphocyte count monitoring necessary for persons with 19. Gale HB, Gitterman SR, Hof counts >=300 cells/muL and HIV-1 suppression? Clin Infect Dis . May 2013;56(9):1340-1343. Available at http://www. ncbi.nlm.nih.gov/pubmed/23315315 . 20. Girard PM, Nelson M, Mohammed P , Hill A, van Delft Y, Moecklinghoff C. Can we stop CD4+ testing in patients with AIDS . Nov 13 2013;27(17):2759-2763. Available at http://www. HIV-1 RNA suppression on antiretroviral treatment? C-11 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

31 . ncbi.nlm.nih.gov/pubmed/23842127 Costiniuk CT 21. , Fergusson DA, Doucette S, Angel JB. Discontinuation of Pneumocystis jirovecii pneumonia prophylaxis . 2011;6(12):e28570. PLoS One with CD4 count <200 cells/microL and virologic suppression: a systematic review. Available at http://www.ncbi.nlm.nih.gov/pubmed/22194853 . 22. Helleber g M, Kronborg G, Larsen CS, et al. CD4 decline is associated with increased risk of cardiovascular disease, Clin Infect Dis . Jul 2013;57(2):314-321. Available at cancer, and death in virally suppressed patients with HIV. http:// www.ncbi.nlm.nih.gov/pubmed/23575194 . , Sax PE, Walensky RP. Potential savings by reduced CD4 monitoring in stable patients with HIV receiving 23. Hyle EP JAMA antiretroviral therapy. . Oct 14 2013;173(18):1746-1748. Available at http://www.ncbi.nlm.nih.gov/ Intern Med pubmed/23978894 . Wood L, Gaglione MM, Polis MA. Effect of splenectomy on T lymphocyte subsets in patients infected with the Zurlo JJ, 24. human immunodeficiency virus. https://www.ncbi.nlm.nih.gov/ . Apr 1995;20(4):768-771. Available at Clin Infect Dis pubmed/7795071 . Bernard NF , Chernoff DN, Tsoukas CM. Effect of splenectomy on T-cell subsets and plasma HIV viral titers 25. J Hum Virol . Jul-Aug 1998;1(5):338-345. Available at https://www.ncbi.nlm.nih.gov/ in HIV-infected patients. pubmed/10195261 . 26. Casseb J, Posada-V ergara MP, Montanheiro P, et al. T CD4+ cells count among patients co-infected with human immunodeficiency virus type 1 (HIV-1) and human T-cell leukemia virus type 1 (HTLV-1): high prevalence of tropical Rev Inst Med Trop Sao Paulo . Jul-Aug 2007;49(4):231- spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM). 233. Available at https://www.ncbi.nlm.nih.gov/pubmed/17823752 . glund O, Engman K, Ehrnst A, et al. Combined treatment of symptomatic human immunodeficiency virus type 1 27. Ber https://www. infection with native interferon-alpha and zidovudine. J Infect Dis . Apr 1991;163(4):710-715. Available at . ncbi.nlm.nih.gov/pubmed/1672701 C-12 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

32 Drug-Resistance Testing (Last updated October 25, 2018; last reviewed October 25, 2018) Panel’s Recommendations For Antiretroviral Therapy-Naive Persons: HIV drug-resistance testing is recommended at entry into care for persons with HIV to guide selection of the initial antiretroviral • therapy (AR (CIII) . If therapy is deferred, repeat testing may be considered at the time of ART initiation (AII) T) regimen . • Genotypic, rather than phenotypic, testing is the preferred resistance testing to guide therapy in antiretroviral (ARV)-naive patients . (AIII) • , or in people who will initiate ART on the day of or In persons with acute or recent (early) HIV infection, in pregnant people with HIV soon after HIV diagnosis , ART initiation should not be delayed while awaiting resistance testing results; the regimen can be modified . (AIII) once results are reported Standard genotypic drug-resistance testing in • ARV-naive persons involves testing for mutations in the reverse transcriptase (RT) and protease (PR) genes. If transmitted integrase strand transfer inhibitor (INSTI) resistance is a concern, providers should ensure that genotypic resistance testing also includes the integrase gene (AIII) . For Antiretroviral Therapy-Experienced Persons: • HIV drug-resistance testing should be performed to assist the selection of active drugs when changing ART regimens in the following patients: levels >1,000 copies/mL • Persons with virologic failure and HIV RNA (AI) • Persons with HIV RNA levels >500 copies/mL but <1,000 copies/mL, drug-resistance testing may be unsuccessful but should still (BII) be considered • (AII) Persons with suboptimal viral load reduction When a person with HIV experiences virologic failure while receiving an INSTI-based regimen, genotypic testing for INSTI • resistance (which may need to be ordered separately) should be performed to determine whether to include a drug from this class in subsequent regimens (AII) . Drug-resistance testing in the setting of virologic failure should be performed while the person is taking prescribed • ARV drugs or, (AII) if that is not possible, within 4 weeks after discontinuing therapy . If more than 4 weeks have elapsed since the ARVs were discontinued, resistance testing may still provide useful information to guide therapy; however, it is important to recognize that . (CIII) previously selected resistance mutations can be missed due to lack of drug-selective pressure Genotypic testing is preferred over phenotypic resistance testing to guide therapy in persons with suboptimal virologic response • and in individuals in whom resistance mutation patterns are known or not or virologic failure while on first- or second-line regimens . (AII) expected to be complex The addition of phenotypic to genotypic resistance testing is recommended for persons with known or suspected complex drug- • resistance mutation patterns (BIII) . All prior and current drug-resistance test results, if available, should be considered when constructing a new regimen for a pa • tient (AIII) . Rating of Recommendations: A = Strong; B = Moderate; C = Optional I = Data from randomized controlled trials; II = Data from well-designed nonrandomized trials or observational Rating of Evidence: cohort studies with long-term clinical outcomes; III = Expert opinion Genotypic and Phenotypic Resistance Assays Genotypic and phenotypic resistance assays are used to assess viral strains and select treatment strategies. These assays provide information on resistance to nucleoside reverse transcriptase inhibitors (NRTIs), non- nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and integrase strand transfer inhibitors (INSTIs). In some circumstances, INSTI-resistance tests may need to be ordered separately, and clinicians should check this with the testing laboratory. INSTI-resistance testing is particularly important in persons who experience virologic failure while taking an INSTI-containing regimen. Testing for fusion inhibitor resistance can also be ordered separately. There is currently no commercially available resistance test for the CD4 T lymphocyte post-attachment inhibitor ibalizumab. For a description of co-receptor tropism Co-receptor Tropism Assays testing, see . C-13 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

33 Genotypic Assays Genotypic assays detect drug-resistance mutations in relevant viral genes; in general, these assays require a plasma viral load of at least 500 to 1,000 copies/mL. Most genotypic assays involve conventional Sanger sequencing of the reverse transcriptase (RT), protease (PR), and integrase (IN) genes of circulating RNA in plasma to detect mutations that are known to confer drug resistance. A genotypic assay that assesses mutations in the gp41 (envelope) gene associated with resistance to the fusion inhibitor enfuvirtide is also commercially available. Genotypic assays can be performed rapidly and results are available within 1 to 2 weeks of sample collection. Interpreting these test results requires knowledge of the mutations selected by different antiretroviral (ARV) drugs and of the potential for cross resistance to other drugs conferred by an updated list of significant certain mutations. The International AIDS Society-USA (IAS-USA) maintains resistance-associated mutations in the RT, PR, IN, and envelope genes. The Stanford University HIV Drug 1 also provides helpful guidance for interpreting genotypic resistance test results. Resistance Database Various 2-5 additional tools are also available to assist providers in interpreting genotypic test results. Clinical trials 6 have demonstrated that consulting with specialists in HIV drug resistance improves virologic outcomes. Clinicians are thus encouraged to consult a specialist to interpret genotypic test results and design optimal new regimens. A next-generation sequencing genotypic resistance assay that analyzes HIV-1 proviral DNA in host cells is now commercially available. This test aims to detect archived resistance mutations in patients with HIV RNA below the limit of detection or with low-level viremia. Phenotypic Assays Phenotypic assays measure the ability of a virus to grow in different concentrations of ARV drugs. RT, PR, and, more recently, IN and envelope gene sequences derived from patient plasma HIV RNA are inserted into the backbone of a laboratory clone of HIV or used to generate pseudotyped viruses that express the patient-derived HIV genes of interest. Replication of these viruses at different drug concentrations is monitored by expression of a reporter gene and is compared with replication of a reference HIV strain. The drug concentration that inhibits viral replication by 50% (i.e., the median inhibitory concentration [IC ]) is 50 (i.e., calculated, and the ratio of the IC of test and reference viruses is reported as the fold increase in IC 50 50 fold resistance). Automated phenotypic assays that can produce results in 2 to 3 weeks are commercially available, but they cost more to perform than genotypic assays. In addition, interpreting phenotypic assay results can be complicated by incomplete information regarding the specific resistance level (i.e., fold increase in IC ) 50 associated with drug failure, although clinically significant fold increase cutof fs have been described for 7-11 some drugs. Again, consulting with a specialist to interpret test results can be helpful. Limitations of Genotypic and Phenotypic Assays Limitations of both genotypic and phenotypic assays include lack of uniform quality assurance testing for all available assays, relatively high cost, and insensitivity to minor viral species. Drug-resistant viruses that constitute <10% to 20% of the circulating virus population will probably not be detected by commercially available assays. This limitation is important to note because a wild-type virus often re-emerges as the predominant population in the plasma after discontinuation of drugs that exert selective pressure on drug- resistant populations. As a consequence, the proportion of virus with resistance mutations can decrease to 12-14 below the 10% to 20% threshold. In the case of some drugs, this reversion to predominantly wild-type virus can occur in the first 4 to 6 weeks after the drugs are discontinued. Prospective clinical studies have shown that despite this plasma reversion, re-initiation of the same ARV agents (or those sharing similar resistance pathways) is usually associated with early drug failure, and that the virus present at failure is 15 derived from previously archived resistant virus. Therefore, resistance testing is most valuable when performed while a person experiencing virologic failure is still taking ARV drugs or, if that is not possible, Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV C- 14 Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

34 then within 4 weeks after discontinuing therapy (AII) . Because resistant viruses may persist longer in the plasma of some patients, resistance testing that is done 4 to 6 weeks after discontinuation of drugs or later may still detect mutations and provide useful information to guide therapy . However, the absence (CIII) of detectable resistance in such patients must be interpreted with caution when designing subsequent ARV regimens. Importantly, in addition to considering prior antiretroviral therapy (ART) history, prior genotypic- or phenotypic-resistance test results should be obtained from old records when possible. Because the most current drug-resistance test may not be able to detect resistance mutations that were previously detected, these prior test results are clinically important and should be used when designing a new regimen . (AIII) A next-generation sequencing genotypic assay that analyzes HIV-1 proviral DNA may provide additional information on drug resistance in patients with low levels of plasma HIV RNA or in patients whose levels are below the limit of detection (CIII) . However, these assays might miss some or all the previous drug- resistance mutations, and they should be interpreted with caution. The usefulness of these assays in the clinic is still under investigation and has yet to be fully determined. Use of Resistance Assays in Clinical Practice (See Table 5 ) Use of Resistance Assays in Determining Initial Treatment Transmission of drug-resistant HIV strains is well documented and associated with suboptimal virologic 16-19 response to initial ART. The risk of acquiring drug-resistant virus is related to the prevalence of drug resistance in people with HIV who engage in high-risk behaviors within a given community. In high-income countries, approximately 10% to 17% of ART-naive individuals have resistance mutations to at least one 20 ARV drug. Up to 8%, but generally <5%, of transmitted viruses will exhibit resistance to drugs from more 20-23 than one class. Transmitted resistant HIV is generally either NNRTI- or NRTI-resistant. Transmitted PI 24,25 resistance is much less common, and to date, transmitted INSTI resistance is rare. Resistance testing can guide therapy selection to optimize virologic response in people with acute or recent (early) HIV infection, in pregnant people with HIV, or in people who will initiate ART on the day of or soon after HIV diagnosis. Therefore, resistance testing in these situations is recommended (AII) . A genotypic . In these settings, treatment initiation should not be delayed assay is preferred for this purpose (AIII) pending resistance testing results if the individual is willing and able to begin treatment. Once results are Acute and Recent HIV [Early] Infection ). In the reported, the regimen can be modified if warranted (see also absence of ART, resistant viruses may decline over time to less than the detection limit of standard resistance tests. However, when ART is eventually initiated, even low levels of resistant viruses may still increase 26-28 the risk of treatment failure. Therefore, if ART is deferred, resistance testing should still be performed during early HIV infection (AIII) . In this situation, the genotypic resistance test result should be used for regimen selection when the person begins ART. Repeat resistance testing at the start of treatment may also be considered, because a patient may acquire drug-resistant virus (i.e., superinfection) between entry-into-care 29 (CIII) . and the initiation of ART Interpretation of drug-resistance testing before ART initiation in persons with chronic HIV is less straightforward. The rate at which transmitted resistance-associated mutations revert to wild-type virus has not been completely delineated, but mutations present at the time of HIV transmission are more stable than those selected under drug pressure. It is often possible to detect resistance-associated mutations in viruses 30-32 that were transmitted several years earlier. Though no prospective trial has directly addressed whether drug-resistance testing before initiation of therapy confers benefit in this population, data from several studies, including one prospective clinical trial, suggest that virologic responses in persons with baseline 16-19,33-37 resistance mutations are suboptimal. In addition, an analysis of early RT and PR genotypic resistance testing in ARV-naive persons suggests that baseline testing in this population is cost effective and should be 38 performed. Therefore, resistance testing in people with chronic infections is recommended at the time of . entry into HIV care (AII) C-15 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

35 Although no definitive prospective data exist to support the choice of one type of resistance testing over another, genotypic testing is generally preferred over phenotypic testing because of lower cost, more rapid turnaround time, greater sensitivity for detecting mixtures of wild-type and resistant virus, and easier interpretation of test results . If therapy is deferred, repeat testing shortly before initiating ART may (AIII) 29 (CIII) be considered, because the patient may have acquired drug-resistant virus (i.e., superinfection) . Standard genotypic drug-resistance testing in ARV-naive persons involves testing for mutations in the RT and PR genes. Although reports of transmission of INSTI-resistant virus are rare, as use of INSTIs increases, the potential for transmission of INSTI-resistant virus may also increase. Therefore, when INSTI resistance is suspected, providers should supplement standard baseline genotypic resistance testing with genotypic testing for resistance to this class of drugs, which may need to be ordered separately (AIII) . The next-generation sequencing genotypic resistance assay that analyzes proviral DNA in host cells can be considered when conventional HIV RNA drug resistance testing is unsuccessful or unavailable for patients initiating therapy (CIII) . As outlined above, the results should be interpreted with caution, as this assay might miss some or all previously existing drug-resistance mutations. Use of Resistance Assays in the Event of Virologic Failure Resistance assays are important tools to inform treatment decisions for patients who experience virologic failure while on ART. Several prospective studies have assessed the utility of resistance testing to guide ARV drug selection in patients who experience virologic failure. These studies involved genotypic assays, 6,39-45 phenotypic assays, or both. In general, these studies found that changes in therapy based on resistance test results produced better early virologic response to salvage regimens than regimen changes guided only by clinical judgment. In addition, one observational cohort study found that the use of genotypic drug-resistance testing in ART-experienced patients with detectable plasma HIV RNA was independently associated with improved 46 survival. Thus, resistance testing is recommended as a tool for selecting active drugs when changing ARV regimens because of virologic failure in persons with HIV RNA >1,000 copies/mL (see also Virologic (AI) Failure ). In persons with HIV RNA >500 copies/mL but <1,000 copies/mL, testing may be unsuccessful but should still be considered (BII) . Conventional drug-resistance testing in persons with plasma viral loads <500 copies/mL is not usually recommended, because resistance assays cannot be consistently performed at low HIV RNA levels (AIII) . Resistance testing can also help guide treatment decisions for patients with suboptimal viral load reduction (AII) . Virologic failure in the setting of ART is, for certain patients, associated with resistance to only one 47-49 component of the regimen. In this situation, substituting individual drugs in a failing regimen may be an Virologic Failure ). option, but this concept will require clinical validation (see Genotyping is preferred for resistance testing in patients who experience virologic failure or suboptimal viral load reduction while on a first or second ARV drug regimen and in individuals in whom resistance mutation patterns are known or not expected to be complex (i.e., mutations that are straightforward, usually limited in number, and/or those that have clear significance) (AII) . Often in these situations, the mutation patterns detected can be interpreted by algorithms used to predict the impact of subsequent regimens on virologic response. For patients with extensive treatment history, complex mutational patterns may occur. In such situations, the interpretation of complex genotypes and the impact of the mutation pattern on subsequent treatment regimens can be challenging. For these individuals, phenotypic resistance testing may provide additional helpful information (BIII) . Rather than only predicting the impact of the detected mutations, the actual fold change in drug susceptibility, as well as the actual impact of in vitro these assays can measure mutation combinations and interactions on each drug under consideration. When compared with phenotypic testing, genotypic testing costs less to perform and has a faster turnaround time C-16 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

36 and greater sensitivity for detecting mixtures of wild-type and resistant virus. In addition, observations show that 50 genotypic and phenotypic assays are comparable predictors of virologic response to subsequent ART regimens. In patients who experience virologic failure while on INSTI-based regimens, testing for INSTI resistance should be performed to determine whether to include drugs from this class in subsequent regimens (AII) . In this circumstance, clinicians should confirm that, when they order a resistance test, their laboratory is testing for INSTI resistance in addition to NNRTI, NRTI, and PI resistance. If INSTI-resistance testing needs to be ordered separately (as is the case in some laboratories), clinicians should request this assay in addition to standard drug- resistance testing. Addition of phenotypic to genotypic testing is generally indicated for persons with known or suspected complex drug-resistance mutation patterns (BIII) . The next-generation sequencing genotypic resistance assay that analyzes proviral DNA can be considered for patients who are experiencing treatment failure and for whom conventional HIV RNA genotypic drug-resistance testing is unavailable or unsuccessful (CIII) . As outlined above, results should be interpreted with caution, as these assays might miss some or all previously existing drug-resistance mutations. When the use of a CCR5 antagonist is being considered, a co-receptor tropism assay should be performed (AI) (see Co-receptor Tropism Assays ). Use of Resistance Assays for Optimizing Antiretroviral Regimen in Persons with Viral Suppression In the past decade, simpler, more potent, and better-tolerated ARV medications have become available and new ARV drugs will likely continue to emerge. Switching individual ARV drugs in a regimen is sometimes considered for patients with a suppressed viral load in order to simplify a regimen, avoid drug interactions or toxicity, or for other reasons. Because the patient’s viral load is suppressed, standard drug-resistance testing will not be successful. The next-generation sequencing genotypic resistance assay that analyzes proviral DNA can be considered for these individuals, particularly if complex or semi-complex pre-existing resistance is suspected. In individuals who have experienced no prior virologic failures and who are on their first or second regimen, or who have genotypic testing results from when they had prior virologic failures, the use of the proviral DNA genotypic test is unlikely to provide additional useful information. However, in individuals who have experienced multiple prior failures, a prolonged history of prior ARV regimens, and/or for whom prior genotypic resistance test results are not available, it may be appropriate to utilize proviral DNA genotypic testing (CIII) . When such testing is obtained, results should be combined with all prior genotypic and phenotypic test results to construct a cumulative genotype, which incorporates all current and previously detected drug-resistance mutations. Results from this test should be interpreted with caution, as these assays might miss some or all previously existing drug-resistance mutations. The usefulness of these assays in the clinic is still under investigation and has yet to be fully determined. Use of Resistance Assays in Pregnancy In pregnancy, the goal of ART is to rapidly and maximally reduce plasma HIV RNA to provide optimal maternal therapy and to prevent perinatal transmission of HIV. Genotypic resistance testing is recommended for all pregnant persons with HIV before initiation of therapy (AIII) and for those entering pregnancy with detectable HIV RNA levels while on therapy (AI) . Phenotypic testing in those found to have complex drug-resistance mutation patterns may provide additional information . Optimal prevention of perinatal transmission (BIII) requires prompt initiation of ART pending resistance testing results. Once the results are available, the ARV regimen can be changed as needed. C-17 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

37 Table 5. Recommendations for Using Drug-Resistance Assays (page 1 of 2) Clinical Setting and Recommendation Rationale Drug-resistance testing can determine whether drug-resistant In Acute or Recent (Early) HIV Infection: virus was transmitted. The initial regimen can be modified, if . A genotypic assay (AII) Drug-resistance testing is recommended necessary, once resistance test results are available. Genotypic is generally preferred . Treatment should not be delayed while (AIII) testing is preferred to phenotypic testing because of lower cost, awaiting results of resistance testing (AIII) . faster turnaround time, and greater sensitivity for detecting mixtures of wild-type and resistant virus. If ART is deferred, repeat resistance testing may be considered Repeat testing when ART is initiated may be considered because the patient may have acquired a drug-resistant virus (i.e., when therapy is initiated (CIII) . A genotypic assay is generally . (AIII) superinfection). preferred In ART-Naive Patients with Chronic HIV: Transmitted HIV with baseline resistance to at least 1 drug is seen in 10% to 17% of patients, and suboptimal virologic responses Drug-resistance testing is recommended at entry into HIV care to may be seen in patients with baseline resistant mutations to ARVs guide selection of initial ART (AII) . A genotypic assay is generally in the prescribed regimen. Some drug-resistance mutations can . preferred (AIII) remain detectable for years in untreated patients with chronic HIV. For pregnant persons, or if ART will be initiated on the day of If necessary, the ART regimen can be modified once resistance or soon after HIV diagnosis, treatment can be initiated prior to test results are available. receiving resistance testing results. If an INSTI is considered for an ART-naive patient and/or Genotypic assays provide information on resistance to NRTIs, transmitted INSTI resistance is a concern, providers should NNRTIs, PIs, and INSTIs. In some circumstances, INSTI resistance tests need to be ordered separately (clinicians should supplement standard resistance testing with a specific INSTI genotypic resistance assay, which may need to be ordered check with the testing laboratory). Currently, transmitted INSTI . (AIII) separately resistance is infrequent, but the risk of a patient acquiring INSTI- resistant strains may be greater in certain known exposure settings. If therapy is deferred, repeat resistance testing may be considered Repeat testing before initiation of ART may be considered before initiation of ART because the patient may have acquired a drug-resistant virus (i.e., (CIII) . A genotypic assay is generally preferred (AIII) . a superinfection). Genotypic testing is preferred to phenotypic testing because of lower cost, faster turnaround time, and greater sensitivity for detecting mixtures of wild-type and resistant virus. If use of a CCR5 antagonist is being considered, a co-receptor See Co-Receptor Tropism Assays section. tropism assay should be performed (AI) . Drug-resistance testing can help determine the role of resistance In Patients with Virologic Failure: in drug failure and maximize the clinician’s ability to select active Drug-resistance testing is recommended in patients on combination drugs for the new regimen. ART with HIV RNA levels >1,000 copies/mL . In patients with (AI) HIV RNA levels >500 copies/mL but <1,000 copies/mL, testing may (BII) not be successful but should still be considered . The absence of detectable resistance in such patients must Resistance testing should be done while the patient is taking ART or, if that is not possible, within 4 weeks after ART discontinuation be interpreted with caution when designing subsequent ARV (AII) . If >4 weeks have elapsed, resistance testing may still be regimens, as mutations may decay with time. useful to guide therapy; however, previously-selected mutations can be missed due to lack of drug selective pressure (CIII) . A standard genotypic resistance assay is generally preferred Genotypic testing is preferred to phenotypic testing because of lower cost, faster turnaround time, and greater sensitivity for for patients experiencing virologic failure on their first or second (AII) . detecting mixtures of wild-type and resistant HIV. regimens and for those with noncomplex resistance patterns All prior and current drug-resistance testing results should be Drug resistance mutations may decay with time, and mutations reviewed and considered when designing a new regimen for a detected in prior resistance tests may not be detected in current . patient experiencing virologic failure (AIII) tests, though they remain clinically relevant. Genotypic assays provide information on resistance to NRTI-, When virologic failure occurs while a patient is on an INSTI- based regimen, genotypic testing for INSTI resistance should be NNRTI-, PI-, and INSTI-associated mutations. In some circumstances, INSTI resistance tests need to be ordered performed to determine whether to include drugs from this class in subsequent regimens (AII) . separately (clinicians should check with the testing laboratory). C-18 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

38 Table 5. Recommendations for Using Drug-Resistance Assays (page 2 of 2) Clinical Setting and Recommendation Rationale Phenotypic testing can provide additional useful information in Adding phenotypic testing to genotypic testing is generally preferred in patients with known or suspected complex drug- patients with complex drug resistance mutation patterns. . (BIII) resistance patterns Testing can determine the role of resistance in suboptimal viral In Patients with Suboptimal Suppression of Viral Load: suppression, and it can help the clinician identify the number of Drug-resistance testing is recommended in patients with suboptimal active drugs available in the current regimen and assess the need . viral load suppression after initiation of ART (AII) for a new regimen. The goals of ART in pregnant persons with HIV are to achieve In Pregnant Persons with HIV: maximal viral suppression for treatment of maternal HIV and to Genotypic resistance testing is recommended for all pregnant prevent perinatal transmission of HIV. Genotypic resistance testing persons before initiation of ART and for those entering (AIII) will assist the clinician in selecting the optimal regimen for the . pregnancy with detectable HIV RNA levels while on therapy (AI) patient. However, treatment should not be delayed while awaiting results of resistance testing. The initial regimen can be modified once resistance test results are available, if needed. In Patients with Undetectable Viral Load or Low-Level Viremia: This test may provide information about previously circulating resistant viral variants that are archived within proviral DNA. 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41 HIV type 1-infected patients: results of the clinical efficacy of resistance testing trial. . 2004;38(5):723- Clin Infect Dis 730. Available at: https://www.ncbi.nlm.nih.gov/pubmed/14986258 . 46. Palella FJ, Jr ., Armon C, Buchacz K, et al. The association of HIV susceptibility testing with survival among HIV- Ann Intern Med . 2009;151(2):73-84. Available at: http:// infected patients receiving antiretroviral therapy: a cohort study. . www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19620160 47. Havlir DV , Hellmann NS, Petropoulos CJ, et al. Drug susceptibility in HIV infection after viral rebound in patients receiving indinavir-containing regimens. JAMA . 2000;283(2):229-234. Available at: https://www.ncbi.nlm.nih.gov/ pubmed/10634339 . , Calvez V, et al. Mechanisms of virologic failure in previously untreated HIV-infected patients Descamps D, Flandre P 48. from a trial of induction-maintenance therapy. Trilege (Agence Nationale de Recherches sur le SIDA 072 Study Team). . 2000;283(2):205-211. Available at: https://www.ncbi.nlm.nih.gov/pubmed/10634336 . JAMA 49. Machouf N, Thomas R, Nguyen VK, et al. Effects of drug resistance on viral load in patients failing antiretroviral therapy. J Med Virol . 2006;78(5):608-613. Available at: http://www.ncbi.nlm.nih.gov/entrez/query. fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16555280 . 50. Anderson JA, Jiang H, Ding X, et al. Genotypic susceptibility scores and HIV type 1 RNA responses in treatment- http:// experienced subjects with HIV type 1 infection. AIDS Res Hum Retroviruses . 2008;24(5):685-694. Available at: . www.ncbi.nlm.nih.gov/pubmed/18462083 C-22 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

42 Co-Receptor Tropism Assays (Last updated October 25, 2018; last reviewed October 25, 2018) Panel’s Recommendations A co-receptor tropism assay should be performed whenever the use of a CCR5 co-receptor antagonist is being considered (AI) . • • . (BIII) Co-receptor tropism testing is recommended for patients who exhibit virologic failure on a CCR5 antagonist • A phenotypic tropism assay is preferred to determine HIV-1 co-receptor usage (AI) . • A genotypic tropism assay should be considered as an alternative test to predict HIV-1 co-receptor usage (BII) . • proviral DNA tropism assay can be utilized for patients with undetectable HIV-1 RNA when a CCR5 antagonist is considered for A use in a new regimen (e.g., as part of a regimen switch or simplification) (BII) . Rating of Recommendations: A = Strong; B = Moderate; C = Optional Rating of Evidence: I = Data from randomized controlled trials; II = Data from well-designed nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinion HIV enters cells by a complex process that involves sequential attachment to the CD4 T lymphocyte (CD4) receptor followed by binding to either the CCR5 or CXCR4 molecules and fusion of the viral and cellular 1 membranes. CCR5 co-receptor antagonists prevent HIV entry into target cells by binding to the CCR5 2 receptors. Phenotypic and genotypic assays have been developed that can determine or predict the co-receptor tropism (i.e., use of CCR5, CXCR4, or both as either dual-tropic virus or a mixed population of viruses referred to for purposes of assay results as dual/mixed [D/M]) of the patient’ s dominant virus population. An ® older generation assay (Trofile, Monogram Biosciences, Inc., South San Francisco, CA) was used to screen patients who were participating in clinical trials that led to the approval of maraviroc (MVC), the only CCR5 antagonist currently available. The assay has been improved and is now available with enhanced sensitivity. In addition, genotypic assays to predict co-receptor usage are commercially available. During acute/recent infection, the vast majority of patients harbor a CCR5-utilizing virus (R5 virus), which suggests that the R5 variant is preferentially transmitted; however, up to 19% of individuals with acute/recent 3-5 infection can harbor CXCR4-tropic virus. Viruses in many untreated patients eventually exhibit a shift in co- receptor tropism from CCR5 usage to either CXCR4 usage or D/M tropism. This shift is temporally associated 6,7 with a more rapid decline in CD4 counts, but whether this tropism shift is a cause or a consequence of 1 progressive immunodeficiency remains undetermined. Antiretroviral-treated patients with extensive drug resistance or persistently high-level viremia are more likely to harbor CXCR4- or D/M-tropic variants 8,9 than untreated patients with comparable CD4 counts. The prevalence of CXCR4- or D/M-tropic variants 8,10 3 increases to more than 50% in treated patients who have CD4 counts <100 cells/mm Since CXCR4-tropic . viruses may be present at initial presentation or a patient may shift to CXCR4-tropism over the course of infection, co-receptor tropism should always be assessed prior to the use of CCR5 antagonists for treatment. Once a patient has ever been documented with detectable CXCR4- or D/M-tropic virus, it is assumed that such viruses will always be present. CCR5 co-receptor antagonists will no longer be active for that patient and should not be used. Phenotypic Assays Phenotypic assays characterize the co-receptor usage of plasma-derived virus. These assays involve the generation of laboratory viruses that express patient-derived envelope proteins (i.e., gp120 and gp41). These pseudoviruses, which are replication-defective, are used to infect target cell lines that express either CCR5 ® 11,12 or CXCR4. Using the Trofile assay, the co-receptor tropism of the patient-derived virus is confirmed by in vitro . This assay takes about 2 testing the susceptibility of the virus to specific CCR5 or CXCR4 inhibitors weeks to perform and requires a plasma HIV RNA level ≥1,000 copies/mL. C-23 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

43 The performance characteristics of these assays have evolved. Most, if not all, patients enrolled in premarketing clinical trials of MVC and other CCR5 antagonists were screened with an earlier, less sensitive ® 12 version of the Trofile This earlier assay failed to routinely detect low levels of CXCR4 utilizing assay. variants. As a consequence, some patients enrolled in these clinical trials harbored low levels of such variants at baseline, which were below the assay limit of detection, and these patients exhibited rapid virologic failure 13 after initiation of a CCR5 antagonist. The assay has been improved and is now able to detect lower levels of CXCR4-utlizing viruses. In vitro , the assay can detect CXCR4-utilizing clones with 100% sensitivity when 14 those clones represent 0.3% or more of the virus population. Although this more sensitive assay has had limited use in prospective clinical trials, it is now the only assay that is commercially available. For unclear ® reasons, a minority of samples cannot be successfully phenotyped with either generation of the Trofile assay. In patients with an undetectable viral load or detectable plasma HIV RNA <1,000 copies/mL, phenotypic co-receptor usage can be determined using proviral DNA obtained from peripheral blood mononuclear ® cells (e.g., Trofile DNA, Monogram Sciences); however, the clinical utility of this assay remains to be 15 determined. Genotypic Assays Genotypic determination of HIV-1 co-receptor usage is based on sequencing of the V3-coding region of HIV-1 env , the principal determinant of co-receptor usage. A variety of algorithms and bioinformatics 16 programs can be used to predict co-receptor usage from the V3 sequence. When compared to the phenotypic assay, genotypic methods show high specificity (~90%) but only modest sensitivity (~50% to 75%) for the presence of a CXCR4-utilizing virus. Studies in which V3 genotyping was performed on samples from patients screened for clinical trials of MVC suggest that genotyping performed as well as 17-19 phenotyping in predicting the response to MVC. An important caveat is that the majority of patients ® rofile who received MVC were first shown to have R5 virus by a phenotypic assay (T ). Consequently, the opportunity to assess treatment response to MVC in patients whose virus was considered R5 by genotype but D/M or X4 by phenotype was limited to a relatively small number of patients. Other studies have also 20,21 demonstrated relatively high concordance between genotypic- and phenotypic-assessed tropism; however, 22 there is variability between different genotypic platforms. Given these performance characteristics, genotypic tropism assays may not be sufficiently robust to 23 completely rule out the presence of an X4 or D/M variant; therefore, the Panel preferentially recommends phenotypic testing. Based on accessibility, capacity, logistics, and cost, European guidelines currently include genotypic testing as an equivalent option to phenotypic testing when determining co-receptor usage among 24 patients with HIV RNA >1,000 copies/mL and preferentially for those with HIV RNA ≤1,000 copies/mL. HIV-1 proviral DNA genotypic tropism testing is available for patients with HIV RNA <1,000 copies/ mL. These assays evaluate the HIV-1 proviral DNA integrated within infected cells for CXCR4-utilizing 25 viral strains. As discussed above, caution is advised when using such assays, as their detection limit, concordance with plasma HIV RNA tropism, and clinical utility are not yet fully determined. Use of Assays to Determine Co-receptor Usage in Clinical Practice An assay for HIV-1 co-receptor usage should be performed whenever the use of a CCR5 antagonist is being considered (AI) . This is true even in the setting of prior tropism testing showing CCR5 usage, as viral evolution may occur over the course of infection. In addition, because virologic failure may occur due to a shift from CCR5-using to CXCR4-using virus, testing for co-receptor usage is recommended in patients who exhibit virologic failure on a CCR5 antagonist (BIII) . Virologic failure may also be caused by resistance of a CCR5-using virus to a CCR5 antagonist, but such resistance is uncommon. Compared to genotypic testing, phenotypic testing has more evidence supporting its utility. Therefore, a phenotypic test for co-receptor usage is generally preferred (AI) . However, because phenotypic testing is more expensive, requires more time to C-24 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

44 perform, and may have logistic challenges, a genotypic test to predict HIV-1 co-receptor usage should be considered as an alternative test . (BII) As with HIV resistance testing, the results of all prior tropism tests should be obtained. If CXCR4-utlizing or D/M-tropic viruses have ever been detected previously, then repeat testing is not necessary and a CCR5 co- . receptor antagonist should not be used If a CCR5 co-receptor antagonist is being considered in a patient with an undetectable HIV RNA (e.g., in tropism assay can be utilized cases of regimen simplification or a toxicity-related switch), a proviral DNA 26-28 . (BII) If CXCR4-utlizing or D/M-tropic viruses are detected, then the CCR5 co-receptor antagonist . should not be used References 1. Moore JP , Kitchen SG, Pugach P, Zack JA. The CCR5 and CXCR4 coreceptors--central to understanding AIDS Res the transmission and pathogenesis of human immunodeficiency virus type 1 infection. . 2004;20(1):111-126. Available at: http://www.ncbi.nlm.nih.gov/entrez/query. Hum Retroviruses fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15000703 . 2. Fatkenheuer G, Pozniak AL, Johnson MA, et al. Efficacy of short-term monotherapy with maraviroc, a new CCR5 antagonist, in patients infected with HIV -1. . 2005;11(11):1170-1172. Available at: http://www.ncbi.nlm.nih.gov/ Nat Med . entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16205738 T, Mo H, Wang N, et al. Genotypic and phenotypic characterization of HIV-1 patients with primary infection. 3. Zhu . 1993;261(5125):1179-1181. Available at: https://www.ncbi.nlm.nih.gov/pubmed/8356453 . Science 4. Brumme ZL, Goodrich J, Mayer HB, et al. Molecular and clinical epidemiology of CXCR4-using HIV -1 in a large population of antiretroviral-naive individuals. . 2005;192(3):466-474. Available at: https://www.ncbi.nlm.nih. J Infect Dis gov/pubmed/15995960 . 5. Raymond S, Nicot F , Saune K, et al. Brief report: HIV-1 tropism during primary Infections in France: 1996-2014. J https://www.ncbi.nlm.nih.gov/pubmed/26959188 Acquir Immune Defic Syndr . 2016;72(4):376-379. Available at: . 6. Connor RI, Sheridan KE, Ceradini D, Choe S, Landau NR. Change in coreceptor use correlates with disease progression -1-infected individuals. J Exp Med http://www.ncbi.nlm.nih.gov/entrez/query. in HIV . 1997;185(4):621-628. Available at: . fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9034141 Koot M, Keet IP , Vos AH, et al. Prognostic value of HIV-1 syncytium-inducing phenotype for rate of CD4+ cell 7. Ann Intern Med . 1993;118(9):681-688. Available at: http://www.ncbi.nlm.nih.gov/ depletion and progression to AIDS. . entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8096374 , Harrigan PR, Huang W, et al. Prevalence of CXCR4 tropism among antiretroviral-treated HIV-1-infected 8. Hunt PW J Infect Dis patients with detectable viremia. http://www.ncbi.nlm.nih.gov/entrez/ . 2006;194(7):926-930. Available at: query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16960780 . 9. Agwu AL, Yao TJ, Eshleman SH, et al. Phenotypic coreceptor tropism in perinatally HIV-infected youth failing antiretroviral therapy. Pediatr Infect Dis J https://www.ncbi.nlm.nih.gov/ . 2016;35(7):777-781. Available at: . pubmed/27078121 W ilkin TJ, Su Z, Kuritzkes DR, et al. HIV type 1 chemokine coreceptor use among antiretroviral-experienced patients 10. Clin Infect Dis . 2007;44(4):591-595. screened for a clinical trial of a CCR5 inhibitor: AIDS Clinical Trial Group A5211. Available at: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_ uids=17243065 . rouplin V, Salvatori F, Cappello F, et al. Determination of coreceptor usage of human immunodeficiency virus type 1 11. T from patient plasma samples by using a recombinant phenotypic assay. J Virol . 2001;75(1):251-259. Available at: http:// www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11119595 . 12. Whitcomb JM, Huang W, Fransen S, et al. Development and characterization of a novel single-cycle recombinant-virus assay to determine human immunodeficiency virus type 1 coreceptor tropism. Antimicrob http://www.ncbi.nlm.nih.gov/entrez/query. Agents Chemother . 2007;51(2):566-575. Available at: C-25 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

45 fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17116663 . W 13. estby M, Lewis M, Whitcomb J, et al. Emergence of CXCR4-using human immunodeficiency virus type 1 (HIV-1) variants in a minority of HIV-1-infected patients following treatment with the CCR5 antagonist maraviroc is from a . 2006;80(10):4909-4920. Available at: pretreatment CXCR4-using virus reservoir. J Virol http://www.ncbi.nlm.nih.gov/ entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16641282 . rinh L, Han D, Huang W, et al. Technical validation of an enhanced sensitivity Trofile HIV coreceptor tropism assay for T 14. selecting patients for therapy with entry inhibitors targeting CCR5. Antivir Ther . 2008;13(Suppl 3):A128. T oma J, Frantzell A, Cook J, et al. Phenotypic determination of HIV-1 coreceptor tropism using cell-associated DNA 15. derived from blood samples. Presented at: Conference on Retroviruses and Opportunistic Infections. 2010. San Francisco, CA. Garrido C, Roulet V, Chueca N, et al. Evaluation of eight different bioinformatics tools to predict viral tropism in 16. different human immunodeficiency virus type 1 subtypes. . 2008;46(3):887-891. Available at: https:// J Clin Microbiol www.ncbi.nlm.nih.gov/pubmed/18199789 . McGovern RA, Thielen A, Mo T, et al. Population-based V3 genotypic tropism assay: a retrospective analysis using 17. AIDS . 2010;24(16):2517-2525. Available at: screening samples from the A4001029 and MOTIVATE studies. http://www. . ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20736814 18. Thielen A, Portsmouth S, et al. Population-based sequencing of the V3-loop can predict the virological McGovern RA, response to maraviroc in treatment-naive patients of the MERIT trial. J Acquir Immune Defic Syndr . 2012;61(3):279- http://www.ncbi.nlm.nih.gov/pubmed/23095934 . 286. Available at: 19. Weber J, Henry K, et al. Use of four next-generation sequencing platforms to determine HIV-1 coreceptor Archer J, PLoS One http://www.ncbi.nlm.nih.gov/pubmed/23166726 . tropism. . 2012;7(11):e49602. Available at: 20. -1 coreceptor proficiency panel test. J Clin V irol . Heger E, Kaiser R, Knops E, et al. Results of the first international HIV 2017;93:53-56. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28633097 . , Siaw MF, et al. Comparison of genotypic and phenotypic HIV type 1 tropism assay: results 21. Kagan RM, Johnson EP from the screening samples of Cenicriviroc Study 202, a randomized phase II trial in treatment-naive subjects. AIDS Res . 2014;30(2):151-159. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23875707 Hum Retroviruses . 22. WW, Mo T, et al. Use of cellular HIV DNA to predict virologic response to maraviroc: performance Swenson LC, Dong of population-based and deep sequencing. . 2013;56(11):1659-1666. Available at: https://www.ncbi.nlm. Clin Infect Dis nih.gov/pubmed/23429552 . Tropism testing in the clinical management of HIV-1 infection. 23. Curr Opin HIV AIDS . Lin NH, Kuritzkes DR. 2009;4(6):481-487. Available at: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt= . Citation&list_uids=20048714 24. andekerckhove LP, Wensing AM, Kaiser R, et al. European guidelines on the clinical management of HIV-1 tropism V Lancet Infect Dis . 2011;11(5):394-407. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21429803 . testing. 25. V, et al. Genotypic tropism testing in HIV-1 proviral DNA can provide useful information Fabeni L, Berno G, Svicher at low-level viremia. . 2015;53(9):2935-2941. Available at: https://www.ncbi.nlm.nih.gov/ J Clin Microbiol . pubmed/26135872 26. itiello P, Brudney D, MacCartney M, et al. Responses to switching to maraviroc-based antiretroviral therapy in treated V patients with suppressed plasma HIV-1-RNA load. Intervirology . 2012;55(2):172-178. Available at: http://www.ncbi. nlm.nih.gov/pubmed/22286889 . 27. Bonjoch A, Pou C, Perez-Alvarez N, et al. Switching the third drug of antiretroviral therapy to maraviroc in aviraemic ob Chemother . 2013;68(6):1382-1387. Available at: subjects: a pilot, prospective, randomized clinical trial. J Antimicr https://www.ncbi.nlm.nih.gov/pubmed/23354282 . Amin J, Horban A, et al. Maraviroc, as a switch option, in HIV-1-infected individuals with stable, well- 28. Pett SL, controlled HIV replication and R5-tropic virus on their first nucleoside/nucleotide reverse transcriptase inhibitor plus ritonavir-boosted protease inhibitor regimen: Week 48 results of the randomized, multicenter MARCH Study. Clin Infect . 2016;63(1):122-132. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27048747 . Dis C-26 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

46 HLA-B*5701 Screening (Last updated December 1, 2007; last reviewed January 10, 2011) Panel’s Recommendations The Panel recommends screening for HLA-B*5701 before starting patients on an abacavir (ABC)-containing regimen to reduce the • . (AI) risk of hypersensitivity reaction (HSR) ABC (AI) . • HLA-B*5701-positive patients should not be prescribed • ABC allergy in the patient’s medical record The positive status should be recorded as an (AII) . • When HLA-B*5701 screening is not readily available, it remains reasonable to initiate ABC with appropriate clinical counseling and monitoring for any signs of HSR (CIII) . Rating of Recommendations: A = Strong; B = Moderate; C = Optional Rating of Evidence: I = Data from randomized controlled trials; II = Data from well-designed nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinion The abacavir (ABC) hypersensitivity reaction (HSR) is a multiorgan clinical syndrome typically seen within the initial 6 weeks of ABC treatment. This reaction has been reported in 5% to 8% of patients participating in clinical trials when using clinical criteria for the diagnosis, and it is the major reason for early discontinuation of ABC. Discontinuing ABC usually promptly reverses HSR, whereas subsequent rechallenge can cause a 1 rapid, severe, and even life-threatening recurrence. Studies that evaluated demographic risk factors for ABC HSR have shown racial background as a risk factor, with white patients generally having a higher risk (5%–8%) than black patients (2%–3%). Several groups reported a highly significant association between ABC HSR and the presence of the major 2,3 histocompatibility complex (MHC) class I allele HLA-B*5701. Because the clinical criteria used for ABC HSR are overly sensitive and may lead to false-positive ABC HSR diagnoses, an ABC skin patch test 4 (SPT) was developed as a research tool to immunologically confirm ABC HSR. A positive ABC SPT is an ABC-specific delayed HSR that results in redness and swelling at the skin site of application. All ABC 5 SPT–positive patients studied were also positive for the HLA-B*5701 allele. The ABC SPT could be falsely negative for some patients with ABC HSR and, at this point, is not recommended for use as a clinical tool. The PREDICT-1 study randomized participants with HIV before starting ABC either to be prospectively screened for HLA-B*5701 (with HLA-B*5701–positive patients not offered ABC) or to standard of care at 6 the time of the study (i.e., no HLA screening, with all patients receiving ABC). The overall HLA-B*5701 prevalence in this predominately white population was 5.6%. In this cohort, screening for HLA-B*5701 eliminated immunologic ABC HSR (defined as ABC SPT positive) compared with standard of care (0% and significantly decreasing the vs. 2.7%), yielding a 100% negative predictive value with respect to SPT rate of clinically suspected ABC HSR (3.4% vs. 7.8%). The SHAPE study corroborated the low rate of immunologically validated ABC HSR in black patients and confirmed the utility of HLA-B*5701 screening 7 for the risk of ABC HSR (100% sensitivity in black and white populations). On the basis of the results of these studies, the Panel recommends screening for HLA-B*5701 before starting . HLA-B*5701–positive patients should not be an ABC-containing regimen in a person with HIV (AI) , and the positive status should be recorded as an ABC allergy in the patient’s medical (AI) prescribed ABC record (AII). HLA-B*5701 testing is needed only once in a patient’s lifetime; thus, efforts to carefully record The specificity of and maintain the test result and to educate the patient about its implications are important. the HLA-B*5701 test in predicting ABC HSR is lower than the sensitivity (i.e., 33%–50% of HLA-B*5701– positive patients would likely not develop confirmed ABC HSR if exposed to ABC). HLA-B*5701 should not be used as a substitute for clinical judgment or pharmacovigilance, because a negative HLA-B*5701 result does not absolutely rule out the possibility of some form of ABC HSR. When HLA-B*5701 screening C-27 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

47 is not readily available, it remains reasonable to initiate ABC with appropriate clinical counseling and (CIII) . monitoring for any signs of ABC HSR References 1. Hetherington S, McGuirk S, Powell G, et al. Hypersensitivity reactions during therapy with the nucleoside reverse transcriptase inhibitor abacavir . Clin Ther . 2001;23(10):1603-1614. 2. Mallal S, Nolan D, Witt C, et al. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet . 2002;359(9308):727-732. 3. Hetherington S, Hughes AR, Mosteller M, et al. Genetic variations in HLA-B region and hypersensitivity reactions to Lancet abacavir . . 2002;359(9312):1121-1122. 4. Phillips EJ, Sullivan JR, Knowles SR, et al. Utility of patch testing in patients with hypersensitivity syndromes associated with abacavir . AIDS . 2002;16(16):2223-2225. Phillips E, Rauch A, Nolan D, et al. Pharmacogenetics and clinical characteristics of patch test confirmed patients with 5. abacavir hypersensitivity . Rev Antivir Ther . 2006:3: Abstract 57. 6. Mallal S, Phillips E, Carosi G, et al. HLA-B*5701 screening for hypersensitivity to abacavir . N Engl J Med . 2008;358(6):568-579. 7. Saag M, Balu R, Phillips E, et al. High sensitivity of human leukocyte antigen-b*5701 as a marker for immunologically . 2008;46(7):1 111-1118. Clin Infect Dis confirmed abacavir hypersensitivity in white and black patients. C-28 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

48 Treatment Goals (Last updated January 28, 2016; last reviewed January 28, 2016) Antiretroviral therapy (ART) has reduced HIV-related morbidity and mortality at all stages of HIV 5-8 1-4 infection and has reduced HIV transmission. Maximal and durable suppression of plasma viremia delays or prevents the selection of drug-resistance mutations, preserves or improves CD4 T lymphocyte 9,10 (CD4) cell numbers, and confers substantial clinical benefits, all of which are important treatment goals. HIV suppression with ART may also decrease inflammation and immune activation thought to contribute to higher rates of cardiovascular and other end-organ damage reported in cohorts with HIV (see Initiating Antiretroviral Therapy ). Despite these benefits, eradication of HIV infection cannot be achieved with available antiretrovirals (ARVs). Treatment interruption has been associated with rebound viremia, 11 worsening of immune function, and increased morbidity and mortality. Thus, once initiated, ART should be continued, with the following key treatment goals: • Maximally and durably suppress plasma HIV RNA; Restore and preserve immunologic function; • • Reduce HIV-associated morbidity and prolong the duration and quality of survival; and • Prevent HIV transmission. ARV regimens that generally include Achieving viral suppression currently requires the use of combination three active drugs from two or more drug classes. Baseline patient characteristics and results from drug resistance testing should guide design of the specific regimen (see What to Start: Initial Combination Regimens for the Antiretroviral-Naive Patient ). When initial HIV suppression is not achieved or not maintained, changing to a new regimen with at least two active drugs is often required (see Virologic ).The increasing number of ARV drugs and drug classes makes viral suppression below detection Failure limits an achievable goal in most patients. After initiation of effective ART, viral load reduction to below limits of assay detection usually occurs within the first 12 to 24 weeks of therapy. Predictors of virologic success include the following: • Low baseline viremia; High potency of the AR V regimen; • • Tolerability of the regimen; • Convenience of the regimen; and • Excellent adherence to the regimen. Strategies to Achieve Treatment Goals Selection of Initial Combination Regimen Several ARV regimens are recommended for use in ART-naive patients (see What to Start ). Most of the recommended regimens have comparable efficacy but vary in pill burden, potential for drug interactions and/ or side effects, and propensity to select for resistance mutations if ART adherence is suboptimal. Regimens should be tailored for the individual patient to enhance adherence and support long-term treatment success. Considerations when selecting an ARV regimen for an individual patient include potential side effects, patient comorbidities, possible interactions with conconcomitant medications, results of pretreatment genotypic drug-resistance testing, and regimen convenience (see Table 7 ). Improving Adherence Suboptimal adherence may result in reduced treatment response. Incomplete adherence can result from complex medication regimens; patient-related factors, such as active substance abuse, depression, or Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV D-1 Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

49 the experience of adverse effects; and health system issues, including interruptions in patient access to medication and inadequate treatment education and support. Conditions that promote adherence should be Adherence to the Continuum of Care maximized before and after initiation of ART (see ). References 1. Severe P , Juste MA, Ambroise A, et al. Early versus standard antiretroviral therapy for HIV-infected adults N Engl J Med . Jul 15 2010;363(3):257-265. Available at http://www.ncbi.nlm.nih.gov/entrez/query. in Haiti. . fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20647201 INSIGHT START Study Group. Initiation of antiretroviral therapy in early asymptomatic HIV infection. 2. . N Engl J Med Jul 20 2015. Available at http://www.ncbi.nlm.nih.gov/pubmed/26192873 . ANRS Study Group, Danel C, Moh R, et al. A trial of early antiretrovirals and isoniazid preventive therapy TEMPRANO 3. N Engl J Med . Aug 27 2015;373(9):808-822. Available at http://www.ncbi.nlm.nih.gov/pubmed/26193126 . in africa. 4. Kitahata MM, Gange SJ, Abraham AG, et al. Effect of early versus deferred antiretroviral therapy for HIV on survival. N Engl J Med . Apr 30 2009;360(18):1815-1826. Available at http://www.ncbi.nlm.nih.gov/entrez/query. fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19339714 . 5. Mofenson LM, Lambert JS, Stiehm ER, et al. Risk factors for perinatal transmission of human immunodeficiency AIDS Clinical Trials Group Study 185 Team. virus type 1 in women treated with zidovudine. Pediatric N Engl J Med . Aug 5 1999;341(6):385-393. Available at http://www.ncbi.nlm.nih.gov/entrez/query. fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10432323 . 6. ood E, Kerr T, Marshall BD, et al. Longitudinal community plasma HIV-1 RNA concentrations and incidence of HIV-1 W among injecting drug users: prospective cohort study. BMJ . 2009;338:b1649. Available at http://www.ncbi.nlm.nih.gov/ . entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19406887 7. YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. Cohen MS, Chen N Engl J Med . Aug 11 2011;365(6):493-505. Available at http://www.ncbi.nlm.nih.gov/entrez/query. . fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21767103 , Nakigozi G, et al. HIV-1 transmission among HIV-1 discordant couples before and after the 8. Reynolds SJ, Makumbi F introduction of antiretroviral therapy. AIDS . Feb 20 2011;25(4):473-477. Available at http://www.ncbi.nlm.nih.gov/ pubmed/21160416 . 9. WA, Hartigan PM, Martin D, et al. Changes in plasma HIV-1 RNA and CD4+ lymphocyte counts and the risk of O’Brien progression to AIDS. Veterans Affairs Cooperative Study Group on AIDS. N Engl J Med . Feb 15 1996;334(7):426-431. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_ uids=8552144 . 10. Garcia F , de Lazzari E, Plana M, et al. Long-term CD4+ T-cell response to highly active antiretroviral therapy according to baseline CD4+ T-cell count. J Acquir Immune Defic Syndr . Jun 1 2004;36(2):702-713. Available at http://www.ncbi. nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15167289 . 11. El-Sadr WM, Lundgren JD, Neaton JD, et al. CD4+ count-guided interruption of antiretroviral treatment. http://www.ncbi.nlm.nih.gov/entrez/query. Available at N Engl J Med . Nov 30 2006;355(22):2283-2296. . fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17135583 D-2 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

50 Initiation of Antiretroviral Therapy (Last updated October 17, 2017; last reviewed October 17, 2017) Panel’s Recommendations T) is recommended for all individuals with HIV, regardless of CD4 T lymphocyte cell count, to reduce the Antiretroviral therapy (AR • morbidity and mortality associated with HIV infection . (AI) AR T is also recommended for individuals with HIV to prevent HIV transmission • (AI) . When initiating • ART, it is important to educate patients regarding the benefits and considerations of ART, and to address strategies to optimize adherence. On a case-by-case basis, ART may be deferred because of clinical and/or psychosocial factors, but therapy should be initiated as soon as possible. Rating of Recommendations: A = Strong; B = Moderate; C = Optional Rating of Evidence: I = Data from randomized controlled trials; II = Data from well-designed nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinion Introduction Without antiretroviral therapy (ART), most individuals with HIV will eventually develop progressive immunodeficiency marked by CD4 T lymphocyte (CD4) cell depletion and leading to AIDS-defining illnesses and premature death. The primary goal of ART is to prevent HIV-associated morbidity and mortality. This goal is best accomplished by using effective ART to maximally inhibit HIV replication to sustain plasma HIV-1 RNA (viral load) below limits of quantification by commercially available assays. Durable viral suppression improves immune function and overall quality of life, lowers the risk of both AIDS-defining and non-AIDS-defining complications, and prolongs life. Furthermore, high plasma HIV-1 RNA is a major risk factor for HIV transmission; effective ART can reduce 1,2 both viremia and transmission of HIV to sexual partners. Modelling studies suggest that expanded use of 3 ART may lower incidence and, eventually, prevalence of HIV on a community or population level. Thus, a secondary goal of ART is to reduce the risk of HIV transmission. 4 Historically, individuals with HIV have had low CD4 counts at presentation to care. However, there have been concerted efforts to increase testing of at-risk individuals and to link individuals with HIV to medical care before they have advanced HIV disease. Deferring ART until CD4 counts decline puts individuals with HIV at risk of both AIDS-defining and certain serious non-AIDS conditions. Furthermore, the magnitude of CD4 recovery is directly correlated with CD4 count at ART initiation. Consequently, many individuals who start treatment with 3 3 5,6 CD4 counts <350 cells/mm and have after up to 10 years on ART never achieve CD4 counts >500 cells/mm 5-7 a shorter life expectancy than those initiating therapy at higher CD4 count thresholds. 8 Two large, randomized controlled trials that addressed the optimal time to initiate ART—START and 9 TEMPRANO —demonstrated approximately a 50% reduction in morbidity and mortality among individuals 3 with HIV who had CD4 counts >500 cells/mm and who were randomized to receive ART immediately versus delaying initiation of ART (described in more detail below). The Panel on Antiretroviral Guidelines for Adults and Adolescents (the Panel) therefore recommends immediate initiation of ART for all people living with (AI) . Prompt initiation of ART is particularly important for patients with certain HIV, regardless of CD4 count clinical conditions, as discussed below. The decision to initiate ART should always include consideration of a patient’s comorbid conditions and his or her willingness and readiness to initiate therapy. Thus, on a case-by-case basis, ART may be deferred because of clinical and/or psychosocial factors; however, therapy should be initiated as soon as possible. Panel’s Recommendations ART is recommended for all individuals with HIV, regardless of CD4 cell count, to reduce the morbidity and E-1 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

51 mortality associated with HIV infection (AI) . ART is also recommended for individuals with HIV to prevent (AI) . When initiating ART, it is important to educate patients about the benefits of ART, and HIV transmission to address barriers to adherence and recommend strategies to optimize adherence. On a case-by-case basis, ART may be deferred because of clinical and/or psychosocial factors; however, therapy should be initiated as soon as possible. Patients should also understand that currently available ART does not cure HIV. To improve and maintain immunologic function and maintain viral suppression, ART should be continued indefinitely. While ART is recommended for all patients, the following conditions increase the urgency to initiate therapy: • Perinatal Guidelines for more detailed recommendations on the management of Pregnancy (refer to the 10 pregnant women with HIV) AIDS-defining conditions, including HIV -associated dementia (HAD) and AIDS-associated malignancies • • Acute opportunistic infections (OIs) (see discussion below) 3 • Lower CD4 counts (e.g., <200 cells/mm ) HIV-associated nephropathy (HIVAN) • Acute/early infection (see discussion in the Acute/Early Infection section) • • HIV/hepatitis B virus coinfection • HIV/hepatitis C virus coinfection Acute Opportunistic Infections and Malignancies In patients who have AIDS-associated opportunistic diseases for which there is no effective therapy (e.g., cryptosporidiosis, microsporidiosis, progressive multifocal leukoencephalopathy), improvement of immune function with ART may improve disease outcomes, thus ART should be started as soon as possible. For patients with mild to moderate cutaneous Kaposi’s sarcoma (KS), prompt initiation of ART alone without chemotherapy has been associated with improvement of the KS lesions, even though initial transient progression of KS lesions as a manifestation of immune reconstitution inflammatory syndrome (IRIS) can 11 also occur. Similarly, although an IRIS-like presentation of non-Hodgkin’s lymphoma after initiation of 12 ART has been described, greater ART-mediated viral suppression is also associated with longer survival 13 among individuals undergoing treatment for AIDS lymphoma. Drug interactions should be considered when selecting ART given the potential for significant interactions between chemotherapeutic agents and some antiretroviral drugs (particularly some non-nucleoside reverse transcriptase inhibitors [NNR TIs] and ritonavir- or cobicistat-boosted regimens). However, a diagnosis of malignancy should not delay initiation of ART nor should initiation of ART delay treatment for the malignancy. In the setting of some OIs, such as cryptococcal and tuberculous meningitis, for which immediate ART may 14-17 increase the risk of serious IRIS, a short delay before initiating ART may be warranted. When ART is initiated in a patient with an intracranial infection, the patient should be closely monitored for signs and symptoms associated with IRIS. In the setting of other OIs, such as Pneumocystis jirovecii pneumonia, early 18 initiation of ART is associated with increased survival; therefore, ART should not be delayed. In patients who have active non-meningeal tuberculosis, initiating ART during treatment for tuberculosis 19-23 confers a significant survival advantage; therefore, ART should be initiated as recommended in Mycobacterium Tuberculosis Disease with HIV Coinfection . Clinicians should refer to the Guidelines for Prevention and Treatment of Opportunistic Infections in HIV- 11 Infected Adults and Adolescents for more detailed discussion on when to initiate ART in the setting of a specific OI. E-2 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

52 The Need for Early Diagnosis of HIV Fundamental to the earlier initiation of ART recommended in these guidelines is the assumption that HIV will be diagnosed early in the course of the disease. Unfortunately, in some patients, HIV infection is not diagnosed until the later stages of the disease. Despite the recommendations for routine, opt-out HIV screening in the 24 health care setting regardless of perceptions about a patient’s risk of infection and the gradual increase in CD4 counts at first presentation to care, the median CD4 count of newly diagnosed patients remains below 350 cells/ 3 4 mm . Diagnosis of HIV infection is delayed more often in nonwhites, those who use injection drugs, and older adults than in other populations, and many individuals in these groups develop AIDS-defining illnesses within 1 25-27 year of diagnosis. Therefore, to ensure that the current treatment guidelines have maximum impact, routine HIV screening per current Centers for Disease Control and Prevention recommendations is essential. It is also critical that all patients who receive an HIV diagnosis are educated about HIV disease and linked to care for full evaluation, follow-up, and management as soon as possible. Once patients are in care, focused effort is required to initiate ART and retain them in the health care system so that both the individuals with HIV and their sexual partners can fully benefit from early diagnosis and treatment (see Adherence to the Continuum of Care ). Evidence Supporting Benefits of Antiretroviral Therapy to Prevent Morbidity and Mortality 28-31 randomized Although observational studies had been inconsistent in defining the optimal time to initiate ART, controlled trials now definitively demonstrate that ART should be initiated in all patients with HIV, regardless of disease stage. The urgency to initiate ART is greatest for patients at lower CD4 counts, where the absolute risk of OIs, non-AIDS morbidity, and death is highest. Randomized controlled trials have long shown that ART 3 improves survival and delays disease progression in patients with CD4 counts <200 cells/mm and/or history of 18,32 AIDS-defining conditions. Additionally, a randomized controlled trial conducted in Haiti showed that patients 3 who started ART with CD4 counts between 200 to 350 cells/mm survived longer than those who deferred ART 3 33 until their CD4 counts fell below 200 cells/mm . Most recently, the published START and TEMPRANO trials provide the evidence for the Panel’s recommendation to initiate ART in all patients regardless of CD4 cell count (AI) . The results of these two studies are summarized below. The START trial is a large, multi-national, randomized controlled clinical trial designed to evaluate the role of early ART in asymptomatic patients with HIV in reducing a composite clinical endpoint of AIDS-defining illnesses, serious non-AIDS events, or death. In this study, ART-naive adults (aged >18 years) with CD4 counts 3 >500 cells/mm were randomized to initiate ART soon after randomization (immediate-initiation arm) or to wait 3 to initiate ART until their CD4 counts declined to <350 cells/mm or until they developed a clinical indication for therapy (deferred-initiation arm). The study enrolled 4,685 participants, with a mean follow-up of 3 years. When the randomized arms of the study were closed, the primary endpoint of serious AIDS or non-AIDS events was reported in 42 participants (1.8%, or 0.60 events/100 person-years) in the immediate ART arm and 96 participants (4.1%, or 1.38 events/100 person-years) in the deferred ART arm (hazard ratio [HR] 0.43, favoring early ART [95% confidence interval (CI), 0.30–0.62, P < .001]). The most common clinical events reported were tuberculosis and AIDS and non-AIDS malignancies. The majority (59%) of clinical events in the deferred 3 ART arm occurred in participants whose CD4 counts were still above 500 cells/mm , evidence for a benefit of immediate ART even before CD4 count declines below this threshold. Furthermore, the benefit of immediate ART was evident across all participant subgroups examined, including men and women, older and younger participants, individuals with high and low plasma HIV RNA levels, and participants living in high-income and low/middle-income countries. Although START was not sufficiently powered to examine the benefit of immediate ART for each category of clinical events, the benefit of immediate ART appeared to be particularly strong for AIDS events (HR 0.28, [95% CI, 0.15–0.50, P < .001]), tuberculosis (HR 0.29, [95% CI, 0.12–0.73, P = .008]), and malignancies (HR 0.36, [95% CI, 0.19 to 0.66; P = .001]). Importantly, immediate ART also 8 significantly reduced the rate of pooled serious non-AIDS events (HR0.61, [95% CI, 0.38–0.97, P = 0.04]). The TEMPRANO ANRS 12136 study was a randomized controlled trial conducted in Cote d’Ivoire. Using 3 a two-by-two factorial design, participants with HIV who had CD4 counts <800 cells/mm were randomized Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents HIV with E- 3 Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

53 to either immediate ART or deferred ART (based on the national guidelines criteria for starting treatment); half of the participants in each group received isoniazid for prevention of tuberculosis for 6 months and half did not. The primary study endpoint was a combination of all-cause deaths, AIDS diseases, non-AIDS malignancies, and non-AIDS invasive bacterial diseases. More than 2,000 participants enrolled in the trial, with a median follow-up of 30 months. Among the 849 participants who had baseline CD4 counts >500 cells/ 3 mm , 68 primary outcome events were reported in 61 patients. The risk of primary events was lower with immediate ART than with deferred ART, with a hazard ratio of 0.56 in favor of early ART (CI, 0.33–0.94). On the basis of these results, the study team concluded that early ART is beneficial in reducing the rate of 9 these clinical events. The TEMPRANO and START trials had very similar estimates of the protective effect of immediate ART 3 among individuals with HIV who had CD4 counts >500 cells/mm , further strengthening the Panel’s recommendation that ART be initiated in all patients regardless of CD4 cell count. Theoretical Continued Benefit of Early Antiretroviral Therapy Initiation Long After Viral Suppression is Achieved While the START and TEMPRANO studies demonstrated a clear benefit of immediate ART initiation in 3 individuals with CD4 cell counts >500 cells/mm , it is plausible that the benefits of early ART initiation continue long after viral suppression is achieved. As detailed in the Poor CD4 Cell Recovery and Persistent Inflammation section, persistently low CD4 counts and abnormally high levels of immune activation and inflammation despite suppressive ART predict an increased risk of not only AIDS events, but also non- AIDS events including kidney disease, liver disease, cardiovascular disease, neurologic complications, and malignancies. Earlier ART initiation appears to increase the probability of restoring normal CD4 counts, a 34-39 normal CD4/CD8 ratio, and lower levels of immune activation and inflammation. Individuals initiating ART very early (i.e., during the first 6 months after infection) also appear to achieve lower immune activation levels and better immune function (as assessed by vaccine responsiveness) during ART-mediated viral suppression 40-42 than those who delay therapy for a few years or more. Thus, while these questions have yet to be addressed in definitive randomized controlled trials, earlier ART initiation may result in less residual immune dysfunction during treatment, which theoretically may result in reduced risk of disease for decades to come. Evidence Supporting the Use of Antiretroviral Therapy to Prevent HIV Transmission Prevention of Sexual Transmission A number of investigations, including biological, ecological, and epidemiological studies and one randomized clinical trial, provide strong evidence that treatment of individuals with HIV can significantly reduce sexual transmission of HIV. Lower plasma HIV RNA levels are associated with decreases in the 43,44 concentration of the virus in genital secretions. Studies of HIV-serodiscordant heterosexual couples have demonstrated a relationship between level of plasma viremia and risk of HIV transmission—when plasma 1,2 HIV RNA levels are lower, transmission events are less common. Most significantly, the multi-continental HPTN 052 trial enrolled 1,763 HIV-serodiscordant couples in which 3 the partner with HIV was ART naive with a CD4 count of 350 to 550 cells/mm at enrollment to compare 3 the effect of immediate ART versus delayed therapy (not started until CD4 count <250 cells/mm ) on HIV 45 transmission to the partner who did not have HIV. At study entry, 97% of the participants reported to be in a heterosexual monogamous relationship. All study participants were counseled on behavioral modification and condom use. The interim results reported 28 linked HIV transmission events during the study period, with only one event in the early therapy arm. This 96% reduction in transmission associated with early ART was statistically significant (HR 0.04; 95% CI, 0.01–0.27; P < 0.001). The final results of this study showed a sustained 93% reduction of HIV transmission within couples when the partner with HIV was taking ART as 2 prescribed and viral load was suppressed. Notably, there were only eight cases of HIV transmission within couples after the partner with HIV started ART; four transmissions occurred before the partner with HIV E-4 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

54 was virologically suppressed and four other transmissions occurred during virologic failure. These results provide evidence that suppressive ART is more effective at preventing transmission of HIV than all other behavioral and biomedical prevention interventions studied. This study, as well as other observational studies and modeling analyses showing a decreased rate of HIV transmission among serodiscordant heterosexual couples following the introduction of ART, demonstrate that suppression of viremia in ART-adherent patients with no concomitant sexually transmitted infections (STIs) substantially reduces the risk of HIV 3,46-49 transmission. HPTN 052 was conducted in heterosexual couples and not in populations at risk of HIV transmission via male-to-male sexual contact or needle sharing. In addition, in this clinical trial, adherence to ART was excellent. However, the prevention benefits of effective ART observed in HPTN 052 can reasonably be presumed to apply broadly. Therefore, the Panel recommends that ART be offered to individuals who are at risk of transmitting HIV to sexual partners (AI) . Clinicians should discuss with patients the potential individual and public health benefits of therapy and the need for adherence to the prescribed regimen. Clinicians should also stress that ART is not a substitute for condom use and behavioral modification and that ART does not protect against other STIs. Prevention of Perinatal Transmission As noted above, effective ART reduces transmission of HIV. The most dramatic and well-established example of this effect is the use of ART in pregnant women to prevent perinatal transmission of HIV. Effective suppression of HIV replication is a key determinant in reducing perinatal transmission. In the setting of maternal viral load suppressed to <50 copies/mL near delivery, use of combination ART during pregnancy has 50,51 reduced the rate of perinatal transmission of HIV from approximately 20% to 30% to 0.1% to 0.5%. ART is thus recommended for all pregnant women with HIV, for both maternal health and for prevention of HIV transmission to the newborn. In ART-naive pregnant women ART should be initiated as soon as possible, with Perinatal Guidelines ). the goal of suppressing plasma viremia throughout pregnancy (see Considerations When Initiating Antiretroviral Therapy ) What to Start ART regimens for treatment-naive patients currently recommended in this guideline (see can suppress and sustain viral loads below the level of quantification in most patients who adhere to their regimens. Most of the recommended regimens have low pill burden and are well tolerated. Once started on treatment, patients must continue ART indefinitely. Optimizing Adherence and Retention in Care The key to successful ART in maintaining viral suppression is adherence to the prescribed regimen. Treatment failure and resultant emergence of drug resistance mutations may compromise future treatment options. While optimizing adherence and linkage to care are critical regardless of the timing of ART initiation, the evidence thus far indicates that drug resistance occurs more frequently in individuals who initiate therapy 8 52 9 later in the course of infection than in those who initiate ART earlier. and TEMPRANO In both the START trials, participants randomized to immediate ART achieved higher rates of viral suppression than those randomized to delayed ART. Nevertheless, it is important to discuss strategies to optimize adherence and retention in care with patients before ART initiation. Several clinical, behavioral, and social factors have been associated with poor adherence. These factors include untreated major psychiatric disorders, neurocognitive impairment, active substance abuse, unstable housing, other unfavorable social circumstances, patient concerns about side effects, and poor adherence to clinic visits. Clinicians should identify areas where additional intervention is needed to improve adherence both before and after initiation of therapy. Some strategies to improve adherence are discussed in Adherence to the Continuum of Care . Nevertheless, clinicians are often inaccurate in predicting ART adherence and ART reduces morbidity and mortality even in patients with relatively poor adherence and established drug resistance. Thus, mental illness, substance abuse, and psychosocial challenges are not reasons to withhold ART from a patient. Rather, these issues indicate the need for additional interventions to support adherence E-5 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

55 and possibly the type of ART regimen to recommend (see What to Start ). Immediate Antiretroviral Therapy Initiation on the Day of HIV Diagnosis Since many individuals may fail to engage in care during the delay between initial HIV diagnosis (or first clinic visit) and the time ART is prescribed, some groups have proposed rapid ART initiation on the same day of HIV diagnosis as a strategy to increase engagement in care and increase the proportion of individuals who achieve and maintain ART-mediated viral suppression. This strategy was recently tested in a randomized controlled trial of 377 individuals in South Africa who had recently received HIV diagnoses. Those randomized to receive immediate ART on the day of diagnosis were significantly more likely than those randomized to usual care (three to five additional visits with adherence counseling over 2 to 4 weeks prior to ART initiation) to be virally 53 suppressed at 10 months (64% vs. 51%). Similar improvements in both the proportion of participants retained in care achieving viral suppression and survival at the end of 1 year were recently reported in a randomized 54 controlled trial of same-day ART initiation conducted in Haiti. While there are many differences between the health care systems, structural barriers to engagement in care, and underlying HIV and TB epidemics in South Africa and Haiti that limit the generalizability of these findings to the United States, these studies suggested that same-day initiation of ART may be feasible and could potentially improve clinical outcomes. While no randomized controlled trials have been performed in the United States, a recent pilot study of 39 individuals in San Francisco suggested that initiating ART on the same day of HIV diagnosis might modestly shorten the time 55 to achieving viral suppression. It should be emphasized, however, that ART initiation on the same day of HIV diagnosis is resource-intensive, requiring “on-call” clinicians, nurses, social workers, and laboratory staff to coordinate the patient transportation, clinical evaluation, counseling, accelerated insurance coverage, required intake laboratory testing, and systems in place to assure linkage to ongoing care. As these resources may not be available in all settings and the long-term clinical benefits of same-day ART initiation have yet to be proven in the United States, this approach remains investigational. Considerations for Special Populations Elite HIV Controllers A small subset of individuals with HIV maintains plasma HIV-1 RNA levels below level of quantification for 56,57 years without ART. These individuals are often referred to as “elite HIV controllers.” There are limited data on the role of ART in these individuals. Given the clear benefit of ART regardless of CD4 count from the START and TEMPRANO studies, delaying ART to see if a patient becomes an elite controller after initial diagnosis is strongly discouraged. Nevertheless, significant uncertainty remains about the optimal management of elite controllers who have maintained undetectable viremia in the absence of ART for years. Given that ongoing HIV replication occurs even in elite controllers, ART is clearly recommended for controllers with evidence of HIV disease progression, as defined by declining CD4 counts or development of HIV-related complications. Nonetheless, even elite controllers with normal CD4 counts also have evidence of abnormally high immune activation and surrogate markers of atherosclerosis, which may contribute to an increased risk 56,58-60 of non-AIDS related diseases. One observational study suggests that elite controllers are hospitalized more often for cardiovascular and respiratory disease than patients from the general population and ART- 61 treated patients. Moreover, elite controllers with preserved CD4 counts appear to experience a decline in 62 immune activation after ART initiation, suggesting that treatment may be beneficial. Whether this potential immunologic benefit of ART in elite controllers outweighs potential ART toxicity and results in clinical benefit is unclear. Unfortunately, randomized controlled trials to address this question are unlikely, given the very low prevalence of elite controllers. Although the START study included a number of participants with very low viral loads and demonstrated the benefit of immediate ART regardless of the extent of viremia, the study did not include a sufficient number of controllers to definitively determine the clinical impact of ART in this specific population. Nevertheless, there is a clear theoretical rationale for prescribing ART to HIV controllers even in the absence of detectable plasma HIV RNA levels. If ART is withheld, elite controllers should be followed closely, as some may experience CD4 cell decline, loss of viral control, or complications related to HIV infection. E-6 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

56 Adolescents with HIV Neither the START trial nor the TEMPRANO trial included adolescents. The Panel’s recommendation to initiate ART in all patients is extrapolated to adolescents based on the expectation that they will derive benefits from early ART similar to those observed in adults. Historically, compared to adults, youth have demonstrated significantly lower levels of ART adherence and viral suppression, and higher rates of viral 63 rebound following initial viral suppression. Because youth often face multiple psychosocial and other barriers to adherence, their ability to adhere to therapy should be carefully considered when making decisions about ART initiation. Although some adolescents may not be ready to initiate therapy, clinicians should offer ART while providing effective interventions to assess and address barriers to accepting and adhering to therapy. To optimize the benefits of ART for youth, a multidisciplinary care team should provide 64 Adolescents with HIV ). psychosocial and adherence support (see Conclusion The results of definitive randomized controlled trials support the Panel’ s recommendation to initiate ART to all individuals with HIV, regardless of CD4 cell count. Early diagnosis of HIV infection, followed by prompt ART initiation, has clear clinical benefits in reducing morbidity and mortality for patients with HIV and decreasing HIV transmission to their sexual partners. Although there are certain clinical and psychosocial factors that may occasionally necessitate a brief delay in ART, ART should be started as soon as possible. Clinicians should educate patients on the benefits and risks of ART and the importance of adherence. References: 1. Quinn TC, Wawer MJ, Sewankambo N, et al. Viral load and heterosexual transmission of human immunodeficiency virus type 1. Rakai Project Study Group. N Engl J Med https://www.ncbi.nlm.nih. . 2000;342(13):921-929. Available at: . gov/pubmed/10738050 2. Cohen MS, Chen YQ, McCauley M, et al. Antiretroviral therapy for the prevention of HIV-1 transmission. N Engl J Med . 2016;375(9):830-839. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27424812 . Granich RM, Gilks CF , Dye C, De Cock KM, Williams BG. Universal voluntary HIV testing with immediate 3. antiretroviral therapy as a strategy for elimination of HIV transmission: a mathematical model. Lancet . 2009;373(9657):48-57. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19038438 . 4. Althoff KN, Gange SJ, Klein MB, et al. Late presentation for human immunodeficiency virus care in the United States and Canada. Clin Infect Dis . . 2010;50(1 1):1512-1520. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20415573 5. Moore RD, Keruly JC. CD4+ cell count 6 years after commencement of highly active antiretroviral therapy in persons Clin Infect Dis Available at: https://www.ncbi.nlm.nih.gov/ with sustained virologic suppression. . 2007;44(3):441-446. pubmed/17205456 . Palella FJJ, Armon C, Chmiel JS, et al. CD4 cell count at initiation of ART, long-term likelihood of achieving CD4 >750 6. The Journal of antimicrobial chemotherapy . 2016;71(9):2654-2662. Available at: https:// cells/mm3 and mortality risk. www.ncbi.nlm.nih.gov/pubmed/27330061 . 7. Samji H, Cescon A, Hogg RS, et al. Closing the gap: increases in life expectancy among treated HIV-positive individuals in the United States and Canada. PloS one . 2013;8(12):e81355. Available at: http://www.ncbi.nlm.nih.gov/ pubmed/24367482 . START Study Group, Lundgren JD, Babiker AG, et al. Initiation of antiretroviral therapy in early 8. INSIGHT N Engl J Med asymptomatic HIV infection. http://www.ncbi.nlm.nih.gov/ . 2015;373(9):795-807. Available at: pubmed/26192873 . 9. ANRS Study Group, Danel C, Moh R, et al. A trial of early antiretrovirals and isoniazid preventive therapy TEMPRANO . N Engl J Med . 2015;373(9):808-822. Available at: http://www.ncbi.nlm.nih.gov/pubmed/26193126 in Africa. 10. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce https://aidsinfo.nih.gov/guidelines/html/3/perinatal- Perinatal HIV Transmission in the United States. 2016. Available at: . guidelines/0 E-7 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

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59 49. Reynolds SJ, Makumbi F , Nakigozi G, et al. HIV-1 transmission among HIV-1 discordant couples before and after . 2011;25(4):473-477. Available at: http://www.ncbi.nlm.nih.gov/ the introduction of antiretroviral therapy. AIDS pubmed/21160416 . ubiana R, Le Chenadec J, Rouzioux C, et al. Factors associated with mother-to-child transmission of HIV-1 despite a T 50. maternal viral load <500 copies/ml at delivery: a case-control study nested in the French perinatal cohort (EPF-ANRS http://www.ncbi.nlm.nih.gov/pubmed/20070234 . Clin Infect Dis CO1). . 2010;50(4):585-596. Available at: 51. ownsend CL, Cortina-Borja M, Peckham CS, de Ruiter A, Lyall H, Tookey PA. Low rates of mother-to-child transmission T . 2008;22(8):973- of HIV following effective pregnancy interventions in the United Kingdom and Ireland, 2000-2006. AIDS https://www.ncbi.nlm.nih.gov/pubmed/18453857 . 981. Available at: 52. Armon C, Buchacz K, Wood K, Brooks JT. Initiation of HAART at higher CD4 cell counts is associated with a lower Uy J, Journal of acquired immune deficiency syndromes . frequency of antiretroviral drug resistance mutations at virologic failure. https://www.ncbi.nlm.nih.gov/pubmed/19474757 . 2009;51(4):450-453. Available at: 53. Rosen S, Maskew M, Fox MP , et al. Initiating antiretroviral therapy for HIV at a patient’s first clinic visit: The RapIT . 2016;13(5):e1002015. Available at: PLoS medicine randomized controlled trial. https://www.ncbi.nlm.nih.gov/ pubmed/27163694 . 54. , Dorvil N, Devieux JG, et al. Same-day HIV testing with initiation of antiretroviral therapy versus standard care Koenig SP for persons living with HIV: A randomized unblinded trial. PLoS medicine . 2017;14(7):e1002357. Available at: https:// . www.ncbi.nlm.nih.gov/pubmed/28742880 55. A, et al. The effect of same-day observed initiation of antiretroviral therapy on Pilcher CD, Ospina-Norvell C, Dasgupta HIV viral load and treatment outcomes in a US public health setting. Journal of acquired immune deficiency syndromes . https://www.ncbi.nlm.nih.gov/pubmed/27434707 . 2017;74(1):44-51. Available at: Hunt PW , Brenchley J, Sinclair E, et al. Relationship between T cell activation and CD4+ T cell count in HIV-seropositive 56. J Infect Dis . 2008;197(1):126-133. individuals with undetectable plasma HIV RNA levels in the absence of therapy. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18171295 . Choudhary SK, Vrisekoop N, Jansen CA, et al. Low immune activation despite high levels of pathogenic human 57. J Virol immunodeficiency virus type 1 results in long-term asymptomatic disease. . 2007;81(16):8838-8842. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17537849 . 58. , Lo J, Triant VA, et al. Increased coronary atherosclerosis and immune activation in HIV-1 elite controllers. AIDS . Pereyra F 2012;26(18):2409-2412. Available at: . http://www.ncbi.nlm.nih.gov/pubmed/23032411 Hsue PY 59. , Hunt PW, Schnell A, et al. Role of viral replication, antiretroviral therapy, and immunodeficiency in HIV- AIDS . 2009;23(9):1059-1067. Available at: associated atherosclerosis. . http://www.ncbi.nlm.nih.gov/pubmed/19390417 Krishnan S, Wilson EM, Sheikh V, et al. Evidence for innate immune system activation in HIV type 1-infected elite 60. controllers. J Infect Dis . 2014;209(6):931-939. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24185941 . 61. TA, Gebo KA, Blankson JN, et al. Hospitalization Rates and Reasons Among HIV Elite Controllers and Persons Crowell J Infect Dis http://www.ncbi.nlm.nih. With Medically Controlled HIV Infection. . 2015;211(11):1692-1702. Available at: . gov/pubmed/25512624 Hatano H, 62. Yukl SA, Ferre AL, et al. Prospective antiretroviral treatment of asymptomatic, HIV-1 infected controllers. PLoS pathogens . 2013;9(10):e1003691. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24130489 . yscavage P, Anderson EJ, Sutton SH, Reddy S, Taiwo B. Clinical outcomes of adolescents and young adults in adult HIV R 63. care. Journal of acquired immune deficiency syndromes . 2011;58(2):193-197. Available at: http://www.ncbi.nlm.nih.gov/ pubmed/21826014 . 64. Rudy BJ, Murphy DA, Harris DR, Muenz L, Ellen J, Adolescent Trials Network for HIVAI. Patient-related risks for nonadherence to antiretroviral therapy among HIV-infected youth in the United States: a study of prevalence . 2009;23(3):185-194. Available at: and interactions. AIDS patient care and STDs http://www.ncbi.nlm.nih.gov/ pubmed/19866536 . E-10 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

60 What to Start: Initial Combination Regimens for the Antiretroviral- (Last updated October 25, 2018; last reviewed October 25, 2018) Naive Patient Panel’s Recommendations • An antiretroviral (ARV) regimen for a treatment-naive patient generally consists of two nucleoside reverse transcriptase inhibitors (NR TIs) administered in combination with a third active ARV drug from one of three drug classes: an integrase strand transfer inhibitor (INSTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI), or a protease inhibitor (PI) with a pharmacokinetic (PK) enhancer (also known as a booster; the two drugs used for this purpose are cobicistat and ritonavir). A • pregnancy test should be performed for those of childbearing potential prior to the initiation of antiretroviral therapy (AIII) . Panel regimens following the classifies on Panel) The as Antiretroviral Guidelines for Adults and Adolescents (the Recommended • Initial Regimens for Most People with HIV (in alphabetical order): (AI) • Bictegravir/tenofovir alafenamide/emtricitabine a • —only for patients who are HLA-B*5701 negative (AI) Dolutegravir/abacavir/lamivudine b a (AI) Dolutegravir (DTG) plus tenofovir • /emtricitabine a b • Raltegravir plus tenofovir /emtricitabine ( BI for tenofovir disoproxil fumerate, BII for tenofovir alafenamide) Preliminary data have raised concerns about an increased risk of neural tube defects in infants born to people who were receiving • please at the time of conception. Before prescribing DTG or another INSTI, DTG refer to T able 6b for specific recommendations on initiating these drugs as part of initial therapy. • To address individual patient characteristics and needs, the Panel also provides a list of Recommended Initial Regimens in Certain Clinical Situations (Table 6a). • Given the many excellent options for initial therapy, selection of a regimen for a particular patient should be guided by factors such as drug-drug frequency, dosing conditions, results, test resistance potential, interaction virologic efficacy, toxicity, pill burden, comorbid access, and cost. Table 7 provides guidance on choosing an ARV regimen based on selected clinical case scenarios. Table 9 highlights the advantages and disadvantages of different components in a regimen. A = Strong; B = Moderate; C = Optional Rating of Recommendations: I = Data from randomized controlled trials; II = Data from well-designed nonrandomized trials, observational cohort Rating of Evidence: studies with long-term clinical outcomes, relative bioavailability/bioequivalence studies, or regimen comparisons from randomized switch studies; III = Expert opinion a Lamivudine may substitute for emtricitabine or vice versa. b enofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) are two forms of tenofovir that are approved by the Food and Drug T Administration. TAF has fewer bone and kidney toxicities than TDF, while TDF is associated with lower lipid levels. Safety, cost, and access are among the factors to consider when choosing between these drugs. Introduction More than 30 antiretroviral (ARV) drugs in seven mechanistic classes are Food and Drug Administration (FDA)-approved for treatment of HIV infection. These seven classes include the nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase strand transfer inhibitors (INSTIs), a fusion inhibitor, a CCR5 antagonist, and a CD4 post-attachment inhibitor. In addition, two drugs, ritonavir (RTV or r) and cobicistat (COBI or c) are ARV drugs (e.g., used as pharmacokinetic (PK) enhancers (or boosters) to improve the PK profiles of some PIs and the INSTI elvitegravir [EVG]). The initial ARV regimen for a treatment-naive patient generally consists of two NRTIs, usually abacavir/ lamivudine (ABC/3TC) or either tenofovir alafenamide/emtricitabine (TAF/FTC) or tenofovir disoproxil fumarate (TDF)/FTC, plus a drug from one of three drug classes: an INSTI, an NNRTI, or a boosted PI. As shown in clinical trials and by retrospective evaluation of cohorts of patients in clinical care, this strategy for initial treatment has resulted in suppression of HIV replication and CD4 T lymphocyte (CD4) cell 1-3 count increases in most persons with HIV. Emerging data support the use of two-drug regimens, such as F-1 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

61 dolutegravir (DTG) plus 3TC, when ABC, TDF, and TAF cannot be used or are not optimal (see the section below titled Other Antiretroviral Regimens for Initial Therapy When Abacavir, Tenofovir Alafenamide, and Tenofovir Disoproxil Fumarate Cannot Be Used or Are Not Optimal). Supporting Evidence and Rationale Used for the Panel’s Recommendations The Panel on Antiretroviral Guidelines for Adults and Adolescents (the Panel)’s recommendations are primarily based on clinical trial data published in peer-reviewed journals and data prepared by manufacturers for FDA review. In select cases, the Panel considers data from abstracts presented at major scientific meetings. The Panel considers published information from a randomized, prospective clinical trial with an adequate sample size that demonstrates that an ARV regimen produces high rates of viral suppression, increases CD4 count, and has a favorable safety profile to be the strongest evidence on which to base recommendations. Comparative clinical trials of initial treatments generally show no significant dif ferences in HIV-related clinical endpoints or survival. Thus, assessment of regimen efficacy and safety are primarily based on surrogate marker endpoints (especially rates of HIV RNA suppression) and the incidence and severity of adverse events. In some instances, the Panel recommends regimens that include medications approved by the FDA based on bioequivalence or relative bioavailability studies demonstrating that the exposure of the drug(s) in the new formulation or combination is comparable to the exposure of a reference drug(s) that has demonstrated safety and efficacy in randomized clinical trials. When developing recommendations, the Panel may also consider data from randomized switch studies, in which a new medication replaces an existing medication from the same class in patients who have achieved virologic suppression on an initial regimen. Switch trials do not evaluate the ability of a drug or regimen to induce viral suppression; they only examine the drug or regimen’s ability to maintain suppression. Therefore, results from switch trials may not be directly applicable to the selection of an initial regimen and should be considered in conjunction with other data, including data from trials conducted in treatment-naive patients and bioequivalence/bioavailability studies. In this section of the guidelines, the definition of an evidence rating of II is expanded to include supporting data from bioavailability/bioequivalence studies or randomized switch studies. When developing recommendations, the Panel also considers tolerability and toxicity profiles, pill burden and dosing frequency, drug interaction potential, cost and access, post-marketing safety data, observational cohort data published in peer-reviewed publications, and the experience of clinicians and community members who are actively engaged in patient care. The Panel reviewed the available data to arrive at two regimen classifications for ARV-naive patients: (1) Recommended Initial Regimens for Most People with HIV and (2) Recommended Initial Regimens in Certain Clinical Situations (Table 6a). Recommended Initial Regimens for Most People with HIV are those regimens with demonstrated durable virologic efficacy, favorable tolerability and toxicity profiles, and ease of use. The Panel also recognizes that, in certain clinical situations, other regimens may be preferred; these options are included in Table 6a in the category of Recommended Initial Regimens in Certain Clinical Situations. Examples of clinical scenarios in which certain drugs in these regimens may be particularly advantageous are outlined in Table 7. There are many other ARV regimens that are effective for initial therapy but have disadvantages when compared with the regimens listed in Table 6a. These disadvantages include greater toxicity, higher pill burden, less supporting data from large comparative clinical trials, or limitations for use in certain patient populations. These other regimens are no longer included in Table 6a. A person with HIV who is virologically suppressed and who is not experiencing any adverse effects on a regimen that is not listed in Table 6a need not necessarily change to a regimen that is in that table. Clinicians should refer to Optimizing Antiretroviral Therapy in the Setting of Viral Suppression for further guidance if switching to a new regimen is desired. F-2 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

62 Regimens and medications listed in Table 10 are not recommended as initial ARV. In most instances, a clinician is urged to consider switching a patient who is on one of the regimens listed in Table 10 to a recommended regimen. In addition to these tables, several tables presented below and at the end of these guidelines provide clinicians with guidance on selecting and prescribing an optimal regimen for an individual patient. Table 9 lists the potential advantages and disadvantages of the different ARV drug components. Appendix B, Tables 1–7 list characteristics of individual ARV agents (e.g., formulations, dosing recommendations, PKs, common Appendix B, Table 8 adverse effects). provides ARV dosing recommendations for patients who have renal or hepatic insufficiency. Changes Since the Last Revision of the Guidelines Since the last revision of the Adult and Adolescent Guidelines, there have been several important changes in the Panel’s recommendations for initial therapy in people with HIV. Among these changes, the following deserve particular emphasis: INSTI-Based Regimens as Initial Antiretroviral Therapy: • Bictegravir (BIC)/T AF/FTC has been added to the category of Recommended Initial Regimens for Most People with HIV (AI) . This regimen was added based on data from randomized Phase 3 clinical trials that demonstrated that its efficacy, safety, and tolerability are similar to other regimens that are recommended 4,5 for most people with HIV—namely, dolutegravir (DTG)/ABC/3TC and DTG plus TAF/FTC. • EVG/c/TDF/FTC and EVG/c/TAF/FTC (BI) have been moved from the category of Recommended Initial Regimens for Most People with HIV to the category of Recommended Initial Regimens in Certain Clinical Situations. This change was made because these combinations include COBI, a pharmacoenhancer that inhibits cytochrome P (CYP) 3A4 and increases the likelihood of drug-drug interactions. EVG also has a lower barrier to resistance than DTG and BIC. Clinicians should review Table 6b before prescribing an INSTI to a person of childbearing potential, as • preliminary data suggest that there is an increased risk of neural tube defects (NTDs) in infants born to 6,7 people who were receiving DTG at the time of conception. Until more information is available: • A negative pregnancy test result should be documented prior to initiating DTG in antiretroviral therapy (ART)-naive individuals of childbearing potential. • DTG is not recommended for those who are pregnant and within 12 weeks post-conception. is also not recommended • DTG for those of childbearing potential who are planning to become pregnant or who are sexually active and not using effective contraception. For those who are using effective contraception, use of a DTG-based regimen can be considered after • discussing the risks and benefits of this drug with the patient. • It is not yet known whether other INSTIs pose a similar risk of NTDs (i.e., a class ef fect). The chemical structure of BIC is similar to that of DTG. As there are no safety data for BIC use around the time of conception, similar considerations should be discussed with those of childbearing potential before using this drug. NNRTI-Based Regimens as Initial Antiretroviral Therapy: • The regimen of doravirine (DOR) plus TDF/3TC or TAF/FTC has been added to the category of Recommended Initial Regimens in Certain Clinical Situations. DOR is a new NNRTI that was recently approved for use in ART-naive individuals when administered with two NRTIs. DOR/TDF/3TC is coformulated as a single-tablet regimen (STR). Clinical trial data have shown that this regimen is 8,9 noninferior to efavirenz (EFV)- and darunavir/ritonavir (DRV/r)-based regimens. DOR compares F-3 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

63 favorably to EFV and DRV/r in terms of side effects. DOR-based therapy has not been directly compared to INSTI-containing combinations for initial therapy. In patients starting their first ART regimen, treatment-emergent resistance to DOR has been observed. • EFV 400 mg/TDF/3TC and EFV 600 mg/TDF/FTC are now available as generic STRs. In a randomized trial (ENCORE-1), EFV 400 mg/TDF/3TC and EFV 600 mg/TDF/3TC had similar virologic efficacy, though EFV 400 mg/TDF/3TC had fewer side effects. There are insufficient data regarding the use of EFV 400 mg/TDF/3TC in pregnancy or in people receiving rifampin to recommend its use in these situations. See the NNRTI section below for considerations regarding the use of these two single-pill regimens. Protease Inhibitor-Based Regimens as Initial Antiretroviral Therapy: • TV/c or ATV/r) plus ABC/3TC is no longer included in the list of Recommended Boosted atazanavir (A Initial Regimens in Certain Clinical Situations because it has disadvantages when compared with other regimens in this category. In a randomized trial, ATV/r plus ABC/3TC was less potent than ATV/r plus 10 TDF/FTC in people with HIV RNA >100,000 copies/mL. In a separate randomized trial, ATV/r was 11 less well tolerated than DRV/r. Other Regimens When Abacavir, Tenofovir Alafenamide, or Tenofovir Disoproxil Fumarate Cannot be Used or Are Not Optimal: • DTG plus 3TC is now recommended by the Panel when ABC, TAF, or TDF cannot be used or are not optimal. This is based on the results of two large Phase 3 randomized clinical trials: DTG plus 3TC was noninferior to DTG plus TDF/FTC in terms of virologic efficacy, and no drug resistance was seen in 12 either treatment group. Longer-term data are needed before this new two-drug regimen is recommended for most people with HIV. • Other regimens that can be considered are DR V/r plus raltegravir (RAL), as long as a patient’s plasma 3 HIV RNA is <100,000 copies/mL and CD4 cell count is >200/mm , or DRV/r plus 3TC, although the data for this regimen are not as extensive as for other combinations. Lopinavir/ritonavir (LPV/r) plus 3TC is no longer recommended because of pill burden and poor • tolerability. Generic Antiretroviral Drugs: • A growing number of generic ARV medications have been approved by the FDA since the last revision of these guidelines. In some situations, cost and access are among the factors to consider when choosing an Cost Considerations and Antiretroviral Therapy ). ARV regimen (see F-4 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

64 Table 6a. Recommended Antiretroviral Regimens for Initial Therapy (page 1 of 2) , potential adverse effects, Selection of a regimen should be individualized based on virologic efficacy childbearing potential and use of effective contraception, pill burden, dosing frequency, drug-drug interaction potential, comorbid conditions, cost, access, and resistance test results. Drug classes and regimens within each class are arranged first by evidence rating, and, when ratings are equal, in alphabetical order . Table 7 provides ARV recommendations based on specific clinical scenarios. Recommended Initial Regimens for Most People with HIV Recommended regimens are those with demonstrated durable virologic efficacy, favorable tolerability and toxicity profiles, and ease of use. INSTI plus 2 NRTIs : For individuals of childbearing potential, see Table 6b before prescribing one of these regimens. Note: (AI) BIC/TAF/FTC • a DTG/ABC/3TC (AI) — if HLA-B*5701 negative • a b for both TAF/FTC and TDF/FTC) DTG plus tenofovir ( AI • /FTC b a c plus tenofovir • /FTC ( BI for TDF/FTC, RAL for TAF/FTC) BII Recommended Initial Regimens in Certain Clinical Situations These regimens are effective and tolerable but have some disadvantages when compared with the regimens listed above or have less supporting data from randomized clinical trials. However, in certain clinical situations, one of these regimens may be preferred (see Table 7 for examples). INSTI plus 2 NRTIs : Note: For individuals of childbearing potential, see Table 6b before prescribing one of these regimens. b /FTC ( BI for both TAF/FTC and TDF/FTC) • EVG/c/tenofovir c a (CII) plus ABC/3TC • — if HLA-B*5701 negative and HIV RNA <100,000 copies/mL RAL Boosted PI plus 2 NRTIs: (In general, boosted DRV is preferred over boosted ATV) a b V/c or DRV/r) plus tenofovir • /FTC (DR (AI) b (A TV/c or ATV/r) plus tenofovir • /FTCa (BI) a (DR V/c or DRV/r) plus ABC/3TC • — if HLA-B*5701 negative (BII) NNRTI plus 2 NRTIs : b b DOR/TDF /3TC (BI) or DOR plus TAF /FTC (BIII) • b a BII EFV plus ( BI for EFV 600 mg/TDF/FTC or EFV 600 mg/TDF/3TC, /FTC for EFV 600 mg plus TAF/FTC) • TDF b a 3 /FTC (BI) — if HIV RNA <100,000 copies/mL and CD4 cell count >200 cells/mm RPV/tenofovir • : Regimens to Consider when ABC, TAF, and TDF Cannot be Used or Are Not Optimal (BI) • DTG plus 3TC 3 • V/r plus RAL BID (CI )— if HIV RNA <100,000 copies/mL and CD4 cell count >200 cells/mm DR a • V/r once daily plus 3TC (CI) DR Rating of Recommendations: A = Strong; B = Moderate; C = Optional Rating of Evidence: I = Data from randomized controlled trials; II = Data from well-designed nonrandomized trials, observational cohort studies with long-term clinical outcomes, relative bioavailability/bioequivalence studies, or regimen comparisons from randomized switch studies; III = Expert opinion Note: The following are available as coformulated drugs: ABC/3TC, ATV/c, BIC/TAF/FTC, DOR/TDF/3TC, DRV/c, DRV/c/TAF/FTC , DTG/ ABC/3TC, EFV 600 mg/TDF/3TC, EFV/TDF/FTC, EVG/c/TAF/FTC, EVG/c/TDF/FTC, RPV/TAF/FTC, RPV/TDF/FTC, TAF/FTC, , TDF/3TC and TDF/FTC. a 3TC may be substituted for FTC, or vice versa. ABC/3TC, TDF/3TC, TDF/FTC, and TAF/FTC are available as coformulated, two-NRTI tablets, and they are also available as part of various STRs. Cost, access, and availability of STR formulations are among the factors to consider when choosing between 3TC and FTC . b TAF and TDF are two forms of tenofovir approved by the FDA. TAF has fewer bone and kidney toxicities than TDF, while TDF is associated with lower lipid levels. Safety, cost, and access are among the factors to consider when choosing between these drugs. c can be given as RAL 400 mg BID or RAL 1200 mg (two, 600-mg tablets) once daily. RAL F-5 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

65 (page 2 of 2) Table 6a. Recommended Antiretroviral Regimens for Initial Therapy 3TC = lamivudine; ABC = abacavir; ART = antiretroviral therapy; ARV = antiretroviral; ATV = atazanavir; ATV/c = Key to Acronyms: atazanavir/cobicistat; ATV/r = atazanavir/ritonavir; BIC = bictegravir; BID = twice daily; CD4 = CD4 T lymphocyte; DOR = doravirine; DRV = darunavir; DRV/c = darunavir/cobicistat; DRV/r = darunavir/ritonavir; DTG = dolutegravir; EFV = efavirenz; EVG = elvitegravir; EVG/c = elvitegravir/cobicistat; FDA = Food and Drug Administration; FTC = emtricitabine; HLA = human leukocyte antigen; INSTI = integrase strand transfer inhibitor; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; PI = protease inhibitor; RAL = raltegravir; RPV = rilpivirine; STR = single-tablet regimen; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate Table 6b. Considerations Before Initiating Dolutegravir and Other Integrase Strand Transfer Inhibitors as Initial Therapy (AIII) . Preliminary data suggest that Pregnancy testing should be performed in those of childbearing potential prior to initiation of ART 6,7 there is an increased risk of NTDs in infants born to women who were receiving DTG at the time of conception. Before Initiating DTG: of and people of childbearing potential should discuss the benefits and NTDs; risks of using DTG, including the possible risk Providers • appropriate counseling should be provided so that the individual can make an informed decision about the use of this drug (AIII) . DTG should not be prescribed for individuals: • • Who are pregnant and within 12 weeks post-conception (AII) ; or • Who are of childbearing potential and planning to become pregnant (AII) ; or . (AIII) fective contraception Who are of childbearing potential, sexually active, and not using ef • the • For those who are using effective contraception, a DTG-based regimen can be considered after weighing DTG risks and benefits of use with the individual (BIII) . fect). • It is not yet known whether other INSTIs pose a similar risk of NTDs (i.e., a class ef The chemical structure of BIC is similar to DTG. There are no safety data on the use of BIC around the time of conception. For those • who are of childbearing potential, but who are not pregnant, an approach similar to that outlined for DTG should be discussed before considering the use of BIC-containing ART (AIII) . • In a person who is pregnant, BIC is not recommended because of insufficient safety data (AIII) . • In a person who is pregnant, EVG/c is also not recommended because low EVG concentrations have been reported when this drug is 13 . (AII) given during the second and third trimesters • Among those who received RAL during pregnancy, the rate of fetal malformations is within the expected range for pregnancy outcomes in the United States; however, not data on RAL use during the first trimester is limited to fewer than 300 deliveries. As it is currently known whether the association between DTG and NTDs represents a class effect, this potential risk should be discussed with people of childbearing potential who prefer an INSTI-containing regimen. Rating of Recommendations: A = Strong; B = Moderate; C = Optional Rating of Evidence: I = Data from randomized controlled trials; II = Data from well-designed nonrandomized trials, observational cohort studies with long-term clinical outcomes, relative bioavailability/bioequivalence studies, or regimen comparisons from randomized switch studies; III = Expert opinion Key to Acronyms: ART = antiretroviral therapy; BIC = bictegravir; DTG = dolutegravir; EVG/c = elvitegravir/cobicistat; INSTI = integrase strand transfer inhibitor; NTD = neural tube defect; RAL = raltegravir Selecting an Initial Antiretroviral Regimen For most patients, initial therapy should be with two NRTIs combined with an INSTI; in some individuals, a combination of an NNRTI or RTV- or COBI-boosted PI should be considered (see below). Choosing Between an INSTI-, PI-, or NNRTI-Based Regimen The choice between an INSTI, PI, or NNRTI as the third drug in an initial ARV regimen should be guided by the regimen’s efficacy, barrier to resistance, adverse effects profile, convenience, comorbidities, concomitant F-6 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

66 medications, and the potential for drug-drug interactions (see Tables 7 and 9 for guidance). The Panel’s Recommended Initial Regimens for Most People with HIV as listed in Table 6a include one of three INSTIs (BIC, DTG, or RAL) plus two NRTIs. For most patients, these INSTI-containing regimens will be highly effective and have relatively infrequent adverse effects and few drug interactions. In several head-to-head comparisons between boosted PI-containing regimens and INSTI-containing regimens, the INSTI was better 11,14,15 tolerated and caused fewer treatment discontinuations. Among the INSTI-based regimens, RAL-containing regimens have the longest clinical experience, and they have been shown to have durable virologic efficacy. However, these regimens have a higher pill burden than BIC- and DTG-containing regimens. RAL also has a lower barrier to resistance than BIC and DTG. In clinical trials of ART-naive patients who were receiving BIC- or DTG-based therapy, resistance has not been seen in patients experiencing virologic failure, and transmitted resistance is rare. Because of its high barrier to resistance, DTG may be considered for patients who must start ART before resistance test results are available (e.g., during acute HIV infection, and in the setting of certain opportunistic infections). BIC may also be effective in this setting, but there is less clinical experience with it than with DTG. BIC-based regimens have 4,5 been shown to be noninferior to DTG-based regimens in clinical trials. DTG is not recommended as initial therapy in those who are pregnant and within 12 weeks post-conception, or in those of childbearing potential who are planning to become pregnant or who are sexually active and not using effective contraception. The safety of BIC use in individuals of childbearing potential who desire pregnancy is unknown. In the category of Recommended Initial Regimens in Certain Clinical Situations, EVG-based regimens have the advantage of being available as STRs. However, these regimens have the potential disadvantages of a lower barrier to resistance than DTG or BIC and, importantly, a greater potential for drug interactions because EVG is combined with COBI, a strong CYP3A4 inhibitor. PK-enhanced, PI-based regimens are also effective in ART-naive patients, but, like EVG/c-based regimens, they also carry the same disadvantage of increased drug interaction potential. For those individuals in whom ART needs to begin urgently before resistance test results are available, boosted DRV may be an appropriate choice, as there is a low rate of transmitted PI resistance, it has a high barrier to resistance, and there is a low rate of treatment-emergent resistance. DRV/c/ TAF/FTC is now available as an STR. Boosted atazanavir has relatively few metabolic adverse effects in comparison to other boosted-PI regimens; however, in a randomized clinical trial, ATV/r had a higher rate 11 of adverse effect-associated drug discontinuation than DRV/r or RAL. In a substudy of this trial, and in a separate cohort study, ATV/r use was associated with slower progression of atherosclerosis, as measured by 16,17 carotid artery intima medial thickness. Large observational cohorts found an association between some PIs (DRV/r, fosamprenavir [FPV], indinavir [IDV], and lopinavir/ritonavir [LPV/r]) and an increased risk of 18-23 cardiovascular events, while this association was not seen with ATV. Further study is needed. NNRTI-based regimens (which include DOR, EFV, or rilpivirine [RPV]) may be optimal choices for some patients, although these drugs, especially EFV and RPV, have low barriers to resistance. The emergence of resistance at the time of virologic failure has been reported with DOR. EFV has a long track record of widespread use and is considered safe in persons of childbearing potential, and its minimal PK interaction with rifamycins makes it an attractive option for patients who require concomitant treatment for tuberculosis (TB). Most EFV-based regimens have excellent virologic efficacy, including in patients with high HIV RNA (except when EFV is used with ABC/3TC); however, the relatively high rate of central nervous system (CNS)-related side effects reduces the tolerability of EFV-based regimens. RPV has fewer adverse effects than EFV, is available as one of the smallest tablet sizes among STRs, and has a favorable lipid profile. However, RPV has lower virologic efficacy in patients with high baseline HIV RNA levels (>100,000 copies/ 3 mL) and low CD4 counts (<200 cells/mm ). DOR is now approved for use in ART-naive individuals with HIV. It is available both as a single-drug pill to be used with two NRTIs and as part of an STR that also includes TDF/3TC. Both formulations are taken once daily without regard to food. In randomized trials, DOR was noninferior to both EFV and to DRV/r when either of these drugs were taken in combination with two NRTIs. DOR has CNS tolerability advantages over EFV and favorable lipid effects when compared F-7 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

67 with both DRV/r and EFV. It also has fewer potential drug interactions than EFV or RPV, and, unlike RPV, virologic effects are not compromised in those with high HIV RNA levels and low CD4 cell counts. In those patients who cannot safely be prescribed a combination regimen that contains two NRTIs, there are now several two-drug treatment options. DTG plus 3TC is an option when ABC, TAF, and TDF cannot be used or are not optimal. Two randomized trials that collectively enrolled >1,400 participants with baseline HIV RNA levels <500,000 copies/mL compared DTG plus 3TC to a three-drug regimen of DTG plus TDF/ FTC. At week 48, DTG plus 3TC was noninferior to DTG plus TDF/FTC in terms of virologic efficacy. 12 No treatment-emergent resistance was seen in either group. Another option that can be considered is the combination of DRV/r (once daily) plus RAL (twice daily), but this combination can only be used in 24 3 those with baseline CD4 cell counts >200 cells/mm and HIV RNA levels <100,000 copies/mL. A small, randomized trial indicated that once-daily DRV/r plus 3TC had similar efficacy to DRV/r plus TDF/3TC, 25 although this study has yet to be published. Factors to Consider When Selecting an Initial Regimen When selecting a regimen for an individual person with HIV, a number of patient- and regimen-specific characteristics should be considered. The goal is to provide a potent, safe, tolerable, and easy-to-adhere-to regimen for the patient in order to achieve sustained virologic control. Some of the factors to consider during regimen selection can be grouped into the categories listed below. Table 7 includes recommendations for regimens to use in specific clinical scenarios. Initial Characteristics to Consider in All Persons with HIV: • Pretreatment HIV RNA level (viral load) • count Pretreatment CD4 HIV genotypic drug resistance test results. Based on current rates of transmitted drug resistance to different • V medications, standard genotypic drug-resistance testing in ARV-naive persons should focus on testing AR for mutations in the reverse transcriptase (RT) and protease (PR) genes. If transmitted INSTI resistance is a concern, providers should consider also testing for resistance mutations to this class of drugs. • HLA-B*5701 status. Those who are positive should not receive ABC. Individual preferences • Anticipated adherence to the regimen • : Specific Comorbidities or Other Conditions Cardiovascular disease, hyperlipidemia, renal disease, liver disease, osteopenia/osteoporosis or conditions • associated with bone mineral density (BMD) loss, psychiatric illness, neurologic disease, drug abuse or dependency requiring narcotic replacement therapy Pregnancy or those with the potential to become pregnant. Clinicians should refer to Table 6b and the • ARV latest Perinatal Guidelines for more detailed recommendations on the safety and effectiveness of drugs during conception and throughout pregnancy. • Coinfections: hepatitis B virus (HBV), hepatitis C virus (HCV), TB Regimen-Specific Considerations : • Regimen’s barrier to resistance • Potential adverse effects • Known or potential drug interactions with other medications (see Drug-Drug Interactions ) • Convenience (e.g., pill burden, dosing frequency, availability of fixed-dose combination (FDC) formulations, food requirements) • Cost and access (see Cost Considerations and Antiretroviral Therapy ) F-8 with HIV Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

68 Table 7. Antiretroviral Regimen Considerations for Initial Therapy Based on Specific Clinical Scenarios (page 1 of 4) This table provides guidance to clinicians in choosing an initial ARV regimen according to various patient and regimen characteristics and specific clinical scenarios. When more than one scenario applies to a person with HIV, clinicians should review considerations for each relevant scenario and use their clinical judgment to select the most appropriate regimen. This table is intended to guide the initial choice of regimen. However, if a person is doing well on a particular regimen, it is not necessary to switch to another regimen based on the scenarios outlined in this table. Please see Table 9 for additional information regarding the advantages and disadvantages of particular ARV medications. Note: Preliminary data suggest that there may be an increased risk of NTDs in infants born to those who were 6,7 receiving DTG at the time of conception. Until more information is available, clinicians should review Table 6b for further guidance before prescribing an INSTI to a person of childbearing potential. Patient or Regimen Clinical Scenario Consideration(s) Rationale/Comments Characteristics A higher rate of virologic failure has been observed in CD4 cell count <200 Pre-ART Do Not Use the Following Regimens: 3 cells/mm Characteristics those with low pretreatment CD4 cell counts. RPV-based regimens • • DRV/r plus RAL HIV RNA >100,000 Do Not Use the Following Regimens: Higher rates of virologic failure have been observed copies/mL in those with high pretreatment HIV RNA levels. RPV-based regimens • • ABC/3TC with EFV or ATV/r DRV/r plus RAL • HLA-B*5701 positive Do not use ABC-containing regimens. ABC hypersensitivity, a potentially fatal reaction, or result unknown is highly associated with the presence of the HLA- B*5701 allele. ARV should be started Avoid NNRTI-based regimens. Transmitted mutations conferring NNRTI resistance before HIV drug are more likely than mutations associated with PI or Avoid ABC. resistance results INSTI resistance. are available (e.g., in Recommended ART Regimens: HLA-B*5701 results may not be available rapidly. a person with acute a • (DRV/r or DRV/c) plus tenofovir /FTC HIV) or when rapid Transmitted resistance to DRV and DTG is rare, and a DTG plus tenofovir /FTC • initiation of ART is these drugs have high barriers to resistance. warranted Refer to Table 6b for further guidance before initiating DTG in persons of childbearing potential. A 1-pill, once-daily ART-Specific Do not use RPV-based regimens if HIV RNA is STR Options as Initial ART Include: 3 Characteristics regimen is desired . >100,000 copies/mL and CD4 cell count is <200/mm F TC • BIC/TAF/ DOR/TDF/3TC • Do not use DTG/ABC/3TC if patient is HLA-B*5701 positive. • DRV/c/TAF/FTC • DTG/ABC/3TC Refer to Table 6b for further guidance before initiating an INSTI in persons of childbearing potential. • EFV/TDF/FTC • EFV/TDF/3TC for ARV dose Appendix B, Table 8 See • EVG/c/TAF/FTC recommendations in the setting of renal impairment. • EVG/c/TDF/FTC • RPV/TAF/FTC • RPV/TDF/FTC Food effects Regimens that Can be Taken Without Oral bioavailability of these regimens is not food. by Regard to Food: significantly affected • BIC-, DOR-, DTG-, or RAL-based Refer to T able 6b for further guidance before initiating regimens an INSTI in persons of childbearing potential. F-9 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

69 Antiretroviral Regimen Considerations for Initial Therapy Based on Specific Clinical 7. Table Scenarios (page 2 of 4) Patient or Consideration(s) Clinical Scenario Regimen Rationale/Comments Characteristics Regimens that Should be Taken with Food: Food effects, ART-Specific Food improves absorption of these regimens. RPV - Characteristics , continued containing regimens should be taken with at least 390 ATV/r- or ATV/c-based regimens • continued calories of food. DRV/r- or DR • V/c-based regimens a EVG/c/T • AF/FTC a EVG/c/TDF/FTC • RPV-based regimens • Food increases EFV absorption and may increase Regimens that Should be Taken on an CNS side ef Empty Stomach: fects. EFV-based regimens • Presence Chronic kidney TDF has been associated with proximal renal Avoid TDF unless the patient has as of Other (defined disease ESRD. Use ABC or TAF. tubulopathy. Higher rates of renal dysfunction have CrCl <60 mL/min) Conditions been reported in patients using TDF in conjunction ABC may be used if patient is HLA- with RTV-containing regimens. B*5701 negative. If HIV RNA >100,000 copies/mL, do not use ABC/3TC plus An adjusted dose of TDF can be used in patients with ESRD or in those who are on hemodialysis. (EFV or ATV/r). for Refer to dosing specific Appendix B, Table 8 TAF may be used if CrCl >30 mL/min. recommendations. Consider avoiding ATV. TAF has less impact on renal function and lower rates of proteinuria than TDF. ART Options When ABC, TAF or TDF Cannot be Used: ATV has been associated with chronic kidney disease • DTG plus 3TC in some observational studies. DRV/r plus 3TC • ABC has not been associated with renal dysfunction. (if CD4 cell count >200 DRV/r plus RAL • 3 Refer to Table 6b for further guidance before initiating cells/mm and HIV RNA <100,000 an INSTI in persons of childbearing potential. copies/mL) Some ARVs are contraindicated or may Liver disease with specific dosing Appendix B, Table 8 for Refer to require cirrhosis dosage modification in patients recommendations. with Child-Pugh class B or C disease. Patients with cirrhosis should be carefully evaluated by an expert in advanced liver disease. Osteoporosis Avoid TDF TDF is associated with decreases in BMD along . with renal tubulopathy, urine phosphate wasting, and Use ABC or TAF. resultant osteomalacia. TAF and ABC are associated with smaller declines in BMD than TDF. ABC may be used if patient is HLA- B*5701 negative. If HIV RNA >100,000 copies/mL, do not use ABC/3TC plus (EFV or ATV/r). Psychiatric illnesses Consider avoiding EFV- and RPV- EFV and RPV can exacerbate psychiatric symptoms based regimens. and may be associated with suicidality. Patients on INSTI-based regimens who INSTIs have been associated with adverse neuropsychiatric effects in some retrospective cohort have pre-existing psychiatric conditions should be closely monitored. studies and case series. Some ARVs are contraindicated and See the drug-drug interaction tables (Tables 19a , 19d ) for dosing recommendations when some psychiatric medications need dose , and 19b adjustments when coadministered with drugs used for psychiatric illnesses are used with certain ARVs. certain ARVs. F-10 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

70 Table 7. Antiretroviral Regimen Considerations for Initial Therapy Based on Specific Clinical Scenarios (page 3 of 4) Patient or Clinical Scenario Regimen Consideration(s) Rationale/Comments Characteristics Presence HAD Avoid EFV-based regimens if EFV-related neuropsychiatric effects may confound beneficial ef of Other possible. fects assessment of ART’ s on improvement of HAD-related symptoms. Conditions , Favor DTG- or DRV-based regimens. continued There is a theoretical CNS penetration advantage of DTG- or DRV -based regimens. Opioid withdrawal may occur when EFV EFV reduces methadone concentrations and may Medication-assisted lead to withdrawal symptoms. is initiated in patients who are on a stable treatment for opioid dose of methadone. dependence See the drug-drug interaction tables (Tables 19a , ) for dosing recommendations. 19d , and Clinical monitoring is recommended, 19b as medications used to treat opioid dependence may need to be adjusted in some patients. High cardiac risk An increased CV risk with ABC has been observed in Consider avoiding ABC- and LPV/r -based regimens. some studies. If a boosted PI is the desired option, Observational cohort studies reported an association an ATV-based regimen may have between some PIs (DRV, IDV, FPV, and LPV/r) and advantages over a DRV-based regimen. an increased risk of CV events; this risk has not been seen with ATV (see text). Further study is needed. BIC-, DOR-, DTG-, RAL-, or RPV-based regimens may be considered for those BIC-, DOR-, DTG-, RAL- or RPV-based regimens with high cardiac risk. other have more favorable lipid than profiles regimens, although evidence on whether this improves CV outcomes is lacking. Refer to T able 6b for further guidance before initiating an INSTI in persons of childbearing potential. Cardiac QTc interval Consider avoiding EFV- or RPV-based High EFV or RPV concentrations may cause QT prolongation. prolongation regimens if patient is taking other medications with known risk of Torsades de Pointes, or in patients at higher risk of Torsades de Pointes. Hyperlipidemia TDF has been associated with lower lipid levels than The Following ARV Drugs Have Been Associated with Dyslipidemia: ABC or TAF. • PI/r or PI/c Refer to Table 6b for further guidance before initiating an INSTI in persons of childbearing potential. • EFV EVG/c • BIC, DOR, DTG, RAL, and RPV have fects. fewer lipid ef Patients with history Consider using regimens with a boosted These regimens have a high genetic barrier to of poor adherence to resistance. PI or DTG. non-ARV medications Refer to Table 6b for further guidance before initiating BIC also has a high barrier to resistance, or inconsistent an INSTI in persons of childbearing potential. but there is currently no data on its engagement in care efficacy in this population. F-11 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

71 Table Antiretroviral Regimen Considerations for Initial Therapy Based on Specific Clinical 7. (page 4 of 4) Scenarios Patient or Regimen Clinical Scenario Consideration(s) Rationale/Comments Characteristics Pregnancy Until more information is available, do not initiate a DTG-based regimen for those who are Presence pregnant and within 12 weeks post-conception, because preliminary data suggest that there of Other , is an increased risk of NTDs in infants born to those who were receiving DTG at the time of Conditions 6,7 continued conception. the Perinatal Guidelines for further guidance on ARV use during Refer to and Table 6b pregnancy. Patients of Until more information is available, do not initiate a DTG-based regimen in these patients , childbearing potential because preliminary data suggest that there is an increased risk of NTDs in infants born to those 6,7 who were receiving DTG at the time of conception. who are planning to become pregnant Table 6b for further guidance before initiating an INSTI. Refer to or who are sexually active and not using effective contraception Presence of HBV infection TDF, TAF, FTC, and 3TC are active against both HIV Use TDF or TAF, with FTC or 3TC, Coinfections and HBV. 3TC- or FTC-associated HBV mutations whenever possible. can emerge rapidly when these drugs are used If TDF and TAF Are Contraindicated: without another drug that is active against HBV. For treatment of HBV, use FTC or 3TC • T with entecavir and a suppressive AR ). HBV/HIV Coinfection regimen (see HCV treatment , with special attention to potential interactions Refer to recommendations in HCV/HIV Coinfection required between ARV drugs and HCV drugs. Treating TB disease TAF and BIC are not recommended BIC and TAF reduce significantly Rifamycins may with rifamycins exposures. with any rifamycin-containing regimen. Rifampin is a strong inducer of CYP3A4 and If Rifampin is Used: UGT1A1 in decreases enzymes, causing significant concentrations of PIs, INSTIs, DOR, and RPV. • The following are not recommended: PI/c or PI/r, BIC, EVG, DOR, RPV , or ef significant less a has EFV on Rifampin fect TAF. concentration than on the concentrations of other NNRTIs, PIs, and INSTIs. EFV can be used without dose • adjustment. Refer to Table 6b for further guidance before initiating • If RAL is used, increase RAL dose to 800 an INSTI in persons of childbearing potential. use once-daily RAL. not mg BID. Do 19a See the drug-drug interaction tables (Tables , • Use DTG at 50 mg BID dose only ) and for and 19b , 19c , 19d 19e TB/HIV Coinfection in patients without selected INSTI information on ARV use with rifamycins. mutations (refer to product label). a TAF and TDF are two approved forms of tenofovir. TAF has fewer bone and kidney toxicities than TDF, whereas TDF is associated with lower , cost, and access are among the factors to consider when choosing between these drugs. lipid levels. Safety Key to Acronyms: 3TC = lamivudine; ABC = abacavir; ART = antiretroviral therapy; ARV = antiretroviral; ATV = atazanavir; ATV/c = atazanavir/ cobicistat; ATV/r = atazanavir/ritonavir; BIC= bictegravir; BID = twice daily; BMD = bone mineral density; COBI = cobicistat; CD4 = CD4 T lymphocyte; CNS = central nervous system; CrCl = creatinine clearance; CV = cardiovascular; CYP = cytochrome P; DOR = doravirine; DRV = darunavir; DRV/c = darunavir/cobicistat; DRV/r = darunavir/ritonavir; DTG = dolutegravir; EFV = efavirenz; ESRD = end stage renal disease; EVG = elvitegravir; EVG/c = elvitegravir/cobicistat; FPV = fosamprenavir; FTC = emtricitabine; HAD = HIV-associated dementia; HBV = hepatitis B virus; HCV = hepatitis C virus; HLA = human leukocyte antigen; IDV = indinavir; INSTI = integrase strand transfer inhibitor; LPV = lopinavir; LPV/r = lopinavir/ritonavir; NNRTI = non-nucleoside reverse transcriptase inhibitor; NTD = neural tube defect; PI = protease inhibitor; PI/c = cobicistat-boosted protease inhibitor; PI/r = ritonavir-boosted protease inhibitor RAL = raltegravir; RPV = rilpivirine; RTV = ritonavir; STR = single-tablet regimen; TAF = tenofovir alafenamide; TB = tuberculosis; TDF = tenofovir disoproxil fumarate; UGT = uridine diphosphate glucuronosyltransferase F-12 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

72 Characteristics of Antiretroviral Drugs Recommended for Initial Therapy The following sections provide detailed information regarding the characteristics, clinical trial results, adverse effects profile, and the Panel’s recommendations for ARV drugs that are recommended as initial therapy for persons with HIV. Dual-Nucleoside Reverse Transcriptase Inhibitor Options as Part of Initial Combination Therapy Table 8a. Characteristics of Dual-Nucleoside Reverse Transcriptase Inhibitor Options Recommended for Antiretroviral Therapy-Naive Patients ABC/3TC TAF/FTC TDF/3TC TDF/FTC Once daily Once daily Once daily Dosing Once daily Frequency Available • TDF/FTC ABC/3TC • • TDF/3TC • TAF 25 mg/FTC Coformulations DOR/TDF/3TC • • • EFV/TDF/FTC DTG/ABC/3TC • BIC/TAF 25 mg/FTC for ART-Naive • • EVG/c/TDF/FTC DR V/c/TAF 10 mg/FTC EFV 600 mg/TDF/3TC • Patients RPV/TDF/FTC • • • EVG/c/TAF 10 mg/FTC EFV 400 mg/TDF/3TC AF 25 mg/FTC RPV/T • Adverse ABC: TDF: TAF : TDF: Effects • Renal insufficiency, Renal • • Renal insufficiency, insufficiency, HSR to ABC is associated • proximal renal proximal renal proximal renal with the presence of HLA- tubulopathy (less tubulopathy tubulopathy B*5701 allele than frequent with TDF) • Decrease in BMD Decrease in BMD • • Increase in CV events is associated with ABC use • Decrease in BMD (less • • Renal and bone toxicity Renal and bone toxicity than with TDF; similar in some, but not all, cohort are exacerbated by are exacerbated by studies to ABC) boosters pharmacologic boosters pharmacologic : significant 3TC No FTC: Nail pigmentation adverse ef fects Other • Perform HLA-B*5701 testing HBV. of flair precipitate may Discontinuation Also used for HBV treatment. Considerations before initiating ABC; if result for dose recommendations in patients with renal Appendix B, Table 8 See is positive, do not start ABC insufficiency . ABC to allergy list and add • >100,000 copies/ If HIV RNA mL, use only with DTG 3TC = lamivudine; ABC = abacavir; ART = antiretroviral therapy; BIC= bictegravir; BMD = bone mineral density; Key to Acronyms: CV = cardiovascular; DOR = doravirine; DRV = darunavir; DRV/c = darunavir/cobicistat; DTG = dolutegravir; EFV = efavirenz; EVG = elvitegravir; EVG/c = elvitegravir/cobicistat; FTC = emtricitabine; HBV = hepatitis B virus; HLA = human leukocyte antigen; HSR = hypersensitivity reaction; NRTI = nucleoside reverse transcriptase inhibitor; PI = protease inhibitor; RPV = rilpivirine; STR = single-tablet regimen; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate F-13 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

73 Summary FDA-approved NRTIs include zidovudine (ZDV), stavudine (d4T), didanosine (ddI), ABC, TDF, TAF, 3TC, and FTC. Older NRTIs (ZDV, d4T, ddI) are no longer recommended for use in clinical practice in the United States due to high rates of serious toxicities, including bone marrow suppression from ZDV use. Other toxicities that mainly occur due to mitochondrial toxicity may lead to myopathy, peripheral neuropathy, hepatic steatosis, lactic acidosis, and lipoatrophy. The incidence of these complications is much lower with 26,27 3TC, FTC, ABC, TDF, and TAF than with older NRTIs. ABC/3TC, TAF/FTC, TDF/3TC, and TDF/FTC are NRTI combinations that are recommended for use as components of initial therapy. Table 6a provides recommendations and ratings for the individual regimens. These recommendations are based on the virologic potency and durability, short- and long-term toxicity, and dosing convenience of these drugs. TAF and TDF are two approved forms of tenofovir. TDF has been 28 associated with bone and kidney toxicities, especially when used with a pharmacologic booster. TAF is less likely to cause kidney and bone toxicities than TDF. TDF is associated with lower lipid levels than TAF. Safety, cost, and access are among the factors to consider when choosing between these drugs. ABC/3TC and TDF/3TC are available as generic formulations. Clinical Trials Comparing Nucleoside Reverse Transcriptase Inhibitors Abacavir/Lamivudine Compared to Tenofovir Disoproxil Fumarate/Emtricitabine Several randomized controlled trials in ART-naive participants compared ABC/3TC to TDF/FTC, each 10,29,30 31 administered in combination with a third ARV drug (see also the discussion in the DTG section). • The ACTG 5202 study, a randomized controlled trial in >1,800 participants, evaluated the efficacy and safety of ABC/3TC and TDF/FTC when each was used in combination with either EFV or ATV/r. In patients with baseline HIV RNA ≥100,00 copies/mL, there was a significantly shorter time to virologic failure with ABC/3TC than with TDF/FTC regardless of whether the third active drug was EFV or 10 ATV/r. In the HEAT study, 688 participants received ABC/3TC or TDF/FTC in combination with once- daily LPV/r. Virologic efficacy was similar in the two study arms, including in a subgroup with HIV 30 RNA ≥100,000 copies/mL. • ASSERT study compared open-label ABC/3TC with TDF/FTC in 385 HLA-B*5701–negative, ART- The naive patients; all participants also received EFV. The primary study endpoint was renal safety of the regimens. At week 48, the proportion of participants with HIV RNA <50 copies/mL was lower among 29 ABC/3TC-treated participants than among TDF/FTC-treated participants. Tenofovir Alafenamide Compared to Tenofovir Disoproxil Fumarate T wo randomized double-blind Phase 3 clinical trials compared the safety and efficacy of EVG/c/TDF/ • FTC and EVG/c/TAF/FTC in 1,733 ART-naive adults with estimated glomerular filtration rate (eGFR) ≥50 mL/min. AF/FTC was virologically noninferior to TDF/FTC at week 48 (92% vs. 90% of participants achieved T • 32 plasma HIV RNA <50 copies/mL, respectively), but TAF/FTC was superior to TDF/FTC at week 144 33 (84.2% vs. 80%), largely driven by a higher rate of treatment discontinuation in the TDF arm. • Participants in the TAF arm had significantly smaller reductions in BMD at the spine and hip than 33 those in the TDF arm through 144 weeks. They also had less pronounced changes in eGFR and 34 renal biomarkers and fewer clinically significant renal events through week 96. Conversely, levels of fasting low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides increased more in the TAF group than in the TDF group at 96 weeks, with no change in 35 total cholesterol to HDL ratio. F-14 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

74 • T wo randomized studies have compared the safety and efficacy of TAF/FTC to TDF/FTC each administered in combination with boosted DRV in ART-naive subjects: • Phase 2 study of coformulated DRV/c plus TAF/FTC versus DRV/c plus TDF/FTC demonstrated A 36 similar virologic suppression rates in both arms (75% vs. 74%) in treatment-naive patients. In the TAF arm, fewer participants developed proteinuria. Changes in BMD were also less pronounced among these participants. • The AMBER study randomized ART-naive participants to receive either coformulated DRV/c/TAF/FTC or DRV/c plus TDF/FTC. At 48 weeks, HIV RNA <50 copies/mL was achieved in 91% of the DRV/c/ TAF/FTC participants versus 88% of the DRV/c plus TDF/FTC participants. Participants in the TAF/ 37 FTC arm showed less decline in hip and spine BMD and eGFR than participants in the TDF/FTC arm. 1 randomized trials that compared the virologic efficacy, frequency • One analysis evaluated data from 1 of renal events, and bone density changes associated with the use of TDF or TAF when either drug was taken with or without PK boosters (RTV or COBI). There were no significant differences between unboosted TDF and TAF in terms of virologic efficacy or in the number of participants who discontinued treatment due to renal or bone adverse events or fractures. However, bone- and renal-related toxicities 28 were more pronounced when TDF was used in combination with RTV or COBI. • T o assess the ability of TAF to maintain HIV and HBV suppression, 72 patients with HIV/HBV coinfection who had HIV RNA <50 copies/mL and HBV DNA <9 log10 IU/mL on a stable regimen 38 were switched to EVG/c/TAF/FTC. In this study, 96% of participants were on a TDF/FTC-containing regimen prior to the switch. Key results of the study showed that: AF/FTC maintained HIV suppression: 94.4% and 91.7% of • Those who switched to EVG/c/T participants at 24 and 48 weeks, respectively. At 24 and 48 weeks, 86.1% and 91.7% of participants had HBV DNA <29 log IU/mL. 10 • Decreases in markers of proximal tubular proteinuria and biomarkers of bone turnover were seen in 38 AF/FTC. those who switched to EVG/c/T (In alphabetical order) Dual-Nucleoside Reverse Transcriptase Inhibitor Choices Abacavir/Lamivudine (ABC/3TC) 31,39-41 ABC plus 3TC has been studied in combination with EFV, several PIs, and DTG in ART-naive patients. Adverse Effects Hypersensitivity Reactions: • Clinically suspected hypersensitivity reactions (HSRs) were observed in 5% to 8% of individuals who started ABC in clinical trials conducted before the use of HLA-B*5701 testing. The risk of HSRs is highly associated with the presence of the HLA-B*5701 allele; approximately 50% of HLA-B*5701– 42,43 positive patients will have an ABC-related HSR if given this drug. HLA-B*5701 testing should be done if the use of ABC is being considered. In a patient who tests positive for HLA-B*5701, ABC should not be given and ABC hypersensitivity should be noted on the allergy list. Patients who are HLA-B*5701 negative are far less likely to experience an HSR, but they should be counseled about the symptoms of the reaction. Patients who discontinue ABC because of a suspected HSR should never be rechallenged, regardless of their HLA-B*5701 status. Cardiovascular Risk: • . ABC use and myocardial infarction (MI) was first reported in the D:A:D study An association between This large, multinational, observational study group found that recent (i.e., within 6 months) or current use of ABC was associated with an increased risk of MI, particularly in participants with pre-existing 19,44 cardiac risk factors. F-15 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

75 • Since the D:A:D report, several studies have evaluated the relationship between ABC therapy and .45-51 cardiovascular events. Some studies have found an association Others, including an FDA meta- 18,52-55 analysis of 26 randomized clinical trials that evaluated ABC, have not. ABC in the previous 6 months was associated An analysis of data from NA-ACCORD found that use of • 56 with an increased risk of both type 1 and type 2 MIs after adjusting for cardiovascular disease risk factors. • No consensus has been reached on the association between ABC use and MI risk or the mechanism for such an association. Other Factors and Considerations: • ABC/3TC is available as a coformulated tablet and as a coformulated STR with DTG. • ABC and 3TC are available separately and as a coformulated tablet in generic tablet formulations. • ABC does not cause renal dysfunction and can be used instead of TDF in patients with underlying renal dysfunction or in those who are at high risk for renal effects. No dose adjustment is required in patients with renal dysfunction. The Panel’ s Recommendations: ABC should only be prescribed for patients who are HLA-B*5701 negative. • • On the basis of clinical trial safety and efficacy data, experience in clinical practice, and the availability of DTG/ABC/3TC as an FDC, the Panel classifies DTG/ABC/3TC as a Recommended Initial Regimen for Most People with HIV (AI) (see the discussion of DTG in this section regarding the clinical efficacy data for ABC/3TC plus DTG). ABC/3TC use with EFV , ATV/r, ATV/c, DRV/c, DRV/r, or RAL is only recommended for patients with • pretreatment HIV RNA levels <100,000 copies/mL. See Table 6a for more detailed recommendations on the use of ABC/3TC with these drugs. • ABC should be used with caution or avoided in patients with known high cardiovascular risk. Tenofovir Alafenamide/Emtricitabine (TAF/FTC) TAF, an oral prodrug of tenofovir (TFV), is hydrolyzed to TFV in plasma and then converted to TFV- diphosphate (TFV-DP) intracellularly, where it exerts its activity as an NRTI. Unlike TDF, which readily converts to TFV in plasma after oral absorption, TAF remains relatively stable in plasma, resulting in lower plasma and higher intracellular TFV concentrations. After oral administration, TAF 25 mg resulted in plasma TFV concentrations that were 90% lower than those seen with TDF 300 mg. Intracellular TFV-DP concentrations, however, were substantially higher with TAF. Adverse Effects Renal and Bone Effects: • The potential for adverse kidney and bone ef fects is lower with TAF than with TDF. In randomized controlled trials that compared TAF and TDF in treatment-naive or virologically suppressed patients, TAF had more favorable effects on renal biomarkers and bone density than TDF (described below). Lipid Effects: In randomized controlled trials in ART-naive patients, as well as in switch studies (described below), • levels of LDL and HDL cholesterol and triglycerides were higher in patients receiving TAF than in patients receiving TDF. However, total cholesterol to HDL ratios did not differ between patients receiving 32,57,58 TAF and TDF. The clinical significance of this finding is not clear. F-16 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

76 Other Factors and Considerations: • T AF/FTC is available in FDCs with DRV/c, EVG/c or RPV, allowing the regimens to be administered as a single pill taken once daily with food. • In Phase 3 randomized trials, BIC/T AF/FTC was comparable to DTG/ABC/3TC and to DTG plus TAF/ FTC (see the INSTI section below). • TAF-containing regimens are approved for patients with eGFR ≥30 mL/min. Renal function, urine glucose, and urine protein should be assessed before initiating treatment with TAF, and these assessments should be repeated periodically during treatment. EVG/c/FTC/TAF was safe and effective in a single-arm 59 switch study that was conducted in patients on hemodialysis with eGFRs <15 mL/min. • Both TAF and FTC are active against HBV. In patients with HIV/HBV coinfection, TAF/FTC may be used as the NRTI pair in an ART regimen because these drugs have activity against both viruses (see 38 ). HBV/HIV Coinfection The Panel’s Recommendation: 60 On the basis of clinical trial safety and efficacy data, supportive bioequivalence data, • and its availability as a component of various FDCs, the Panel considers TAF/FTC a recommended NRTI combination for initial ART in most persons with HIV when prescribed with BIC, DTG, and RAL. Tenofovir Disoproxil Fumarate/Emtricitabine (TDF/FTC) and Tenofovir Disoproxil Fumarate/ Lamivudine (TDF/3TC) TDF, with either 3TC or FTC, has been studied in combination with DOR, EFV, RPV, several boosted PIs, 61,62-70 EVG/c, RAL, and DTG in randomized clinical trials. In a 10-day, open-label, randomized monotherapy trial that was not powered to find a difference between the arms, FTC 200 mg once daily demonstrated a viral load reduction of 1.7 log from baseline for 3TC from baseline, compared with a reduction of 1.5 log 10 10 71 150 mg twice daily. In a meta-analysis of 12 trials, no significant difference in treatment success was found 72 between 3TC and FTC. In the ATHENA cohort, virologic efficacy of TDF/FTC was compared to TDF/3TC 73 74 when either was combined with an NNRTI (EFV or NVP) TDF/3TC was associated or with a boosted PI. with higher rates of virologic failure than TDF/FTC in the NNRTI analysis; however, it is worth noting that the people in this cohort who were taking 3TC generally had higher viral loads, lower CD4 cell counts, and 73 were more likely to be using injection drugs at the start of the study than people who were taking FTC. There was no difference in the rates of virologic failure in people who were taking TDF/FTC and people who 74 were taking TDF/3TC when these drug combinations were used with a boosted PI. A retrospective analysis of an Italian national database found that viral resistance was more common with TDF/3TC than with TDF/ 75 FTC, but this was not observed in clinical trials. Adverse Effects Renal Effects: 76,77 • TDF use. New onset or worsening renal impairment has been associated with Risk factors may 78 disease, longer treatment history, low body weight (especially in females) include advanced HIV and 79 pre-existing renal impairment. Concomitant use of a PK-enhanced regimen (with a PI or EVG) can increase TDF concentrations; studies have suggested that there is a greater risk of renal dysfunction when TDF is used in these regimens. As previously noted, adverse effects on renal biomarkers such as 77,79-83 proteinuria, especially tubular proteinuria, were more frequent with TDF than with TAF. Adverse renal outcomes are more likely when TDF/FTC is coadministered with PK boosters (RTV or • COBI). A meta-analysis of randomized trials found that discontinuation due to renal adverse events is 28 more frequent in people who take TDF/FTC with PK boosting. F-17 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

77 Bone Effects: While initiation of all NRTI-containing regimens has been associated with a decrease in BMD, the • loss of BMD is greater with TDF-containing regimens. For example, in two randomized studies that compared TDF/FTC with ABC/3TC, participants who received TDF/FTC experienced a significantly 84,85 greater decline in BMD than ABC/3TC-treated participants. BMD generally stabilizes following an ART initiation. Loss of BMD with TDF is also greater than with TAF (see above). early decline after • Cases of osteomalacia associated with proximal renal tubulopathy have been reported with the use of 86 . TDF • Adverse bone outcomes are more likely when TDF/FTC is coadministered with PK boosters (RTV or COBI). A meta-analysis of randomized trials found that fractures and discontinuation due to bone 28 adverse events occur more frequently among patients who take TDF/FTC with PK boosting. Other Factors and Considerations: • , EVG/c, and RPV, allowing the regimens to be administered as TDF/FTC is available in FDCs with EFV a single pill taken once daily. • 600 mg, and EFV 400 mg. TDF/3TC is available in FDCs with DOR 100 mg, EFV • Renal function, urine glucose, and urine protein should be assessed before initiating treatment with TDF and periodically during treatment (see ). In Laboratory Testing for Initial Assessment and Monitoring 87 patients who have pre-existing renal insufficiency (creatinine clearance [CrCl] <60 mL/min), use of TDF is used, a dose adjustment is required if the patient’s CrCl falls TDF should generally be avoided. If Appendix B, Table 8 for dose recommendations). below 50 mL/min (see • TDF, FTC, and 3TC are active against HBV. In patients with HIV/HBV coinfection, TDF/FTC or TDF/3TC may be used as the NRTI pair of the ART regimen because these drugs have activity against both viruses (see ). HBV/HIV Coinfection The Panel’s Recommendations: • On the basis of clinical trial safety and efficacy data, long-term experience in clinical practice, and the combination’ s availability as a component of FDC drugs, the Panel considers TDF/FTC and TDF/3TC as recommended NRTI combinations for initial ART in most persons with HIV when combined with DTG or RAL. See Table 6a for recommendations regarding use of TDF/FTC with other drugs. TDF should be used with caution or avoided in patients with renal disease and osteoporosis. • TDF is used, especially with • Specific attention should be given to renal and bone safety monitoring when PK boosters. Boosters should be avoided when possible in patients taking TDF. F-18 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

78 Integrase Strand Transfer Inhibitor–Based Regimens Table 8b. Characteristics of Integrase Strand Transfer Inhibitors That Are Recommended for Antiretroviral Therapy-Naive Patients Preliminary data suggest that there may be an increased risk of NTDs in infants born to those who Note: 6,7 were receiving DTG at the time of conception. Until more information is available: • Pregnancy testing should be performed for those of childbearing potential prior to initiation of AR T. • is not r DTG for ART-naive individuals: ecommended or • Who are pregnant and within 12 weeks post-conception, Who are of childbearing potential and who are planning to become pregnant or who are sexually active • and not using effective contraception. Clinicians should refer to Table 6b for further guidance before initiating an INSTI. EVG RAL BIC DTG Dosing Frequency Once Daily: 400 mg BID, requires daily; Once or Once daily • boosting with COBI T-naive or INSTI-naive • • 1200 mg (two 600-mg In AR tablets) once daily persons Twice Daily: • If used with certain CYP3A4 and UGT1A1 inducers; or • In INSTI-experienced persons with certain INSTI DRMs AF/FTC for ART- • BIC/TAF/FTC DTG/ABC/3TC No EVG/c/T STR Available Naive Patients • EVG/c/TDF/FTC A vailable as a Single-Drug No Ye s No Ye s Tablet No Approved for ART- Yes, for patients with Yes, with BID dosing for No DRM to PI/r or NNRTIs, patients with some INSTI Experienced Patients DRMs but no DRM to INSTIs Virologic Efficacy Against No In vitro data indicate No Yes, for some isolates; effective with 50 mg BID dose activity, but no clinical EVG- or RAL-Resistant HIV trial data are available Adverse Effects Nausea, diarrhea (GI disturbance greater with EVG/c), headache, insomnia. Depression and suicidality are rare, occurring primarily in patients with pre-existing psychiatric conditions. ↑ CPK (4%) Hypersensitivity, hepatotoxicity , , myopathy CPK, ↑ ↑ TG, ↑ LDL myositis ↑ hypersensitivity, SJS/TEN CPK, No EVG is a CYP3A4 substrate; CYP3A4 substrate (minor) CYP3A4 Drug-Drug CYP3A4 substrate COBI is a CYP3A4 inhibitor Interactions Chelation with Poly- for recommendations regarding Table 19d Oral absorption of all INSTIs may be reduced by polyvalent cations. See valent Cation Supplements dosing separation of INSTIs and these drugs. and Antacids UGT1A1 substrate EVG is a UGT1A1 substrate; p-gp substrate, UGT1A1 Other Key Potential Drug UGT1A1 substrate, COBI is a p-gp inhibitor substrate Interactions 2 and MATE 1 O C T inhibitor Key to Acronyms: 3TC = lamivudine; ABC = abacavir; ART = antiretroviral therapy; BIC = bictegravir; BID = twice daily; COBI = cobicistat; CPK = creatine phosphokinase; CYP = cytochrome P; DRM = drug resistance mutation; DTG = dolutegravir; EVG = elvitegravir; EVG/c = elvitegravir/ cobicistat; FTC = emtricitabine; GI = gastrointestinal; INSTI = integrase strand transfer inhibitor; LDL = low density lipoprotein; MATE = multidrug and toxic compound extrusion; NNRTI = non-nucleoside reverse transcriptase inhibitor; NTD = neural tube defect; OAT = organic anionic transporter; p-gp = p-glycoprotein; PI = protease inhibitor; PI/r = ritonavir-boosted protease inhibitor; RAL = raltegravir; SJS/TEN = Stevens Johnson Syndrome/ toxic epidermal necrolysis; STR = single-tablet regimen; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; TG = triglyceride; UGT = uridine diphosphate glucuronosyltransferase F-19 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

79 Summary Four INSTIs— BIC, DTG, EVG, and RAL—are approved for use in ART-naive patients with HIV. All INSTIs are generally well tolerated, though there are reports of insomnia in some patients. Depression and suicidal ideation, primarily in patients with a history of psychiatric illnesses, have rarely been reported in patients receiving INSTI-based regimens. BIC, DTG, and EVG are available as components of STRs—BIC is coformulated with TAF/FTC, DTG is coformulated with ABC/3TC, and EVG is coformulated with a PK TAF/FTC or TDF/FTC. The Panel classifies the three unboosted INSTI-based enhancer (COBI) and either regimens (BIC, DTG, and RAL) as Recommended Initial Regimens for Most People with HIV. Among the INSTI-based regimens, RAL-containing regimens have the longest clinical experience, and they have been shown to have durable virologic efficacy; however, they have a higher pill burden than BIC- and DTG- containing regimens. EVG and RAL have lower barriers to resistance than BIC and DTG. In clinical trials of ART-naive patients who received BIC or DTG plus two NRTIs, resistance was not seen at virologic failure. Because of its high barrier to resistance, DTG may be considered for patients who must start ART before resistance test results are available (e.g., during acute HIV infection and in the setting of certain opportunistic infections). EVG-based regimens are now considered Recommended Initial Regimens in Certain Clinical Situations, because they require boosting with COBI, which results in a greater potential for interaction with concomitant medications. Preliminary data from an observational study in Botswana suggest that there may be an increased risk of 6,7 NTDs in infants born to those who were receiving DTG at the time of conception. Until more information is available, DTG-based regimens are not recommended for use in ART-naive patients who are pregnant and within 12 weeks post-conception . These regimens also should not be used in those of childbearing potential who are sexually active and not using effective contraception or who are planning to become pregnant. It is unclear whether DTG is the only INSTI with the potential to cause NTDs, or if other INSTIs also carry this risk (i.e., a class effect). Table 6b provides recommendations on the use of INSTIs in those who are pregnant or of childbearing potential. Integrase Strand Transfer Inhibitors Recommended as Part of an Initial Regimen for Most People with HIV Bictegravir (BIC) BIC is an INSTI that is approved by the FDA for initial therapy in adults with HIV as a component of a single-tablet, once-daily regimen with TAF and FTC. Efficacy in Clinical Trials : The efficacy of BIC in • ART-naive adults has been evaluated in two large Phase 3 randomized double- blind clinical trials that compared BIC to DTG administered in combination with two NRTIs. The primary efficacy endpoint was the proportion of participants with plasma HIV RNA <50 copies/mL at week 48. • The GS-US-380-1490 trial randomized participants 1:1 to receive either BIC/TAF/FTC or DTG with coformulated TAF/FTC. Both regimens were given once daily. At week 48, 89% of participants in the 31 BIC arm and 93% of those in the DTG arm achieved HIV RNA <50 copies/mL ( P = 0.12). • The GS-US-380-1489 trial randomized participants 1:1 to receive BIC/TAF/FTC or coformulated . At week 48, 92.4% of participants in the BIC/TAF/FTC arm and 93% of DTG/ABC/3TC once daily 5 those in the DTG/ABC/3TC arm achieved HIV RNA <50 copies/mL ( P = 0.78). Adverse Effects: BIC is generally well tolerated. In clinical trials, the most commonly reported adverse reactions of all • grades with an incidence ≥5% included diarrhea, nausea, and headache. F-20 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

80 Other Factors and Considerations: • BIC is a CYP3A4 substrate and a UGT1A1 substrate, and its metabolism may be affected by concomitant use of CYP3A4 and UGT1A1 inducers or inhibitors. Rifampin or other rifamycins may decrease BIC or TAF concentrations, which may result in a loss of therapeutic effect. For patients who require rifamycins, BIC/FTC/TAF should not be used. Use of certain anticonvulsants and St. John’s wort 88 should also be avoided. • BIC is an inhibitor of the drug transporters O C T2 and MATE1, which may lead to increased concentrations of drugs that are substrates of these transporters. For this reason, dofetilide is contraindicated with BIC/TAF/FTC. BIC is not a CYP3A4 inducer or inhibitor; thus, unlike EVG/c, it is unlikely to affect the metabolism of • medications that are CYP3A4 substrates. • Like other INSTIs, oral absorption of BIC may be reduced when BIC is coadministered with polyvalent cations (e.g., aluminum-, magnesium-, or calcium-containing antacids, or calcium or iron supplements). See Table 19d for dosing recommendations when using BIC with these products. • BIC decreases tubular secretion of creatinine without affecting glomerular function. Increases in serum after 48 creatinine are typically observed within the first 4 weeks (with a median increase of 0.10 mg/dL weeks). This effect on creatinine secretion is similar to that seen with other medications used in people with HIV, including DTG and COBI. • Treatment-emergent mutations that confer BIC resistance have not yet been reported in people receiving BIC for initial therapy. BIC has not been studied in people with prior INSTI failure or INSTI-related resistance mutations, and BIC should not be used in these individuals until more data are available. • BIC and DTG share a similar chemical structure. It is unclear whether DTG is the only INSTI with the potential to cause NTDs or if other INSTIs also carry this risk. The Panel’s Recommendation: • On the basis of clinical trial data, the Panel categorizes the combination of BIC/TAF/FTC administered once daily as a Recommended Initial Regimen for Most People with HIV (AI) . • Because there are no safety data for the use of BIC around the time of conception to guide evidence- based recommendations, a similar approach to the one outlined for DTG should be discussed before T in those of childbearing potential. The use of BIC-containing considering the use of BIC-containing AR ART is not recommended during pregnancy. Dolutegravir (DTG) DTG is an INSTI with a higher barrier to resistance than EVG or RAL. In ART-naive patients, DTG plus two NRTIs demonstrated high efficacy in achieving HIV suppression. It is given once daily, with or without food. Preliminary data from Botswana suggest that there may be an increased risk of NTDs in infants born to 6,7 women who were receiving DTG at the time of conception. More detailed discussions of this potential risk and recommendations for the use of this drug are found below and in Table 6b. Efficacy in Clinical Trials The efficacy of DTG in ART-naive patients has been evaluated in several fully powered randomized controlled clinical trials. In these five trials, DTG-based regimens were noninferior or superior to a comparator INSTI-, NNRTI-, or PI-based regimen. The primary efficacy endpoint in these clinical trials was the proportion of participants with plasma HIV RNA <50 copies/mL. F-21 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

81 DTG plus Two NRTIs versus Other INSTIs plus Two NRTIs: • DTG-based regimens (with TAF/FTC or ABC/3TC) have been compared to BIC/TAF/FTC in two randomized controlled trials. These regimens have shown virologic efficacy that is similar to BIC/TAF/ 4,5 FTC (see the discussion in the BIC section above). The SPRING-2 trial compared DTG 50 mg once daily to RAL 400 mg twice daily. Each drug was • administered in combination with an investigator-selected, two-NRTI regimen (either ABC/3TC or TDF/ 70 FTC) to 822 participants. At week 96, DTG was noninferior to RAL. DTG/ABC/3TC versus EFV/TDF/FTC: • The SINGLE trial compared the use of DTG 50 mg once daily plus ABC/3TC to EFV/TDF/FTC At week 48, DTG was superior to EFV, primarily because the study treatment in 833 participants. 31 discontinuation rate was higher in the EFV arm than in the DTG arm. At week 144, DTG plus 89 ABC/3TC remained superior to EFV/TDF/FTC. DTG plus Two NRTIs versus PI/r plus Two NRTIs: The FLAMINGO study, a randomized open-label clinical trial, compared DTG 50 mg once daily • to DR V/r 800 mg/100 mg once daily, each administered in combination with investigator-selected ABC/3TC or TDF/FTC. At week 48, DTG was superior to DRV/r because of the higher rate of 90 discontinuation in the DRV/r arm. The difference in efficacy between the DTG and DRV/r regimens was more pronounced in patients with pretreatment HIV RNA levels >100,000 copies/mL. At week 96, 91 DTG remained superior to DRV/r. The • ARIA trial, an open-label, Phase 3b randomized controlled trial, compared the efficacy and safety of DTG/ABC/3TC to ATV/r plus TDF/FTC in ART-naive, nonpregnant women. At week 48, 82% of participants in the DTG group achieved HIV RNA viral loads <50 copies/mL compared with 71% in the P ATV group ( = 0.005). The difference was driven by a lower rate of virologic nonresponse and fewer 92 withdrawals due to adverse events in the DTG group. DTG plus T wo NRTIs versus DTG plus 3TC: • ging that support the use of two-drug therapy with DTG plus 3TC. The results of a large Data are emer randomized controlled trial that compared DTG plus TDF/FTC with DTG plus 3TC are discussed in the Other Antiretroviral Regimens for Initial Therapy When Abacavir, Tenofovir Alafenamide, and Tenofovir Disoproxil Fumarate Cannot Be Used section below. Adverse Effects: • DTG is generally well tolerated. The most commonly reported adverse reactions of moderate-to-severe intensity were insomnia and headache. Case series of neuropsychiatric adverse events (sleep disturbances, depression, anxiety, suicidal • 93,94 ideation) associated with the initiation of DTG and RAL have been reported. Two observational cohort studies reported a higher frequency of neuropsychiatric adverse events leading to treatment 95,96 discontinuation in patients receiving DTG than in patients receiving other INSTIs. However, analyses of data from large randomized controlled trials as well as a health care database demonstrated similar 97 rates of neuropsychiatric adverse events between DTG-based regimens and other ARV regimens, with neuropsychiatric events rarely leading to DTG discontinuation. Another report from the World Health Organization international pharmacovigilance database reported neuropsychiatric events with 98 all approved INSTIs, not just DTG. Further studies will be needed to clarify the true incidence and A pathophysiologic mechanism for these neuropsychiatric implications of these neuropsychiatric events. F-22 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

82 adverse events has not been defined. • Preliminary data from an observational surveillance study of birth outcomes among pregnant women ART in Botswana identified NTDs in four infants born to 596 women (0.67%) who initiated a on DTG-based regimen prior to pregnancy, and who were still receiving it at the time of conception. The incidence of NTDs among infants born to women who were receiving other ARV drugs at the time of 6 conception was 0.1%. This study is ongoing, and more data from births among women who were using a DTG-based regimen around the time of conception are expected. See Table 6b for recommendations on prescribing INSTIs as part of initial therapy. Other Factors and Considerations: • DTG, like BIC, decreases tubular secretion of creatinine without affecting glomerular function, with increases in serum creatinine observed within the first 4 weeks of treatment (mean increase in serum creatinine was 0.11 mg/dL after 48 weeks). • DTG has fewer drug interactions than EVG/c. See Drug-Drug Interactions for specific drug-drug interactions that require dosage adjustment. DTG absorption, like absorption for other INSTIs, may be reduced when the ARV is coadministered with • polyvalent cations (see Drug-Drug Interactions ). DTG should be taken at least 2 hours before or 6 hours after cation-containing antacids or laxatives. Alternatively, DTG and supplements containing calcium or iron can be taken simultaneously with food. • T reatment-emergent mutations that confer DTG resistance have not been reported in patients receiving DTG as part of a three-drug regimen for initial therapy, which suggests that DTG, like BIC, has a higher barrier to resistance than EVG or RAL. The Panel’s Recommendations: On the basis of clinical trial data, the Panel categorizes DTG in combination with • (AI) ABC/3TC , TAF/ FTC (AI) as a Recommended Initial Regimen for Most People with HIV. , or TDF/FTC (AI) • A pregnancy test should be performed for those of childbearing potential prior to initiation of DTG (AIII) . For those of childbearing potential who are using effective contraception, a DTG-based regimen can be • (BIII) . considered after weighing the risks and benefits of DTG with the individual • Until more information is available, DTG should not be prescribed for individuals: , or (AII) Who are pregnant and within 12 weeks post-conception • • Who are of childbearing potential and who are planning to become pregnant (AII) or who are sexually active and not using ef fective contraception (AIII) . Raltegravir (RAL) RAL was the first INSTI approved for use in both ARV-naive and ARV-experienced patients. Efficacy in Clinical Trials RAL 400 mg Twice Daily plus Two NRTIs versus Comparator Drug plus Two NRTIs: • The efficacy of RAL at a dose of 400 mg twice daily (with either TDF/FTC or ABC/3TC) as initial therapy was evaluated in two randomized, double-blind, controlled clinical trials and a third open-label, randomized trial. ARTMRK compared RAL 400 mg twice daily to EFV 600 mg once daily, each administered in • ST F-23 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

83 66 combination with TDF/FTC. RAL was noninferior to EFV at 48 weeks. RAL was superior to EFV at 69,99 4 and 5 years, in part because of more frequent discontinuations due to adverse events in the EFV group than in the RAL group. The SPRING-2 trial compared DTG 50 mg once daily to RAL 400 mg twice daily, each administered • in combination with investigator-selected ABC/3TC or TDF/FTC. At week 96, DTG was noninferior to RAL. • The SPRING-2 trial also provided nonrandomized data on the efficacy of RAL plus ABC/3TC. In this trial, 164 participants (39 participants with baseline viral loads ≥100,000 copies/mL and 125 participants with baseline viral loads <100,000 copies/mL) received RAL in combination with ABC/3TC. After 96 weeks, there was no difference in virologic response between the ABC/3TC and 70 TDF/FTC groups when RAL was given as the third drug. • ACTG A5257, a large randomized open-label trial, compared three NNRTI-sparing regimens that contained RAL, ATV/r, or DRV/r, each given with TDF/FTC. At week 96, all three regimens had similar virologic efficacy, but RAL was superior to both ATV/r and DRV/r for the combined endpoints of virologic efficacy and tolerability. Participants had greater increases in lipid levels in the PI/r arms than in the RAL arm, and BMD decreased to a greater extent in participants in the PI/r arms than in 11 participants in the RAL arm. RAL 1,200 mg Once Daily plus TDF/FTC versus RAL 400 mg Twice Daily plus TDF/FTC: • In a Phase 3, randomized, double-blind, active comparator-controlled trial (the ONCEMRK trial), the 400 mg efficacy of once-daily RAL 1,200 mg (formulated as two 600-mg tablets) was compared to RAL twice daily, each administered with TDF/FTC. At 96 weeks, a similar proportion of participants in both groups achieved HIV RNA suppression (81.5% in the once-daily arm vs. 80.1% in the twice-daily arm). 100 The responses were similar regardless of baseline HIV RNA or CD4 cell count. Adverse Ef fects: RAL use has been associated with creatine kinase elevations. Myositis and rhabdomyolysis have been • reported. • Rare cases of severe skin reactions and systemic HSRs in patients who received RAL have been reported 101 during post-marketing surveillance. • Neuropsychiatric adverse events (e.g., insomnia, headache, depression, and suicidal ideation) have been 97,102 reported in people receiving INSTIs (see the discussion under DTG). Other Factors and Considerations: • RAL can be administered as 1,200 mg (two 600-mg tablets) once daily or as 400 mg twice daily with or without food in ART-naive patients. Coadministration of RAL as either 400 mg twice daily or 1,200 mg once daily with aluminum- • containing and/or magnesium-containing antacids is not recommended . Calcium carbonate-containing antacids may be coadministered with RAL 400 mg twice daily, but not with RAL 1,200 mg once daily. Polyvalent cation-containing supplements may also reduce absorption of RAL. See Table 19d for dosing recommendations. • RAL has a lower barrier to resistance than RTV-boosted PIs, BIC, and DTG. The Panel’s Recommendations: On the basis of these clinical trial data, the Panel considers RAL given as 1,200 mg (two 600-mg tablets) • F-24 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

84 once daily or as 400 mg twice daily plus TDF/FTC (BI) (BII) as a Recommended Initial or TAF/FTC Regimen for Most People with HIV. • Because fewer patients have received RAL plus ABC/3TC in clinical trials or practice and there has not been a randomized trial comparing ABC/3TC plus RAL to TDF/FTC plus RAL, the Panel categorizes (BII) . RAL plus ABC/3TC as a Recommended Initial Regimen in Certain Clinical Situations Integrase Strand Transfer Inhibitors Recommended as Part of an Initial Regimen in Certain Clinical Situations Elvitegravir (EVG) EVG is available as a component of two STRs: EVG/c/TDF/FTC and EVG/c/T AF/FTC. COBI is a specific, potent CYP3A inhibitor that has no activity against HIV. It acts as a PK enhancer of EVG, which allows for once-daily dosing of the combination but increases the likelihood of significant drug interactions. Efficacy in Clinical Trials : • The efficacy of EVG/c/TDF/FTC in ART-naive participants has been evaluated in two randomized, double-blind active-controlled trials. 103 • At 144 weeks, EVG/c/TDF/FTC was noninferior to fixed-dose EFV/TDF/FTC. 104 EVG/c/TDF/FTC was also found to be noninferior to ATV/r plus TDF/FTC. • • In a randomized, blinded trial performed in women with HIV, EVG/c/TDF/FTC had superior efficacy when compared to ATV/r plus TDF/FTC, in part because of a lower rate of treatment 15 discontinuation. • AF/FTC in ART-naive participants has been evaluated in two randomized, The efficacy of EVG/c/T 32,35 double-blind controlled trials in adults with eGFR ≥50 mL/min. • At 48 and 96 weeks, TAF was noninferior to TDF when both drugs were combined with EVG/c/FTC; 33 at 144 weeks, EVG/c/TAF/FTC was superior to EVG/c/TDF/FTC. Adverse Effects: • The most common adverse events reported with EVG/c/TDF/FTC were diarrhea, nausea, upper 103,104 respiratory infection, and headache. • The most common adverse events reported with EVG/c/TAF/FTC were nausea, diarrhea, headache, and 105 fatigue. • Neuropsychiatric adverse events have been reported in people receiving INSTIs (see the discussion under DTG). Other Factors and Considerations: • EVG is metabolized primarily by CYP3A enzymes; as a result, CYP3A inducers or inhibitors may alter EVG concentrations. • Because COBI inhibits CYP3A, it interacts with a number of medications that are metabolized by this 106 enzyme (see Drug-Drug Interactions ). • Administering EVG simultaneously with polyvalent cation-containing antacids or supplements lowers EVG plasma concentrations (see ). Separate EVG/c/TDF/FTC or EVG/c/TAF/ Drug-Drug Interactions FTC and polyvalent antacid administration by at least 2 hours; administer polyvalent cation-containing supplements at least 2 hours before or 6 hours after EVG dosing. F-25 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

85 • COBI inhibits active tubular secretion of creatinine, resulting in increases in serum creatinine and 107 a reduction in estimated CrCl without reducing glomerular function. Patients with a confirmed increase in serum creatinine >0.4 mg/dL from baseline while taking EVG/c/TDF/FTC should be closely 83 monitored and evaluated for evidence of TDF-related proximal renal tubulopathy. 83 EVG/c/TDF/FTC ecommended • for patients with pretreatment estimated CrCl <70 mL/min. is not r EVG/c/TAF/FTC is not r ecommended for patients with pretreatment estimated CrCl <30 mL/min. • • At the time of virologic failure, INSTI-associated mutations were detected in some EVG/c/TDF/FTC- 103,104 treated patients whose therapy failed. These mutations conferred cross-resistance to RAL, with most patients retaining susceptibility to DTG. The Panel’s Recommendation: • On the basis of the above considerations, the Panel classifies EVG/c/T AF/FTC and EVG/c/TDF/FTC as Recommended Initial Regimens in Certain Clinical Situations (BI) . EVG/c/TAF/FTC should only be used in people with estimated CrCl ≥30 mL/min; EVG/c/TDF/FTC should only be used in people with estimated CrCl ≥70 mL/min. Non-Nucleoside Reverse Transcriptase Inhibitor-Based Regimens Table 8c. Characteristics of Non-Nucleoside Reverse Transcriptase Inhibitors that are Recommended for Antiretroviral Therapy-Naive Patients DOR EFV RPV Dosing Frequency Once daily Once daily Once daily With a meal Food Requirement With or without food On an empty stomach DOR/TDF/3TC STR Available for ART- RPV/TAF/FTC • • • EFV 600 mg/TDF/FTC Naive Patients EFV 600 mg/TDF/3TC • • RPV/TDF/FTC EFV 400 mg/TDF/3TC • Available as a Single-Drug Ye s Ye s Ye s Tablet Depression, headache Adverse Effects Generally well • • CNS side effects, including dizziness, abnormal dreams, headache, tolerated • Skin rash depression, suicidality, somnolence, and prolongation QT • insomnia Skin rash • CYP3A4 substrate CYP3A4 Drug-Drug CYP3A4 substrate CYP3A4 substrate, mixed inducer/ inhibitor Interactions None CYP2B6 and 2C19 inducer Other Significant Drug RPV oral absorption is reduced with Interactions increased gastric pH. Use of RPV with PPIs is not recommended; see Drug-Drug Interactions for dosing recommendations when RPV is coadministered with H2 blocker or antacids. 3TC = lamivudine; CNS = central nervous system; CYP = cytochrome P; DOR = doravirine; EFV = efavirenz; FTC = Key to Acronyms: emtricitabine; H2 = histamine 2; PPI = proton pump inhibitor; RPV = rilpivirine; STR = single-tablet regimen; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate F-26 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

86 Summary Five NNRTIs (delavirdine [DLV], DOR, EFV, etravirine [ETR], nevirapine [NVP], and RPV) are currently approved by the FDA for the treatment of HIV when used in combination with other ARV drugs. NNRTI-based regimens have demonstrated virologic potency and durability. The major disadvantages of currently available NNRTIs (especially EFV and RPV) are the prevalence of NNRTI-resistant viral strains in 108 ART-naive patients and the drugs’ low barrier for the development of resistance. Resistance testing should be performed to guide therapy selection for ART-naive patients (see Drug-Resistance Testing ). High-level resistance to all NNRTIs (except ETR or DOR) may occur with a single mutation. In RPV-treated patients, the presence of RPV resistance mutations at virologic failure may confer cross-resistance to other NNRTIs, 109,110 including ETR. DOR-, EFV-, and RPV-based regimens are now categorized as Recommended Initial Regimens in Certain Clinical Situations for ART-naive patients. Doravirine (DOR) Efficacy in Clinical Trials The efficacy of DOR-based therapy for treatment of HIV in ART-naive individuals was demonstrated in two randomized, double-blind, placebo-controlled trials. DOR-Based Regimen versus EFV-Based Regimen: 9 In DRIVE-AHEAD, 734 participants received either DOR/TDF/3TC or EFV/TDF/FTC, both as STRs. • • At 48 weeks, DOR/TDF/3TC was found to be noninferior to EFV/TDF/FTC, with 84.3% of participants who received DOR/TDF/3TC and 80.8% of those who received EFV/TDF/FTC achieving HIV RNA <50 copies/mL. Virologic responses overall were lower in participants with pre-ART HIV RNA >100,000 copies/mL, but there was no difference between the DOR and EFV groups. • A greater proportion of participants in the EFV arm discontinued their assigned ART due to adverse events than in the DOR arm (6.3% vs. 2.7%). Neuropsychiatric side effects were more common in the EFV arm. • Genotype resistance results were reported for 13 participants with virologic failure in the DOR arm and 10 participants in the EFV arm. For the DOR arm, seven out of 13 participants had NNRTI resistance and five out of 13 had NRTI resistance; for EFV, nine out of 10 participants had NNRTI resistance and five out of 10 had NRTI resistance. The DOR group had no change in LDL cholesterol and non-HDL cholesterol among participants, • whereas both LDL and non-HDL cholesterol increased with EFV use. • At 96 weeks, 77.5% and 73.6% of participants in the DOR arm and the EFV arm had maintained HIV 111 RNA <50 copies/mL, respectively. DOR-Based Regimen versus DRV/r-Based Regimen: • In DRIVE-FOR WARD, 769 participants received DOR or DRV/r once daily along with two investigator- 8 selected NRTIs, either ABC/3TC or TDF/FTC. • At 48 weeks, DOR was found to be noninferior to DRV/r when these drugs were administered with two NR TIs. Eighty-four percent of study participants receiving DOR achieved HIV RNA <50 copies/mL at 48 weeks, compared to 80% of participants receiving DRV/r. • Participants who received DOR plus ABC/3TC (n = 48) and those who received DOR plus TDF/FTC (n = 316) had similar virologic responses. 112 • At week 96, DOR was superior to DR V/r in terms of virologic suppression; there was a higher rate of discontinuation in the DR V/r group. F-27 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

87 • Genotype resistance results were reported for seven and eight participants with virologic failure in the V/r arms, respectively. No drug resistance mutations were detected in either group. DOR and DR reatment-related diarrhea was more frequently reported in the DRV/r arm, and greater increases in • T fasting LDL cholesterol and triglycerides were seen in the participants who received DRV/r than in those who received DOR. Other Factors and Considerations: 113 • DOR is available as a single-drug, 100-mg tablet and as part of an STR that contains DOR/TDF/FTC 114 100 mg/300 mg/300 mg and is dosed once daily, with or without food. • DOR is primarily metabolized by the CYP3A4 enzyme and should not be coadministered with strong CYP3A4 inducers. DOR concentration may increase in the presence of a CYP3A4 inhibitor (see Table 19b). DOR is not a CYP3A4 inducer or inhibitor , so it is not expected to affect the concentrations of • concomitant CYP3A4 substrates. • reatment-emergent resistance mutations to DOR may confer cross-resistance to certain other NNRTIs. T 115 Most isolates with DOR mutations remain susceptible to ETR. • DOR-based regimens have not been directly compared to INSTI-based regimens in clinical trials. • There are currently no data on the safety of DOR use during pregnancy . The Panel’s Recommendations: • (BI) On the basis of the clinical trial data discussed above, the Panel classifies DOR/TDF/3TC and DOR plus two NR TIs ( for TDF/FTC and BIII for TAF/FTC) as Recommended Initial Regimens in Certain BI Clinical Situations. • Because the number of participants who received DOR plus ABC/3TC is much lower than the number TDF/FTC plus DOR, the Panel considers ABC/3TC plus DOR to be an option for initial who received therapy, but the Panel has less confidence in this regimen than in the other DOR-containing regimens listed above . (CI) Efavirenz (EFV) Efficacy in Clinical Trials : Lar ge randomized controlled trials and cohort studies in ART-naive patients have demonstrated potent • and durable viral suppression in patients treated with EFV plus two NRTIs. In clinical trials, EFV-based regimens have demonstrated superiority or noninferiority to several comparator regimens in ART-naive patients. In • ACTG 5202, EFV was comparable to ATV/r when each was given with either TDF/FTC or 116 ABC/3TC. • In the ECHO and THRIVE studies, EFV was noninferior to RPV, with less virologic failure. However, EFV caused more discontinuations due to adverse events. The virologic advantage of EFV was most notable in participants with pre-ART viral loads >100,000 copies/mL, and NRTI and NNRTI resistance 117 occurred more frequently in patients who experienced failure on a regimen that included RPV. 103 • In the GS 102 study , EFV/TDF/FTC was noninferior to EVG/c/TDF/FTC. The DRIVE-AHEAD study compared EFV/TDF/FTC to DOR/TDF/3TC in ART-naive patients. At 48 • F-28 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

88 weeks, DOR/TDF/3TC was found to be noninferior to EFV/TDF/FTC, as discussed in the DOR section. Neuropsychiatric side effects were more common in the EFV arm. Some regimens have demonstrated superiority to EFV, based primarily on fewer discontinuations because of adverse events: • In the SINGLE trial, a DTG-based regimen was superior to EFV at the primary endpoint of viral 31 suppression at week 48. 66 ARTMRK trial, RAL was noninferior to EFV at 48 weeks, • In the ST but RAL was superior to EFV at 4 69,99 and 5 years, in part because of more frequent discontinuations due to adverse events in the EFV group than in the RAL group. • In the open-label ST aR trial, participants with baseline viral loads ≤100,000 copies/mL had higher rates 118 of treatment success on RPV than on EFV. ENCORE 1 (a multinational, randomized, placebo-controlled trial) compared two once-daily doses of EFV (combined with TDF/FTC): EFV 600 mg (standard dose) versus EFV 400 mg (reduced dose). At 96 weeks, 119 EFV 400 mg was noninferior to EFV 600 mg for rate of viral suppression. While the frequency of overall adverse events was not different between groups, EFV-related adverse events occurred less frequently in the EFV 400 mg group than in the EFV 600 mg group. Although there were fewer self-reported CNS events in the 400 mg group, the groups had similar rates of psychiatric events. The 400-mg dose of EFV is now approved in the United States for initial treatment of HIV infection and is coformulated with TDF and 3TC in an FDC tablet. However, long-term experience and clinical efficacy data regarding its use during pregnancy and in patients with TB/HIV coinfection are lacking. Adverse Effects: EFV can cause CNS side effects (e.g., abnormal dreams, dizziness, headache, and depression) that • resolve over a period of days to weeks in most patients. However, subtler, long-term neuropsychiatric effects can occur. • EFV use has also been associated with suicidality; however, various large studies have provided different results. An analysis of four ACTG comparative trials showed a higher rate of suicidality (i.e., reported suicidal ideation or attempted or completed suicide) among EFV-treated patients than among patients 120 taking comparator regimens (LPV/r, ATV, ATV/r, or ABC-based regimens). Similarly, a subgroup analysis of the START trial revealed higher risk of suicidal or self-injurious behavior among participants in the immediate ART group who took EFV than among ART-naive controls; the risk increased for 121 those with previous psychiatric diagnoses. This association, however, was not found in analyses of 122,123 three large observational cohorts, or in a retrospective cohort study that used U.S. administrative 124 pharmacy claims data. A prospective observational cohort study among people with HIV in Uganda revealed no evidence that EFV carried an increased risk of suicidal ideation or depression compared to 125 NVP. • EFV may cause elevation in LDL cholesterol and triglycerides. 126,127 QT c interval prolongation has been observed with EFV use. • Consider an alternative therapy to EFV in patients taking medications known to increase the risk of Torsades de Pointes, or in patients at higher risk of Torsades de Pointes. Other Factors and Considerations: EFV is formulated both as a single-drug, 600-mg tablet and in an FDC tablet of EFV/TDF/FTC that • allows for once-daily dosing. F-29 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

89 • EFV is also available as a generic single-drug, 600-mg tablet and as a generic once-daily STR tablet that uses 3TC, TDF, and either 600 mg or 400 mg of EFV; the lower-dose EFV/TDF/3TC tablet is approved 128,129 for treating adults and children who weigh ≥35 kg. • EFV is a substrate of CYP3A4 and an inducer of CYP3A4 and 2D6; therefore, it may potentially interact with other drugs that use the same pathways (see , 20a , and 20b Tables 19b ). • EFV has been associated with CNS birth defects in nonhuman primates, and cases of NTDs have been 130 reported after first-trimester exposure in humans. A link between EFV and birth defects in humans has 131 Perinatal Guidelines ). not been supported in meta-analyses (see the Screening for depression and suicidality is recommended for people with HIV who are taking a regimen • . that includes EFV The Panel’s Recommendations: Given the availability of regimens with fewer treatment-limiting adverse events and also with noninferior • or superior efficacy , the Panel classifies EFV/TDF/FTC or EFV/TDF/3TC or EFV plus TAF/FTC (BI) (BII) as Recommended Initial Regimens in Certain Clinical Situations. 119 Randomized clinical trial data have demonstrated the efficacy of lower -dose (400 mg) EFV , • but this dose has not been studied in a U.S. population, in pregnant women, or in patients with TB/HIV The Panel therefore classifies the use of reduced-dose EFV as a Recommended Initial coinfection. (CI) . Regimen in Certain Clinical Situations Rilpivirine (RPV) RPV is an NNRTI that is approved for use in combination with NRTIs for ART-naive patients with pretreatment viral loads <100,000 copies/mL. Efficacy in Clinical Trials : T • wo Phase 3 randomized, double-blind clinical trials—ECHO and THRIVE—compared RPV and EFV, 117 each combined with two NRTIs. At 96 weeks, the following findings were reported: was noninferior to EFV overall. RPV • • T viral loads >100,000 copies/mL, more RPV-treated participants Among participants with pre-AR than EFV-treated participants experienced virologic failure. Moreover, in this subgroup of participants with virologic failure, NNRTI and NRTI resistance was more frequently identified in those treated with RPV. • Among the RPV-treated participants, the rate of virologic failure was greater in those with 3 3 pretreatment CD4 cell counts <200 cells/mm . than in those with CD4 cell counts ≥200 cells/mm • aR, a Phase 3b, open-label study, compared the FDC of RPV/TDF/FTC and EFV/TDF/FTC in 786 ST 132 118 treatment-naive patients. The results at 96 weeks were similar to the findings reported at 48 weeks. • RPV was noninferior to EFV overall. • RPV was superior to EFV in patients with pre-ART viral loads ≤100,000 copies/mL and noninferior in those with pre-ART viral loads >100,000 copies/mL. Among patients with pre-ART viral loads >500,000 copies/mL, virologic failure was more common in RPV-treated patients than in EFV-treated patients. • There were more participants with emer gent resistance in the RPV/FTC/TDF arm than in the EFV/ FTC/TDF arm (4% vs. 1%, respectively). • The FDC tablet of RPV/TAF/FTC was approved by the FDA based on results from a bioequivalence F-30 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

90 study. In this study, participants taking the coformulated drug had plasma concentrations of RPV, FTC, and TAF 25 mg that were similar to concentrations seen in participants who received RPV as the single- 60 drug tablet and TAF/FTC when given as part of the FDC of EVG/c/TAF 10 mg/FTC. Adverse Effects: • RPV is generally well tolerated. In the ECHO, THRIVE, and STaR trials, fewer instances of CNS adverse events (e.g., abnormal dreams, dizziness, psychiatric side effects), skin rash, and dyslipidemia were reported in the RPV arms than in the EFV arms, and fewer patients in the RPV arms discontinued therapy due to adverse events. However, up to 9% of clinical trial participants experienced depressive disorders, including approximately 1% of participants who had suicidal thoughts or who attempted suicide. Patients with severe depressive symptoms should be evaluated to assess whether symptoms may be due to RPV and if the risks of continuing the same regimen outweigh the benefits. Other Factors and Considerations: • RPV is formulated both as a single-drug tablet and in STRs with TAF/FTC and with TDF/FTC. Among available STRs, RPV/TAF/FTC is the smallest tablet. RPV/TAF/FTC and RPV/TDF/FTC are given once daily and must be administered with a meal • (containing at least 390 kcal). • RPV is also coformulated as a once-daily FDC tablet with DTG that is used as continuation therapy 133 who have achieved viral suppression. for persons with HIV However, this combination has not been studied in ART-naive individuals, and it is not recommended for initial therapy (see Optimizing ). Antiretroviral Therapy in the Setting of Viral Suppression The oral drug absorption of RPV can be significantly reduced in the presence of acid-lowering agents. • RPV is in patients who are receiving proton pump inhibitors (PPIs), and should be contraindicated Drug-Drug Interactions used with caution in those receiving H2 antagonists or antacids (see for dosing recommendations). • RPV is primarily metabolized in the liver by the CYP3A enzyme; its plasma concentration may be affected in the presence of CYP3A inhibitors or inducers (see Drug-Drug Interactions ). may cause QTc interval prolongation. RPV should be At doses above the approved dose of 25 mg, RPV • used with caution when coadministered with a drug known to increase the risk of Torsades de Pointes. The Panel’s Recommendations: • Given the availability of other effective regimens that do not have virologic and immunologic prerequisites to initiate treatment, the Panel recommends RPV/TDF/FTC and RPV/TAF/FTC as Recommended Initial Regimens in Certain Clinical Situations. • Use of RPV with TAF/FTC (BII) or TDF/FTC (BI) should be limited to ART-naive patients with 3 pretreatment viral loads <100,000 copies/mL and CD4 cell counts >200 cells/mm . Data on RPV plus ABC/3TC are insufficient to consider recommending this regimen. • F-31 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

91 Protease Inhibitor-Based Regimens Table 8d. Characteristics of Protease Inhibitor Options that are Recommended for Antiretroviral Therapy-Naive Patients DRV ATV • Once daily for PI-naive patients Dosing Frequency Once daily Twice daily for PI-experienced patients with certain PI • mutations PK-boosting with R TV or COBI is generally PK Boosting DRV should only be used with a PK booster (i.e., RTV or COBI). recommended. Unboosted ATV is also FDA- approved for ART-naive patients. Fixed-Dose Formulation • ATV/c • DRV/c • DRV/c/TAF/FTC Available as a Single- Ye s Ye s Drug Tablet • Adverse Effects • Jaundice Skin rash • Indirect hyperbilirubinemia Increase in serum transaminases • Hyperlipidemia • Cholelithiasis • • • A higher cardiovascular risk was reported in participants Nephrolithiasis taking DR V-based regimens than in those taking ATV- • PR prolongation based regimens in an observational cohort study. CYP3A4 substrate, inhibitor CYP34A substrate, inhibitor CYP3A4 Drug-Drug Interactions Other Significant Drug ATV absorption is reduced when ATV is given N/A Interactions with acid-lowering therapies. See Table 19a for ATV dosing recommendations when the drug is coadministered with acid-lowering agents. Key to Acronyms: ART = antiretroviral therapy; ATV = atazanavir; ATV/c = atazanavir/cobicistat; COBI = cobicistat; CYP = cytochrome P; DRV = darunavir; DRV/c = darunavir/cobicistat; FDA = Food and Drug Administration; FTC = emtricitabine; PI = protease inhibitor; PK = pharmacokinetic; RTV = ritonavir; TAF = tenofovir alafenamide Summary FDA-approved PIs include ATV, ATV/c, DRV, DRV/c, fosamprenavir (FPV), indinavir (IDV), LPV/r, nelfinavir (NFV), RTV, saquinavir (SQV), and tipranavir (TPV). PI-based regimens with PK enhancement (also called boosting) have demonstrated virologic potency, durability in treatment-naive patients, and a high barrier to resistance. Because transmitted PI resistance is uncommon, PI-based regimens are generally recommended if early ART initiation is necessary, before resistance test results are available. Few or no PI mutations are detected when a patient’s first PI-based regimen fails, which is not the case with NNRTI- 134,135 based regimens and some INSTI-based regimens. For this reason, PI-based regimens may be useful for patients at risk for intermittent therapy due to poor adherence. All PIs (boosted by either RTV or COBI) inhibit the CYP3A4 isoenzyme, which may lead to significant drug-drug interactions (see Drug-Drug Interactions ). Each PI has specific characteristics related to its virologic potency , adverse effects profile, and . PK properties. The characteristics of recommended PIs are listed in Table 9 and Appendix B, Table 3 PIs that are recommended for use in ART-naive patients should have proven virologic efficacy, once-daily dosing, a lower pill count than older PI-based regimens, and good tolerability. On the basis of these criteria, the Panel considers once-daily DRV/r, DRV/c, ATV/c, or ATV/r together with two NRTIs as PI-based regimen options in the category of Recommended Initial Regimens in Certain Clinical Situations. DRV/c/ TAF/FTC is now available as an STR. In a large, randomized controlled trial comparing DRV/r, ATV/r, F-32 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

92 and RAL, each administered in combination with TDF/FTC, all three regimens achieved similar virologic suppression rates; however, the proportion of patients who discontinued their assigned treatment because of 11 adverse effects, mainly hyperbilirubinemia, was greater in the ATV/r arm than in the other two arms. Several metabolic abnormalities, including dyslipidemia and insulin resistance, have been associated with PI use. The currently available PIs differ in their propensity to cause these metabolic complications, which also depends on the dose of RTV used as a PK-enhancing agent. Large observational cohort studies found an association between some PIs (i.e., DRV/r, FPV, IDV, and LPV/r) and an increased risk of cardiovascular 18-20,23 events; this risk was not seen with ATV. Another observational cohort study of predominantly male participants found a lower rate of cardiovascular events in those receiving ATV-containing regimens 22 compared to those receiving other regimens. Further study is needed. Compared to other PIs, LPV/r, FPV/r, unboosted ATV, and SQV/r have disadvantages such as greater pill burden, lower efficacy, or increased toxicity, and thus are no longer included as options for initial therapy. Darunavir/Ritonavir (DRV/r) Efficacy in Clinical Trials : The • ARTEMIS study compared DRV/r (800 mg/100 mg once daily) with LPV/r (800 mg/200 mg once daily or 400 mg/100 mg twice daily), both administered in combination with TDF/FTC, in a randomized, 64 open-label, noninferiority trial. DRV/r was noninferior to LPV/r at week 48, and superior at week 136 192. Among participants with baseline HIV RNA levels >100,000 copies/mL, virologic response rates were lower in the LPV/r arm than in the DRV/r arm. • The FLAMINGO study compared DR V/r with DTG, each administered in combination with two NRTIs, in 488 ART-naive participants. The rate of virologic suppression at week 96 was significantly greater among those who received DTG than in those who received DRV/r. The excess failure observed in the DRV/r group was primarily related to a higher rate of virologic failure among those with a viral loads 14 >100,000 copies/mL and secondarily due to more drug discontinuations in the DRV/r group. • ACTG A5257, a large randomized open-label trial, compared ATV/r with DRV/r or RAL, each given with TDF/FTC. The trial showed similar virologic efficacy for DRV/r, ATV/r, and RAL, but more 11 participants in the ATV/r group discontinued randomized treatment because of adverse events. • The DRIVE-FOR WARD study compared DRV/r to DOR, both administered with two investigator- selected NRTIs, in ART-naive participants. At 48 weeks, DOR was found to be noninferior to DRV/r, with 80% of participants who received DOR achieving HIV RNA levels <50 copies/mL compared with 84% of participants who received DRV/r. Adverse Effects: • Patients taking DR V/r may develop a skin rash, which is usually mild-to-moderate in severity and self- limited. Treatment discontinuation is necessary on rare occasions when severe rash with fever or elevated transaminases occur. • ACTG A5257 showed similar lipid changes in participants in the ATV/r and DRV/r arms. BMD decreased to a greater extent in participants in the ATV/r and DRV/r arms than in participants in the 11 RAL arm. The likelihood of developing metabolic syndrome was equivalent between the three arms, although a larger increase in waist circumference was observed at 96 weeks in participants assigned to 137 the RAL arm than in those assigned to the DRV/r arm ( P ≤ 0.02). An observational cohort study suggested that DRV/r is associated with increased rates of cardiovascular • 23 disease. F-33 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

93 Other Factors and Considerations: • DR V/r is administered once daily with food in treatment-naive patients. • DR V has a sulfonamide moiety and should be used with caution in patients with severe sulfonamide allergies. In clinical trials, the incidence and severity of rash were similar in participants who did or did not have a history of sulfonamide allergy. Most patients with sulfonamide allergy are able to tolerate DRV. • DR V/r is a potent CYP3A4 inhibitor, and this may lead to significant interactions with other medications metabolized through this same pathway (see Drug-Drug Interactions ). The Panel’s Recommendations: • On the basis of efficacy and safety data from clinical trials and clinical experience, the Panel classifies V/r with TDF/FTC (AI) , with TAF/FTC DR , or with ABC/3TC (BII) as Recommended Initial (AII) Regimens in Certain Clinical Situations. Darunavir/Cobicistat (DRV/c) A combination of DRV 800 mg with COBI 150 mg is bioequivalent to DRV 800 mg with RTV 100 mg in healthy volunteers, based on the maximum concentration and area under the concentration time curve for 138 D RV. ) of DRV combined with COBI was 31% lower than that of Because the minimum concentration (C min 139 was not achieved. DRV combined with RTV, bioequivalence for the C min Efficacy in Clinical Trials : • The AMBER trial enrolled 725 ART-naive participants in a Phase 3 randomized controlled trial that compared the STR DRV/c/TAF/FTC and DRV/c plus TDF/FTC. At 48 weeks, similar virologic suppression rates among participants were achieved in both arms of the study (91% and 88%, respectively). No treatment-emergent mutations associated with DRV or TAF/TDF resistance were observed in either group. In the DRV plus TAF/FTC arm, fewer participants developed proteinuria. Changes in BMD were also less 37 pronounced among these participants. • In a single-arm trial in which most of the patients were treatment-naive (94%), the coformulated DRV/c 800 mg/150 mg tablet was evaluated in combination with two investigator -selected NRTIs (99% of participants were given TDF/FTC). At week 48, 83% of treatment-naive participants achieved HIV RNA <50 copies/mL; 140 5% of participants discontinued treatment because of adverse events. Adverse Ef fects: • The most common drug-related adverse events were diarrhea, naus ea, fatigue, flatulence, rash, and headache. Other Factors: V/c 800 mg/150 mg is available as a coformulated boosted PI or as an STR with TAF/FTC 10 mg/200 mg. DR • The Panel’s Recommendations: • The Panel recommends DR V/c plus TAF/FTC or TDF/FTC and DRV/c plus ABC/3TC (BII) as (AI) Recommended Initial Regimens in Certain Clinical Situations. • DRV/c plus TDF/FTC is not recommended for patients with CrCl <70 mL/min, whereas DRV/c plus TAF/ FTC is not recommended for patients with CrCl <30 mL/min. Atazanavir/Ritonavir (ATV/r) or Atazanavir/Cobicistat (ATV/c) Efficacy in Clinical Trials : ATV/r plus Two NRTIs versus LPV/r plus Two NRTIs F-34 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

94 • ATV/r (300 mg/100 mg) with twice-daily LPV/r (400 mg/100 The CASTLE study compared once-daily mg), each administered in combination with TDF/FTC. In this open-label, noninferiority study, the two 141 regimens showed similar virologic and CD4 responses at 96 weeks. TV/r plus Two NRTIs versus EFV plus Two NRTIs A • The ACTG A5202 study compared open-label ATV/r and EFV, each given in combination with placebo- 116 controlled TDF/FTC or ABC/3TC. Efficacy was similar in the ATV/r and EFV groups. In a separate ATV/r were found to have a higher risk of virologic failure than analysis, women assigned to receive 142 women assigned to receive EFV or men assigned to receive ATV/r. ATV/r plus Two NRTIs versus INSTI plus Two NRTIs ATV/r plus TDF/FTC to EVG/c/TDF/FTC, virologic suppression rates through • In a study that compared 104 144 weeks were similar among participants in the two groups. A Phase 3 clinical trial of 575 women 15 evaluated EVG/c plus FTC/TDF versus ATV/r plus FTC/TDF. At week 48, the virologic suppression rate in the EVG/c arm was superior to that in the ATV/r arm. Nineteen women in the PI arm discontinued therapy because of adverse events, compared to five women in the INSTI arm. In a Phase 3 trial, 499 ART-naive women were randomized to receive either ATV/r plus TDF/FTC or • DTG/ABC/3TC. At 48 weeks, DTG was found to have a rate of virologic suppression (<50 copies/mL) that was noninferior to the rate seen in the ATV/r arm, and fewer drug-related adverse events occurred in 92 the DTG arm. ATV/r plus Two NRTIs versus DRV/r plus Two NRTIs versus RAL plus Two NRTIs • In ACTG A5257, a significantly higher proportion of patients in the ATV/r arm discontinued randomized treatment because of adverse events, mostly for elevated indirect bilirubin/jaundice or gastrointestinal toxicities. Lipid changes in participants in the ATV/r and DRV/r arms were similar. BMD decreased to a 11 greater extent in participants in the ATV/r and DRV/r arms than in participants in the RAL arm. ATV/c versus ATV/r plus Two NRTIs • 14, all patients received TDF/FTC and ATV and were randomized to receive either In the Gilead Study 1 RTV or COBI as PK enhancers. Both RTV and COBI were given as a separate tablet with matching 143 placebos. Through 144 weeks, the percentage of patients who achieved virologic suppression was similar in both study arms. The percentage of adverse events that caused patients to discontinue treatment 144 and changes in serum creatinine and indirect bilirubin levels were comparable. Adverse Effects: The main adverse ef • fect associated with ATV/c or ATV/r is reversible indirect hyperbilirubinemia, with or without jaundice or scleral icterus, but without concomitant hepatic transaminase elevations. The risk for treatment-limiting indirect hyperbilirubinemia is greatest for patients who carry two UGT1A1 145 decreased-function alleles. 146-148 21 149 Nephrolithiasis, • nephrotoxicity, and cholelithiasis have also been reported in patients who received ATV. • Both ATV/c and ATV/r can cause gastrointestinal side effects, including diarrhea. Other Factors and Considerations: • A TV/c and ATV/r are dosed once daily and with food. TV requires acidic gastric pH for dissolution. As a result, concomitant use of drugs that raise gastric pH • A (e.g., antacids, H2 antagonists, and particularly PPIs) may impair absorption of ATV. provides Table 19a F-35 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

95 recommendations for use of ATV/c or ATV/r with these agents. • TV/c and ATV/r are potent CYP3A4 inhibitors and may have significant interactions with other A medications that are metabolized through this same pathway (see ). Drug-Drug Interactions • Lar ge observational cohort studies found an association between some PIs (DRV/r, FPV, IDV, and LPV/r) 18-20,23 and an increased risk of cardiovascular events; this risk was not seen with ATV. Another study of an observational cohort of predominantly male participants found a lower rate of cardiovascular events in 22 participants receiving ATV-containing regimens compared with participants receiving other regimens. Further study is needed. The Panel’ s Recommendations: • On the basis of clinical trial safety and efficacy data, the Panel classifies A TV/r and ATV/c plus TAF/FTC (BII) or TDF/FTC (BI) as Recommended Initial Regimens in Certain Clinical Situations. • A TV/c or ATV/r plus ABC/3TC is no longer included in the list of Recommended Initial Regimens in Certain Clinical Situations, because it has disadvantages when compared with other regimens in this category. In a randomized trial, when combined with ATV/r, ABC/3TC was less potent than TDF/FTC in 10 people with HIV RNA >100,000 copies/mL. is not r ecommended • ATV/c plus TDF/FTC for patients with CrCl <70 mL/min, whereas ATV/c plus TAF/FTC for patients with CrCl <30 mL/min. is not recommended Other Antiretroviral Regimens for Initial Therapy When Abacavir, Tenofovir Alafenamide, and Tenofovir Disoproxil Fumarate Cannot Be Used or Are Not Optimal All currently recommended ARV regimens consist of two NRTIs plus a third active drug. This strategy, however, may not be possible or optimal in all patients. In some situations, it may be necessary to avoid ABC, TAF, and TDF, such as in patients who are HLA-B*5701 positive or at high risk of cardiovascular disease and with significant renal impairment. To address these concerns, several clinical studies have evaluated strategies using initial regimens that avoid the use of two NRTIs or the NRTI drug class altogether. Clinicians should refer to HBV/HIV Coinfection for guidance on treatment of patients with HBV infection when TAF or TDF cannot be used as part of the ARV regimen. Strategies Supported by Evidence from Clinical Trials Dolutegravir plus Lamivudine (DTG plus 3TC) In the GEMINI-1 and -2 trials, a total of 1,433 • ART-naive participants with baseline HIV RNA <500,000 copies/mL were randomized to receive DTG plus 3TC or DTG plus TDF/FTC. At week 48, DTG plus 3TC was noninferior to DTG plus TDF/FTC with respect to the proportion of participants with viral 12 loads <50 copies/mL (91% and 93%, respectively). Virologic nonresponse was uncommon, occurring in 3% of participants who received DTG plus 3TC and 2% of participants who received DTG plus TDF/ FTC. No instances of treatment-emergent NRTI or INSTI resistance occurred in either treatment group. Longer term follow up is ongoing. • ADDLE trial was a small, single-arm study of DTG plus 3TC in 20 ART-naive adults with baseline The P HIV RNA <100,000 copies/mL. At 48 weeks, 18 out of 20 subjects (90%) achieved HIV RNA <50 150 copies/mL. Fifteen of these 18 participants completed 96 weeks of treatment and maintained HIV RNA 151 <50 copies/mL. The • ACTG A5353 trial evaluated this same regimen in a single-arm trial that included ART-naive participants with a baseline HIV RNA of up to 500,000 copies/mL and no genotypic NRTI, INSTI, or PI resistance. The trial enrolled 120 participants; 37 participants (30.8%) had a baseline HIV RNA >100,000 F-36 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

96 copies/mL. At week 24, 90% of participants had HIV RNA <50 copies/mL; there were similar response rates in participants with baseline HIV RNA >100,000 copies/mL and ≤100,000 copies/mL (89% and 90%, respectively). Three participants experienced virologic failure, all of whom had suboptimal adherence; one participant developed an NRTI resistance mutation (M184V) and an INSTI resistance 152 mutation (R263K). The Panel’s Recommendation: • On the basis of these study results, the Panel recommends the use of DTG plus 3TC in AR T-naive adults with baseline HIV RNA <500,0000 copies/mL in instances where ABC, TAF, or TDF cannot be used or are not optimal (BI) . • Preliminary data from an observational study in Botswana suggest that there may be an increased risk of 6,7 NTDs in infants born to those who were receiving DTG at the time of conception. Clinicians should Table 6b prior to initiation of DTG in those who are pregnant or those who are of childbearing refer to potential. Darunavir/Ritonavir plus Lamivudine (DRV/r plus 3TC) • In the ANDES trial, 145 participants were randomized 1:1 to receive open-label, once-daily dual therapy with DR V/r plus 3TC or triple therapy with DRV/r plus TDF/3TC. This study was conducted in Argentina, and the researchers used an FDC of DRV/r 800 mg/100 mg that is available in that country. The median baseline HIV RNA was 4.5 log copies, and 24% of participants had HIV RNA >100,000 10 copies/mL. At week 48, 93% of the participants in the dual-therapy group and 94% of the participants in the triple-therapy group achieved an HIV RNA <50 copies/mL; dual therapy was noninferior to triple 25 therapy. The dual- and triple-therapy groups had similar rates of virologic suppression among study participants who had pre-therapy HIV RNA levels >100,000 copies/mL (91% and 92%, respectively). The Panel’s Recommendation: • V/r plus 3TC can On the basis of results from a small study with a relatively short follow-up period, DR be considered for use in people who cannot take ABC, TAF, or TDF (CI) . Although the ANDES trial supports the use of DRV/r plus 3TC, it is smaller than other trials of NRTI-limiting regimens, and larger studies are warranted. Darunavir/Ritonavir plus Raltegravir (DRV/r plus RAL) In the NEA T/ANRS 143 study, 805 treatment-naive participants were randomized to receive twice-daily • RAL or once-daily TDF/FTC, each with DRV/r (800 mg/100 mg once daily). At week 96, DRV/r plus RAL was noninferior to DRV/r plus TDF/FTC based on the primary endpoint of proportion of patients 3 with virologic or clinical failure. Among those with baseline CD4 cell counts <200 cells/mm , however, there were more failures in the two-drug arm; a trend towards more failure was also observed for those 24 with pretreatment HIV RNA ≥100,000 copies/mL. High rates of virologic failure in patients with HIV 153,154 RNA >100,000 copies/mL were also seen in two smaller studies of DRV/r plus RAL. The Panel’s Recommendation: • On the basis of these study results, the Panel recommends that DR V/r plus RAL be considered for use 3 only in patients with HIV RNA <100,000 copies/mL and CD4 cell counts >200 cells/mm , and only in those patients who cannot take ABC, TAF, or TDF (CI) . A Nucleoside-Limiting Regimen that is Efficacious but has Disadvantages Lopinavir/Ritonavir plus Lamivudine (LPV/r plus 3TC) plus either e GARDEL study, 426 ART-naive patients were randomized to receive twice-daily LPV/r In th • Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV 37 F- Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

97 open-label 3TC (twice daily) or two NRTIs selected by the study investigators. At 48 weeks, a similar proportion of patients in each arm had HIV RNA <50 copies/mL (88.3% vs. 83.7%), meeting the study’s noninferiority criteria. The LPV/r plus 3TC regimen was better tolerated than the LPV/r plus two NRTI 155 regimen. • This regimen is used infrequently due to the requirement of twice-daily dosing, the relatively high pill burden (a total of 5–6 tablets per day), and the adverse ef fect profile of LPV/r. In view of these substantial limitations, the Panel recommends that LPV/r plus 3TC be considered for use only in patients who cannot take (CI) . ABC, TAF, or TDF and in whom the other alternatives listed above cannot be used Table 9. Advantages and Disadvantages of Antiretroviral Components Recommended as Initial Antiretroviral Therapy (page 1 of 5) Note: All drugs within an ARV class are listed in alphabetical order. ARV Class Disadvantage(s) ARV Agent(s) Advantage(s) • Coformulated with DTG May cause life-threatening HSRs in patients who test ABC/3TC • Dual-NRTI positive for the HLA-B*5701 allele. As a result, HLA- Generic formulations are available for • B*5701 testing is required before use. ABC/3TC, ABC, and 3TC. In the • ACTG 5202 study, patients with baseline HIV RNA copies/mL showed inferior virologic ≥100,000 responses when ABC/3TC was given with EFV or ATV/r as opposed to TDF/FTC. This difference was not seen when ABC/3TC was used in combination with DTG. ABC use has been associated with CV disease and • cardiac events in some, but not all, observational studies. T AF/FTC • Coformulated with BIC, DRV/c, EVG/c, or RPV TAF, TDF is associated with lower lipid levels than • perhaps because TDF results in higher plasma levels of Active against HBV • ; a recommended dual- tenofovir, which lowers lipids. NRTI option for patients with HIV/HBV coinfection Smaller decline in renal function, less • proteinuria, and smaller reductions in BMD than TDF/FTC Approved with eGFR ≥30 mL/min • for patients TDF/3TC • Coformulated with DOR and EFV Renal toxicity, including proximal tubulopathy and acute or • combined insufficiency, when renal chronic with especially • Available as the following generic formulations: pharmacologic boosters. TDF • reported as a has consequence been of • Osteomalacia 3TC • . proximal tubulopathy TDF/3TC • • TDF, Decreased BMD has been associated with use of • EFV/TDF/3TC especially when combined with pharmacologic boosters. Long-term clinical experience • • Active against HBV • TDF/FTC Coformulated with EFV, EVG/c, and RPV as Renal toxicity, including proximal tubulopathy and acute or • STRs chronic renal especially when combined with insufficiency, pharmacologic boosters. ; a recommended dual- • Active against HBV NRTI option for patients with HIV/HBV Osteomalacia • a as reported been of consequence has coinfection proximal tubulopathy . • Better virologic responses than ABC/3TC in • Decreased BMD has been associated with use of TDF, baseline with ≥100,000 loads viral patients especially when combined with pharmacologic boosters. when combined with ATV/r or EFV copies/mL Associated with lower lipid levels than ABC or • F TA F-38 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

98 Table 9. Advantages and Disadvantages of Antiretroviral Components Recommended as Initial Antiretroviral Therapy (page 2 of 5) Disadvantage(s) ARV Agent(s) Advantage(s) ARV Class Coformulated with TAF/FTC INSTI • BIC • Compared to other INSTIs, BIC has the shortest post- marketing experience. In trials in ART-naive participants, BIC • resistance was not detected • Oral absorption of BIC can be reduced by simultaneous administration with drugs or supplements containing • requirement No food polyvalent cations (e.g., Al-, Ca-, or Mg-containing antacids or supplements, or multivitamin tablets with minerals). See dosing recommendations in Table 19d . • Inhibits tubular secretion of creatinine without affecting glomerular function. CYP3A4 and UGT1A1 substrate (but not a CYP3A4 • inducer or inhibitor); potential for drug interactions. DTG • Higher barrier to resistance than EVG or RAL Preliminary data suggests that DTG use before pregnancy • and through conception may be associated with an Coformulated with ABC and 3TC • Table 6b increased risk of NTDs in the infant. See text and • food requirement No for recommendations. No CYP3A4 interactions • • Oral absorption of DTG can be reduced by simultaneous Favorable • profile lipid administration with drugs containing polyvalent cations (e.g., Al-, Ca-, or Mg-containing antacids or supplements, or multivitamin tablets with minerals). See dosing recommendations in . Table 19d • Inhibits renal tubular secretion of Cr and can increase fecting glomerular function. serum Cr without af • UGT1A1 substrate; potential for drug interactions (see Table 19d ). Depression and suicidal ideation (rare; usually in patients • with pre-existing psychiatric conditions). Coformulated with TDF/FTC or TAF/FTC EVG/c • EVG/c/TDF/FTC is only recommended for patients • regimen be should with baseline CrCl ≥70 mL/min; this ATV/r, causes smaller • Compared with discontinued if CrCl decreases to <50 mL/min. increases in total and LDL cholesterol COBI is a potent CYP3A4 inhibitor, which can result in • significant CYP3A interactions substrates. with Oral absorption of EVG can be reduced by simultaneous • administration with drugs containing polyvalent cations (e.g., Al-, Ca-, or Mg-containing antacids or supplements, or multivitamin tablets with minerals). See dosing recommendations in Table 19d . • COBI inhibits active tubular secretion of Cr and can increase serum Cr without affecting renal glomerular function. • Has a lower barrier to resistance than boosted PI-, BIC-, or DTG-based regimens. • Food requirement. Depression and suicidal ideation (rare; usually in patients • with pre-existing psychiatric conditions). F-39 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

99 Table 9. Advantages and Disadvantages of Antiretroviral Components Recommended as Initial (page 3 of 5) Antiretroviral Therapy ARV Agent(s) Disadvantage(s) Advantage(s) ARV Class RAL • • Has a lower barrier to resistance than boosted PI-, BIC-, INSTI , Compared to other INSTIs, has longest post- or DTG-based regimens. marketing experience continued requirement Increases in creatine kinase, myopathy, and • • No food rhabdomyolysis have been reported. No CYP3A4 interactions • • Rare cases of severe HSRs (including SJS and TEN) lipid Favorable profile • have been reported. Higher pill burden than other INSTI-based regimens. • • No STR formulation. • Oral absorption of RAL can be reduced by simultaneous administration with drugs containing polyvalent cations (e.g., Al-, Ca-, or Mg-containing antacids or supplements, or multivitamin tablets with minerals). See dosing Table 19d . recommendations in UGT1A1 substrate; potential for drug interactions (see • ). Table 19d Depression and suicidal ideation (rare; usually in patients • with pre-existing psychiatric conditions). NNRTI DOR • Coformulated with TDF/3TC • . Shorter-term clinical experience than with EFV and RPV Compared to EFV , CNS side effects are less • , 19b Tables Potential for CYP450 drug interactions (see • frequent 20a 20b ). and No requirement food • Treatment-emergent DOR resistance mutations may • confer resistance to certain NNR TIs. lipid profile Favorable • EFV EFV 600 mg is Short-and long-term neuropsychiatric (CNS) side effects, • • coformulated with TDF/FTC including depression and, in some studies, suicidality and TDF/3TC and catatonia. Screening for depression and suicidality EFV 400 mg is coformulated with TDF/3TC • is recommended in people with HIV who are taking a EFV 600-mg dose has long-term clinical • regimen that includes EFV . EFV-based regimens (except experience and Teratogenic in nonhuman primates, although no rate • for EFV plus ABC/3TC) have well-documented increase has been seen in humans. RNA efficacy in patients with high HIV • Dyslipidemia • Rash QTc interval prolongation; consider using an alternative • to EFV in patients taking medications with known risk of causing Torsades de Pointes or in those at higher risk of Torsades de Pointes. Transmitted resistance is more common than with PIs and • INSTIs. • Greater risk of resistance at the time of treatment failure than with PIs. Potential for CYP450 drug interactions (see Tables 19b • and 20a ). • Should be taken on an empty stomach (food increases drug absorption and CNS toxicities). F-40 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

100 Table 9. Advantages and Disadvantages of Antiretroviral Components Recommended as Initial (page 4 of 5) Antiretroviral Therapy Advantage(s) ARV Agent(s) Disadvantage(s) ARV Class RPV • Coformulated with TDF/FTC and TAF/FTC in patients with pre-ART HIV RNA Not recommended NNRTI • , 3 >100,000 copies/mL or CD4 cell counts <200 cells/mm continued RPV/TDF/FTC and RPV/TAF/FTC have • because of higher rate of virologic failure in these patients. smaller pill sizes than other coformulated ARV Depression and suicidality drugs • QTc interval prolongation; consider using an alternative • Compared with EFV • : to RPV in patients taking medications with known risk of • Fewer CNS adverse effects causing Torsades de Pointes or in those at higher risk of Fewer lipid ef • fects Torsades de Pointes. • Fewer rashes Rash • • Transmitted resistance is more common than with PIs and INSTIs. • TI-, TDF-, and 3TC-associated mutations at More NNR virologic failure than with regimens that contain EFV and 2 NRTIs. Tables 19b Potential for CYP450 drug interactions (see • and ). 20a Meal kcal) (>390 requirement • Requires acid • for adequate absorption. Contraindicated with PPIs. • • Use with H2 antagonists or antacids with caution (see for detailed dosing information). Table 19a PIs ATV/c Commonly causes indirect hyperbilirubinemia, which may • Higher barrier to resistance than NNRTIs, • or EVG, and RAL manifest as scleral icterus or jaundice. ATV/r • • PI resistance at the time of treatment failure is requirement Food uncommon with PK-enhanced PIs Absorption depends on food and low gastric pH (see • TV/c and ATV/r have similar virologic activity Table 19a for interactions with H2 antagonists, antacids, A • profiles and toxicity and PPIs). Nephrolithiasis, cholelithiasis, nephrotoxicity • Observational cohort studies have found an • association between some PIs (DR V, LPV/r, fects • GI adverse ef FPV, IDV) and an increased risk of CV events; CYP3A4 inhibitors and substrates: potential for drug • this risk has not been seen with ATV. Further ). Table 19a interactions (see study is needed. See text for discussion. ATV and RTV components available • Individual as generics ATV/c • Coformulated tablet • COBI inhibits active tubular secretion of Cr and can increase serum Cr without affecting renal glomerular (Specific function. considerations) TDF is not recommended in • Coadministration with patients with CrCl <70 mL/min. • TV) is a potent CYP3A4 inhibitor, which can COBI (like R result CYP3A significant interactions with substrates. in DRV/c • Higher barrier to resistance than NNRTIs, Skin rash • EVG, and RAL or • Food requirement DRV/r • PI resistance at the time of treatment failure is • fects GI adverse ef uncommon with PK-enhanced PIs • CYP3A4 inhibitors and substrates: potential for drug ). interactions (see Table 19a • Increased CV risk reported in one observational cohort study . F-41 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

101 Table 9. Advantages and Disadvantages of Antiretroviral Components Recommended as Initial Antiretroviral Therapy (page 5 of 5) ARV Class Disadvantage(s) ARV Agent(s) Advantage(s) DRV/c Coformulated as DR V/c and DRV/c/TAF/FTC • • COBI inhibits active tubular secretion of Cr and can PIs , fecting renal glomerular increase serum Cr without af continued (Specific function. considerations) TDF Coadministration with • is not recommended in patients with CrCl <70 mL/min. TV) is a potent CYP3A4 inhibitor, which can • COBI (like R significant result interactions with CYP3A substrates. in Only R LPV/r • TV-coformulated PI Requires mg RTV per day. • 200 No food requirement • Possible higher risk of MI associated with cumulative use • . of LPV/r • PR and QT interval prolongation have been reported. Use with caution in patients at risk of cardiac conduction abnormalities or in patients receiving other drugs with similar ef fects. Possible nephrotoxicity • CYP3A4 inhibitors and substrates: potential for drug • ). Table 19a interactions (see Key to Acronyms: 3TC = lamivudine; ABC = abacavir; Al = aluminum; ART = antiretroviral therapy; ARV = antiretroviral; ATV = atazanavir; ATV/c = atazanavir/cobicistat; ATV/r = atazanavir/ritonavir; BIC= bictegravir; BMD = bone mineral density; Ca = calcium; CD4 = CD4 T lymphocyte; CNS = central nervous system; COBI = cobicistat; Cr = creatinine; CrCl = creatinine clearance; CV = cardiovascular; CYP = cytochrome P; DOR = doravirine; DRV = darunavir; DRV/c = darunavir/cobicistat; DRV/r = darunavir/ritonavir; DTG = dolutegravir; eGFR = estimated glomerular EVG filtration rate; EFV = efavirenz; = elvitegravir; EVG/c = elvitegravir/cobicistat; FDC = fixed=dose combination; FPV = fosamprenavir; FTC = emtricitabine; GI = gastrointestinal; HBV = hepatitis B virus; HLA = human leukocyte antigen; HSR = hypersensitivity reaction; IDV = indinavir; INSTI = integrase strand transfer inhibitor; LDL = low-density lipoprotein; LPV = lopinavir; LPV/r = lopinavir/ritonavir; Mg = magnesium; MI = myocardial infarction; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; NTD = neural tube defect; PI = protease inhibitor; PK = pharmacokinetic; PPI = proton pump inhibitor; RAL = raltegravir; RPV = rilpivirine; RTV = ritonavir; SJS = Stevens-Johnson syndrome; STR = single-tablet regimen; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; TEN = toxic epidermal necrosis; UGT = uridine diphosphate glucuronosyltransferase Table 10. Antiretroviral Components or Regimens Not Recommended as Initial Therapy (page 1 of 3) ARV Components or Regimens Reasons for Not Recommending as Initial Therapy NRTIs Inferior ABC/3TC/ZDV (Coformulated) virologic • efficacy As triple-NRTI combination regimen • ABC/3TC/ZDV plus TDF Inferior virologic efficacy quadruple-NRTI combination As regimen d4T plus 3TC • Significant neuropathy) (including lipoatrophy, peripheral and hyperlactatemia toxicities (including symptomatic and life-threatening lactic acidosis, hepatic steatosis, and pancreatitis) ddI plus 3TC (or FTC) • Inferior virologic efficacy • Limited clinical trial experience in ART-naive patients ddI toxicities, such as pancreatitis and peripheral neuropathy • ddI plus TDF • High rate of early virologic failure • Rapid selection of resistance mutations • Potential for immunologic nonresponse/CD4 cell decline • Increased ddI drug exposure and toxicities F-42 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

102 (page 2 of 3) Table 10. Antiretroviral Components or Regimens Not Recommended as Initial Therapy Reasons for Not Recommending as Initial Therapy ARV Components or Regimens NRTIs , continued • Greater toxicities (including bone marrow suppression, GI toxicities, skeletal muscle ZDV/3TC myopathy , cardiomyopathy, and mitochondrial toxicities such as lipoatrophy, lactic acidosis, and hepatic steatosis) than recommended NRTIs NNRTIs DLV • Inferior virologic efficacy Inconvenient (three times daily) dosing • • Insufficient ETR AR data T-naive patients in • Associated with serious and potentially fatal toxicity (hepatic events and severe rash, NVP TEN) including SJS and When compared to EFV • , NVP did not meet noninferiority criteria PIs ATV (Unboosted) • Less potent than boosted ATV DRV (Unboosted) • Use without R TV or COBI has not been studied FPV (Unboosted) • V irologic failure with unboosted FPV-based regimen may result in selection of mutations that confer resistance to FPV and DRV or Less clinical trial data for FPV/r than for other R • TV-boosted PIs FPV/r Inconvenient dosing (3 times daily with meal restrictions) • IDV (Unboosted) Fluid requirement • IDV toxicities, such as nephrolithiasis and crystalluria • IDV/r • Fluid requirement IDV toxicities, such as nephrolithiasis and crystalluria • • Higher pill burden than other PI-based regimens LPV/r • Higher R TV dose than other PI-based regimens • GI intolerance NFV Inferior • virologic efficacy Diarrhea • RTV as sole PI High pill burden • • GI intolerance Metabolic toxicity • SQV (Unboosted) Inadequate • bioavailability Inferior efficacy virologic • High pill burden • SQV/r • Can cause QT and PR prolongation; requires pretreatment and follow-up ECG Inferior TPV/r • virologic efficacy Higher rate of adverse events than other R TV-boosted PIs • Higher • boosting dose of RTV required for than other RTV-boosted PIs Entry Inhibitors T-20 Only studied in patients with virologic failure • wice-daily subcutaneous injections • T Fusion Inhibitor • High rate of injection site reactions IBA Only studied in a very small number of patients with virologic failure • Requires IV • therapy CD4 Post-Attachment Inhibitor • High cost F-43 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

103 (page 3 of 3) Table 10. Antiretroviral Components or Regimens Not Recommended as Initial Therapy ARV Components or Regimens Reasons for Not Recommending as Initial Therapy Entry Inhibitors , continued Requires testing for CCR5 tropism before initiation of therapy • MVC with No virologic benefit when compared other recommended regimens • CCR5 Antagonist Requires twice-daily dosing • Key to Acronyms: 3TC = lamivudine; ABC = abacavir; ART = antiretroviral therapy; ARV = antiretroviral; ATV = atazanavir; CD4 = CD4 T lymphocyte; COBI = cobicistat; d4T = stavudine; ddI = didanosine; DLV = delavirdine; DRV = darunavir; ECG = electrocardiogram; EFV = efavirenz; ETR = etravirine; FPV = fosamprenavir; FPV/r = fosamprenavir/ritonavir; FTC = emtricitabine; GI = gastrointestinal; IBA = ibalizumab; IDV = indinavir; IDV/r = indinavir/ritonavir; IV = intravenous; LPV = lopinavir; LPV/r = lopinavir/ritonavir; MVC = maraviroc; NFV = nelfinavir; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; NVP = nevirapine; PI = protease inhibitor; RTV = ritonavir; SJS = Stevens Johnson Syndrome; SQV = saquinavir; SQV/r = saquinavir/ritonavir; T -20 = enfuvirtide; TDF = tenofovir disoproxil fumarate; TEN = toxic epidermal necrolysis; TPV = tipranavir; TPV/r = tipranavir/ritonavir; ZDV = zidovudine References 1. -1 RNA level over calendar time in a large urban HIV practice. 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Dolutegravir-lamivudine as initial therapy in HIV-infected, ARV naive patients: 96-week results of the PADDLE trial. Presented at: IAS Conference on HIV Science; 2017; Paris, France. Available at: http://www.ias2017.org/Portals/1/Files/IAS2017_LO.compressed.pdf?ver=2017-07-27-211231-197 . aiwo BO, Zheng L, Stefanescu A, et al. ACTG A5353: A pilot study of dolutegravir plus lamivudine for initial treatment 152. T Clin Infect Dis . of Human Immunodeficiency Virus-1 (HIV-1)-infected participants with HIV-1 RNA <500000 copies/mL. https://www.ncbi.nlm.nih.gov/pubmed/29253097 . 2018;66(11):1689-1697. Available at: 153. Taiwo B, Zheng L, Gallien S, et al. Efficacy of a nucleoside-sparing regimen of darunavir/ritonavir plus raltegravir in treatment-naive HIV -1-infected patients (ACTG A5262). AIDS . 2011;25(17):2113-2122. Available at: http://www.ncbi. nlm.nih.gov/pubmed/21857490 . 154. Bedimo RJ, Drechsler H, Jain M, et al. 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112 What Not to Use (Last updated October 17, 2017; last reviewed October 17, 2017) Some antiretroviral (ARV) regimens or components are not generally recommended because of suboptimal antiviral potency, unacceptable toxicities, or pharmacologic concerns. These are summarized below. Antiretroviral Drugs Not Recommended The following ARV drugs are no longer recommended for use because of suboptimal antiviral potency, unacceptable toxicities, high pill burden, or pharmacologic concerns: delavirdine (DLV), didanosine (ddI), indinavir (IDV), nelfinavir (NFV), and stavudine (d4T). Antiretroviral Regimens Not Recommended Monotherapy 1 Protease Nucleoside reverse transcriptase inhibitor (NRTI) monotherapy is inferior to dual-NRTI therapy. 2-6 inhibitor (PI) monotherapy is inferior to combination antiretroviral therapy (ART). Integrase strand transfer 7,8 (AI) . inhibitor (INSTI) monotherapy has resulted in virologic rebound and INSTI resistance Dual-NRTI Regimens 9 (AI) . These regimens are inferior to triple-drug combination regimens Triple-NRTI Regimens 10-12 Triple-NRTI regimens have suboptimal virologic activity or a lack of data (AI) . Antiretroviral Components Not Recommended Atazanavir plus Indinavir Both PIs can cause Grade 3 to 4 hyperbilirubinemia and jaundice. Additive adverse effects may be possible . when these agents are used concomitantly (AIII) Cobicistat plus Ritonavir as Pharmacokinetic Enhancers This combination may be prescribed inadvertently, which may result in additive CYP3A4 enzyme inhibition Tables 19a and may further increase the concentrations of ARV drugs or other concomitant medications (see and 19d ). Didanosine plus Stavudine The combination of ddI and d4T can result in peripheral neuropathy, pancreatitis, and lactic acidosis, and it 13 has been implicated in the deaths of several pregnant women (AII) . Didanosine plus Tenofovir Disoproxil Fumarate 14 15,16 serious ddI-associated toxicities, Tenofovir disoproxil fumarate (TDF) increases ddI concentrations, 18,19 18,20 17 immunologic nonresponse, and resistance early virologic failure, (AII) . Two Non-Nucleoside Reverse Transcriptase Inhibitor Combinations Excess clinical adverse events and treatment discontinuation were reported in patients randomized to 21 receive treatment with two non-nucleoside reverse transcriptase inhibitors (NNRTIs). Efavirenz (EFV) and nevirapine (NVP) are enzyme inducers, and both of these drugs can reduce concentrations of etravirine 22 . (ETR) and rilpivirine (RPV) (AI) G-1 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

113 Emtricitabine plus Lamivudine Both drugs have similar resistance profiles and have minimal additive antiviral activity . Inhibition of 23 (AIII) . intracellular phosphorylation may occur in vivo Etravirine plus Unboosted Protease Inhibitor ETR may induce the metabolism and significantly reduce the drug exposure of unboosted PIs. Appropriate 22 . doses of the PIs have not been established (AII) Etravirine plus Fosamprenavir/Ritonavir ETR may alter the concentrations of these PIs. Appropriate doses of the PIs have not been established 22 (AII) . Etravirine plus Tipranavir/Ritonavir 22 (AII) . Tipranavir/ritonavir (TPV/r) significantly reduces ETR concentrations 3 Nevirapine Initiated in ARV-Naive Women with CD4 Counts >250 cells/mm or in ARV-Naive 3 Men with CD4 Counts >400 cells/mm Initiating NVP in ART-naive individuals with CD4 counts above these thresholds increases the risk of 24-26 symptomatic, and sometimes life-threatening, hepatic events. ART-experienced patients can safely switch 27 (BI) . to NVP if they have CD4 counts above these thresholds as a result of receiving effective ART Unboosted Darunavir, Saquinavir, or Tipranavir The virologic benefit of these PIs has been demonstrated only when they were used with concomitant R TV, or in the case of DRV, also with COBI (AII) . Stavudine plus Zidovudine 28 29 in vitro and in vivo These NRTIs are antagonistic (AII) . Tenofovir Alafenamide plus Tenofovir Disoproxil Fumarate This combination may be prescribed inadvertently, especially during transition from one formulation to another. There is no data supporting any potential additive efficacy or toxicity if TAF and TDF are used in combination. References 1. Katlama C, Ingrand D, Loveday C, et al. Safety and efficacy of lamivudine-zidovudine combination therapy in antiretroviral-naive patients: a randomized controlled comparison with zidovudine monotherapy . JAMA . Jul 10 1996;276(2):118-125. Available at . https://www.ncbi.nlm.nih.gov/pubmed/8656503 2. Delfraissy JF , Flandre P, Delaugerre C, et al. Lopinavir/ritonavir monotherapy or plus zidovudine and lamivudine in antiretroviral-naive HIV-infected patients. AIDS . Jan 30 2008;22(3):385-393. Available at https://www.ncbi.nlm.nih.gov/ pubmed/18195565 . 3. Swindells S, DiRienzo AG, Wilkin T, et al. Regimen simplification to atazanavir-ritonavir alone as maintenance antiretroviral therapy after sustained virologic suppression. JAMA . Aug 16 2006;296(7):806-814. Available at https:// www.ncbi.nlm.nih.gov/pubmed/16905786 . 4. Arribas JR, Horban A, Gerstoft J, et al. The MONET trial: darunavir/ritonavir with or without nucleoside analogues, for patients with HIV RNA below 50 copies/ml. AIDS . Jan 16 2010;24(2):223-230. Available at https://www.ncbi.nlm.nih. gov/pubmed/20010070 . 5. Katlama C, Valantin MA, Algarte-Genin M, et al. Efficacy of darunavir/ritonavir maintenance monotherapy in patients . Sep 24 AIDS with HIV-1 viral suppression: a randomized open-label, noninferiority trial, MONOI-ANRS 136. G-2 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

114 2010;24(15):2365-2374. Available at https://www.ncbi.nlm.nih.gov/pubmed/20802297 . Stohr 6. W, Dunn DT, Arenas-Pinto A, et al. Factors associated with virological rebound in HIV-infected patients receiving . Nov 13 2016;30(17):2617-2624. Available at https://www.ncbi.nlm.nih.gov/ AIDS protease inhibitor monotherapy. pubmed/27456983 . Wolf E, Ritter A, et al. Dolutegravir monotherapy as treatment de-escalation in HIV-infected adults with 7. Oldenbuettel C, Antivir Ther. 2017;22(2):169-172. Available at https://www.ncbi.nlm.nih. virological control: DoluMono cohort results. . gov/pubmed/27588613 Thomas R, Blanco JL, et al. Development of a G118R mutation in HIV-1 integrase following a 8. Brenner BG, switch to dolutegravir monotherapy leading to cross-resistance to integrase inhibitors. J Antimicrob Chemother . Jul 2016;71(7):1948-1953. Available at . https://www.ncbi.nlm.nih.gov/pubmed/27029845 9. Hirsch M, Steigbigel R, Staszewski S, et al. A randomized, controlled trial of indinavir, zidovudine, and lamivudine in adults with advanced human immunodeficiency virus type 1 infection and prior antiretroviral therapy . J Infect Dis . Sep 1999;180(3):659-665. Available at https://www.ncbi.nlm.nih.gov/pubmed/10438352 . AE, Weinberg WG, et al. Early virologic nonresponse to tenofovir, abacavir, and lamivudine in Gallant JE, Rodriguez 10. J Infect Dis . Dec 1 2005;192(11):1921-1930. Available at HIV-infected antiretroviral-naive subjects. https://www.ncbi. nlm.nih.gov/pubmed/16267763 . 11. Bartlett JA, Johnson J, Herrera G, et al. Long-term results of initial therapy with abacavir and lamivudine combined with . Nov 1 2006;43(3):284-292. Available at , or stavudine. J Acquir Immune Defic Syndr efavirenz, amprenavir/ritonavir . https://www.ncbi.nlm.nih.gov/pubmed/16967040 12. . Clonal resistance analyses of HIV type-1 after failure of Barnas D, Koontz D, Bazmi H, Bixby C, Jemsek J, Mellors JW therapy with didanosine, lamivudine and tenofovir. Antivir Ther. 2010;15(3):437-441. Available at https://www.ncbi.nlm. nih.gov/pubmed/20516563 . 13. Administration. Caution issued for HIV combination therapy with Zerit and Videx in pregnant women. Food and Drug HIV Clin. https://www.ncbi.nlm.nih.gov/pubmed/11810823 2001;13(2):6. Available at . 14. , Sayre JR, Flaherty JF, Chen SS, Kaul S, Cheng AK. Drug-drug and drug-food interactions between Kearney BP tenofovir disoproxil fumarate and didanosine. https://www. J Clin Pharmacol. Dec 2005;45(12):1360-1367. Available at . ncbi.nlm.nih.gov/pubmed/16291710 15. Murphy MD, O’Hearn M, Chou S. Fatal lactic acidosis and acute renal failure after addition of tenofovir to an https://www. Apr 15 2003;36(8):1082-1085. Available at Clin Infect Dis. antiretroviral regimen containing didanosine. ncbi.nlm.nih.gov/pubmed/12684925 . 16. Martinez E, Milinkovic A, de Lazzari E, et al. Pancreatic toxic effects associated with co-administration of didanosine Lancet https://www.ncbi.nlm.nih.gov/ and tenofovir in HIV-infected adults. . Jul 3-9 2004;364(9428):65-67. Available at pubmed/15234858 . 17. A, Rendon A, Negredo E, et al. Paradoxical CD4+ T-cell decline in HIV-infected patients with complete virus Barrios suppression taking tenofovir and didanosine. AIDS . Mar 24 2005;19(6):569-575. Available at https://www.ncbi.nlm.nih. gov/pubmed/15802975 . 18. A, Martinez E, Mallolas J, et al. Early virological failure in treatment-naive HIV -infected adults receiving Leon didanosine and tenofovir plus efavirenz or nevirapine. . Jan 28 2005;19(2):213-215. Available at https://www.ncbi. AIDS nlm.nih.gov/pubmed/15668550 . 19. Maitland D, Moyle G, Hand J, et al. Early virologic failure in HIV -1 infected subjects on didanosine/tenofovir/efavirenz: https://www.ncbi.nlm.nih. . Jul 22 2005;19(11):1183-1188. Available at AIDS 12-week results from a randomized trial. . gov/pubmed/15990571 20. , didanosine and Podzamczer D, Ferrer E, Gatell JM, et al. Early virological failure with a combination of tenofovir Available at https://www.ncbi.nlm.nih.gov/pubmed/15751775 . efavirenz. Antivir Ther. 2005;10(1):171-177. , Phanuphak P, Ruxrungtham K, et al. Comparison of first-line antiretroviral therapy with regimens including 21. van Leth F nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study. . Apr 17 2004;363(9417):1253-1263. Available at https://www.ncbi.nlm.nih.gov/pubmed/15094269 . Lancet G-3 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

115 22. ibotec Inc. Intelence package insert. 2009. Available at http://www.intelence.com/shared/product/intelence/prescribing- T information.pdf . Bethell R, Adams J, DeMuys J, et al. Pharmacological evaluation of a dual deoxycytidine analogue combination: 3TC 23. and SPD754. Presented at Conference on Retroviruses and Opportunistic Infections; February 8-11, 2004; San Francisco, California. . Apr 15 24. J Acquir Immune Defic Syndr Baylor MS, Johann-Liang R. Hepatotoxicity associated with nevirapine use. 2004;35(5):538-539. Available at . https://www.ncbi.nlm.nih.gov/pubmed/15021321 25. Sanne I, Mommeja-Marin H, Hinkle J, et al. Severe hepatotoxicity associated with nevirapine use in HIV -infected subjects. J Infect Dis . Mar 15 2005;191(6):825-829. Available at https://www.ncbi.nlm.nih.gov/pubmed/15717255 . 26. Boehringer Ingelheim. Dear Health Care Professional Letter: Clarification of risk factors for severe, life-threatening and fatal hepatotoxicity with VIRAMUNE® (nevirapine). 2004. Kesselring AM, Wit FW, Sabin CA, et al. Risk factors for treatment-limiting toxicities in patients starting nevirapine- 27. containing antiretroviral therapy. . Aug 24 2009;23(13):1689-1699. Available at https://www.ncbi.nlm.nih.gov/ AIDS pubmed/19487907 . 28. Hoggard PG, Kewn S, Barry MG, Khoo SH, Back DJ. Effects of drugs on 2’,3’-dideoxy-2’,3’-didehydrothymidine ob Agents Chemother . Jun 1997;41(6):1231-1236. Available at https://www.ncbi.nlm. phosphorylation in vitro. Antimicr nih.gov/pubmed/9174176 . 29. , Tierney C, Friedland GH, et al. In vivo antagonism with zidovudine plus stavudine combination therapy. J Havlir DV . Jul 2000;182(1):321-325. Available at . https://www.ncbi.nlm.nih.gov/pubmed/10882616 Infect Dis G-4 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

116 Management of the Treatment-Experienced Patient Virologic Failure (Last updated October 25, 2018; last reviewed October 25, 2018) Panel’s Recommendations • Assessing and managing a patient who is experiencing failure of antiretroviral therapy (ART) is complex. Expert advice is critical and should be sought. Evaluation of virologic • failure should include an assessment of adherence, drug-drug and drug-food interactions, drug tolerability, HIV RNA level and CD4 T lymphocyte (CD4) cell count trends over time, ART history, and prior and current drug-resistance test results. • Drug-resistance testing should be performed while the patient is taking the failing antiretroviral (AR V) regimen (AI) or within 4 weeks of treatment discontinuation . Even if more than 4 weeks have elapsed since ARVs were discontinued, resistance testing can still (AII) (CIII) . provide useful information to guide therapy, although it may not detect previously selected resistance mutations • The goal of treatment for ART-experienced patients with drug resistance who are experiencing virologic failure is to establish virologic suppression (i.e., HIV RNA levels below the lower limits of detection of currently used assays) (AI) . • A new regimen should include at least two, and preferably three, fully active agents (AI) . A fully active agent is one that is expected to have uncompromised activity on the basis of the patient’s ART history and his or her current and past drug-resistance test results. A fully active agent may also have a novel mechanism of action. ARV agent to a virologically failing regimen is not recommended , because this may risk the development • In general, adding a single of resistance to all drugs in the regimen . (BII) • For some highly ART-experienced patients with extensive drug resistance, maximal virologic suppression may not be possible. In this case, ART should be continued (AI) with regimens designed to minimize toxicity, preserve CD4 cell counts, and delay clinical progression. It is crucial to provide continuous adherence support to all patients before and after regimen changes due to virologic failure. • • Preliminary data suggest that there is an increased risk of neural tube defects in infants born to individuals who were receiving dolutegravir (DTG) at the time of conception. In patients with virologic failure who are of childbearing potential, pregnancy testing should be performed before starting DTG (AIII) . For patients who are pregnant and within 12 weeks post-conception, or those who are of childbearing potential and who are not • using ef fective contraception or who are contemplating pregnancy, the following factors should be considered: If an alternative active • ARV option to DTG exists, DTG should not be prescribed (AII) . • If no alternatives exist, providers and individuals of childbearing potential should discuss the possible association between neural tube defects and DTG use during conception, and the risks of persistent viremia in the patient and HIV transmission to the fetus if pregnancy occurs while the patient is not on ef fective ART. The decision of whether to initiate or continue DTG should be made after careful consideration of these risks. • When it is not possible to construct a viable suppressive regimen for a patient with multidrug-resistant HIV, the clinician should consider enrolling the patient in a clinical trial of investigational agents or contacting pharmaceutical companies that may have investigational agents available. • When switching an ARV regimen in a patient with hepatitis B virus (HBV)/HIV coinfection, ARV drugs that are active against HBV should be continued as part of the new regimen. Discontinuation of these drugs may lead to the reactivation of HBV, which may result in serious hepatocellular damage. Discontinuing to increase or briefly interrupting therapy may lead a rapid increase in HIV RNA, a decrease in CD4 cell count, and an • in the risk of clinical progression. Therefore, this strategy is not recommended in the setting of virologic failure (AI) . A = Strong; B = Moderate; C = Optional Rating of Recommendations: I = Data from randomized controlled trials; II = Data from well-designed nonrandomized trials or observational Rating of Evidence: cohort studies with long-term clinical outcomes; III = Expert opinion H-1 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

117 Antiretroviral (ARV) regimens that are currently recommended for initial therapy in patients with HIV have a high likelihood of achieving and maintaining plasma HIV RNA levels that are below the lower limits of detection (LLOD) of currently used assays (see What to Start ). Patients on antiretroviral therapy (ART) who do not achieve this treatment goal or who experience virologic rebound can develop resistance mutations to one or more components of their regimen. Adherence to ART regimens can be challenging for some patients, and poor adherence can result in detectable viral loads. Depending on their treatment histories, some of these patients may have minimal or no drug resistance; others may have extensive resistance. Managing patients with extensive resistance is complex and usually requires consultation with an HIV expert. This section of the guidelines defines virologic failure in patients on ART and discusses strategies to manage ART in these individuals. Virologic Response Definitions The following definitions are used in this section to describe the dif ferent levels of virologic response to ART: Virologic Suppression: A confirmed HIV RNA level below the LLOD of available assays. Virologic Failure: The inability to achieve or maintain suppression of viral replication to an HIV RNA level <200 copies/mL. Incomplete Virologic Response: Two consecutive plasma HIV RNA levels ≥200 copies/mL after 24 weeks on an ARV regimen in a patient who has not yet had documented virologic suppression on this regimen. A patient’s baseline HIV RNA level may affect the time course of response, and some regimens may take longer than others to suppress HIV RNA levels. Confirmed HIV RNA level ≥200 copies/mL after virologic suppression. Virologic Rebound: Virologic Blip: After virologic suppression, an isolated detectable HIV RNA level that is followed by a return to virologic suppression. Low-Level Viremia: Confirmed detectable HIV RNA level <200 copies/mL. Antiretroviral Therapy Treatment Goals and Presence of Viremia While on Antiretroviral Therapy The goal of ART is to suppress HIV replication to a level below which drug-resistance mutations do not emerge. Although not conclusive, the evidence suggests that selection of drug-resistance mutations does not 1 occur in patients with HIV RNA levels persistently suppressed to below the LLOD of current assays. 2 Virologic blips are not usually associated with subsequent virologic failure. In contrast, there is controversy regarding the clinical implications of persistently low HIV RNA levels that are between the LLOD and <200 copies/mL in patients on ART. Viremia at this threshold is detected with some frequency by commonly used real-time polymerase chain reaction (PCR) assays, which are more sensitive than the PCR-based viral load 3-5 platforms used in the past. Findings from a large retrospective analysis showed that, as a threshold for virologic failure, HIV RNA levels of <200 copies/mL and <50 copies/mL had the same predictive value for 6 subsequent rebound as HIV RNA levels of >200 copies/mL. Two other retrospective studies also support the supposition that virologic rebound is more likely to occur in patients with viral loads >200 copies/mL than in 7,8 those with low-level viremia between 50 and 199 copies/mL. However, other studies have suggested that 9,10 detectable viremia at this low level (<200 copies/mL) can be predictive of progressive viral rebound and can 11 be associated with the evolution of drug resistance. Persistent HIV RNA levels ≥200 copies/mL are often associated with evidence of viral evolution and 12 accumulation of drug-resistance mutations. This association is particularly common when HIV RNA levels 13 are >500 copies/mL. Therefore, persistent plasma HIV RNA levels ≥200 copies/mL are considered virologic failure. H-2 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescent with HIV s Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

118 Causes of Virologic Failure Virologic failure can occur for many reasons. Data from patient cohorts in the earlier era of combination ART suggested that suboptimal adherence and drug intolerance/toxicity are key contributors to virologic failure 14,15 and regimen discontinuations. The presence of pre-existing (transmitted) drug resistance may also lead to 16 virologic failure. Virologic failure may be associated with various patient/adherence-, HIV-, and regimen- related factors, as listed below. (see Adherence to the Continuum of Care ) Patient/Adherence-Related Factors Comorbidities that may affect adherence (e.g., active substance abuse, mental health disorders, • neurocognitive impairment) • Unstable housing and other psychosocial factors • Missed clinic appointments • Interruption of or intermittent access to ART • Cost and af fordability of ARVs (i.e., these factors may affect the ability to access or continue therapy) Drug adverse effects • • High pill burden and/or dosing frequency HIV-Related Factors Presence of transmitted or acquired drug-resistant virus documented by current or past resistance test • results • Prior treatment failure • Innate resistance to ARVs due to viral tropism or the presence of HIV-2 infection/coinfection Higher pretreatment HIV RNA level (some regimens may be less effective at higher levels) • Antiretroviral Regimen-Related Factors • Suboptimal pharmacokinetics (PKs) (e.g., variable absorption, metabolism, or possible penetration into reservoirs) • Suboptimal virologic potency • Low genetic barrier to resistance • Reduced efficacy due to prior exposure to suboptimal regimens (e.g., monotherapy , dual nucleoside reverse transcriptase inhibitor (NR TI) therapy, or the sequential introduction of drugs) • Food requirements • Adverse drug-drug interactions with concomitant medications Prescription errors • Managing Patients with Virologic Failure If virologic failure is suspected or confirmed, a thorough assessment of whether one or more of the above factors could have been the cause(s) of failure is indicated. Often the causes of virologic failure can be identified, but in some cases they are not obvious. It is important to distinguish among the causes of virologic failure because the approaches to subsequent therapy may differ. Potential causes of virologic failure should H-3 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

119 be explored in depth. Once virologic failure is confirmed, steps should be undertaken to improve virologic outcomes. Those approaches are outlined below. Key Factors to Consider When Designing a New Antiretroviral Regimen , a new ARV regimen should contain at least two, and preferably three, fully active drugs whose Ideally • predicted activity is based on the patient’s ART history, current and previous resistance test results, or a 9,17-26 . new mechanistic action (AI) • ARV drugs in the regimen may still have Despite the presence of some drug resistance mutations, some partial activity against the patients’ HIV and may be retained as part of a salvage regimen. These drugs 27 may include NRTIs or protease inhibitors (PIs). Other agents will likely have to be discontinued, as their continued use may lead to further accumulation of resistance mutations and jeopardize treatment options with newer drugs from the same drug class. These drugs may include enfuvirtide (T-20); non- nucleoside reverse transcriptase inhibitors (NNRTIs), especially efavirenz (EFV), nevirapine (NVP), and rilpivirine (RPV); and the first-generation integrase strands transfer inhibitors (INSTIs) raltegravir (RAL) 28-30 and elvitegravir (EVG). Using a “new” drug that a patient has never used previously does not ensure that the drug will be fully • active; there is a potential for cross-resistance among drugs from the same class. • Archived drug-resistance mutations may not be detected by standard drug-resistance tests, particularly if testing is performed when the patient is not taking the drug in question. • When constructing a salvage regimen, it is more important to consider drug potency and viral susceptibility based on cumulative genotype data than the number of component drugs. • Resistance testing should be performed while the patient is still taking the failing regimen or within s plasma HIV RNA level is >1,000 copies/mL (AI) , 4 weeks of regimen discontinuation if the patient’ (BII) (see and possibly even if it is between 500 to 1,000 copies/mL Drug-Resistance Testing ). In some patients, resistance testing should still be considered even after treatment interruptions of >4 weeks, though clinicians should recognize that the lack of evidence of resistance in this setting does not (CIII) exclude the possibility that resistance mutations may be present at low levels . Drug resistance is cumulative; thus, clinicians should evaluate the extent of drug resistance, taking into account prior ART history and, importantly, prior genotypic or phenotypic resistance test results. Some assays only detect resistance to NRTIs, NNRTIs, or PIs, whereas INSTI-resistance testing may need to be ordered separately. INSTI-resistance testing should be ordered in patients who experience virologic failure on an INSTI-based regimen. Additional drug-resistance tests for patients who experience failure on a fusion (AII) inhibitor (BIII) and viral tropism tests for patients who experience failure on a CCR5 antagonist are also available (see Drug-Resistance Testing ). • Discontinuing or briefly interrupting therapy in a patient with overt or low-level viremia is not r ecommended , as it may lead to a rapid increase in HIV RNA and a decrease in CD4 T lymphocyte 27,31 (CD4) cell count, and it increases the risk of clinical progression (AI) (see Discontinuation or Interruption of Antiretroviral Therapy ). • When switching an ARV regimen in a patient with hepatitis B virus (HBV)/HIV coinfection, ARV drugs that are active against HBV should be continued as part of the new regimen. Discontinuation of these drugs may lead to the reactivation of HBV, which may result in serious hepatocellular damage (see Hepatitis B (HBV)/HIV Coinfection ). Antiretroviral Strategies In general, patients who receive at least three active drugs experience better and more sustained virologic • H-4 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

120 response than those receiving fewer active drugs. These three drugs should be selected based on the patient’s 18,19,21,22,32-34 ART history and a review of their drug-resistance test results, both past and present. • Active drugs are ARVs that, based on current and previous resistance test results and ART history, are expected to have antiviral activity equivalent to the activity seen when there is no resistance to the specific drugs. ARVs with partial activity are those predicted to reduce HIV RNA, but to a lesser extent than when there is no underlying drug resistance. • Active drugs may be newer members of existing drug classes that are active against HIV isolates that are resistant to older drugs in the same classes (e.g., etravirine [ETR], darunavir [DRV], and dolutegravir [DTG]). • An active drug may also be one with a mechanism of action that is dif ferent from the mechanisms of the ARV drugs that were previously used in that individual (e.g., the fusion inhibitor enfuvirtide, the CCR5 antagonist maraviroc in patients with no detectable CXCR4-using virus, and some investigational ARV drugs). An increasing number of studies in ART-naive and ART-experienced patients have shown that an active, • pharmacokinetically enhanced PI plus one other active drug or several partially active drugs will effectively 35-38 reduce viral load in most patients. • In the presence of certain resistance mutations, some ARVs, such as DTG, darunavir/ritonavir (DRV/r), and lopinavir/ritonavir (LPV/r), need to be given twice daily instead of once daily to achieve the higher drug 39,40 concentrations necessary to be active against a less-sensitive virus. Addressing Patients with Different Levels of Viremia Patients with detectable viral loads comprise a heterogenous group of individuals with different ART exposure histories, extents of drug resistance, durations of virologic failure, and levels of plasma viremia. Management strategies should be individualized. The first steps for all patients with detectable viral loads are to confirm the level of HIV viremia and assess and address adherence and potential drug-drug interactions (including interactions with over-the-counter products and supplements) and drug-food interactions. Some general approaches based on level of viremia are addressed below. • Patients who have these HIV RNA levels (i.e., blips) do HIV RNA Above the LLOD and <200 copies/mL: 4 . (AII) not typically require a change in treatment Although there is no consensus on how to manage these patients, the risk that resistance will emerge is believed to be relatively low. Therefore, these patients should continue their current regimens and have HIV RNA levels monitored at least every 3 months to assess the need for changes to ART in the future (AIII) . • HIV RNA Levels ≥200 and <1,000 copies/mL: In contrast to patients with detectable HIV RNA levels that are persistently <200 copies/mL, those with levels that are persistently ≥200 copies/mL often develop drug 7,8 resistance, particularly when HIV RNA levels are >500 copies/mL. Persistent plasma HIV RNA levels in the 200 to 1,000 copies/mL range should be considered virologic failure, and resistance testing should be attempted, particularly in patients with HIV RNA levels >500 copies/mL. Management approaches should be the same as for patients with HIV RNA >1,000 copies/mL (as outlined below). When resistance testing cannot be performed because of low HIV RNA levels, the decision of whether to empirically change ARVs should be made on a case-by-case basis, taking into account whether a new regimen that is expected to fully suppress viremia can be constructed. • HIV RNA ≥1,000 copies/mL and No Drug Resistance Mutations Identified Using Current or Previous Genotypic Resistance Test Results: This scenario is almost always associated with suboptimal adherence. Conduct a thorough assessment to determine the level of adherence, identify and address the underlying cause(s) for incomplete adherence and, if possible, simplify the regimen (e.g., decrease pill count, simplify ). Approaches include: food requirement or dosing frequency; see Adherence to the Continuum of Care H-5 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

121 • Assessing the patient’ s tolerance of the current regimen and the severity and duration of side effects, keeping in mind that even minor side effects can affect adherence. Addressing intolerance by treating symptoms (e.g., with antiemetics or antidiarrheals), switching • one ARV in a regimen to another agent in the same drug class, or switching from one drug class to Adverse Effects of Antiretroviral Agents ). another class (e.g., from a NNRTI to a PI or an INSTI; see • Reviewing food requirements for each medication and assessing whether the patient adheres to the requirements. • Assessing whether there is a recent history of gastrointestinal symptoms (e.g., vomiting or diarrhea) that may result in short-term malabsorption. • Reviewing concomitant medications and dietary supplements for possible adverse drug-drug Drug Interactions interactions (consult 19a – 20b for common interactions) and, if possible, and Tables making appropriate substitutions for ARV agents and/or concomitant medications. Considering therapeutic drug monitoring if PK drug-drug interactions or impaired drug absorption • leading to decreased ARV exposure is suspected. • Considering the timing of the drug-resistance test (e.g., was the patient mostly or completely ART- nonadherent for >4 weeks before testing?). If the current regimen is well tolerated and there are no significant drug-drug or drug-food • interactions, it is reasonable to continue the same regimen. If the agents are poorly tolerated or there are important drug-drug or drug-food interactions, • consider changing the regimen to an equally effective but more tolerable regimen. Repeat viral load testing 2 to 4 weeks after treatment is resumed or started; if viral load remains • >500 copies/mL, perform genotypic testing to determine whether a resistant viral strain has emer ged (CIII) . HIV RNA >1,000 copies/mL and Drug Resistance Identified: If new or previously detected resistance • mutations compromise the regimen, the regimen should be modified as soon as possible in order to 41 avoid progressive accumulation of resistance mutations. In addition, several studies have shown that virologic responses to new and active regimens are greater in individuals with lower HIV RNA levels and/or higher CD4 cell counts at the time of regimen changes; thus, the change is best done before 9,42 viremia worsens or CD4 count declines. The availability of newer ARVs, including some with new mechanisms of action, makes it possible to suppress HIV RNA levels to below the LLOD in most of these patients. The options in this setting depend on the extent of drug resistance and are addressed in the clinical scenarios outlined below. Managing Virologic Failure in Different Clinical Scenarios See Table 11 for a summary of these recommendations. Virologic Failure with First Antiretroviral Regimen • NNRTI plus NRTI Regimen Failure: These patients often have viral resistance to the NNRTI, with or without the M184V/I mutation, which confers high-level resistance to lamivudine (3TC) and emtricitabine (FTC). Additional NR TI mutations may also be present. Below are some switch options. Three large randomized controlled trials (primarily conducted in • Boosted PI plus Two NRTIs: resource-limited settings where NNRTI-based regimens have been used as first-line therapy) have explored different second-line regimen options. The studies found that regimens containing LPV/r 37,38,43 plus two NRTIs were as effective as regimens containing LPV/r plus RAL. Even though H-6 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

122 LPV/r was the PI used in these studies, it is likely that other PK-boosted PIs (DRV/r or atazanavir/ ritonavir [ATV/r]) would have similar activities and may be tolerated better, although this has not been demonstrated in large clinical trials. The EARNEST study randomized participants to receive LPV/r plus two or three investigator-selected NRTIs, LPV/r plus RAL, or LPV alone. Participants 38 did not undergo resistance testing before randomization. Lower rates of virologic suppression were seen with LPV/r monotherapy, confirming that ritonavir-boosted PI (PI/r) monotherapy cannot be 38,44 (AI) recommended . The virologic responses were similar in the LPV/r plus NRTIs arm and the LPV/r plus RAL arm. A post-hoc analysis showed that viral suppression was achieved in over 80% of 45 the participants who received either no active NRTIs or one active NRTI in their new regimens. It should be noted that most of the participants received thymidine analogs (stavudine or zidovudine— NRTIs that are no longer used in first-line regimens in the United States) plus 3TC. The authors of this trial suggest that, as a public health approach, resistance testing after first-line failure may not be necessary in resource-limited countries. However, in settings where genotype resistance tests are available, the Panel recommends using a PK-boosted PI plus two NRTIs (at least one of which is active) in a regimen (AIII) . • DTG plus One or Two Active NRTIs: In the DAWNING trial, patients who experienced virologic failure while on a first-line, NNRTI-based regimen were randomized to receive either LPV/r or DTG; each of these drugs was given with two NRTIs, one of which had to be fully active based on real-time resistance testing. The study was stopped early after an interim analysis showed that the DTG arm 46 was superior to the LPV/r arm. Thus, DTG plus two NRTIs (at least one of which is active) can be an option after failure of a first-line, NNRTI-based therapy (AI) . Bictegravir (BIC) may have activity that is similar to that of DTG; however, there are currently no data to support its use. There are limited to no data available on the efficacy of EVG or RAL to recommend the use of these INSTIs in the setting of first line NNRTI-based therapy failure. • As noted earlier, a regimen consisting of LPV/r plus RAL was found to Boosted PI plus an INSTI: 37,38,43 be as effective as LPV/r plus two NRTIs. Thus, LPV/r plus RAL can also be a treatment option for those who experienced virologic failure on an NNRTI-based regimen (AI) . Although data are limited, DTG combined with a PK-boosted PI may also be an option in this setting (AIII) . There are no data on the efficacy of BIC or EVG with boosted PI in the setting of first line NNR TI-based therapy failure. Preliminary data from Botswana suggested that there is an increased risk of neural tube defects (NTDs) in 47,48 infants born to individuals who were receiving DTG at the time of conception. Pregnancy testing should therefore be performed for those of childbearing potential prior to initiation of DTG. DTG should not be prescribed for patients who are pregnant and within 12 weeks post-conception. It is also not recommended for those of childbearing potential who desire pregnancy or who are sexually active and not using effective contraception. Though BIC is not specifically considered in this section, clinicians should be aware of the structural similarity of BIC and DTG. Since there are no safety data on the use of BIC around the time of conception to guide evidence-based recommendations, an approach similar to that outlined for DTG may be implemented before considering the use of BIC-containing ART in those of childbearing potential. • PK-Boosted PI plus NRTI Regimen Failure: In this scenario, most patients will have either no 49,50 resistance or resistance that is limited to 3TC and FTC. Failure in this setting is often attributed to poor adherence, drug-drug interactions, or drug-food interactions. Below are some management options. • Maintain on Same Regimen: A systematic review of multiple randomized trials that investigated the failures of first-line, PI/r-based regimens showed that maintaining the same regimen while making efforts to enhance adherence is as effective as changing to new regimens with or without drugs from 51 . new classes (AII) If the regimen is well tolerated and there are no concerns regarding drug-drug or H-7 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

123 drug-food interactions or drug resistance, then the regimen can be continued with adherence support and viral monitoring. Switch to Another Regimen: If poor tolerability, drug interactions, or drug resistance may be • contributing to virologic failure, then the regimen can be modified to: A different boosted PI plus two NRTIs (at least one of which is active) (AIII) ; or • • A different boosted PI plus an INSTI (BIII) ; or • An INSTI plus two NR TIs (at least one of which is active) (AIII) . As noted above, if only one of the NRTIs is fully active or if adherence is a concern, DTG is the recommended INSTI (AIII) . Before considering the use of DTG in persons who are pregnant or who are of childbearing potential, please refer to the earlier discussion regarding the use of DTG and the potential risk of NTDs in infants. There are limited to no data on the efficacy of BIC or EVG in this setting. • INSTI plus NRTI Regimen Failure: Virologic failure in patients on a regimen that consists of RAL or 52 EVG plus two NRTIs may be associated with emergent resistance to 3TC/FTC and possibly the INSTI. 42 V iruses with EVG or RAL resistance often remain susceptible to DTG. In contrast, in clinical trials, persons who experienced virologic failure while receiving BIC or DTG plus two NRTIs as first-line 52-54 therapy were unlikely to develop phenotypic resistance to BIC or DTG. There are no clinical trial data to guide therapy for first-line INSTI failures; therefore, treatment strategy should be based on resistance test results and the potential potency of the next regimen. Below are some treatment options, based on resistance pattern considerations. Virologic Failure without Any Resistance Mutations: The patient should be managed as outlined • above in the section on virologic failure without resistance. irologic Failure without INSTI Resistance: The regimen can be modified to: V • A boosted PI plus two NRTIs (at least one of which is active) (AIII) ; or • • A boosted PI plus an INSTI (AIII) ; or DTG plus two NR TIs (at least one of which is active) (AIII) . • • Virologic Failure with Resistance to RAL and EVG but Susceptibility to DTG: The regimen can be modified to: • or A boosted PI plus two NRTIs (at least one of which is active) (AIII) ; T wice-daily DTG plus two NRTIs (at least one of which is active) (AIII) ; or • • T wice-daily DTG plus a PK-boosted PI (AIII) . There are currently no data on the efficacy of BIC in patients who experience virologic failure while on an EVG- or RAL-based regimen; therefore, this drug cannot be recommended in this setting. Second-Line Regimen Failure and Beyond Drug Resistance with Fully Active Antiretroviral Therapy Options Using a patient’s treatment history and drug-resistance data, a clinician can decide whether to include a fully active PK-boosted PI in future regimens. For example, those who have no documented PI resistance and have previously never been treated with an unboosted PI likely harbor virus that is fully susceptible to PIs. In this setting, viral suppression should be achievable using a PK-boosted PI combined with either two NRTIs or an INSTI—provided the virus is susceptible to these drugs. If a fully active, PK-boosted PI is not an option, the new regimen should include at least two, and preferably three, fully active agents. Drugs should be selected based on the likelihood that they will be active, as determined by the patient’s treatment history, past and present drug-resistance testing, and tropism testing if a CCR5 antagonist is being considered. H-8 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

124 Multidrug Resistance without Fully Active Antiretroviral Therapy Options Use of currently available ARVs has resulted in a dramatic decline in the number of patients who have few 55,56 treatment options because of multiclass drug resistance. Despite this progress, there remain patients who have experienced toxicities and/or developed resistance to all or most currently available drugs. If maximal virologic suppression cannot be achieved, the goals of ART will be to preserve immunologic function, prevent clinical progression, and minimize the development of further resistance that may compromise future regimens. Consensus on the optimal management of these patients is lacking. If resistance to NNRTIs, T-20, DTG, EVG, or RAL are identified, there is rarely a reason to continue using these drugs, as (BII) . Moreover, there is little evidence that keeping them on the regimen helps delay disease progression continuing these drugs (in particular INSTIs) may allow for selection of additional resistance mutations and development of within-class cross resistance that may limit future treatment options. It should be noted that even partial virologic suppression of HIV RNA to >0.5 log copies/mL from baseline correlates with 10 55,57 clinical benefit. Cohort studies provide evidence that continuing therapy, even in the presence of viremia 58 and the absence of CD4 cell count increases, reduces the risk of disease progression. Other cohort studies 59,60 suggest continued immunologic and clinical benefits with even modest reductions in HIV RNA levels. However, these potential benefits must be balanced with the ongoing risk of accumulating additional resistance mutations. In general, adding a single fully active ARV to the regimen is not recommended because of the risk of rapid development of resistance (BII) . Before considering the use of DTG in persons who are pregnant or who are of childbearing potential, please refer to the earlier discussion regarding the use of DTG and the potential risk of NTDs in infants. When DTG is the only treatment option, or one of few treatment options, providers should counsel individuals who are pregnant or of childbearing potential about the possible association between NTDs and DTG use during conception. Providers should also discuss the risks of persistent viremia in the patient and the risk of HIV transmission to the fetus if pregnancy occurs while the patient is not on effective ART. The decision of whether to initiate or continue DTG should be made after careful consideration of all these risks. Patients with ongoing detectable viremia who lack sufficient treatment options to construct a fully suppressive regimen may be candidates for the recently approved CD4 post-attachment inhibitor ibalizumab 61 (IBA). A single-arm, multicenter clinical trial enrolled 40 heavily ART-experienced participants who had multidrug-resistant HIV and who were experiencing virologic failure on an ARV regimen. Subjects received intravenous infusions of IBA every 2 weeks in addition to an optimized background regimen that included at least one additional agent to which the subject’s virus was susceptible. At week 24, 43% of participants 62 achieved HIV RNA <50 copies/mL, and 50% of participants achieved HIV RNA <200 copies/mL. Of the 27 participants who continued on to the 48-week follow-up study , 59% and 63% had HIV RNA <50 copies/mL and <200 copies/mL, respectively. All 15 patients who had HIV RNA <50 copies/mL at week 24 63 maintained viral suppression up to week 48. Patients with ongoing detectable viremia who lack sufficient treatment options to construct a fully suppressive regimen may also be candidates for research studies or expanded access programs, or they may qualify for single-patient access to an investigational new drug as specified in Food and Drug Administration regulations . Information about agents that are in late-stage clinical studies (e.g., fostemsavir , PRO-140 ), can be found in the drug fact sheets available on AIDS info ’s website. Previously Treated Patients with Suspected Drug Resistance Who Present with Limited Information (Incomplete or No Self-Reported History, Medical Records, or Resistance Test Results) Every effort should be made to obtain the patient’s ARV history and prior drug-resistance test results; however, this may not always be possible. One strategy is to restart the most recent ARV regimen and assess drug resistance in 2 to 4 weeks to guide the selection of the next regimen. Another strategy is to start two or three drugs that are predicted to be active based on the patient’s treatment history. If there is no available H-9 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

125 ARV history, a clinician may consider using agents with a high barrier to resistance, such as twice-daily DTG and/or boosted DRV, as part of the regimen. Before considering the use of DTG in persons who are pregnant or who are of childbearing potential, please refer to the earlier discussion regarding the use of DTG and the HIV RNA and resistance testing should be obtained approximately 2 to 4 potential risk of NTDs in infants. weeks after re-initiation of therapy, and patients should be closely monitored for virologic responses. Lastly, clinicians should be aware of the structural similarity between BIC and DTG. Since there are no safety data for the use of BIC around the time of conception to guide evidence-based recommendations, an approach similar to that outlined for DTG may be implemented before considering BIC-containing ART in those of childbearing potential. Table 11. Antiretroviral Options for Patients with Virologic Failure Designing a new regimen for patients with treatment failure should always be guided by ARV history and results from current and past resistance testing. This table summarizes the text above and displays the most common or likely clinical scenarios seen in patients with virologic failure. For more detailed descriptions, please refer to the text above and/or consult an expert in drug resistance to assist in the design of a new regimen. It is also crucial to provide continuous adherence support to all patients before and after regimen changes. Preliminary data from Botswana suggested that there is an increased risk of NTDs in infants born to 47,48 individuals who were receiving DTG at the time of conception. Pregnancy testing should therefore be performed for those of childbearing potential prior to initiation of DTG. If there is an alternative option, DTG should not be prescribed for those who are pregnant and within 12 weeks post-conception or those who are of childbearing potential and who are planning to become pregnant or who are not using effective contraception. When DTG is the only treatment option, or one of few treatment options, providers should counsel individuals who are pregnant or of childbearing potential about the possible association between NTDs and DTG use during conception. The decision of whether to initiate or continue DTG should be made after careful consideration of this risk and the risks of persistent viremia in the patient and HIV transmission to the fetus if pregnancy occurs while the patient is not on effective ART. Type of Clinical a,b Goal Failing Resistance Considerations New Regimen Options Scenario Regimen Resuppression First Regimen NNRTI plus Most likely resistant to NNRTI +/- Boosted PI plus 2 NRTIs (at least 1 active) • or ; (AIII) 2 NRTIs Failure 3TC/FTC (i.e., NNRTI mutations c Additional NRTI +/- M184V/I). d or ; plus 2 NRTIs (at least 1 active) (AI) • DTG mutations may also be present. • (AIII) Boosted PI plus INSTI Most likely no resistance, or Boosted Resuppression ; (AII) Continue same regimen • or resistance only to 3TC/FTC (i.e., PI plus 2 • Another boosted PI plus 2 NRTIs (at least 1 M184V/I, without resistance to NRTIs (AII) or ; active) c other NRTIs) • INSTI plus 2 NRTIs (at least 1 active; if only 1 of the NR TIs is fully active, or, if adherence d is preferred over the other is a concern, DTG INSTIs) (AIII) ; or • Another boosted PI plus INSTI (BIII) INSTI plus No INSTI resistance (can Resuppression Boosted PI plus 2 NRTIs (at least 1 active) • 2 NR TIs have 3TC/FTC resistance, i.e., or ; (AIII) only M184V/I, usually without d plus 2 NRTIs (at least 1 active) or • ; (AIII) DTG c resistance to other NRTIs) • (BIII) Boosted PI plus INSTI H-10 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

126 Table 11. Antiretroviral Options for Patients with Virologic Failure Type of Clinical a,b Goal Resistance Considerations New Regimen Options Failing Scenario Regimen INSTI plus Boosted PI plus 2 NRTIs (at least 1 active) EVG or RAL +/- 3TC/FTC • First Regimen Resuppression or resistance Failure 2 NRTIs (AIII) ; , continued d,e • DTG twice daily (if patient is sensitive to Resistance BIC or to first-line TIs (AIII) ; or DTG) plus 2 active NR DTG is rare d,e twice daily (if patient is sensitive to DTG • DTG) plus a boosted PI (AIII) BIC has not been studied in this setting and • cannot be recommended . Resuppression At least 2, and preferably 3, fully active agents Use past and current genotypic Second Drug • (AI) +/- phenotypic resistance testing Regimen Failure resistance and ART history in designing new with active and Beyond Partially active drugs may be used when no • treatment regimen other options are available options • Consider using an ARV with a different mechanism of action Identify as many active or partially active drugs Resuppression, • Use past and current genotypic Multiple or as possible based on resistance test results extensive if possible; and phenotypic resistance testing drug otherwise, to guide therapy • Consider using an ARV with a different resistance keeping viral mechanism of action Consider viral tropism assay if with few load as low as Consider enrollment into clinical trials or use of MVC is considered • treatment possible and expanded access programs for investigational CD4 cell count options Consult an expert in drug agents, if available as high as resistance, if needed Discontinuation of • ARVs . is not recommended possible Previously Unknown Obtain medical records if possible Consider restarting the old regimen, and obtain • Resuppression on Treatment, viral load and resistance testing 2–4 weeks Resistance testing may be helpful Suspected Drug after reintroduction of therapy in identifying drug resistance Resistance, If there is no available ARV history, consider • mutations, even if the patient has Limited or initiating a regimen with drugs with high been off ART. Keep in mind that Incomplete ART d,e and/ genetic barriers to resistance (e.g., DTG resistance mutations may not be and Resistance or boosted DRV) detected in the absence of drug History pressure. a There are insufficient data to provide a recommendation for the continuation of 3TC/FTC in the presence of M184V/I. b When switching an ARV regimen in a patient with HIV/HBV coinfection, ARV drugs that are active against HBV should be continued as part of the new regimen. Discontinuation of these drugs may lead to the reactivation of HBV, which may result in serious hepatocellular damage. c If other NRTI resistance mutations are present, use resistance test results to guide NRTI usage in the new regimen. d Preliminary data from Botswana suggested that there is an increased risk of NTDs in infants born to those who were receiving DTG at 47,48 the time of conception. Pregnancy testing should therefore be performed for those of childbearing potential prior to initiation of DTG. Please refer to the discussion at the beginning of this table for further recommendations. e Response to DTG depends on the type and number of INSTI mutations. Key to Acronyms: 3TC = lamivudine; ART = antiretroviral therapy; ARV = antiretroviral; BIC = bictegravir; CD4 = CD4 T lymphocyte; DRV = darunavir; DTG = dolutegravir; EVG = elvitegravir; FTC = emtricitabine; HBV = hepatitis B virus; INSTI = integrase strand transfer inhibitor; MVC = maraviroc; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; NTD = neural tube defect; PI = protease inhibitor; RAL = raltegravir H-11 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

127 Isolated Central Nervous System Virologic Failure and Neurologic Symptoms Presentation with new-onset central nervous system (CNS) signs and symptoms has been reported as a rare form of “compartmentalized” virologic failure. These patients present with new, usually subacute, neurological symptoms associated with breakthrough of HIV infection within the CNS compartment despite 64-66 plasma HIV RNA suppression. Clinical evaluation frequently shows abnormalities on magnetic resonance 67 imaging and abnormal cerebrospinal fluid (CSF) findings with characteristic lymphocytic pleocytosis. Measurement of CSF HIV RNA shows higher concentrations in the CSF than in plasma, and in most (though not all) patients, there is evidence of drug-resistant CSF virus. Drug-resistance testing of HIV in CSF can be used to guide changes in the treatment regimen according to principles outlined above for plasma HIV RNA resistance . In these patients, it may also be useful to consider CNS PKs in drug selection to assure (CIII) adequate concentrations of drugs within the CNS (CIII) . If CSF HIV resistance testing is not available, the regimen may be changed based on the patient’s treatment history or on predicted drug penetration into the 68-71 CNS (CIII) . This “neurosymptomatic” CNS viral escape should be distinguished from: • The incidental detection of asymptomatic and mild CSF HIV RNA elevation that is usually transient with 72,73 low levels of CSF HIV RNA, likely equivalent to plasma blips; or • A transient increase in CSF HIV RNA that is related to other CNS infections that can induce a brief 74 increase in CSF HIV RNA (e.g., herpes zoster ). There does not appear to be an association between these asymptomatic CSF HIV RNA elevations and the relatively common chronic, usually mild, neurocognitive impairment in patients with HIV who show 75 no evidence of CNS viral breakthrough. Unlike the “neurosymptomatic” CNS viral escape, these latter 76 conditions do not currently warrant a change in ART. Summary The management of treatment-experienced patients with virologic failure often requires expert advice to construct virologically suppressive regimens. Before modifying a regimen, it is critical to carefully evaluate the potential cause(s) of virologic failure, including incomplete adherence, poor tolerability, and drug and food interactions, as well as review HIV RNA and CD4 cell count changes over time, complete treatment history, and current and previous drug-resistance test results. If HIV RNA suppression is not possible with currently approved agents, consider the use of investigational agents through participation in clinical trials or expanded/single-patient access programs. If virologic suppression is still not achievable, the choice of regimens should focus on minimizing toxicity and preserving treatment options while maintaining CD4 cell counts to delay clinical progression. References 1. fer TL, Finucane MM, Nettles RE, et al. Genotypic analysis of HIV-1 drug resistance at the limit of detection: Kief virus production without evolution in treated adults with undetectable HIV loads. J Infect Dis . 2004;189(8):1452-1465. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15073683 . 2. Nettles RE, Kief fer TL, Kwon P, et al. Intermittent HIV-1 viremia (blips) and drug resistance in patients receiving HAART. . 2005;293(7):817-829. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15713771 . JAMA 3. Lima V, Harrigan R, Montaner JS. Increased reporting of detectable plasma HIV-1 RNA levels at the critical threshold of 50 copies per milliliter with the Taqman assay in comparison to the Amplicor assay. J Acquir Immune Defic Syndr . 2009;51(1):3-6. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19247185 . Gatanaga H, 4. Tsukada K, Honda H, et al. Detection of HIV type 1 load by the Roche Cobas TaqMan assay in patients with viral loads previously undetectable by the Roche Cobas Amplicor Monitor. Clin Infect Dis . 2009;48(2):260-262. . https://www.ncbi.nlm.nih.gov/pubmed/19113986 Available at: H-12 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

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131 58. V, Sabin C, Hertogs K, et al. Virological and immunological effects of treatment interruptions in HIV-1 Miller . 2000;14(18):2857-2867. Available at: https://www.ncbi.nlm.nih.gov/ infected patients with treatment failure. AIDS pubmed/11153667 . gerber B, Lundgren JD, Walker AS, et al. Predictors of trend in CD4-positive T-cell count and mortality among Leder 59. HIV-1-infected individuals with virological failure to all three antiretroviral-drug classes. Lancet . 2004;364(9428):51-62. . Available at: https://www.ncbi.nlm.nih.gov/pubmed/15234856 fanti SP, Fusco JS, Sherrill BH, et al. Effect of persistent moderate viremia on disease progression during 60. Raf . 2004;37(1):1147-1154. Available at: J Acquir Immune Defic Syndr HIV therapy. https://www.ncbi.nlm.nih.gov/ . pubmed/15319674 61. Ibalizumab [package insert]. Food and Drug Administration. 2018. Available at: https://www.accessdata.fda.gov/ drugsatfda_docs/label/2018/761065lbl.pdf. Emu B, Fessel J, Schrader S, et al. Phase 3 study of ibalizumab for multidrug-resistant HIV -1. N Engl J Med . 62. https://www.ncbi.nlm.nih.gov/pubmed/30110589 . 2018;379(7):645-654. Available at: Emu B, Fessel WJ, Schrader S, et al. 48-week safety and efficacy on-treatment analysis of Ibalizumab in patients with 63. multi-drug resistant HIV -1. Presented at: ID Week. 2017. San Diego, CA. A, Lescure FX, Jaureguiberry S, et al. Discordance between cerebral spinal fluid and plasma HIV replication 64. Canestri . in patients with neurological symptoms who are receiving suppressive antiretroviral therapy. Clin Infect Dis . https://www.ncbi.nlm.nih.gov/pubmed/20100092 2010;50(5):773-778. Available at: 65. , Peterson J, et al. Cerebrospinal fluid HIV escape associated with progressive neurologic Peluso MJ, Ferretti F AIDS . 2012;26(14):1765-1774. dysfunction in patients on antiretroviral therapy with well controlled plasma viral load. http://www.ncbi.nlm.nih.gov/pubmed/22614889 . Available at: 66. Ferretti F , Gisslen M, Cinque P, Price RW. Cerebrospinal fluid HIV escape from antiretroviral therapy. Curr HIV/AIDS . 2015;12(2):280-288. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25860317 . Rep 67. Kugathasan R, Collier DA, Haddow LJ, et al. Diffuse white matter signal abnormalities on magnetic resonance imaging Type 1 viral escape in the central nervous system among patients are associated with human immunodeficiency virus with neurological symptoms. Clin Infect Dis . 2017;64(8):1059-1065. Available at: https://www.ncbi.nlm.nih.gov/ pubmed/28329096 . Top Antivir disease: HIV-associated neurocognitive disorder. 68. Letendre S. Central nervous system complications in HIV Med . 2011;19(4):137-142. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22156215 . AM, Tashima KT, et al. ING116070: a study of the pharmacokinetics and antiviral activity 69. Letendre SL, Mills Clin Infect Dis . of dolutegravir in cerebrospinal fluid in HIV-1-infected, antiretroviral therapy-naive subjects. 2014;59(7):1032-1037. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24944232 . 70. Calcagno A, Di Perri G, Bonora S. Pharmacokinetics and pharmacodynamics of antiretrovirals in the central nervous Clin Pharmacokinet http://www.ncbi.nlm.nih.gov/pubmed/25200312 . . 2014;53(10):891-906. Available at: system. 71. Wu K, Letendre S, et al. Effects of central nervous system antiretroviral penetration on cognitive Smurzynski M, AIDS . 2011;25(3):357-365. Available at: https://www.ncbi.nlm.nih.gov/ functioning in the ALLRT cohort. . pubmed/21124201 72. A, Fuchs D, Hagberg L, et al. HIV-1 viral escape in cerebrospinal fluid of subjects on suppressive antiretroviral Eden treatment. J Infect Dis https://www.ncbi.nlm.nih.gov/pubmed/21050119 . . 2010;202(12):1819-1825. Available at: A, Nilsson S, Hagberg L, et al. Asymptomatic cerebrospinal fluid HIV-1 viral blips and viral escape during 73. Eden J Infect Dis . 2016;214(12):1822-1825. Available at: https://www.ncbi.nlm. antiretroviral therapy: a longitudinal study. . nih.gov/pubmed/27683820 74. Moling O, Rossi P , Rimenti G, Vedovelli C, Mian P. Varicella-zoster virus meningitis and cerebrospinal fluid HIV RNA. Scand J Infect Dis . 2001;33(5):398-399. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11440237 . 75. Heaton RK, Franklin DR, Ellis RJ, et al. HIV-associated neurocognitive disorders before and during the era of ferences in rates, nature, and predictors. J Neurovirol . 2011;17(1):3-16. Available combination antiretroviral therapy: dif at: http://www.ncbi.nlm.nih.gov/pubmed/21174240 . Vaida F, et al. Randomized trial of central nervous system-targeted antiretrovirals for HIV- 76. Ellis RJ, Letendre S, . 2014;58(7):1015-1022. Available at: associated neurocognitive disorder. Clin Infect Dis http://www.ncbi.nlm.nih.gov/ pubmed/24352352 . H-16 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

132 Poor CD4 Cell Recovery and Persistent Inflammation Despite Viral Suppression (Last updated April 8, 2015; last reviewed April 8, 2015) Panel’s Recommendations Morbidity and mortality from several AIDS and non-AIDS conditions are increased in individuals with HIV despite antiretroviral • T)-mediated viral suppression, and are predicted by persistently low CD4 T lymphocyte (CD4) cell counts and/or therapy (AR persistent immune activation. T intensification by adding antiretroviral (ARV) drugs to a suppressive ART regimen does not consistently improve CD4 cell AR • (AI) . recovery or reduce immune activation and is not recommended • In individuals with viral suppression, switching ARV drug classes does not consistently improve CD4 cell recovery or reduce immune activation and is not recommended (BIII) . • No interventions designed to increase CD4 cell counts and/or decrease immune activation are recommended at this time (in ) because no intervention has been proven to decrease morbidity or mortality [AI] is not recommended , interleukin-2 particular during ART-mediated viral suppression. • Monitoring markers of immune activation and inflammation is not recommended because no immunologically targeted intervention has proven to improve the health of individuals with abnormally high biomarker levels, and many markers that predict morbidity and . mortality fluctuate widely in individuals (AII) Because there are no proven interventions to improve CD4 cell recovery and/or inflammation, ef • forts should focus on addressing modifiable risk factors for chronic disease (e.g., encouraging smoking cessation, a healthy diet, and exercise; treating hypertension and hyperlipidemia) (AII) . Rating of Recommendations: A = Strong; B = Moderate; C = Optional Rating of Evidence: I = Data from randomized controlled trials; II = Data from well-designed nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinion Despite marked improvements in antiretroviral treatment (ART), morbidity and mortality in individuals with HIV continues to be greater than in the general population, particularly when ART is delayed until advanced disease stages. These morbidities include cardiovascular disease, many non-AIDS cancers, non-AIDS infections, chronic obstructive pulmonary disease, osteoporosis, type II diabetes, thromboembolic disease, 1 liver disease, renal disease, neurocognitive dysfunction, and frailty. Although health-related behaviors and toxicities of antiretroviral (ARV) drugs may also contribute to the increased risk of illness and death, poor CD4 T lymphocyte (CD4) cell recovery, persistent immune activation, and inflammation likely also contribute to the risk. Poor CD4 Cell Recovery As long as ART-mediated viral suppression is maintained, peripheral blood CD4 cell counts in most individuals with HIV will continue to increase for at least a decade. The rate of CD4 cell recovery is typically 2-4 most rapid in the first 3 months of suppressive ART, followed by more gradual increases over time. If ART- mediated viral suppression is maintained, most individuals will eventually recover CD4 counts in the normal 3 range (>500 cells/mm ); however, approximately 15% to 20% of individuals who initiate ART at very low 3-5 3 CD4 counts (<200 cells/mm ) may plateau at abnormally low CD4 cell counts. Early initiation of ART in 6 individuals with recent HIV diagnoses likely provides the best opportunity for maximal CD4 cell recovery. Persistently low CD4 cell counts despite ART-mediated viral suppression are associated with increased 3 risk of morbidity and mortality. For example, individuals with HIV who have CD4 counts <200 cells/mm despite at least 3 years of suppressive ART had a 2.6-fold greater risk of mortality than those with higher 7 CD4 cell counts. Lower CD4 cell counts during ART-mediated viral suppression are associated with an 8-11 12 increased risk of non-AIDS morbidity and mortality, osteoporosis and including cardiovascular disease, H-17 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

133 13 14 15 and infection-related cancers. fractures, The prognostic importance of higher CD4 cell liver disease, counts likely spans all ranges of CD4 cell counts, though incremental benefits are harder to discern once CD4 16 3 counts increase to >500 cells/mm . Individuals with poor CD4 cell recovery should be evaluated for modifiable causes of CD4 cell lymphopenia. Concomitant medications should be reviewed, with a focus on those known to decrease white blood cells or, 17 specifically, CD4 cells (e.g., cancer chemotherapy, interferon, zidovudine, or the combination of tenofovir 18,19 disoproxil fumarate [TDF] and didanosine [ddI]). If possible, these drugs should be substituted for or discontinued. Untreated coinfections (e.g., HCV, HIV-2) and serious medical conditions (e.g., malignancy) should also be considered as possible causes of CD4 lymphopenia, particularly in individuals with consistently declining CD4 cell counts (and percentages) and/or in those with CD4 counts consistently below 3 100 cells/mm . In many cases, no obvious cause for suboptimal immunologic response can be identified. Despite strong evidence linking low CD4 cell counts and increased morbidity during ART-mediated viral suppression, no adjunctive therapies that increase CD4 cell count beyond levels achievable with ART alone have been proven to decrease morbidity or mortality. Adding ARV drugs to an already suppressive ART 20-25 regimen does not improve CD4 cell recovery, and does not reduce morbidity or mortality. Therefore, ART intensification is not recommended as a strategy to improve CD4 cell recovery (AI) . In individuals maintaining viral suppression, switching ARV drug classes in a suppressive regimen also does not 26 consistently improve CD4 cell recovery and is not recommended (BIII) . Two large clinical trials, powered to assess impact on clinical endpoints (AIDS and death), evaluated the role of interleukin-2, an immune- based therapy, in improving CD4 cell recovery. Interleukin-2 adjunctive therapy resulted in CD4 cell count 27 increases but with no observable clinical benefit. Therefore, interleukin-2 is not recommended (AI) . Other immune-based therapies that increase CD4 cell counts (e.g., growth hormone, interleukin-7) are under investigation. However, none of the therapies have been evaluated in clinical endpoint trials; therefore, whether any of these approaches will offer clinical benefit is unclear. Currently, such immune-based therapies should not be used except in the context of a clinical trial. Persistent Immune Activation and Inflammation Although poor CD4 cell recovery likely contributes to morbidity and mortality during ART-mediated viral suppression, there is increasing focus on persistent immune activation and inflammation as potentially independent mediators of risk. HIV infection results in heightened systemic immune activation and inflammation, effects that are evident during acute infection, persist throughout chronic untreated infection, and predict more rapid CD4 cell decline and progression to AIDS and death, independent of plasma HIV 28 RNA levels. Although immune activation declines with suppressive ART, it often persists at abnormal levels in many individuals with HIV maintaining long-term ART-mediated viral suppression—even in 29,30 those with CD4 cell recovery to normal levels. Immune activation and inflammatory markers (e.g., IL-6, D-dimer, hs-CRP) also predict mortality and non-AIDS morbidity during ART-mediated viral suppression, 28 including cardiovascular and thromboembolic events, cancer, neurocognitive dysfunction, and frailty. 3 Although individuals with poor CD4 cell recovery (i.e., counts persistently <350 cells/mm ) tend to have 29 , greater immune activation and inflammation than those with greater recovery the relationship between innate immune activation and inflammation and morbidity/mortality is lar gely independent of CD4 cell 31,32 3 count. Even in individuals with CD4 counts >500 cells/mm , there is evidence that immune activation and 33 inflammation contribute to morbidity and mortality . Thus, innate immune activation and inflammation are potentially important targets for future interventions. Although the drivers of persistent immune activation during ART are not completely understood, HIV 28 persistence, coinfections, and microbial translocation likely play important roles. Interventions to reduce each of these presumed drivers are currently being investigated. Importantly, adding ARV drugs to an already 20-23,25 suppressive ART regimen (ART intensification) does not consistently improve immune activation. H-18 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

134 Although some studies have suggested that switching an ART regimen to one with a more favorable lipid profile may improve some markers of immune activation and inflammation,34,35 these studies have limitations and results are not consistent across markers and among studies. Thus, at this time, ART (BIII) . Other commonly modification cannot be recommended as a strategy to reduce immune activation used medications with anti-inflammatory properties (e.g., statins, aspirin) are being studied, and preliminary 36,37 evidence suggests that some may reduce immune activation in treated HIV infection. However, because no intervention specifically targeting immune activation or inflammation has been studied in a clinical outcomes trial in treated HIV infection, no interventions to reduce immune activation are recommended at this time. In the absence of proven interventions, there is currently no clear rationale to monitor levels of immune activation and inflammation in treated HIV infection. Furthermore, many of the inflammatory markers that predict morbidity and mortality fluctuate significantly in individuals with HIV . Thus, clinical monitoring with immune activation or inflammatory markers . The focus of care to is not currently recommended (AII) reduce chronic non-AIDS morbidity and mortality should be on maintaining ART-mediated viral suppression and addressing strategies to reduce risk factors (e.g., smoking cessation, healthy diet, and exercise) and . managing chronic comorbidities such as hypertension, hyperlipidemia, and diabetes (AII) References 1. Deeks SG. HIV infection, inflammation, immunosenescence, and aging. Annu Rev Med . Feb 18 2011;62:141-155. http://www.ncbi.nlm.nih.gov/pubmed/21090961 . Available at 2. Bartlett JA, DeMasi R, Quinn J, Moxham C, Rousseau F . Overview of the effectiveness of triple combination therapy in . Jul 27 2001;15(11):1369-1377. Available at https://www.ncbi.nlm.nih. AIDS antiretroviral-naive HIV-1 infected adults. gov/pubmed/11504958 . 3. Kelley CF , Kitchen CM, Hunt PW, et al. Incomplete peripheral CD4+ cell count restoration in HIV-infected patients Clin Infect Dis . Mar 15 2009;48(6):787-794. Available at http://www.ncbi. receiving long-term antiretroviral treatment. . nlm.nih.gov/pubmed/19193107 T-cell counts during combination antiretroviral therapy Lok JJ, Bosch RJ, Benson CA, et al. Long-term increase in CD4+ 4. AIDS . Jul 31 2010;24(12):1867-1876. Available at http://www.ncbi.nlm.nih.gov/pubmed/20467286 . for HIV-1 infection. 5. Moore RD, Keruly JC. CD4+ cell count 6 years after commencement of highly active antiretroviral therapy in persons with sustained virologic suppression. Clin Infect Dis Available at https://www.ncbi.nlm.nih. . Feb 1 2007;44(3):441-446. . gov/pubmed/17205456 Le T, Wright EJ, Smith DM, et al. Enhanced CD4+ T-cell recovery with earlier HIV-1 antiretroviral therapy. N Engl J 6. http://www.ncbi.nlm.nih.gov/pubmed/23323898 . . Jan 17 2013;368(3):218-230. Available at Med Engsig FN, Zangerle R, Katsarou O, et al. Long-term mortality in HIV-positive individuals virally suppressed for >3 7. . years with incomplete CD4 recovery . May 2014;58(9):1312-1321. Available at http://www.ncbi.nlm.nih. Clin Infect Dis . gov/pubmed/24457342 3 V, De Wit S, et al. All-cause mortality in treated HIV-infected adults with CD4 >=500/mm 8. Lewden C, Bouteloup compared with the general population: evidence from a lar ge European observational cohort collaboration{dagger}. Int J Epidemiol . Apr 2012;41(2):433-445. Available at . http://www.ncbi.nlm.nih.gov/pubmed/22493325 Baker JV 9. , Peng G, Rapkin J, et al. CD4+ count and risk of non-AIDS diseases following initial treatment for HIV infection. AIDS . Apr 23 2008;22(7):841-848. Available at https://www.ncbi.nlm.nih.gov/pubmed/18427202 . 10. Achhra AC, Amin J, Law MG, et al. Immunodeficiency and the risk of serious clinical endpoints in a well studied cohort of treated HIV-infected patients. . Jul 31 2010;24(12):1877-1886. Available at http://www.ncbi.nlm.nih.gov/ AIDS pubmed/20588170 . Smurzynski M, Wu K, Benson CA, Bosch RJ, Collier AC, Koletar SL. Relationship between CD4+ T-cell counts/HIV-1 11. RNA plasma viral load and AIDS-defining events among persons followed in the ACTG longitudinal linked randomized . Sep 1 2010;55(1):117-127. Available at trials study. J Acquir Immune Defic Syndr https://www.ncbi.nlm.nih.gov/ pubmed/20622677 . H-19 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

135 12. Armon C, Buchacz K, et al. Low CD4+ T cell count is a risk factor for cardiovascular disease events Lichtenstein KA, Clin Infect Dis https://www.ncbi.nlm.nih.gov/ . Aug 15 2010;51(4):435-447. Available at in the HIV outpatient study. pubmed/20597691 . 13. Y ong MK, Elliott JH, Woolley IJ, Hoy JF. Low CD4 count is associated with an increased risk of fragility fracture in . Jul 1 2011;57(3):205-210. Available at http://www.ncbi.nlm.nih. HIV-infected patients. J Acquir Immune Defic Syndr . gov/pubmed/21522014 eber R, Sabin CA, Friis-Moller N, et al. Liver-related deaths in persons infected with the human immunodeficiency 14. W virus: the D:A:D study. . Aug 14-28 2006;166(15):1632-1641. Available at https://www.ncbi.nlm.nih. Arch Intern Med gov/pubmed/16908797. 15. Monforte A, Abrams D, Pradier C, et al. HIV-induced immunodeficiency and mortality from AIDS-defining and non-AIDS-defining malignancies. . Oct 18 2008;22(16):2143-2153. Available at https://www.ncbi.nlm.nih.gov/ AIDS pubmed/18832878 . 16. Y oung J, Psichogiou M, Meyer L, et al. CD4 cell count and the risk of AIDS or death in HIV-Infected adults on combination antiretroviral therapy with a suppressed viral load: a longitudinal cohort study from COHERE. PLoS Med . http://www.ncbi.nlm.nih.gov/pubmed/22448150 . 2012;9(3):e1001194. Available at Huttner AC, Kaufmann GR, Battegay M, Weber R, Opravil M. Treatment initiation with zidovudine-containing potent 17. antiretroviral therapy impairs CD4 cell count recovery but not clinical efficacy AIDS . May 11 2007;21(8):939-946. . Available at https://www.ncbi.nlm.nih.gov/pubmed/17457087 . 18. A, Rendon A, Negredo E, et al. Paradoxical CD4+ T-cell decline in HIV-infected patients with complete virus Barrios suppression taking tenofovir and didanosine. AIDS . Mar 24 2005;19(6):569-575. Available at https://www.ncbi.nlm.nih. gov/pubmed/15802975 . 19. Negredo E, Bonjoch A, Paredes R, Puig J, Clotet B. Compromised immunologic recovery in treatment-experienced patients with HIV infection receiving both tenofovir disoproxil fumarate and didanosine in the TORO studies. Clin Infect . Sep 15 2005;41(6):901-905. Available at Dis https://www.ncbi.nlm.nih.gov/pubmed/16107993 . 20. T, Zheng L, Bosch RJ, et al. The effect of raltegravir intensification on low-level residual viremia in HIV- Gandhi R PLoS Med . 2010;7(8). Available at infected patients on antiretroviral therapy: a randomized controlled trial. https://www. . ncbi.nlm.nih.gov/pubmed/20711481 21. Terminal Repeat Circles and Decrease in D-dimer After Hatano H, Strain MC, Scherzer R, et al. Increase in 2-Long Raltegravir Intensification in Patients With Treated HIV Infection: A Randomized, Placebo-Controlled Trial. J Infect Dis . http://www.ncbi.nlm.nih.gov/pubmed/23975885 . Nov 2013;208(9):1436-1442. Available at 22. , Shulman NS, Hayes TL, et al. The immunologic effects of maraviroc intensification in treated HIV-infected Hunt PW individuals with incomplete CD4+ T-cell recovery: a randomized trial. . Jun 6 2013;121(23):4635-4646. Available Blood http://www.ncbi.nlm.nih.gov/pubmed/23589670 at . 23. Dinoso JB, Kim SY , Wiegand AM, et al. Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy. Proc Natl Acad Sci USA . Jun 9 2009;106(23):9403-9408. Available at https://www. ncbi.nlm.nih.gov/pubmed/19470482 . 24. Cuzin L, Trabelsi S, Delobel P, et al. Maraviroc intensification of stable antiviral therapy in HIV-1-infected patients with J Acquir Immune Defic Syndr poor immune restoration: MARIMUNO-ANRS 145 study. . Dec 15 2012;61(5):557-564. Available at http://www.ncbi.nlm.nih.gov/pubmed/22986949 . -1 replication and immune dynamics are affected by raltegravir Buzon MJ, Massanella M, Llibre JM, et al. HIV 25. intensification of HAART-suppressed subjects. Nat Med . Apr 2010;16(4):460-465. Available at https://www.ncbi.nlm. nih.gov/pubmed/20228817 . 26. - Martinez E, Larrousse M, Llibre JM, et al. Substitution of raltegravir for ritonavir -boosted protease inhibitors in HIV infected patients: the SPIRAL study. AIDS . Jul 17 2010;24(11):1697-1707. Available at http://www.ncbi.nlm.nih.gov/ pubmed/20467288 . 27. Y, Losso MH, et al. Interleukin-2 therapy in patients with HIV infection. N Engl J Med . Oct 15 Abrams D, Levy https://www.ncbi.nlm.nih.gov/pubmed/19828532 . 2009;361(16):1548-1559. Available at H-20 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

136 28. g NT, Sekaly RP, Klatt NR, Hunt PW. Residual immune dysregulation syndrome in treated Lederman MM, Funderbur Adv Immunol http://www.ncbi.nlm.nih.gov/pubmed/23886064 . HIV infection. . 2013;119:51-83. Available at Lederman MM, Calabrese L, Funderbur g NT, et al. Immunologic failure despite suppressive antiretroviral therapy is 29. related to activation and turnover of memory CD4 cells. . Oct 15 2011;204(8):1217-1226. Available at http:// J Infect Dis www.ncbi.nlm.nih.gov/pubmed/21917895 . , Martin JN, Sinclair E, et al. T cell activation is associated with lower CD4+ T cell gains in human 30. Hunt PW immunodeficiency virus-infected patients with sustained viral suppression during antiretroviral therapy. J Infect Dis . May 15 2003;187(10):1534-1543. Available at . https://www.ncbi.nlm.nih.gov/pubmed/12721933 31. Hunt PW , Sinclair E, Rodriguez B, et al. Gut Epithelial Barrier Dysfunction and Innate Immune Activation Predict Mortality in Treated HIV Infection. J Infect Dis . Apr 21 2014. Available at http://www.ncbi.nlm.nih.gov/ pubmed/24755434 . enorio AR, Zheng Y, Bosch RJ, et al. Soluble Markers of Inflammation and Coagulation but Not T-Cell Activation 32. T Predict Non-AIDS-Defining Morbid Events During Suppressive Antiretroviral Treatment. J Infect Dis . May 1 2014. http://www.ncbi.nlm.nih.gov/pubmed/24795473 Available at . 33. T ien PC, Choi AI, Zolopa AR, et al. Inflammation and mortality in HIV-infected adults: analysis of the FRAM . Nov 2010;55(3):316-322. Available at http://www.ncbi.nlm.nih.gov/ J Acquir Immune Defic Syndr study cohort. . pubmed/20581689 34. -infected patients Martinez E, D’Albuquerque PM, Llibre JM, et al. Changes in cardiovascular biomarkers in HIV -boosted protease inhibitors to raltegravir. AIDS . Nov 28 2012;26(18):2315-2326. Available at switching from ritonavir http://www.ncbi.nlm.nih.gov/pubmed/23018438 . T, et al. Switch to raltegravir decreases soluble CD14 in virologically suppressed 35. Lake JE, McComsey GA, Hulgan overweight women: the Women, Integrase and Fat Accumulation Trial. . Aug 2014;15(7):431-441. Available at HIV Med http://www.ncbi.nlm.nih.gov/pubmed/24506429 . 36. Funderbur g NT, Jiang Y, Debanne SM, et al. Rosuvastatin treatment reduces markers of monocyte activation in HIV- infected subjects on antiretroviral therapy. Clin Infect Dis . Feb 2014;58(4):588-595. Available at http://www.ncbi.nlm. nih.gov/pubmed/24253250 . 37. Aspirin attenuates platelet activation and immune activation in HIV -infected O’Brien M, Montenont E, Hu L, et al. http://www. subjects on antiretroviral therapy: A Pilot Study. J Acquir Immune Defic Syndr . Feb 12 2013. Available at . ncbi.nlm.nih.gov/pubmed/23406976 H-21 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

137 Optimizing Antiretroviral Therapy in the Setting of Viral Suppression (Last updated October 25, 2018; last reviewed October 25, 2018) Panel’s Recommedations Advances in antiretroviral (ARV) treatment and a better understanding of HIV drug resistance make it possible to consider switching • fective regimen to an alternative regimen in some situations. an ef • . (AI) The fundamental principle of regimen switching is to maintain viral suppression without jeopardizing future treatment options • It is critical to review a patient’ s full ARV history, including virologic responses, past ARV-associated toxicities and intolerances, and cumulative resistance test results, before selecting a new antiretroviral therapy regimen (AI) . • Adverse events, drug-drug or drug-food interactions, pill burden, pregnancy, cost, or the desire to simplify a regimen may prompt a regimen switch. Within-class and between-class switches can usually maintain viral suppression, provided that there is no viral . resistance to the ARV agents in the new regimen (AI) table • Monotherapy with either a boosted protease inhibitor or an integrase strand transfer inhibitor has been associated with unaccep . (AI) is not recommended rates of virologic failure and the development of resistance; therefore, monotherapy as a switching strategy • When switching an ARV regimen in a person with hepatitis B virus (HBV)/HIV coinfection, ARV drugs that are active against HBV infection should be continued. Discontinuation of HBV drugs may lead to reactivation of HBV, which may result in serious hepatocellular damage. Consultation with an HIV specialist should be considered when planning a regimen switch for a patient with a history of resistance to • one or more drug classes . (BIII) Close monitoring to assess tolerability, viral suppression, adherence, and safety is recommended during the first 3 months after a • . regimen switch (AIII) Rating of Recommendations: A = Strong; B = Moderate; C = Optional I = Data from randomized controlled trials; II = Data from well-designed nonrandomized trials or observational Rating of Evidence: cohort studies with long-term clinical outcomes; III = Expert opinion With currently available antiretroviral therapy (ART), most patients living with HIV can achieve and maintain HIV viral suppression. Furthermore, advances in treatment and a better understanding of drug resistance make it possible to consider switching from an effective regimen to another regimen in some situations (see below). When considering such a switch, clinicians must keep several key principles in mind in order to maintain viral suppression while addressing the concerns with the current regimen. Reasons to Consider Regimen Switching in the Setting of Viral Suppression • T o simplify a regimen by reducing pill burden and/or dosing frequency • T o enhance tolerability and/or decrease short- or long-term toxicity (see Adverse Effects of Antiretroviral Agents and Table 16 for a more in-depth discussion of possible toxicities) ) Drug-Drug Interactions o prevent or mitigate drug-drug interactions (see • T • T o eliminate food or fluid requirements o allow for optimal use of ART during pregnancy or in cases where pregnancy may occur (see the • T Perinatal Guidelines ) • T o reduce costs (see Cost Considerations and Antiretroviral Therapy ) General Principles of Regimen Switching Maintain Viral Suppression The fundamental principle of regimen switching is to maintain viral suppression without jeopardizing future (AI) treatment options . If a regimen switch results in virologic failure with the emergence of new resistance H-22 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

138 mutations, the patient may require more complex or expensive regimens. Careful Review of Antiretroviral History Before Switch The review of a patient’s full antiretroviral (ARV) history—including virologic responses, past ARV- associated toxicities, and cumulative resistance test results—is warranted before any treatment switch (AI) . If a patient with pre-ART wild-type HIV achieves and maintains viral suppression after ART initiation, one can assume that no new resistance mutation emerged while the patient was on the suppressive regimen. Assess Prior Resistance Before Switch Review of cumulative resistance test results is essential when designing a new regimen. Cumulative resistance test results refer to all previous and currently available results from standard genotype, proviral DNA genotype, phenotype, and tropism assays that can be used to guide the selection of a new regimen. Once selected, a resistance mutation is generally archived in the HIV reservoir and is likely to re-emerge under the appropriate selective drug pressure, even if it is not detected in the patient’s most recent resistance test. When resistance data are not available, resistance may often be inferred from a patient’s treatment history. For example, a patient who experienced virologic failure on a lamivudine (3TC)-containing regimen or an emtricitabine (FTC)-containing regimen in the past is likely to have the M184V substitution, even if it is not documented. For patients with documented failure on a regimen that contains elvitegravir (EVG), raltegravir (RAL), or a non-nucleoside reverse transcriptase inhibitor (NNRTI), resistance to these drugs should be assumed because these drugs generally have a lower barrier to resistance than other ARV drugs. If there is uncertainty about prior resistance, it is generally not advisable to switch a suppressive ARV regimen unless the new regimen is likely to be at least as active against potential resistant virus as the suppressive regimen. This is particularly applicable when switching ARV-experienced individuals from a regimen with a high barrier to resistance to 1 one with a lower barrier to resistance. Consulting an HIV specialist is recommended when contemplating a (BIII) . regimen switch for a patient with a history of resistance to one or more drug classes If switching is considered in patients with suppressed viral loads who do not have prior resistance data, next- generation proviral DNA genotypic resistance testing can be considered. For patients who have no prior virologic failures and who are on their first or second regimen, or those who have genotypic test results from prior virologic failures, the use of the proviral DNA genotypic test is unlikely to provide useful information. In individuals with multiple prior failures or a history of multiple prior ARV regimens, the use of proviral DNA genotypic testing may be useful. However, the results must be interpreted with caution, as these assays may not detect all of a patient’s drug resistance mutations, especially those that were selected by a previous ART regimen. In addition, these assays may identify mutations that appear to be inconsistent with a patient’s response to treatment, making the clinical relevance of the assay results questionable. Overall, the clinical utility of these assays remains an area of active investigation (see Drug-Resistance Testing ). Switching in a Person with Hepatitis B Virus Coinfection When switching an ARV regimen in a patient with hepatitis B virus (HBV)/HIV coinfection, tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF) should be continued as part of the new regimen, 2 unless these drugs are contraindicated. Both TDF and TAF are active against HBV infection. Discontinuation of these drugs may lead to reactivation of HBV, which may result in serious hepatocellular damage. Using 3TC or FTC as the only active drug for HBV infection is not recommended , as HBV resistance to these drugs can emerge rapidly. If TDF or TAF cannot be used as part of the ARV regimen, refer to Hepatitis B Virus/HIV Coinfection for recommendations. Assess for Potential Drug Interactions Before switching a regimen, it is important to review the ARV drugs in the new regimen and concomitant medications to assess whether there are any potential drug-drug interactions. For example, rilpivirine (RPV) may interact with acid-lowering agents, and TAF and bictegravir (BIC) may interact with rifamycins (see H-23 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

139 Drug-Drug Interactions ). In addition to new drug interactions, the discontinuation of some ARV drugs may also necessitate adjusting the dosage of concomitant medications. For example, discontinuation of pharmacokinetic boosters (ritonavir or cobicistat) may reduce the concentrations of some concomitant medications. Concomitant medications which may have previously been managed with dose adjustments will need to be re-evaluated in the context of the new ART regimen. Assess for Potential for Pregnancy A pregnancy test should be performed for those of childbearing potential prior to switching ART. If a person Perinatal Guidelines for recommendations with HIV is found to be pregnant, clinicians should refer to the on the safety and efficacy of ARV use in pregnancy. Preliminary data from Botswana suggest there may be an increased risk of neural tube defects (NTDs) in infants born to women who were receiving dolutegravir 3,4 (DTG) at the time of conception. Until more information is available: • Clinicians should discuss the possible association between NTDs and DTG use during conception and the benefits of DTG for HIV treatment with individuals of childbearing potential; clinicians should also provide appropriate counseling so that the individual can make an informed decision about the use of DTG (AIII) . for those: DTG is not recommended • Who are pregnant and within 12 weeks post-conception; • Who are of childbearing potential, sexually active, and not using ef fective contraception; • or Who are contemplating pregnancy. • • It is unknown whether the possible risk of NTDs associated with DTG use at the time of conception is shared by other integrase strand transfer inhibitors (INSTIs) (i.e., a class ef fect). • BIC is structurally similar to DTG, but there are no safety data on the use of BIC around the time of conception. For those who are of childbearing potential, but who are not pregnant, an approach similar to that outlined for DTG should be taken before considering BIC-containing ART. Monitoring after Switch Close monitoring to assess tolerability, viral suppression, adherence, and safety is recommended during the first 3 months after a regimen switch (see below). Specific Regimen Switching Considerations (also see Adverse Effects of Antiretroviral ) Agents As with AR T-naive patients, the use of a three-drug combination regimen is generally recommended when switching patients with suppressed viral loads to a new regimen. Patients with no resistance mutations can likely switch to any regimen that has been shown to be highly effective in AR T-naive patients. In addition, there is growing evidence that certain two-drug regimens can maintain virologic suppression, as discussed below. Monotherapy with either a boosted protease inhibitor (PI) or an INSTI has been explored in several trials or cohort studies. Monotherapy has been associated with a higher rate of virologic failure than other regimens and has been associated with the development of resistance, especially INSTI monotherapy; . (AI) is not recommended therefore, monotherapy as a switching strategy Strategies with Good Supporting Evidence Three-Drug Regimens Within-Class Switches Within-class switches that are prompted by adverse events or the availability of ARVs within the same class Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV 24 H- Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

140 that offer a better safety profile, reduced dosing frequency, higher barrier to resistance, or lower pill burden usually maintain viral suppression, provided there is no drug resistance to the new ARV. Some examples of within-class switch strategies are switching from: 7 5,6 • TDF to TAF or abacavir (ABC) 8 • to elvitegravir/cobicistat (EVG/c) RAL or DTG 9,10 DTG • , EVG/c, or RAL to BIC 6,11 • Efavirenz (EFV) to RPV ritonavir-boosted PI (PI/r) to a PI coformulated with cobicistat (PI/c) A • 12-14 • Boosted atazanavir (A TV/c or ATV/r) to unboosted ATV (when used with ABC/3TC) Between-Class Switches Between-class switches generally maintain viral suppression, provided there is no resistance to the other components of the regimen. Such switches should be avoided if there is any doubt about the activity of the other agents in the regimen. As noted earlier, prior resistance test results will be very informative in guiding this switch. Some examples of between-class switch strategies are: 15 17,18 16 Replacing a boosted PI with an INST (e.g., DTG, • BIC, ) or EVG 19 • Replacing a boosted PI with RPV 20,21 • Replacing an NNR TI with an INSTI 22 • Replacing a boosted PI with maraviroc (MVC). When switching to MVC, co-receptor usage in patients with virologic suppression can be determined from proviral DNA (see Co-receptor Tropism Assays ) 22-24 obtained from peripheral blood mononuclear cells. Two-Drug Regimens There is growing evidence that some two-drug regimens are effective in maintaining virologic control in patients who initiated therapy and achieved virologic suppression with three-drug regimens. However, caution should be taken in patients with HBV coinfection, as these simplified regimens may not have adequate anti-HBV activity. Below are examples of successful strategies for switching from three- to two- drug regimens in persons with suppressed HIV. Dolutegravir plus Rilpivirine Two Phase 3 trials enrolled 1,024 participants with viral suppression for ≥1 year and no history of virologic 25 failure. Participants were randomized to stay on their combination ART regimen or to switch to a regimen of once-daily DTG plus RPV. Viral suppression was maintained in 95% to 96% of the participants in both arms at 48 weeks. DTG plus RPV is available as a coformulated single-tablet regimen. This regimen is a reasonable option when the use of nucleoside reverse transcriptase inhibitors (NRTIs) is neither desirable nor necessary. It should only be given to patients who do not have chronic HBV infection, have no evidence of resistance to either DTG or RPV, and have no significant drug-drug interaction that might reduce either . drug’s concentration (AI) Ritonavir-Boosted Protease Inhibitor plus Lamivudine or Emtricitabine There is growing evidence that a PI/r-based regimen plus 3TC can maintain viral suppression in patients who who achieved sustained viral suppression for ≥1 year, and who have no evidence initiated triple-drug therapy, of, or risk of resistance to, either the PI/r or 3TC. A PI/r plus 3TC/FTC may be a reasonable option when the H-25 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

141 continued use of TDF, TAF, or ABC is contraindicated or not desirable. Examples of boosted PI plus 3TC regimens which have been studied in clinical trials include the following: 26,27 ATV/r plus 3TC (CI) , • 28 Darunavir/ritonavir (DRV/r) plus 3TC (BI) , • or 29 Lopinavir/ritonavir (LPV/r) plus 3TC (CI) . • Strategies for Patients with Viral Suppression and a History of Treatment Failure Elvitegravir/Cobicistat/T enofovir Alafenamide/Emtricitabine plus Darunavir The combination of EVG/c/TAF/FTC plus DRV has been shown to be a potential simplification strategy 30 in patients with complicated salvage regimens. A randomized controlled trial enrolled 135 virologically suppressed patients who were receiving DR V-containing ART and had resistance to at least two ARV drug classes, but no INSTI resistance. Eligible participants could have up to three thymidine analog resistance mutations and/or the K65R mutation, but no history of either the Q151M mutation or T69 insertion mutations. The patients were randomized 2:1 to either switch to a regimen of EVG/c/TAF/FTC plus DRV or arm remain on their original regimen. At 24 weeks, 97% of the patients in the EVG/c/TAF/FTC plus DRV maintained virologic suppression. The pill burden was reduced from an average of five tablets per day to two tablets per day . This regimen would be an appropriate option for individuals with similar treatment and drug . (AI) resistance histories as those included in this study Strategies with Some Supporting Evidence Other switching strategies in patients with viral suppression have some evidence to support their use. These strategies cannot be recommended until further evidence is available. If used, patients should be closely monitored to assure that viral suppression is maintained. Some of these strategies are listed below. Boosted Protease Inhibitor plus Integrase Strand Transfer Inhibitor 56 participants) in which participants In two small observational studies (which included 13 participants and were switched from their current ART regimens to DRV/r plus DTG, viral suppression was maintained in over 31,32 97% of the patients for a mean of 12.8 months in the first cohort and at 48 weeks in the second cohort. Dolutegravir plus Lamivudine switch to DTG plus 3TC as maintenance strategy in patients with viral suppression has been examined in A two small clinical trials and in two observational studies. Clinical Trials The LAMIDOL trial evaluated a regimen of DTG and 3TC as a maintenance strategy in patients with 33 virologic suppression who had no evidence of NRTI, INSTI, or PI resistance. At 24 weeks, 103 of the 104 participants remained virologically suppressed. The ASPIRE study included 90 participants with viral suppression on three-drug ART and no history of virologic failure. These participants were randomized to remain on their current regimen or to switch to DTG plus 3TC. The DTG plus 3TC regimen was noninferior to continuing the three-drug ART regimens (91% vs. 34 89% of participants remained virologically suppressed by Week 48, respectively). Observational Studies A prospective observational study included 94 patients with viral suppression who were switched to DTG 35 plus 3TC and who maintained viral suppression for 24 weeks following the switch. Another study evaluated the safety and efficacy of this regimen in 206 patients who switched due to either drug toxicity or a desire to Week 48, the estimated probability of maintaining viral suppression was 98.2%; At simplify their regimens. 36 at Week 96, the estimated probability was 95.1%. H-26 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

142 Strategies Not Recommended Boosted Protease Inhibitor Monotherapy The strategy of switching patients with virologic suppression without PI resistance from one ART regimen to PI/r monotherapy has been evaluated in several studies. The rationale for this strategy is to avoid NRTI toxicities and decrease costs while taking advantage of the high barrier to resistance of PIs. PI/r monotherapy maintains 37- virologic suppression in most patients, but at lower rates than regimens that include one or two NRTIs. 39 Low-level viremia, generally without the emergence of PI resistance, appears to be more common with monotherapy than with regimens that include one or two NRTIs. In most studies, resuming NRTIs in patients 40-43 who are experiencing low-level viral rebound has led to re-suppression. No clinical trials evaluating the use of coformulated PI/c regimens as monotherapy or comparing different PI/r monotherapy regimens have been conducted. On the basis of the results from these studies, boosted PI monotherapy is not recommended (AI) . Dolutegravir Monotherapy The strategy of switching virologically suppressed patients to DTG monotherapy has been evaluated in 44,45 46 cohort studies and in clinical practice, as well as in a randomized controlled trial. This strategy has been associated with an unacceptable risk of virologic failure and subsequent development of INSTI resistance; therefore, it is not recommended (AI) . Boosted Atazanavir plus Raltegravir In a randomized study, virologically suppressed patients switched to a regimen consisting of ATV/r plus RAL or ATV/r plus TDF/FTC. The ATV/r plus RAL regimen switch was associated with higher rates of virologic 47 failure and treatment discontinuations than switching to ATV/r plus TDF/FTC. A regimen consisting of ATV/r plus RAL cannot currently be recommended (AI) . Maraviroc plus Boosted Protease Inhibitor In a randomized controlled trial, virologically suppressed patients who were on a regimen of two NRTIs plus a boosted PI and who had only CCR5-tropic HIV (as detected by proviral DNA testing) were randomized to continue their present regimen or to switch to MVC plus two NR TIs or to MVC plus a boosted PI. The boosted PI plus MVC regimen switch was associated with higher rates of virologic failure and treatment discontinuations than the other two regimens. Based on these results, a regimen consisting of a boosted PI and 48 MVC cannot be recommended . (AI) Maraviroc plus Raltegravir In a nonrandomized pilot study, virologically suppressed patients were switched from their prescribed regimen 49 to MVC plus RAL. This combination led to virologic relapse in five out of 44 patients. On the basis of these study results, use of a combination of MVC and RAL is not recommended (AII) . Monitoring after Treatment Changes After a treatment switch, patients should be evaluated closely for 3 months (e.g., a clinic visit or phone call 1 to 2 weeks after the change and a viral load test to check for rebound viremia 4 to 8 weeks after the switch) (AIII) . The purpose of this close monitoring is to assess medication tolerance and conduct targeted laboratory testing if the patient had pre-existing laboratory abnormalities or if there are potential concerns with the new regimen. For example, if lipid abnormalities were present and were a reason for the ARV change, or if lipid abnormalities are a concern with the new regimen, fasting cholesterol subsets and triglycerides should be assessed within 3 months after the change in therapy. In the absence of any new complaints, laboratory abnormalities, or evidence of viral rebound at this 3-month visit, clinical and laboratory monitoring of the patient may resume on a Laboratory Testing for Initial Assessment and Monitoring ). regularly scheduled basis (see H-27 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

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144 regimens: week 96 results of STRATEGY-PI. 2017;18(3):118-125. Available at: HIV Clin Trials. https://www.ncbi.nlm. . nih.gov/pubmed/28555519 18. Hodder S, Squires K, Kityo C, et al. Brief report: efficacy and safety of switching to coformulated elvitegravir , cobicistat, emtricitabine, and tenofovir alafenamide (E/C/F/T . AF) in virologically suppressed women. J Acquir Immune Defic Syndr https://www.ncbi.nlm.nih.gov/pubmed/29481486 . 2018;78(2):209-213. Available at: Palella FJ Jr , Fisher M, Tebas P, et al. Simplification to rilpivirine/emtricitabine/tenofovir disoproxil fumarate from 19. ritonavir-boosted protease inhibitor antiretroviral therapy in a randomized trial of HIV-1 RNA-suppressed participants. . 2014;28(3):335-344. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24670520 . AIDS 20. Pozniak A, Markowitz M, Mills A, et al. Switching to coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus continuation of non-nucleoside reverse transcriptase inhibitor with emtricitabine and tenofovir in virologically suppressed adults with HIV (STRATEGY-NNRTI): 48 week results of a randomised, open-label, phase 3b non-inferiority trial. Lancet Infect Dis . 2014;14(7):590-599. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24908550 . 21. Arribas JR, Pialoux G, Gathe J, et al. Simplification to coformulated elvitegravir , cobicistat, emtricitabine, and tenofovir versus continuation of ritonavir-boosted protease inhibitor with emtricitabine and tenofovir in adults with virologically suppressed HIV Lancet (STRATEGY-PI): 48 week results of a randomised, open-label, phase 3b, non-inferiority trial. . 2014;14(7):581-589. Available at: . Infect Dis http://www.ncbi.nlm.nih.gov/pubmed/24908551 Pett SL, HIV Amin J, Horban A, et al. Week 96 results of the randomized, multicentre Maraviroc Switch (MARCH) study. 22. Med . 2018;19(1):65-71. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28703491 . 23. itiello P, Brudney D, MacCartney M, et al. Responses to switching to maraviroc-based antiretroviral therapy in treated V patients with suppressed plasma HIV-1-RNA load. Intervirology . 2012;55(2):172-178. Available at: http://www.ncbi.nlm. nih.gov/pubmed/22286889 . 24. Bonjoch A, Pou C, Perez-Alvarez N, et al. Switching the third drug of antiretroviral therapy to maraviroc in aviraemic Available at: subjects: a pilot, prospective, randomized clinical trial. J Antimicrob Chemother . 2013;68(6):1382-1387. . http://www.ncbi.nlm.nih.gov/pubmed/23354282 , safety, and tolerability of dolutegravir-rilpivirine for the maintenance of 25. Llibre JM, Hung CC, Brinson C, et al. Efficacy virological suppression in adults with HIV-1: phase 3, randomised, non-inferiority SWORD-1 and SWORD-2 studies. . 2018;391(10123):839-849. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29310899 Lancet . 26. Perez-Molina JA, Rubio R, Rivero A, et al. Dual treatment with atazanavir-ritonavir plus lamivudine versus triple treatment with atazanavir-ritonavir plus two nucleos(t)ides in virologically stable patients with HIV-1 (SALT): 48 week . 2015;15(7):775-784. Available at: http:// results from a randomised, open-label, non-inferiority trial. Lancet Infect Dis . www.ncbi.nlm.nih.gov/pubmed/26062881 27. Fabbiani M, Gagliardini R, Ciccarelli N, et al. Atazanavir/ritonavir with lamivudine as maintenance therapy in virologically suppressed HIV J Antimicrob Chemother . 2018. -infected patients: 96 week outcomes of a randomized trial. Available at: . https://www.ncbi.nlm.nih.gov/pubmed/29668978 28. Pulido F, Ribera E, Lagarde M, et al. Dual therapy with darunavir and ritonavir plus lamivudine versus triple therapy with darunavir and ritonavir plus tenofovir disoproxil fumarate and emtricitabine or abacavir and lamivudine for maintenance of -1 viral suppression: randomised, open label, non-inferiority DUAL-GESIDA 8014-RIS-EST45 trial. HIV Clin Infect Dis. 2017. Available at: http://www.ncbi.nlm.nih.gov/pubmed/29020293 . Arribas JR, Girard PM, Landman R, et al. Dual treatment with lopinavir 29. -ritonavir plus lamivudine versus triple treatment with lopinavir-ritonavir plus lamivudine or emtricitabine and a second nucleos(t)ide reverse transcriptase inhibitor Lancet Infect Dis . -1 viral suppression (OLE): a randomised, open-label, non-inferiority trial. for maintenance of HIV http://www.ncbi.nlm.nih.gov/pubmed/26062880 2015;15(7):785-792. Available at: . 30. Huhn GD, Tebas P, Gallant J, et al. A randomized, open-label trial to evaluate switching to elvitegravir/cobicistat/ J Acquir Immune Defic emtricitabine/tenofovir alafenamide plus darunavir in treatment-experienced HIV-1-infected adults. Syndr . 2017;74(2):193-200. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27753684 . AF, Cossu MV, Orofino G, et al. A dual regimen of ritonavir/darunavir plus dolutegravir for rescue or simplification Capetti 31. of rescue therapy: 48 weeks’ observational data. BMC Infect Dis . 2017;17(1):658. Available at: https://www.ncbi.nlm.nih. gov/pubmed/28964268 . 32. Y. Dolutegravir with boosted darunavir treatment Wheeler J, Chan S, Harrigan PR, Becker M, Kasper K, Keynan simplification for the transmitted HIV thymidine analog resistance in Manitoba, Canada. Int J STD AIDS . 2018;29(5):520- 522. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29513131 . 33. Joly V, Burdet C, Landman R, et al. Promising results of dolutegravir + lamivudine maintenance in ANRS 167 LAMIDOL H-29 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

145 Trial. Presented at: Conference on Retroviruses and Opportunistic Infections. 2017. Seattle, WA. Available at: http://www. . croiconference.org/sessions/promising-results-dolutegravir-lamivudine-maintenance-anrs-167-lamidol-trial T aiwo BO, Marconi VC, Berzins B, et al. Dolutegravir Plus Lamivudine Maintains Human Immunodeficiency Virus-1 34. 2018;66(11):1794-1797. Available at: Clin Infect Dis. Suppression Through Week 48 in a Pilot Randomized Trial. https:// www.ncbi.nlm.nih.gov/pubmed/29293895 . Maggiolo F , Gulminetti R, Pagnucco L, et al. Lamivudine/dolutegravir dual therapy in HIV -infected, virologically 35. BMC Infect Dis suppressed patients. https://www.ncbi.nlm.nih.gov/pubmed/28302065 . . 2017;17(1):215. Available at: 36. Bor ghetti A, Baldin G, Lombardi F, et al. Efficacy and tolerability of lamivudine plus dolutegravir as a switch strategy in a HIV Med . 2018. Available at: multicentre cohort of patients with suppressed HIV-1 replication. https://www.ncbi.nlm.nih. gov/pubmed/29573320 . Bierman 37. WF, van Agtmael MA, Nijhuis M, Danner SA, Boucher CA. HIV monotherapy with ritonavir-boosted protease inhibitors: a systematic review. AIDS . 2009;23(3):279-291. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19114854 . A, van Delft Y, Moecklinghoff C. The MONET trial: week 144 analysis of the Arribas JR, Clumeck N, Nelson M, Hill 38. efficacy of darunavir/ritonavir (DRV/r) monotherapy versus DRV/r plus two nucleoside reverse transcriptase inhibitors, for patients with viral load < 50 HIV-1 RNA copies/mL at baseline. . 2012;13(7):398-405. Available at: http://www. HIV Med . ncbi.nlm.nih.gov/pubmed/22413874 Ciaffi L, Koulla-Shiro S, Sawadogo AB, et al. Boosted protease inhibitor monotherapy versus boosted protease inhibitor 39. plus lamivudine dual therapy as second-line maintenance treatment for HIV -1-infected patients in sub-Saharan Africa (ANRS12 286/MOBIDIP): a multicentre, randomised, parallel, open-label, superiority trial. Lancet HIV . 2017. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28566227 . 40. Guiguet M, Ghosn J, Duvivier C, et al. Boosted protease inhibitor monotherapy as a maintenance strategy: an observational study . AIDS . 2012;26(18):2345-2350. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22695301 . 41. Karlstrom O, Josephson F , Sonnerborg A. Early virologic rebound in a pilot trial of ritonavir-boosted atazanavir as . 2007;44(4):417-422. Available at: maintenance monotherapy. J Acquir Immune Defic Syndr http://www.ncbi.nlm.nih.gov/ pubmed/17159658 . Katlama C, Valantin MA, Algarte-Genin M, et al. Efficacy of darunavir/ritonavir maintenance monotherapy in patients with 42. AIDS HIV-1 viral suppression: a randomized open-label, noninferiority trial, MONOI-ANRS 136. . 2010;24(15):2365-2374. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20802297 . 43. V ernazza P, Daneel S, Schiffer V, et al. The role of compartment penetration in PI-monotherapy: the Atazanavir-Ritonavir Monomaintenance (ATARITMO) Trial. AIDS . 2007;21(10):1309-1315. Available at: http://www.ncbi.nlm.nih.gov/ . pubmed/17545707 44. Blanco JL, Rojas J, Paredes R, et al. Dolutegravir-based maintenance monotherapy versus dual therapy with lamivudine: J Antimicrob Chemother Available at: https:// a planned 24 week analysis of the DOLAM randomized clinical trial. . 2018. www.ncbi.nlm.nih.gov/pubmed/29608685 . 45. Oldenbuettel C, Wolf E, Ritter A, et al. Dolutegravir monotherapy as treatment de-escalation in HIV-infected adults with virological control: DoluMono cohort results. Antivir Ther . 2017;22(2):169-172. Available at: https://www.ncbi.nlm.nih. gov/pubmed/27588613 . 46. W ijting I, Rokx C, Boucher C, et al. Dolutegravir as maintenance monotherapy for HIV (DOMONO): a phase 2, randomised Lancet . HIV . 2017;4(12):e547-e554. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29107562 non-inferiority trial. A, Gatell JM, et al. Brief report: switch to ritonavir-boosted atazanavir plus raltegravir in virologically van Lunzen J, Pozniak 47. suppressed patients with HIV-1 infection: a randomized pilot study. J Acquir Immune Defic Syndr . 2016;71(5):538-543. Available at: http://www.ncbi.nlm.nih.gov/pubmed/26605505 . 48. Pett SL, Amin J, Horban A, et al. Maraviroc, as a switch option, in HIV-1-infected individuals with stable, well-controlled HIV replication and R5-tropic virus on their first nucleoside/nucleotide reverse transcriptase inhibitor plus ritonavir-boosted protease inhibitor regimen: Week 48 results of the randomized, multicenter MARCH Study. Clin Infect Dis. 2016;63(1):122- 132. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27048747 . Assoumou L, Valantin MA, et al. Maraviroc plus raltegravir failed to maintain virological suppression in Katlama C, 49. HIV-infected patients with lipohypertrophy: results from the ROCnRAL ANRS 157 study. J Antimicrob Chemother . . https://www.ncbi.nlm.nih.gov/pubmed/24535278 2014;69(6):1648-1652. Available at: H-30 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

146 Discontinuation or Interruption of Antiretroviral Therapy (Last updated April 8, 2015; last reviewed April 8, 2015) Discontinuation of antiretroviral therapy (ART) may result in viral rebound, immune decompensation, 1-5 and clinical progression. Thus, planned interruptions of ART are not generally recommended. However, unplanned interruption of ART may occur under certain circumstances as discussed below. Short-Term Therapy Interruptions Reasons for short-term interruption (days to weeks) of ART vary and may include drug toxicity; intercurrent illnesses that preclude oral intake, such as gastroenteritis or pancreatitis; surgical procedures; or interrupted access to drugs. Stopping ART for a short time (i.e., less than 1 to 2 days) because of a medical/surgical procedure can usually be done by holding all drugs in the regimen. Recommendations for some other scenarios are listed below: Unanticipated Short-Term Therapy Interruption When a Patient Experiences a Severe or Life-Threatening Toxicity or Unexpected Inability to Take Oral Medications: • All components of the drug regimen should be stopped simultaneously , regardless of drug half-life. Planned Short-Term Therapy Interruption (Up to 2 Weeks) When All Regimen Components Have Similar Half-Lives and Do Not Require Food for Proper Absorption: All drugs may be given with a sip of water, if allowed; otherwise, all drugs should be stopped • simultaneously . All discontinued regimen components should be restarted simultaneously. When All Regimen Components Have Similar Half-Lives and Require Food for Adequate Absorption, and the Patient Cannot Take Anything by Mouth for a Short Time: • T emporary discontinuation of all drug components is indicated. The regimen should be restarted as soon as the patient can resume oral intake. When the Antiretroviral Regimen Contains Drugs with Different Half-Lives: • Stopping all drugs simultaneously may result in functional monotherapy with the drug with the longest half-life (typically a non-nucleoside reverse transcriptase inhibitor [NNR TI]), which may increase the risk of selection of NNR TI-resistant mutations. Some experts recommend stopping the NNRTI first and the other antiretroviral drugs 2 to 4 weeks later. Alternatively, the NNRTI may be replaced with a ritonavir- or cobicistat-boosted protease inhibitor (PI/r or PI/c) for 4 weeks. The optimal time sequence for staggered discontinuation of regimen components, or replacement of the NNRTI with a PI/r or PI/c, has not been determined. Planned Long-Term Therapy Interruptions Planned long-term therapy interruptions are not recommended outside of controlled clinical trials (AI) . Several research studies are evaluating approaches to a functional (virological control in the absence of therapy) or sterilizing (virus eradication) cure of HIV infection. Currently, the only way to reliably test the effectiveness of these strategies may be to interrupt ART and closely monitor viral rebound over time in the setting of a clinical trial. If therapy must be discontinued, patients should be aware of and understand the risks of viral rebound, acute retroviral syndrome, increased risk of HIV transmission, decline of CD4 count, HIV disease progression, development of minor HIV-associated manifestations such as oral thrush or serious non-AIDS complications (e.g., renal, cardiac, hepatic, or neurologic complications), development of drug resistance, and the need for H-33 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

147 chemoprophylaxis against opportunistic infections as a result of CD4 decline. Patients should be counseled about the need for close clinical and laboratory monitoring during therapy interruptions. References 1. Holkmann Olsen C, Mocroft A, Kirk O, et al. Interruption of combination antiretroviral therapy and risk of clinical HIV Med disease progression to http://www.ncbi.nlm.nih.gov/entrez/ AIDS or death. . 2007;8(2):96-104. Available at . query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17352766 Kousignian I, 2. Abgrall S, Grabar S, et al. Maintaining antiretroviral therapy reduces the risk of AIDS-defining events in patients with uncontrolled viral replication and profound immunodeficiency . Clin Infect Dis . 2008;46(2):296-304. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_ uids=18171266 . - Danel C, Moh R, Minga A, et al. CD4-guided structured antiretroviral treatment interruption strategy in HIV 3. infected adults in west Africa (Trivacan ANRS 1269 trial): a randomised trial. . 2006;367(9527):1981-1989. Lancet Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_ . uids=16782488&itool=iconabstr&query_hl=147&itool=pubmed_docsum DAR 4. T Trial Team DTT. Fixed duration interruptions are inferior to continuous treatment in African adults starting therapy with CD4 cell counts < 200 cells/microl. AIDS . 2008;22(2):237-247. Available at http://www.ncbi.nlm.nih.gov/ entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18097226 . 5. El-Sadr WM, Lundgren JD, Neaton JD, et al. CD4+ count-guided interruption of antiretroviral treatment. http://www.ncbi.nlm.nih.gov/entrez/query. Available at N Engl J Med . 2006;355(22):2283-2296. . fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17135583 H-34 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

148 Considerations for Antiretroviral Use in Special Patient Populations (Last updated October 25, 2018; last reviewed October 25, 2018) Acute and Recent (Early) HIV Infection Panel’s Recommendations a T) is recommended for all individuals with HIV-1 infection , including those with early (AI) HIV-1 infection. Antiretroviral therapy (AR • • . Testing for plasma HIV-1 RNA levels, (AIII) ART is to suppress plasma HIV-1 RNA to undetectable levels Once initiated, the goal of CD4 T lymphocyte cell counts, and toxicity monitoring should be performed as recommended for patients with chronic HIV-1 infection . (AII) Genotypic drug resistance testing should be performed before initiation of • ART to guide the selection of the regimen (AII) . • AR T can be initiated before drug resistance test results are available. Either boosted darunavir (DRV) or dolutegravir (DTG) with emtricitabine (FTC) plus either tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF) are recommended regimens in this setting . The rationales and precautions for these regimens are discussed below. (AIII) DRV-based regimen is a good option for people with early HIV-1 infection, because resistance to pharmacokinetically enhanced A • protease inhibitors (PIs) emerges slowly and clinically significant transmitted resistance to PIs is uncommon. A • DTG-based regimen is also a reasonable option; however, data regarding transmission of integrase strand transfer inhibitor (INSTI)- resistant HIV and the efficacy of DTG regimens in early HIV infection are more limited . (AIII) Preliminary data from Botswana suggested that infants born to women who were receiving dolutegravir (DTG) at the time of • should not be prescribed for conception have an increased risk of neural tube defects. Until more information are available, DTG individuals: • Who are pregnant and within 12 weeks post-conception; • Who are of childbearing potential, who are sexually active, and who are not using ef fective contraception; or Who are contemplating pregnancy. • . In patients without (AII) When results of drug resistance testing are available, the treatment regimen can be modified if warranted • transmitted drug-resistant virus, therapy should be initiated with one of the combination regimens that is recommended for patients with chronic HIV -1 infection (see What to Start ) (AIII) . Patients starting ART should be willing and able to commit to life-long treatment and should understand the importance of adherence • (AIII) . Patients may choose to postpone ART, and providers, on a case-by-case basis, may recommend that patients defer therapy because of clinical or psychosocial factors. Rating of Recommendations: A = Strong; B = Moderate; C = Optional I = Data from randomized controlled trials; II = Data from well-designed nonrandomized trials or observational cohort Rating of Evidence: studies with long-term clinical outcomes; III = Expert opinion a Early infection represents either acute or recent infection. Definitions: Acute HIV-1 infection, the phase of HIV-1 disease that occurs immediately after transmission, is typically characterized by an initial burst of viremia; although anti-HIV-1 antibodies are undetectable during this phase, HIV-1 RNA or p24 antigen are present. Recent infection is generally considered the phase up to 6 months after infection, during which detectable anti-HIV-1 antibodies develop. Throughout this section, the term “early HIV-1 infection” is used to refer to either acute or recent HIV-1 infection. Although some patients with acute HIV-1 infection experience fever, lymphadenopathy, pharyngitis, skin 1-6 rash, myalgia, arthralgia, and other symptoms, a recent prospective study shows that most patients have 7 nonspecific and relatively mild signs and symptoms. Primary care clinicians may fail to recognize acute HIV-1 infection because its manifestations are often similar to those of many other viral infections, such as influenza and infectious mononucleosis. Acute infection can also be asymptomatic. Table 12 provides practitioners with guidance to recognize, diagnose, and manage acute HIV-1 infection. I-1 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

149 Diagnosing Acute HIV-1 Infection Health care providers should consider a diagnosis of acute HIV-1 infection in patients who have a suggestive 8 clinical syndrome—especially those who report recent high-risk behavior (see Table 12). Patients may not always disclose high-risk behaviors or perceive that such behaviors put them at risk for HIV-1 acquisition. Thus, even in the absence of reported high-risk behaviors, practitioners should have a low threshold for considering a diagnosis of acute HIV-1 infection, especially in high-prevalence areas (areas where ≥1% of people have HIV infection). Current statistics on the prevalence of HIV in different geographical areas in the AIDSVu and the Centers for Disease Control and Prevention United States can be found at these websites: (CDC)’s AtlasPlus . Acute HIV-1 infection is usually defined as detectable HIV-1 RNA or p24 antigen in serum or plasma in the 8,9 setting of a negative or indeterminate HIV-1 antibody test result. Combination immunoassays that detect HIV-1 and HIV-2 antibodies and HIV-1 p24 antigen (often referred to as fourth-generation assays) are now approved by the Food and Drug Administration. The most recent CDC testing algorithm recommends these assays as the preferred assays to use for HIV screening, including in cases of possible acute HIV-1 infection. Specimens that are reactive on an initial antigen/antibody (Ag/Ab) assay should be tested with an immunoassay 10 that differentiates HIV-1 from HIV-2 antibodies. Specimens that are reactive on the initial assay and have either negative or indeterminate antibody differentiation test results should be tested for quantitative or qualitative HIV-1 RNA; an undetectable HIV-1 RNA test result indicates that the original Ag/Ab test result was 10 a false positive. Detection of HIV-1 RNA in this setting indicates that acute HIV-1 infection is highly likely. HIV-1 infection should be confirmed later by subsequent testing to document HIV antibody seroconversion. Some health care facilities may still be following HIV testing algorithms that recommend initial testing with an assay that only tests for anti-HIV antibodies. In such settings, when acute HIV-1 infection is suspected in a patient with a negative or indeterminate HIV antibody test result, a quantitative or qualitative HIV-1 RNA test should be performed. A negative or indeterminate HIV antibody test result and a positive HIV-1 RNA test result indicate that acute HIV-1 infection is highly likely. Providers should be aware that a low-positive quantitative HIV-1 RNA level (e.g., <10,000 copies/mL) may represent a false-positive result, because 5-7 HIV-1 RNA levels in acute infection are generally (but not always) very high (e.g., >100,000 copies/mL). Therefore, when a low-positive quantitative HIV-1 RNA test result is obtained, the HIV-1 RNA test should be repeated using a different specimen from the same patient, because repeated false-positive HIV-1 RNA tests 6 are unlikely. The diagnosis of HIV-1 infection should be confirmed by subsequent documentation of HIV antibody seroconversion (see Table 12). Treating Early HIV-1 Infection Clinical trial data regarding the treatment of early HIV-1 infection are limited. However, a number of studies suggest that individuals who are treated during early infection may experience immunologic and 11-19 virologic benefits. In addition, because early HIV-1 infection is often associated with high viral loads and 20 increased infectiousness, and the use of antiretroviral therapy (ART) by individuals with HIV reduces the 21 risk of transmission to sexual partners without HIV, treatment during early HIV-1 infection is expected to substantially reduce the risk of HIV-1 transmission. The START and TEMPRANO trials evaluated the timing of ART initiation (see Initiation of Antiretroviral ). Although neither trial collected specific information on patients with early infection, the strength of Therapy the two studies’ overall results and the evidence from the other studies described above strongly suggest that, whenever possible, patients should begin ART upon diagnosis of early infection. Considerations When Treating Early HIV-1 Infection As with chronic infection, patients with early HIV-1 infection must be willing and able to commit to life- long ART. On a case-by-case basis, providers may recommend that patients defer therapy for clinical or I-2 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

150 psychosocial reasons. If ART is deferred, patients should be maintained in care and every effort should be made to initiate therapy as soon as they are ready. Patients should also be reminded regularly of the importance of using condoms consistently and correctly during sex. The consistent use of condoms will reduce a patient’s risk of transmitting HIV infection or being re-infected and help them to avoid exposure to condom effectiveness ). sexually transmitted infections (see the CDC’s fact sheets on Treating Early HIV-1 Infection During Pregnancy All patients of childbearing potential who receive a diagnosis of early HIV-1 infection should have a pregnancy test. Because early HIV-1 infection, especially in the setting of high-level viremia, is associated with a high risk of perinatal transmission, all pregnant women with HIV-1 infection should start combination 22 ART as soon as possible to prevent perinatal transmission of HIV-1. Treatment Regimens for Early HIV-1 Infection Prior to the widespread use of integrase strand transfer inhibitors (INSTIs), data from the United States and Europe demonstrated that transmitted virus may be resistant to at least one antiretroviral (ARV) drug in up 23,24 to 16% of patients. In one study, 21% of isolates from patients with acute HIV-1 infection demonstrated 25 resistance to at least one drug. Therefore, before initiating ART in a person with early HIV-1 infection, a specimen for genotypic ARV drug resistance testing should be obtained and the results of the test should be used to help guide selection of an ARV regimen (AII) . However, treatment initiation itself should not be delayed pending resistance testing results. Once the resistance test results are available, the treatment regimen can be modified, if warranted (AII) . As in chronic infection, the goal of ART during early HIV-1 infection is to suppress plasma HIV-1 RNA to . ART should be initiated with one of the combination regimens recommended for undetectable levels (AIII) patients with chronic infection (AIII) ). If available, the results of ARV drug resistance What to Start (see testing or the ARV resistance pattern of the source person’s virus should be used to guide selection of the ARV regimen. If ART will be initiated before the results of drug resistance testing are available, a pharmacologically boosted protease inhibitor (PI)-based regimen is an appropriate choice (e.g., boosted darunavir [DRV] plus either tenofovir disoproxil fumarate [TDF] or tenofovir alafenamide [TAF] with emtricitabine [FTC]), because resistance to PIs emerges slowly and clinically significant transmitted resistance to PIs is uncommon (AIII) . Dolutegravir (DTG) plus TAF/FTC or TDF/FTC can also be used in certain patients (AIII) . Although data regarding the efficacy of a DTG-based regimen in persons with acute/early HIV infection are limited, there are several reasons why DTG is a good treatment option—transmission of DTG-resistant HIV is rare, and DTG’s barrier to resistance exceeds that of raltegravir (RAL) and elvitegravir (EVG). On the basis of data from in vitro studies and clinical trials in ART-naive patients, it is anticipated that, like DTG, bictegravir (BIC) has a high barrier to resistance. However, clinical data and experience are relatively limited at this time. Preliminary data from Botswana suggested that infants born to women who were receiving dolutegravir 26,27 (DTG) at the time of conception have an increased risk of neural tube defects. DTG is therefore not recommended for persons with acute/early HIV who are pregnant and within 12 weeks post-conception (AII) . DTG is also not recommended for individuals of childbearing potential who are sexually active and . These patients should receive cannot use effective contraception or who are contemplating pregnancy (AII) a boosted PI-based regimen. It is unknown whether this possible risk of neural tube defects is shared by other INSTIs (i.e., whether this is a class effect). BIC is structurally similar to DTG, and there are no safety data on the use of BIC around the time of conception. For individuals who are of childbearing potential and who are not pregnant, an approach similar to that outlined for DTG should be taken before considering BIC- containing ART. I-3 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

151 Clinicians should refer to the for information on the safety and efficacy of ARV use in Perinatal Guidelines pregnancy. Abacavir/lamivudine is not recommended as part of an empiric treatment of acute infection unless the patient is known to be HLA-B* 5701 negative—information that is seldom available when patients with acute infection present for care. Therefore, TDF/FTC or TAF/FTC is generally recommended as a backbone in this setting. 28-30 Given the increasing use of TDF/FTC as pre-exposure prophylaxis (PrEP) in HIV-negative individuals, early infection may be diagnosed in some patients while they are taking TDF/FTC for PrEP. In this setting, drug resistance testing should be performed; however, as described above, use of a boosted PI (e.g., boosted DRV) or DTG plus TDF/FTC or TAF/FTC remain reasonable treatment options pending resistance testing results, while keeping in mind the caveats discussed above concerning DTG use among patients who are pregnant or of childbearing potential (see also What to Start ). Patient Follow-Up Testing for plasma HIV-1 RNA levels, CD4 T lymphocyte cell counts, and toxicity monitoring should be performed as described in (e.g., HIV-1 Laboratory Testing for Initial Assessment and Monitoring RNA should be assessed at initiation of ART, after 2 to 8 weeks, and then every 4 to 8 weeks until viral suppression, and thereafter, every 3 to 4 months) (AII) . Duration of Therapy for Early HIV-1 Infection Once ART is initiated in patients with early HIV infection, therapy should be continued indefinitely, following the guidelines for patients with chronic infection. A large randomized controlled trial of patients with chronic HIV-1 infection found that treatment interruption was harmful, leading to increased risk 31 of AIDS and non-AIDS events in these patients compared to those who continued ART, and that this 32 strategy was associated with increased markers of inflammation, immune activation, and coagulation. For these reasons, and the potential benefit of ART in reducing the risk of HIV-1 transmission, the Panel on Antiretroviral Guidelines for Adults and Adolescents recommends indefinite continuation of ART in patients . treated for early HIV-1 infection (AIII) I-4 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

152 Table 12. Identifying, Diagnosing, and Treating Acute and Recent HIV-1 Infection Suspicion of Acute HIV-1 Infection: • Health care providers should consider the possibility of acute HIV-1 infection in individuals with signs, symptoms, or the laboratory a -1. findings described below and recent (within 2 to 6 weeks) high risk of exposure to HIV -1 infection may include but are not limited to one or more of the following: Signs, symptoms, or laboratory findings of acute HIV • fever, lymphadenopathy, skin rash, myalgia, arthralgia, headache, diarrhea, oral ulcers, leucopenia, thrombocytopenia, and transaminase elevation. High-risk exposures include sexual contact with a person who ha s HIV-1 infection or a person at risk of HIV-1 infection, sharing • of injection drug use paraphernalia, or any exposure in which an individual’ s mucous membranes or breaks in the skin come in contact with bodily fluid that potentially carries HIV-1. Differential Diagnosis: The differential diagnosis of HIV-1 infection may include but is not limited to viral illnesses such as EBV and • non-EBV (e.g., cytomegalovirus) infectious mononucleosis syndromes, influenza, viral hepatitis, streptococcal infection, or syphilis. Evaluation/Diagnosis of Acute HIV-1 Infection: Acute HIV -1 infection is defined as detectable HIV-1 RNA or p24 antigen (the antigen used in currently available HIV Ag/Ab combination • assays) in the setting of a negative or indeterminate HIV-1 antibody test result. A reactive HIV antibody test result or Ag/Ab combination test result must be followed by supplemental confirmatory testing. • A • negative or indeterminate HIV-1 antibody test result in a person with a reactive Ag/Ab test result or in whom acute HIV-1 infection is suspected requires plasma HIV-1 RNA testing to diagnose acute HIV-1 infection. A positive result on a quantitative or qualitative plasma HIV-1 RNA test in the setting of a negative or indeterminate antibody test result • indicates that acute HIV-1 infection is highly likely. In this case, the diagnosis of HIV-1 infection should be later confirmed by subsequent documentation of HIV-1 antibody seroconversion. Antiretroviral Therapy After Diagnosis of Early HIV-1 Infection: AR T is recommended for all individuals with HIV-1 • and should be offered to all patients with early HIV-1 infection. (AI) • A pregnancy test should be performed for all individuals who receive a diagnosis of early HIV infection and who are of childbearing (AIII) . potential Pregnant patients with early HIV • -1 infection should begin ART as soon as possible for their own health and to prevent perinatal transmission of HIV-1 (AI) . ART to guide the selection of the regimen A blood sample for genotypic drug resistance testing should be obtained before initiation of • (AII) , but ART should be initiated as soon as possible, often prior to availability of resistance test results. If resistance is subsequently identified, treatment should be modified appropriately. • If no resistance data are available, then a pharmacologically boosted PI-based regimen is recommended, because resistance to PIs emerges slowly and clinically significant transmitted resistance to PIs is uncommon. Boosted DRV (DRV/r or DRV/c) plus FTC and either TDF or TAF is a recommended regimen in this setting (AIII) . For similar reasons, DTG plus FTC and either TDF or TAF are reasonable options, although the data regarding transmission of INSTI-resistant HIV and the efficacy of this regimen in early HIV infection are (AIII) . limited Preliminary data from Botswana suggested that infants born to women who were receiving DTG at the time of conception have an • should not be prescribed increased risk of neural tube defects. Until more information is available, DTG for individuals: Who are pregnant and within 12 weeks post-conception (AII) ; • or ; (AII) fective contraception ho are not using ef Who are of childbearing potential, who are sexually active, and w • Who are contemplating pregnancy (AII) . • In patients without transmitted drug-resistant virus, • ART should be initiated with one of the combination regimens recommended for What to Start ) (AIII) . patients with chronic HIV-1 infection (see ART should be sustained plasma virologic suppression, and ART should be continued indefinitely (AIII) . Once initiated, the goal of • a In some settings, behaviors that increase the risk of HIV-1 infection may not be recognized or perceived as risky by the health care provider or the patient, or both. Thus, even in the absence of reported high-risk behaviors, symptoms and signs consistent with acute retroviral syndrome should motivate practitioners to consider a diagnosis of acute HIV -1 infection. Key to Acronyms: Ag/Ab = antigen/antibody; ART = antiretroviral therapy; DRV = darunavir; DRV/c = darunavir/cobicistat; DRV/r = darunavir/ritonavir; DTG = dolutegravir; EBV = Epstein-Barr virus; FTC = emtricitabine; INSTI = integrase strand transfer inhibitor; PI = protease inhibitor; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate I-5 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

153 References 1. indall B, Cooper DA. Primary HIV infection: host responses and intervention strategies. AIDS . 1991;5(1):1-14. Available T . at: https://www.ncbi.nlm.nih.gov/pubmed/1812848 , Stein DS, Schnittman SM. Primary human immunodeficiency virus type 1 infection: review of pathogenesis and 2. Niu MT early treatment intervention in humans and animal retrovirus infections. vailable at: J Infect Dis . 1993;168(6):1490-1501. A https://www.ncbi.nlm.nih.gov/pubmed/8245534 . Kinloch-de Loes S, de Saussure P , Saurat JH, Stalder H, Hirschel B, Perrin LH. Symptomatic primary infection due to 3. . 1993;17(1):59-65. Available at: https://www. Clin Infect Dis human immunodeficiency virus type 1: review of 31 cases. . ncbi.nlm.nih.gov/pubmed/8353247 Schacker T, Collier AC, Hughes J, Shea T, Corey L. Clinical and epidemiologic features of primary HIV 4. infection. http://www.ncbi.nlm.nih.gov/entrez/query. Ann Intern Med . 1996;125(4):257-264. Available at: . fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8678387 Daar ES, Little S, Pitt J, et al. Diagnosis of primary HIV Infection 5. -1 infection. Los Angeles County Primary HIV Ann Intern Med . 2001;134(1):25-29. Available at: https://www.ncbi.nlm.nih.gov/pubmed/11187417 . Recruitment Network. 6. , Rawal B, et al. Use of laboratory tests and clinical symptoms for identification of primary HIV Hecht FM, Busch MP . 2002;16(8):1119-1129. Available at: . AIDS https://www.ncbi.nlm.nih.gov/pubmed/12004270 infection. Robb ML, Eller LA, Kibuuka H, et al. Prospective study of acute HIV-1 infection in adults in east Africa and Thailand. 7. N . 2016;374(22):2120-2130. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27192360 . Engl J Med Branson BM, Handsfield HH, Lampe MA, et al. Revised recommendati ons for HIV testing of adults, adolescents, and 8. MMWR Recomm Rep . 2006;55(RR-14):1-17. Available at: https://www.ncbi.nlm. pregnant women in health-care settings. . nih.gov/pubmed/16988643 9. Pilcher CD, Christopoulos KA, Golden M. Public health rationale for rapid nucleic acid or p24 antigen tests for HIV. J Infect . 2010;201 Suppl 1:S7-15. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20225950 . Dis Centers for Disease Control and Prevention, Association of Public Health Laboratories. Laboratory testing for the diagnosis 10. https://stacks.cdc.gov/view/cdc/23447 . Accessed October of HIV infection: Updated recommendations. 2014. Available at: 4, 2018. Hogan CM, Degruttola fect of immediate versus deferred antiretroviral 11. V, Sun X, et al. The setpoint study (ACTG A5217): ef J Infect Dis http:// -1-infected individuals. . 2012;205(1):87-96. Available at: therapy on virologic set point in recently HIV www.ncbi.nlm.nih.gov/pubmed/22180621 . Grijsen ML, Steingrover R, reatment during primary 12. Wit FW, et al. No treatment versus 24 or 60 weeks of antiretroviral t http://www.ncbi.nlm.nih. HIV infection: the randomized Primo-SHM trial. PLoS Med . 2012;9(3):e1001196. Available at: gov/pubmed/22479156 . 13. Hamlyn E, Ewings FM, Porter K, et al. Plasma HIV viral rebound following protocol-indicated cessation of ART PLoS One http://www.ncbi.nlm.nih. commenced in primary and chronic HIV infection. . 2012;7(8):e43754. Available at: gov/pubmed/22952756 . Strain MC, Little SJ, Daar ES, et al. Ef 14. nd clearance of cellular fect of treatment, during primary infection, on establishment a reservoirs of HIV -1. J Infect Dis . 2005;191(9):1410-1418. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15809898 . 15. ARTAC Trial Investigators, Fidler S, Porter K, et al. Short-course antiretroviral therapy in primary HIV infection. SP N Engl . 2013;368(3):207-217. Available at: . J Med http://www.ncbi.nlm.nih.gov/pubmed/23323897 Rosenber g ES, Altfeld M, Poon SH, et al. Immune control of HIV-1 after early treatment of acute infection. Nature . 16. vailable at: http://www.ncbi.nlm.nih.gov/pubmed/11029005 . 2000;407(6803):523-526. A 17. Schuetz A, Deleage C, Sereti I, et al. Initiation of ART during early acute HIV infection preserves mucosal Th17 function and reverses HIV -related immune activation. PLoS Pathog . 2014;10(12):e1004543. Available at: http://www.ncbi.nlm.nih. . gov/pubmed/25503054 18. Mehandru S, Poles MA, Tenner-Racz K, et al. Primary HIV-1 infection is associated with preferential depletion of CD4+ T https://www. J Exp Med lymphocytes from effector sites in the gastrointestinal tract. . 2004;200(6):761-770. Available at: ncbi.nlm.nih.gov/pubmed/15365095 . 19. T Guadalupe M, Reay E, Sankaran S, et al. Severe CD4+ -cell depletion in gut lymphoid tissue during primary human restoration following highly active antiretroviral therapy. immunodeficiency virus type 1 infection and substantial delay in J irol . 2003;77(21):11708-11717. Available at: V https://www.ncbi.nlm.nih.gov/pubmed/14557656 . I-6 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

154 20. awer MJ, Gray RH, Sewankambo NK, et al. Rates of HIV-1 transmission per coital act, by stage of HIV -1 infection, in W J Infect Dis . 2005;191(9):1403-1409. Available at: . Rakai, Uganda. http://www.ncbi.nlm.nih.gov/pubmed/15809897 Cohen MS, Chen N Engl J Med . 21. YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. https://www.ncbi.nlm.nih.gov/pubmed/21767103 . 201 1;365(6):493-505. Available at: Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal T ransmission. Recommendations for 22. the use of antiretroviral drugs in pregnant women with HIV infection and interventions to reduce perinatal HIV transmission Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf . in the United States. 2018. 23. Trend in transmitted HIV-1 ARV drug resistance-associated mutations: 10 HIV Kim D, Ziebell R, Saduvala N, et al. surveillance areas, US, 2007–2010. Presented at: Conference on Retroviruses and Opportunistic Infections. 2013. Atlanta. 24. Hofstra LM, Sauvageot N, Albert J, et al. Transmission of HIV drug resistance and the predicted ef fect on current first-line Clin Infect Dis . 2015;62(5):655-663. Available at: http://www.ncbi.nlm.nih.gov/pubmed/26620652 . regimens in Europe. Y fers between acutely and anik EL, Napravnik S, Hurt CB, et al. Prevalence of transmitted antiretroviral drug resistance dif 25. chronically HIV http://www.ncbi.nlm. -infected patients. J Acquir Immune Defic Syndr . 2012;61(2):258-262. Available at: nih.gov/pubmed/22692092 . 26. Zash R, Makhema J, Shapiro RL. Neural-tube defects with doluteg ravir treatment from the time of conception. N Engl J Med . 2018;379(10):979-981. Available at: . https://www.ncbi.nlm.nih.gov/pubmed/30037297 e defects following antiretroviral exposure from conception. Zash R, Holmes L, Makhema J, et al. Surveillance for neural tub 27. Presented at: 22nd International AIDS Conference. 2018. Amsterdam. Anderson PL, et al. Preexposure chemoprophylaxis for HIV Grant RM, Lama JR, 28. prevention in men who have sex with men. . 2010;363(27):2587-2599. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21091279 . N Engl J Med Baeten JM, Donnell D, Ndase P N , et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. 29. Engl J Med . 2012;367(5):399-410. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22784037 . 30. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission Thigpen MC, Kebaabetswe PM, Paxton LA, et al. N Engl J Med . 2012;367(5):423-434. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22784038 . in Botswana. Strategies for Management of WM, Lundgren J, et al. CD4+ count-guided Antiretroviral Therapy Study G, El-Sadr 31. interruption of antiretroviral treatment. . 2006;355(22):2283-2296. Available at: http://www.ncbi.nlm.nih.gov/ N Engl J Med pubmed/17135583 . 32. Kuller LH, Tracy R, Belloso W, et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. https://www.ncbi.nlm.nih.gov/pubmed/18942885 . 2008;5(10):e203. Available at: . PLoS Med I-7 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

155 (Last updated October 25, 2018; last reviewed Adolescents and Young Adults with HIV October 25, 2018) Key Summary and Panel’s Recommendations • Adolescents living with HIV largely belong to two distinct groups—those who acquired HIV in infancy and are heavily antiretroviral therapy (AR T)-experienced, and those who acquired HIV more recently during their teens. • T is recommended for all individuals with HIV (AI) to reduce morbidity and mortality. Thus, ART is also recommended for ART- AR naive adolescents. Before initiation of therapy, adolescents’ readiness and ability to adhere to therapy within their psychosocial context need to be carefully considered as part of therapeutic decision making . (AIII) • Once ART is initiated, appropriate support is essential to reduce potential barriers to adherence and maximize the likelihood of achieving sustained viral suppression (AII) . Preliminary data from Botswana suggested that infants born to women who were receiving dolutegravir (DTG) at the time of • conception have an increased risk of neural tube defects. Until more information is available, DTG should not be prescribed for adolescents: Who are pregnant and within 12 weeks post-conception; • fective contraception; or Who are of childbearing potential, are sexually active, and who are not using ef • Who are contemplating pregnancy. • The adolescent sexual maturity rating (SMR) can be helpful to guide regimen selection for initiation of or changes in ART as • recommended by either these Adult and Adolescent Antiretroviral Guidelines or the Pediatric Guidelines . These Adult and Adolescent (AIII) Guidelines are more appropriate for postpubertal adolescents (i.e., those with SMRs of 4 or 5) . • Pediatric and adolescent care providers should prepare adolescents for the transition into adult care settings. Adult providers should be sensitive to the challenges associated with such transitions, consulting and collaborating with adolescent HIV care providers to . successful transition and continued engagement in care (AIII) ensure adolescents’ Rating of Recommendations: A = Strong; B = Moderate; C = Optional Rating of Evidence: I = Data from randomized controlled trials; II = Data from well-designed nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinion Older children and adolescents now make up the largest percentage of children with HIV who are cared for at pediatric HIV clinics in the United States. The Centers for Disease Control and Prevention (CDC) estimates that 26% of the approximately 50,000 people newly diagnosed with HIV in 2010 were youth 13 to 24 years of age. In this age group, 57% of the infections were among young black/African Americans and 75% were 1 among young men who have sex with men (MSM). Among youth living with HIV in 2010, CDC estimates 1 that almost 60% had undiagnosed infections and were unaware they had HIV. Trends in HIV/AIDS prevalence indicate that the disproportionate burden of HIV among racial minorities is even greater among 2 minority youth 13 to 24 years of age than among those older than 24 years. Furthermore, trends for all HIV diagnoses among adolescents and young adults in 46 states and 5 U.S.-dependent areas from 2007 to 2010 Adolescents with decreased or remained stable for all transmission categories except among young MSM. HIV represent a heterogeneous group in terms of socio-demographics, mode of HIV acquisition, sexual and substance abuse history, clinical and immunologic status, psychosocial development, and readiness to adhere to medications. Many of these factors may influence decisions concerning when to start antiretroviral therapy (ART) and what antiretroviral (ARV) medications to use. Most adolescents who acquire HIV do so through sex. Many of them are recently infected and unaware of their HIV status. Many are in an early stage of HIV infection, which makes them ideal candidates for early 3 interventions, such as prevention counseling, linkage to and engagement in care, and initiation of ART. High-grade viremia was reported in a cohort of youth living with HIV who were identified by adolescent HIV specialty clinics in 15 major metropolitan U.S. cities. The mean HIV viral load for the cohort was I-8 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

156 4 94,398 copies/mL; 30% of the youth were not successfully linked to care. In a study of youths with recent HIV infection, primary genotypic resistance mutations were reported in 18% of the samples, as determined by the detuned antibody testing assay strategy that defined recent infection as occurring within 180 days of 5 testing. In an ARV treatment trial, a cohort of ART-naive youth who had behaviorally acquired HIV showed 6 substantial multiclass resistance. As these youth were naive to all ARV drugs, this reflects transmission of resistant virus. This transmission dynamic indicates that a substantial proportion of the study participants’ sexual partners were likely to be older and ART-experienced; thus, using baseline resistance testing to guide initial therapy in youth who have recently acquired HIV and are naive to ART is imperative. A limited but increasing number of adolescents with HIV are long-term survivors of HIV acquired perinatally or in infancy through blood products. These adolescents are usually heavily ART-experienced and may have 7 a unique clinical course that differs from that of adolescents who acquire HIV later in life. Adolescents who acquired HIV perinatally or in infancy were often started on ART early in life with mono- or dual-therapy regimens, resulting in incomplete viral suppression and emergence of viral resistance. If these heavily ART- experienced adolescents harbor resistant virus, optimal ARV regimens should be selected on the basis of the same guiding principles used for heavily ART-experienced adults (see Virologic Failure ). Developmentally, adolescents are at a difficult crossroad. Their needs for autonomy and independence and their evolving decisional capacity compete with their concrete thinking processes, risk-taking behaviors, preoccupation with self-image, and need to fit in with their peers. This makes it challenging to attract and sustain adolescents’ focus on maintaining their health, particularly for those with chronic illnesses. These challenges are not specific to any particular transmission mode or stage of disease. Thus, irrespective of disease duration or mode of HIV transmission, every effort must be made to engage and retain adolescents in care so they can improve and maintain their health for the long term. Given the challenges of retaining 8 youth in care and achieving long-term viral suppression, more intensive case management approaches may 9,10 be considered for adolescents with HIV. Adolescents may seek care in several settings, including pediatric- 11 focused HIV clinics, adolescent/young adult clinics, and adult-focused clinics. When available, youth services may be helpful to consider as one approach to enhancing HIV care engagement and retention among 12 adolescents. Regardless of the setting, expertise in caring for adolescents is critical to creating a supportive 11 environment for engaging youth in care. Antiretroviral Therapy Considerations in Adolescents The results from the START and TEMPRANO trials that favor initiating ART in all individuals who are able and willing to commit to treatment, and who can understand the benefits and risks of therapy and the importance of excellent adherence, are discussed elsewhere in these guidelines (see Initiation of Antiretroviral Therapy ). Neither of these trials included adolescents; however, recommendations based on these trials have been extrapolated to adolescents based on the expectation that they will derive benefits from early ART that are similar to those observed in adults. Given the psychosocial turmoil that may occur frequently in the lives of American youth with HIV, their ability to adhere to therapy needs to be carefully considered as part of therapeutic decision making concerning the risks and benefits of starting treatment. Once ART is initiated, appropriate support is essential to reduce potential barriers to adherence and maximize the likelihood of achieving sustained viral suppression. The adolescent sexual maturity rating (SMR; also known as the Tanner stage) can be helpful when ART initiation is being considered for this population (see this SMR table ). Adult guidelines for ART initiation What to Start (see ) or regimen changes are usually appropriate for postpubertal adolescents (SMR 4 or 5) because the clinical course of HIV infection in postpubertal adolescents who acquired HIV sexually or through injection drug use during adolescence is more similar to that in adults than that in children. Adult guidelines can also be useful for postpubertal youth who acquired HIV perinatally and whose long-term HIV infection has not affected their sexual maturity (SMR 4 or 5). Pediatric guidelines for ART may be I-9 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

157 more appropriate for adolescents who acquired HIV during their teen years (e.g., through sex), but who are perinatally with stunted sexual sexually immature (SMR 3 or less) and for adolescents who acquired HIV maturation (i.e., delayed puberty) from long-standing HIV infection or other comorbidities (SMR 3 or less) What to Start ). Postpubertal youth who acquired HIV perinatally often have in the (see Pediatric Guidelines treatment challenges associated with the long-term use of ART that mirror those of ART-experienced adults, , Virologic Failure Poor such as extensive resistance, complex regimens, and adverse drug effects (see also , and CD4 Cell Recovery , Optimizing Antiretroviral Therapy in the Setting of Viral Suppression Adverse ). Postpubertal adolescents who acquired HIV perinatally may also have Effects of Antiretroviral Agents 13 comorbid cognitive impairments that compound adherence challenges that are common among youth. Dosage of ARV drugs should be prescribed according to the SMR and not solely on the basis of age. Adolescents in early puberty (i.e., SMR 3 or less) should be administered doses on pediatric schedules, whereas those in late puberty (i.e., SMR 4 or 5) should follow adult dosing schedules. However , SMR and age are not necessarily directly predictive of drug pharmacokinetics (PKs). Because puberty may be 14 delayed in children with perinatally acquired HIV, continued use of pediatric doses in puberty-delayed adolescents can result in medication doses that are higher than the usual adult doses. Because data are not available to predict optimal medication doses for each ARV medication for this group of children, issues such as toxicity, pill or liquid volume burden, adherence, and virologic and immunologic parameters should be considered in determining when to transition youth from pediatric to adult doses. Youth who are in their growth spurt period (i.e., SMR 3 in females and SMR 4 in males) and who are following adult or pediatric dosing guidelines and adolescents who have transitioned from pediatric to adult doses should be closely monitored for medication efficacy and toxicity. Therapeutic drug monitoring can be considered in each of these circumstances to help guide therapy decisions. PK studies of drugs in youth are needed to better define 15 Pediatric Guidelines . appropriate dosing. For a more detailed discussion, see the Preliminary data from a study on birth outcomes among pregnant women on ART in Botswana suggested an increased rate of neural tube defects (NTDs) among infants born to women who initiated a dolutegravir 16,17 (DTG)-based regimen prior to pregnancy and who were still receiving it at the time of conception. Until more information is available, DTG is not recommended for adolescents who are pregnant and within 12 weeks post-conception. It is also not recommended for those of childbearing potential who are sexually active and not using effective contraception or those who are contemplating pregnancy. It is not known whether this possible risk of NTDs is shared by other integrase strand transfer inhibitors (i.e., a class effect). Bictegravir (BIC) is structurally similar to DTG, but there are no safety data on the use of BIC near the time of conception. For those who are of childbearing potential, but who are not pregnant, an approach similar to that outlined for DTG should be discussed before considering the use of BIC-containing ART. Clinicians should refer to the Perinatal Guidelines for information on the safety and efficacy of ARV use in pregnancy. Adherence Concerns in Adolescents Adolescents with HIV are especially vulnerable to specific adherence problems because of their psychosocial and cognitive developmental trajectory. To meet the medical and psychosocial needs of adolescents with HIV, who frequently lack both health insurance and experience with health care systems, comprehensive systems of care are required. Studies of adolescents who acquired HIV during their teen years and adolescents with perinatal acquisition demonstrate that many adolescents in both groups face numerous 18-20 barriers to adherence. Compared with adults, these youth have lower rates of viral suppression and higher 21 rates of virologic rebound and loss to follow up. Reasons that adolescents with HIV often have difficulty adhering to medical regimens include the following: • Denial and fear of their HIV diagnosis; Misinformation; • I-10 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

158 • Distrust of the medical establishment; Fear of ART and lack of confidence in the effectiveness of medications; • • Low self-esteem; Unstructured and chaotic lifestyles; • • Mood disorders and other mental illness; • Lack of familial and social support; and Lack of or inconsistent access to care or health insurance; • Risk of inadvertent disclosure of their HIV status if parental health insurance is used. • Clinicians selecting treatment regimens for adolescents must balance the goal of prescribing a maximally potent ART regimen with a realistic assessment of existing and potential support systems to facilitate adherence. Adolescents benefit from reminder systems (e.g., apps, timers, and pill boxes) that are stylish 22 and/or inconspicuous. In a randomized controlled study among nonadherent youth aged 15 years to 24 years, youth who received medication reminders through their cell phones demonstrated significantly better 23 adherence and lower viral loads than youth who did not receive the reminder calls. It is important to make medication adherence user-friendly and to avoid HIV-related stigma as much as possible for the older child or adolescent. Adolescents may not understand the importance of taking medications when they are asymptomatic, particularly if the medications have side effects. Adherence to complex regimens is particularly 24-26 challenging at a time of life when adolescents do not want to be different from their peers. Directly 27-31 observed therapy may be considered for some adolescents with HIV, such as those with mental illness. Difficult Adherence Problems Because adolescence is characterized by rapid changes in physical maturation, cognitive processes, and life style, predicting long-term adherence in an adolescent can be very challenging. A young person’s ability to adhere to therapy needs to be considered as part of therapeutic decision making when considering the risks and benefits of starting ART. Erratic adherence may result in the loss of future regimens due to the development of resistance mutations. Clinicians who care for adolescents with HIV frequently manage youth who pose significant concerns regarding their ability to adhere to therapy . In these cases, the following strategies can be considered: 1. short-term deferral of ART until adherence is more likely or while adherence-related problems are A aggressively addressed; 2. An adherence testing period in which a placebo (e.g., vitamin pill) is administered; and 3. The avoidance of any regimens with low resistance barriers. Such decisions should ideally be individualized to reflect each patient’ s clinical status. For a more detailed discussion on specific therapy and adherence issues for adolescents with HIV Adherence to the , see 15 Pediatric Guidelines . in these guidelines and the Continuum of Care Special Considerations in Adolescents All adolescents should be screened for sexually transmitted infections (STIs), especially human papilloma virus (HPV). In young MSM, screening for STIs may require sampling from several body sites because 32 oropharyngeal, rectal, and urethral infections may be present in this population. For a more detailed 33 discussion on STIs, see the most recent CDC guidelines, Adult and Adolescent Opportunistic Infections 34,35 Guidelines , and Pediatric Opportunistic Infections Guidelines on HPV among adolescents with HIV. Family planning counseling, including a discussion of the risks of perinatal transmission of HIV and methods to reduce those risks, should be provided to all youth. Providing gynecologic care for female adolescents with HIV is especially important. Choice of ART may also be affected by a patient’s potential for pregnancy I-11 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

159 and use of contraception, since some ARV drugs can interact with hormonal contraceptives (see Drug-Drug tables). Finally, transgender youth with HIV represent an important population that requires Interaction additional psychosocial and health care considerations. For a more detailed discussion, see Adolescent Trials . Network Transgender Youth Resources Transitioning Care Given lifelong infection with HIV and the need for treatment through several stages of growth and development, HIV care programs and providers need flexibility to appropriately transition care for children, adolescents, and young adults with HIV. A successful transition requires an awareness of the fundamental differences between many adolescent and adult HIV care models. In most adolescent HIV clinics, care is more teen-centered and multidisciplinary, with primary care highly integrated into HIV care. Teen services, such as sexual and reproductive health, substance abuse treatment, mental health, treatment education, and adherence counseling are all found in one clinic setting. In contrast, some adult HIV clinics may rely more on referring the patient to separate subspecialty care settings, such as gynecology. Transitioning the care of an emerging young adult includes considering areas such as access to medical insurance; the adolescent’s degree of independence/autonomy and decisional capacity; patient confidentiality; and informed consent. Also, adult clinic settings tend to be larger and can easily intimidate younger, less-motivated patients. As an additional complication to this transition, adolescents with HIV belong to two epidemiologically distinct subgroups with unique biomedical and psychosocial considerations and needs: • perinatally, who likely have a longer history of disease burden, Adolescents who acquired HIV complications, and chronicity; less functional autonomy; a greater need for ART; and a higher mortality risk; and Y • outh who more recently acquired HIV during their adolescence, who are likely to be in earlier stages of HIV infection and have higher CD4 T lymphocyte cell counts; these adolescents would be less likely to have viral drug resistance and may benefit from simpler treatment regimen options. 36 Interventions to facilitate transition should be implemented early to ensure a successful transition. These interventions include the following: • Developing an individualized transition plan to address comprehensive care needs, including medical, psychosocial, and financial aspects of transitioning; • Optimizing provider communication between adolescent and adult clinics; • Identifying adult care providers that are willing to care for adolescents and young adults; • Addressing patient and family resistance to transition of care caused by lack of information, concerns about stigma or risk of disclosure, and differences in practice styles; Helping youth develop life skills, including counseling them on the appropriate use of a primary • care provider and how to manage appointments; the importance of prompt symptom recognition and reporting; and the importance of self-efficacy in managing medications, insurance, and assistance benefits; • Identifying an optimal clinic model based on specific needs (i.e., simultaneous transition of mental health and/or case management versus a gradual phase-in); Implementing ongoing evaluation to measure the success of a selected clinic model; • • Engaging adult and adolescent care providers in regular multidisciplinary case conferences; • Implementing interventions that may improve outcomes, such as support groups and mental health consultation; • Incorporating a family planning component into clinical care; and • Educating HIV care teams and staff about transitioning. I-12 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

160 37 Discussions regarding transition should begin early, before the actual transition process. Attention to the key interventions noted above will likely improve adherence to appointments and allow the youth to be retained in care. For a more detailed discussion on specific topics on transitioning care for adolescents and young adults, see HIV Clinical Guidelines Program’s . Adolescent Transition to Adult Care References Centers for Disease C, Prevention. 1. Vital signs: HIV infection, testing, and risk behaviors among youths - United States. . 2012;61(47):971-976. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23190571 . MMWR Morb Mortal Wkly Rep Centers for Disease Control and Prevention. HIV surveillance in adolescents and young adults 2011. Available at: http:// 2. . www.cdc.gov/hiv/pdf/statistics_surveillance_Adolescents.pdf Philbin MM, Tanner AE, Duval A, Ellen J, Kapogiannis B, Fortenberry JD. Linking HIV-positive adolescents to care in 3. AIDS 15 different clinics across the United States: Creating solutions to address structural barriers for linkage to care. 2014;26(1):12-19. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23777542 . Care. Ellen JM, Kapogiannis B, Fortenberry JD, et al. HIV AIDS viral load levels and CD4+ cell counts of youth in 14 cities. 4. . 2014;28(8):1213-1219. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25028912 . iani RM, Peralta L, Aldrovandi G, et al. Prevalence of primary HIV-1 drug resistance among recently infected 5. V J Infect Dis adolescents: a multicenter adolescent medicine trials network for HIV/AIDS interventions study. . 2006;194(11):1505-1509. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17083034 . 6. Agwu AL, Bethel J, Hightow-Weidman LB, et al. Substantial multiclass transmitted drug resistance and drug-relevant polymorphisms among treatment-naive behaviorally HIV-infected youth. . 2012;26(4):193-196. AIDS Patient Care STDS Available at: http://www.ncbi.nlm.nih.gov/pubmed/22563607 . 7. V an Dyke RB, Patel K, Siberry GK, et al. Antiretroviral treatment of US children with perinatally acquired HIV infection: temporal changes in therapy between 1991 and 2009 and predictors of immunologic and virologic outcomes. J Acquir Immune Defic Syndr . 2011;57(2):165-173. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21407086 . The adolescent and young adult HIV cascade of care in the United States: exaggerated health 8. Zanoni BC, Mayer KH. AIDS Patient Care STDS . 2014;28(3):128-135. Available at: disparities. . http://www.ncbi.nlm.nih.gov/pubmed/24601734 9. eidman LB, Smith JC, Valera E, Matthews DD, Lyons P. Keeping them in “STYLE”: finding, linking, Hightow-W AIDS Patient Care STDS and retaining young HIV-positive black and Latino men who have sex with men in care. . http://www.ncbi.nlm.nih.gov/pubmed/21162690 . 2011;25(1):37-45. Available at: 10. Sitapati AM, Limneos J, Bonet-Vazquez M, Mar-Tang M, Qin H, Mathews WC. Retention: building a patient- centered medical home in HIV primary care through PUFF (Patients Unable to Follow-up Found). J Health Care Poor Underserved . 2012;23(3 Suppl):81-95. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22864489 . 11. T anner AE, Philbin MM, Duval A, et al. “Youth friendly” clinics: Considerations for linking and engaging HIV-infected adolescents into care. AIDS Care. 2014;26(2):199-205. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23782040 . 12. . Centralization of HIV services in HIV- Davila JA, Miertschin N, Sansgiry S, Schwarzwald H, Henley C, Giordano TP positive African-American and Hispanic youth improves retention in care. AIDS Care. 2013;25(2):202-206. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22708510 . 13. Nichols SL, Brummel SS, Smith RA, et al. Executive Functioning in Children and Adolescents With Perinatal HIV Infection. Pediatr Infect Dis J . 2015;34(9):969-975. Available at: http://www.ncbi.nlm.nih.gov/pubmed/26376309 . Buchacz K, Rogol AD, Lindsey JC, et al. Delayed onset of pubertal development in children and adolescents with 14. infection. J Acquir Immune Defic Syndr . 2003;33(1):56-65. Available at: https://www.ncbi.nlm. perinatally acquired HIV nih.gov/pubmed/12792356 . 15. Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV. Guidelines for the use of antiretroviral agents in pediatric HIV infection. 2018. Available at: http://aidsinfo.nih.gov/contentfiles/lvguidelines/ pediatricguidelines.pdf . ube Defects with Dolutegravir Treatment from the Time of Conception. N 16. Zash R, Makhema J, Shapiro RL. Neural-T . Engl J Med . 2018;379(10):979-981. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30037297 17. Zash R, Holmes L, Makhema J, et al. Surveillance for neural tube defects following antiretroviral exposure from conception. 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161 18. Adolescent Trials Network for HIVAI. Prevalence and interactions Rudy BJ, Murphy DA, Harris DR, Muenz L, Ellen J, of patient-related risks for nonadherence to antiretroviral therapy among perinatally infected youth in the United States. AIDS Patient Care STDS . . 2010;24(2):97-104. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20059354 Rudy BJ, Murphy DA, Harris DR, Muenz L, Ellen J, Adolescent Trials Network for HIVAI. Patient-related risks 19. for nonadherence to antiretroviral therapy among HIV-infected youth in the United States: a study of prevalence and interactions. http://www.ncbi.nlm.nih.gov/ AIDS Patient Care STDS . 2009;23(3):185-194. Available at: . pubmed/19866536 MacDonell K, Naar-King S, Huszti H, Belzer M. Barriers to medication adherence in behaviorally and perinatally 20. . AIDS Behav. 2013;17(1):86-93. Available at: http://www.ncbi.nlm.nih.gov/ infected youth living with HIV . pubmed/23142855 R yscavage P, Anderson EJ, Sutton SH, Reddy S, Taiwo B. Clinical outcomes of adolescents and young adults in 21. adult HIV care. . 2011;58(2):193-197. Available at: http://www.ncbi.nlm.nih.gov/ J Acquir Immune Defic Syndr pubmed/21826014 . 22. L yon ME, Trexler C, Akpan-Townsend C, et al. A family group approach to increasing adherence to therapy in HIV- infected youths: results of a pilot project. https://www.ncbi. . 2003;17(6):299-308. Available at: AIDS Patient Care STDS nlm.nih.gov/pubmed/12880493 . Belzer ME, Kolmodin MacDonell K, Clark LF , et al. Acceptability and Feasibility of a Cell Phone Support Intervention 23. AIDS Patient Care STDS . 2015;29(6):338-345. for Youth Living with HIV with Nonadherence to Antiretroviral Therapy. http://www.ncbi.nlm.nih.gov/pubmed/25928772 . Available at: 24. . J Brooks-Gunn J, Graber JA. Puberty as a biological and social event: implications for research on pharmacology Adolesc Health https://www.ncbi.nlm.nih.gov/pubmed/7696287 . . 1994;15(8):663-671. Available at: 25. Adolescents’ perceptions of physicians, nurses, parents and friends: help or Kyngas H, Hentinen M, Barlow JH. hindrance in compliance with diabetes self-care? J Adv Nurs . 1998;27(4):760-769. Available at: https://www.ncbi.nlm. nih.gov/pubmed/9578206 . J Pediatr Psychol 26. . 1992;17(6):775-784. Available AM. Peer influences in pediatric chronic illness: an update. La Greca at: . https://www.ncbi.nlm.nih.gov/pubmed/1484338 Wilson CM, Durako SJ, Muenz LR, Belzer M. Antiretroviral medication adherence among the REACH 27. Murphy DA, AIDS Care. 2001;13(1):27-40. Available at: https://www.ncbi.nlm.nih.gov/ HIV-infected adolescent cohort in the USA. . pubmed/11177463 28. TP. Enhancing adherence to HAART: a pilot program of modified Stenzel MS, McKenzie M, Mitty JA, Flanigan directly observed therapy. AIDS Read . 2001;11(6):317-319, 324-318. Available at: https://www.ncbi.nlm.nih.gov/ pubmed/11449925 . 29. AF, Martin SC, et al. Virologic response using directly observed therapy in adolescents with HIV: Purdy JB, Freeman an adherence tool. J Assoc Nurses AIDS Care. 2008;19(2):158-165. Available at: https://www.ncbi.nlm.nih.gov/ pubmed/18328966 . 30. Garvie PA, Lawford J, Flynn PM, et al. Development of a directly observed therapy adherence intervention for adolescents with human immunodeficiency virus-1: application of focus group methodology to inform design, feasibility , J Adolesc Health and acceptability . . . 2009;44(2):124-132. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19167660 AH, Belzer M, Britto P, et al. Directly observed therapy (DOT) for nonadherent HIV-infected youth: lessons 31. Gaur learned, challenges ahead. AIDS Res Hum Retroviruses . 2010;26(9):947-953. Available at: http://www.ncbi.nlm.nih.gov/ . pubmed/20707731 ermund SH, Wilson CM, Rogers AS, Partlow C, Moscicki AB. Sexually transmitted infections among HIV infected and 32. V HIV uninfected high-risk youth in the REACH study. Reaching for Excellence in Adolescent Care and Health. J Adolesc http://www.ncbi.nlm.nih.gov/pubmed/11530303 . 2001;29(3 Suppl):49-56. Available at: . Health 33. orkowski KA, Berman S. Sexually transmitted diseases treatment guidelines, 2010. MMWR Recomm Rep . W 2010;59(RR-12):1-110. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21160459 . -Infected Adults and Adolescents. Guidelines for the prevention and treatment 34. Panel on Opportunistic Infections in HIV of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases . Society of America. 2018. Available at: http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf 35. -Exposed and HIV-Infected Children. Guidelines for the prevention and Panel on Opportunistic Infections in HIV I-14 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

162 http://aidsinfo.nih. treatment of opportunistic infections in HIV-exposed and HIV-infected children. 2018. Available at: gov/contentfiles/lvguidelines/oi_guidelines_pediatrics.pdf . 36. V alenzuela JM, Buchanan CL, Radcliffe J, et al. Transition to adult services among behaviorally infected adolescents J Pediatr Psychol with HIV--a qualitative study. . 2011;36(2):134-140. Available at: http://www.ncbi.nlm.nih.gov/ pubmed/19542198 . AIDS. Transitioning HIV-infected youth into adult health care. Pediatrics . 2013;132(1):192- 37. Committee On Pediatric . http://www.ncbi.nlm.nih.gov/pubmed/23796739 197. Available at: I-15 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

163 HIV and People Who Use Illicit Drugs (Last updated March 27, 2012; last reviewed March 27, 2012) Treatment Challenges in People with HIV Who Use Illicit Drugs Injection drug use is the second most common mode of HIV transmission in the United States. In addition, noninjection illicit drug use may facilitate sexual transmission of HIV. Injection and noninjection illicit drugs include the following: heroin, cocaine, marijuana, and club drugs (i.e., methamphetamine, ketamine, gamma- hydroxybutyrate [GHB], and amyl nitrate [i.e., poppers]). The most commonly used illicit drugs associated with HIV infection are heroin and stimulants (e.g., cocaine and amphetamines); however, the use of club drugs has increased substantially in the past several years and is common among individuals who have HIV infection or who are at risk of HIV infection. The association between club drugs and high-risk sexual behavior in men who have sex with men (MSM) is strongest for methamphetamine and amyl nitrate; this .1 association is less consistent with the other club drugs Illicit drug use has been associated with depression and anxiety, either as part of the withdrawal process or as a consequence of repeated use. This is particularly relevant in the treatment of HIV infection because 2 depression is one of the strongest predictors of poor adherence and poor treatment outcomes. Treatment of HIV disease in people who use illicit drugs can be successful, but this group presents special treatment challenges. These challenges may include the following: (1) an array of complicating comorbid medical and mental health conditions; (2) limited access to HIV care; (3) inadequate adherence to therapy; (4) medication side effects and toxicities; (5) the need for substance abuse treatment; and (6) drug interactions that can 3 complicate HIV treatment. Underlying health problems in people who use injection and/or noninjection drugs result in increased morbidity and mortality, either independent of or accentuated by HIV disease. Many of these problems are the consequence of prior exposures to infectious pathogens from nonsterile needle and syringe use. Such problems can include hepatitis B or C virus infection, tuberculosis (TB), skin and soft tissue infections, recurrent bacterial pneumonia, and endocarditis. Other morbidities such as alteration in levels of consciousness and neurologic and renal disease are not uncommon. Furthermore, these comorbidities are associated with a higher risk of drug overdoses in people with HIV who use illicit drugs than in people who use illicit drugs and do not have HIV, due in part to respiratory, hepatic, and neurological impairments 4 associated with HIV infection. Success of antiretroviral therapy (ART) in people with HIV who use illicit drugs often depends on clinicians becoming familiar with and managing these comorbid conditions and providing overdose prevention support. People with HIV who use illicit drugs have less access to HIV care and are less likely to receive ART than 5-6 other populations. Factors associated with low rates of ART use among people who use illicit drugs include active drug use, younger age, female gender, suboptimal health care, recent incarceration, lack 5-6 of access to rehabilitation programs, and health care providers’ lack of expertise in HIV treatment. The typically unstable, chaotic life patterns of many people who use illicit drugs; the powerful pull of addictive ART all contribute to substances; and common misperceptions about the dangers, impact, and benefits of 7 decreased adherence. The chronic and relapsing nature of substance abuse as a biologic and medical disease, compounded by the high rate of mental illness that antedates and/or is exacerbated by illicit substance use, 8-9 additionally complicate the relationship between health care workers and people who use illicit drugs. The first step in provision of care and treatment for these individuals is to recognize the existence of a substance use problem. It is often obvious that the problem exists, but some patients may hide these problem behaviors from clinicians. Assessment of a patient for a substance use disorder should be part of routine medical history taking and should be done in a professional, straightforward, and nonjudgmental manner. I-16 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

164 Treatment Efficacy in Populations of People Who Use Illicit Drugs Although people who use illicit drugs are underrepresented in HIV therapy clinical trials, available data indicate that efficacy of ART in people who use illicit drugs—when they are not actively using drugs—is 10 similar to that seen in other populations. Furthermore, therapeutic failure in this population generally 11 correlates with the degree that drug use disrupts daily activities rather than with drug use per se. Providers need to remain attentive to the possible impact of disruptions caused by drug use on the patient both before and while receiving ART. Although many people who use illicit drugs can sufficiently control their drug use for a long enough time to benefit from care, treatment for substance use disorders is often necessary for successful HIV management. Successful HIV treatment requires close collaboration with treatment programs for substance use disorders and proper support and attention to this population’s special multidisciplinary needs. HIV care sites should be accommodating, flexible, and community-based, with experience in managing a wide array of needs for people who use drugs. HIV care sites must also have experience in developing effective strategies to 9 promote medication adherence. These strategies should include, if available, the use of adherence support mechanisms such as modified directly observed therapy (mDOT), which has shown promise among people 12 with HIV who use illicit drugs. Antiretroviral Agents and Opioid Substitution Therapy Compared with people receiving ART who do not use illicit drugs, people who use illicit drugs are more likely to experience an increased frequency of side effects and toxicities of ART. Although not systematically studied, this is likely because underlying hepatic, renal, neurologic, psychiatric, gastrointestinal (GI), and hematologic disorders are highly prevalent among people who use injection drugs. These comorbid conditions should be considered when selecting antiretroviral (ARV) agents in this population. Opioid substitution therapies such as methadone and buprenorphine/naloxone and extended-release naltrexone are commonly used for management of opioid dependence in patients with HIV. Methadone and Antiretroviral Therapy. Methadone, an orally administered, long-acting opioid agonist, is the most common pharmacologic treatment for opioid addiction. Its use is associated with decreased heroin use, decreased needle sharing, and improved quality of life. Because of its opioid-induced effects on gastric emptying and the metabolism of cytochrome P (CYP) 450 isoenzymes 2B6, 3A4, and 2D6, pharmacologic 13 effects and interactions with ARV agents may commonly occur. These may diminish the effectiveness of either or both therapies by causing opioid withdrawal or overdose, increased methadone toxicity, and/ or decreased ARV efficacy. Efavirenz (EFV), nevirapine (NVP), and lopinavir/ritonavir (LPV/r) have been associated with significant decreases in methadone levels. Patients and substance abuse treatment facilities should be informed of the likelihood of this interaction. The clinical effect is usually seen after 7 days of coadministration and may be managed by increasing the methadone dosage, usually in 5-mg to 10-mg increments daily until the desired effect is achieved. Buprenorphine and Antiretroviral Therapy. Buprenorphine, a partial μ-opioid agonist, is administrated sublingually and is often coformulated with naloxone. It is increasingly used for opioid dependence treatment. Compared with methadone, buprenorphine has a lower risk of respiratory depression and overdose. This allows physicians in primary care to prescribe buprenorphine for the treatment of opioid dependency. The flexibility of the primary care setting can be of significant value to patients with HIV and opioid addiction who require ART because it enables one physician or program to provide both medical and substance abuse services. Limited information is currently available about interactions between 13-14 buprenorphine and ARV agents. Findings from available studies show that the drug interaction profile of buprenorphine is more favorable than that of methadone. Naltrexone and Antiretroviral Therapy. A once-monthly extended-release intramuscular formulation of naltrexone was recently approved for prevention of relapse in patients who have undergone an opioid I-17 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

165 detoxification program. Naltrexone is also indicated for treatment of alcohol dependency . Naltrexone is not metabolized via the CYP450 enzyme system and is not expected to interact with protease inhibitors (PIs) or 15 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Currently available pharmacokinetic (PK) interaction data that clinicians can use as a guide for managing Tables 19a-d . Effective patients receiving ART and methadone or buprenorphine can be found in communication between HIV care providers and drug treatment programs is essential to prevent additive drug toxicities and drug interactions resulting in opiate withdrawal or excess. Methylenedioxymethamphetamine (MDMA), GHB, ketamine, and methamphetamine all have the potential to interact with ARV agents because all are metabolized, at least in part, by the CYP450 system. Overdoses secondary to interactions between the party drugs (i.e., MDMA or GHB) and PI-based ART have been 16 reported. Summary It is usually possible over time to support most people with HIV who actively use drugs such that acceptable 17-18 adherence levels with ARV agents can be achieved. Providers must work to combine all available resources to stabilize someone who actively uses drugs in preparation for ART. This should include identification of concurrent medical and psychiatric illnesses, drug treatment and needle and syringe exchange programs, strategies to reduce high-risk sexual behavior, and harm-reduction strategies. A history of drug use alone is insufficient reason to withhold ART because individuals with a history of prior drug use have adherence rates similar to those who do not use drugs. Important considerations in the selection of successful regimens and the provision of appropriate patient monitoring in this population include need for supportive clinical sites, linkage to substance abuse treatment, and awareness of the interactions between illicit drugs and ARV agents, including the increased risk of side effects and toxicities. Simple regimens should be considered to enhance medication adherence. Preference should be given to ARV agents that have a lower risk of hepatic and neuropsychiatric side effects, simple dosing schedules, and minimal interaction with methadone. References 1. Colfax G, Guzman R. Club drugs and HIV infection: a review. Clin Infect Dis . May 15 2006;42(10):1463-1469. Available at https://www.ncbi.nlm.nih.gov/pubmed/16619161 . 2. T ucker JS, Burnam MA, Sherbourne CD, Kung FY, Gifford AL. Substance use and mental health correlates of nonadherence to antiretroviral medications in a sample of patients with human immunodeficiency virus infection. Am J . May 2003;114(7):573-580. Available at Med https://www.ncbi.nlm.nih.gov/pubmed/12753881 . 3. Bruce RD, Altice FL, Gourevitch MN, Friedland GH. Pharmacokinetic drug interactions between opioid agonist therapy J Acquir Immune Defic Syndr and antiretroviral medications: implications and management for clinical practice. . Apr 15 2006;41(5):563-572. Available at https://www.ncbi.nlm.nih.gov/pubmed/16652030 . W ang C, Vlahov D, Galai N, et al. The effect of HIV infection on overdose mortality. AIDS 4. . Jun 10 2005;19(9):935-942. Available at https://www.ncbi.nlm.nih.gov/pubmed/15905674 . 5. Strathdee SA, Palepu A, Cornelisse PG, et al. Barriers to use of free antiretroviral therapy in injection drug users. JAMA . Aug 12 1998;280(6):547-549. Available at https://www.ncbi.nlm.nih.gov/pubmed/9707146 . Celentano DD, Vlahov D, Cohn S, Shadle VM, Obasanjo O, Moore RD. Self-reported antiretroviral therapy in injection 6. drug users. JAMA . Aug 12 1998;280(6):544-546. Available at https://www.ncbi.nlm.nih.gov/pubmed/9707145 . Altice FL, Mostashari F 7. , Friedland GH. Trust and the acceptance of and adherence to antiretroviral therapy. J Acquir Immune Defic Syndr . Sep 01 2001;28(1):47-58. Available at https://www.ncbi.nlm.nih.gov/pubmed/11579277 . A, Soriano VV, Schechter M, Friedland GH. Treatment of medical, psychiatric, and substance- Altice FL, Kamarulzaman 8. use comorbidities in people infected with HIV who use drugs. . Jul 31 2010;376(9738):367-387. Available at Lancet I-18 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

166 https://www.ncbi.nlm.nih.gov/pubmed/20650518 . Altice FL, Friedland GH, Volberding P. HIV Disease Among Substance Misusers: Treatment Issues. Global 9. Bruce RD, AIDS/HIV Medicine . San Diego, CA: Elsevier Ince; 2007:513-526. , Mehta SH, Jacobson LP, Gange SJ. Injection drug use and patterns of highly active antiretroviral 10. Morris JD, Golub ET therapy use: an analysis of ALIVE, WIHS, and MACS cohorts. AIDS Res Ther . Jun 06 2007;4:12. Available at https:// www.ncbi.nlm.nih.gov/pubmed/17553140 . 11. Bouhnik AD, Chesney M, Carrieri P, et al. Nonadherence among HIV-infected injecting drug users: the impact of social instability. . Dec 15 2002;31 Suppl 3:S149-153. Available at https://www.ncbi.nlm.nih.gov/ J Acquir Immune Defic Syndr pubmed/12562040 . 12. Altice FL, Maru DS, Bruce RD, Springer SA, Friedland GH. Superiority of directly administered antiretroviral therapy over self-administered therapy among HIV -infected drug users: a prospective, randomized, controlled trial. Clin Infect Dis . Sep 15 2007;45(6):770-778. Available at https://www.ncbi.nlm.nih.gov/pubmed/17712763 . Gruber VA, McCance-Katz EF. Methadone, buprenorphine, and street drug interactions with antiretroviral medications. 13. Curr HIV/AIDS Rep . Aug 2010;7(3):152-160. Available at https://www.ncbi.nlm.nih.gov/pubmed/20532839 . 14. Bruce RD, McCance-Katz E, Kharasch ED, Moody DE, Morse GD. Pharmacokinetic interactions between Available at https:// Clin Infect Dis buprenorphine and antiretroviral medications. . Dec 15 2006;43 Suppl 4:S216-223. . www.ncbi.nlm.nih.gov/pubmed/17109308 15. Administration (FDA). Vivitrol (package insert). 2015. Food and Drug 16. Bruce RD, Altice FL, Friedland GH. Pharmacokinetic drug interactions between drugs of abuse and antiretroviral medications: implications and management for clinical practice. Expert Rev Clin Pharmacol . Jan 2008;1(1):115-127. A https://www.ncbi.nlm.nih.gov/pubmed/24410515 . vailable at 17. , Chander G, et al. The impact of illicit drug use and substance abuse treatment on adherence to Hicks PL, Mulvey KP HAART. AIDS Care . Oct 2007;19(9):1134-1140. Available at https://www.ncbi.nlm.nih.gov/pubmed/18058397 . 18. ., Scherzer R, Tien PC, et al. Illicit drug use and HIV treatment outcomes in a US cohort. AIDS . Jan 30 Cofrancesco J, Jr https://www.ncbi.nlm.nih.gov/pubmed/18195562 . 2008;22(3):357-365. Available at I-19 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

167 (Last updated October 25, 2018; last reviewed October 25, 2018) Women with HIV Panel’s Recommendations Antiretroviral therapy (ART) is recommended for all persons living with HIV to improve their health and to reduce the risk of HIV • . (AI) transmission to sex partners without HIV When prescribing antiretroviral (AR V) drugs, clinicians should take into account that some ARV drugs have significant • pharmacokinetic (PK) interactions with hormonal contraceptives; an alternative or additional effective contraceptive method to (AIII) prevent unplanned pregnancy is recommended . Switching to an ARV drug without interactions with hormonal contraceptives may also be considered . (BIII) A • pregnancy test should be performed for those of childbearing potential prior to initiation of ART . (AIII) • Preliminary data suggest there may be an increased risk of neural tube defects (NTD) in infants born to women who were receiving for use in individuals dolutegravir (DTG) at the time of conception. Until more information is available, DTG is not recommended who are pregnant and within 12 weeks post-conception and those who are contemplating pregnancy, unless there are no alternative . (AII) options • Providers should discuss the potential risks and benefits of DTG with individuals of childbearing potential and provide appropriate counseling so that the individual can make an informed decision. For those who are sexually active and not using effective contraception, choosing an alternative to DTG is recommended. For those who are using ef fective contraception, use of a DTG- based regimen is reasonable after discussing the risks and benefits with the individual. Individuals who become pregnant and present for antenatal care at 12 weeks post-conception or later may initiate or continue DTG- • based regimens (CIII) . In a patient with multidrug-resistant HIV who has no alternatives to DTG, the decision of whether to use DTG should be made after • careful consideration of the risk of NTDs in the infant if pregnancy occurs while a patient is taking DTG, and the risks of persistent viremia in the patient and potential HIV transmission to the fetus if pregnancy occurs while the patient is not on ef fective ART. , an additional goal of ART is to maintain a viral load below the limit of detection throughout pregnancy to reduce During pregnancy • . (AI) the risk of transmission to the fetus and newborn • When selecting an ARV combination regimen for a pregnant woman, clinicians should consider the available safety, efficacy, and PK data on use during pregnancy for each agent. The risks and benefits of ARV use during pregnancy should be discussed with (AIII) Perinatal Guidelines when designing a all individuals of childbearing potential and clinicians should consult the most current (AIII) regimen . Rating of Recommendations: A = Strong; B = Moderate; C = Optional I = Data from randomized controlled trials; II = Data from well-designed nonrandomized trials or observational Rating of Evidence: cohort studies with long-term clinical outcomes; III = Expert opinion This section focuses on some unique clinical and therapeutic issues to consider and basic principles to follow when caring for cisgender women living with HIV. Cisgender women are defined as women who were assigned female at birth and who identify themselves as women. Some topics discussed in this section, such as contraception, drug-drug interactions between antiretroviral (ARV) drugs and hormonal therapy, and pregnancy, also apply to transgender men (men assigned female at birth), and individuals assigned female at birth who identify as nonbinary (gender identities that are not exclusively feminine or masculine) or gender fluid (gender identity is not fixed). A new section focused on transgender health and HIV is currently in development and will be added to the Special Patient Population section soon. Clinicians who care for pregnant patients should consult the current for a more in-depth discussion and guidance Perinatal Guidelines on managing these patients. Sex Difference Considerations in Antiretroviral Therapy In general, studies to date have not shown sex differences in virologic responses to antiretroviral therapy 1-4 (ART). However, there are limited data showing that pharmacokinetics (PKs) for some ARV drugs may differ between men and women, possibly because of variations in factors such as body weight, plasma I-20 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

168 volume, gastric emptying time, plasma protein levels, cytochrome P (CYP) 450 activity, drug transporter 5-7 function, and excretion activity. Adverse Effects Several studies with older ARV drugs have suggested that sex may influence the frequency, presentation, and severity of some ARV-related adverse events. Most notably, women are more likely to develop severe 8,9 symptomatic hepatotoxicity with nevirapine (NVP) use and are more likely to develop symptomatic lactic acidosis with prolonged use of older nucleoside reverse transcriptase inhibitors (NRTIs) such as zidovudine 10 (ZDV), stavudine, and didanosine. These agents are no longer recommended for use in people with HIV in the United States; although ZDV is still administered intravenously (IV) to some patients during delivery, it is not generally recommended for long-term use. Some studies have investigated how metabolic complications associated with ARV use differ between women and men. Over 96 weeks following initiation of ART, women with HIV are less likely to have decreases in limb fat but more likely to have decreases in bone mineral density (BMD) than men with 11,12 HIV. Women have an increased risk of osteopenia, osteoporosis, and fractures, particularly after 13-16 menopause, and this risk is exacerbated by HIV and ART. ART regimens that contain tenofovir disoproxil fumarate (TDF), ritonavir-boosted protease inhibitors (PI/r), or both are associated with a significantly 17-20 greater loss of BMD than regimens containing other NRTIs and raltegravir. Abacavir, NRTI-sparing regimens, and tenofovir alafenamide (a new oral tenofovir prodrug that induces less bone loss than TDF) may be considered as alternatives to the use of TDF in patients who are at risk of osteopenia or osteoporosis. 21 Recommendations for management of bone disease in people with HIV have been published. Adults and Adolescents with HIV Who Are of Childbearing Potential All adults and adolescents with HIV who are of childbearing potential should be offered comprehensive reproductive and sexual health counseling and care as part of routine primary medical care. Topics for discussion should include safe sex practices, reproductive desires and options for conception, the HIV status of sex partner(s), and use of effective contraception to prevent unplanned pregnancy. Counseling should also include discussion of special considerations pertaining to ARV use when using hormonal contraceptives, Perinatal Guidelines ). when trying to conceive, and during pregnancy (see the Antiretroviral Regimen Considerations When Trying to Conceive or For Individuals Who Cannot Use Effective Contraception Efavirenz (EFV) is teratogenic in nonhuman primates. However, a meta-analysis that included data from 23 studies found no evidence for an increased risk of birth defects in infants born to women on EFV during the 22 first trimester compared with infants born to women on other ARV drugs during the first trimester. EFV can be used in individuals of childbearing potential who are not using effective contraception or who are contemplating pregnancy. Individuals who become pregnant on EFV-containing regimens should continue their current regimens. A preliminary report from an observational surveillance study of birth outcomes among pregnant women on ART in Botswana found an increase in the risk of in neural tube defects (NTDs) in infants born to women who received dolutegravir (DTG) prior to conception. In this report, four infants born to 596 women (0.67%) who initiated a DTG-based regimen prior to pregnancy and who were still receiving that regimen at the time 23,24 of conception were affected compared to 0.1% of infants born to women who received other ARV drugs. This study is ongoing. By contrast, the same study identified no NTDs in the infants born to 1 16 women who initiated DTG-based regimens during the first trimester or the infants born to 396 women who initiated EFV - 25 based regimens. DTG is not recommended for individuals who are pregnant and within 12 weeks post-conception. It is not recommended also if an individual of childbearing potential is sexually active and cannot use effective I-21 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

169 contraception or is contemplating pregnancy, unless there is no alternative option (AII) . For those not known (AIII) to be pregnant, a negative pregnancy test result should be documented prior to the initiation of DTG . Women who are currently receiving DTG or who wish to start DTG should be counseled about the potential risk of NTDs when DTG is taken near the time of conception. In a patient with multidrug-resistant HIV who has no alternatives to DTG, the decision of whether to use DTG should be made after careful consideration of the risk of NTDs in the infant if pregnancy occurs while a patient is taking DTG, and the risks of persistent viremia in the patient and potential HIV transmission to the fetus if pregnancy occurs while the patient is not on effective ART. Reproductive Options for Serodiscordant Couples An individual who wishes to conceive with a serodiscordant partner should be informed of options to prevent sexual transmission of HIV while attempting conception. Interventions include screening and treating both partners for sexually transmitted infections (STIs), use of ART to maximally suppress and maintain the 26-28 viral load of the partner with HIV, use of pre-exposure prophylaxis by the partner without HIV, male circumcision, and/or self-insemination with the sperm of the partner without HIV during the periovulatory 29 period of the individual with HIV. Hormonal Contraception Safe and effective reproductive health and family planning services to prevent unplanned pregnancies and perinatal transmission of HIV are an essential component of care for individuals with HIV of childbearing age. These individuals should receive ongoing counseling on reproductive issues. Regardless of hormonal contraceptive use, individuals with HIV should be advised to consistently use condoms (male or female) during sex and adhere to an HIV regimen that effectively maintains viral suppression. Both strategies are crucial to prevent transmission of HIV to partners without HIV and to protect against infection with other STIs. The following sections describe some factors to consider when hormonal contraceptives are used. Drug-Drug Interactions PK interactions between ARV drugs and hormonal contraceptives may reduce contraceptive efficacy. However, there are limited clinical data regarding drug interactions between ARVs and hormonal contraceptives, and the clinical implications of these interactions are unclear. The magnitudes of changes in drug concentrations that may reduce contraceptive efficacy or increase the risk of adverse ef fects are not known for all forms of contraceptives. Combined Oral Contraceptives (COCs): • Several PIs, EFV, and elvitegravir/cobicistat (EVG/c)-based regimens have drug interactions with COCs. Interactions include either a decrease or an increase in , 19b , and 19d ), which 19a blood levels of ethinyl estradiol, norethindrone, or norgestimate (see Tables potentially decreases contraceptive efficacy or increases the risk of estrogen- or progestin-related adverse effects (e.g., thromboembolism). EFV can decrease etonogestrel bioavailability and plasma progestin 30 concentrations of COCs containing ethinyl estradiol and norgestimate. Several regimens that include 31-34 a cobicistat-boosted PI, PI/r, and EVG/c decrease oral contraceptive estradiol levels. One PK study 35 showed that DTG did not affect ethinyl estradiol or norgestimate levels. Several studies have shown that use of etravirine, rilpivirine, and NVP did not significantly affect estradiol or progestin levels in 36-38 individuals with HIV using COCs. • Injectable Contraceptives: Small studies of women with HIV who were receiving injectable depot- medroxyprogesterone acetate (DMP A) while on ART showed no significant interactions between DMPA 39-42 and EFV, lopinavir/ritonavir (LPV/r), NVP, nelfinavir (NFV), or NRTI drugs. Contraceptive Implants: • Contraceptive failure of the etonogestrel implant in women on EFV-based 43,44 therapy has been reported. Studies of women with levonorgestrel- and etonogestrel-releasing implants reported that participants receiving EFV-based ART had decreased bioavailability of levonorgestrel and I-22 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

170 45-47 etonogestrel. These studies did not identify any change in hormone concentrations when the implants 45,47 46 were used in those taking NVP Similarly, two retrospective cohort evaluations conducted or LPV/r. in Swaziland and Kenya showed an increased risk of contraceptive failure in women using contraceptive 48,49 implants and receiving EFV. Concerns about PK interactions between oral or implantable hormonal contraceptives and ARV drugs should not prevent clinicians from prescribing hormonal contraceptives for individuals on ART who prefer this contraceptive method. However, an alternative or additional effective contraceptive method is recommended when there are significant drug interactions between hormonal contraceptives and ARV drugs (see drug interaction Tables 19a , 19b , and 19d and the Perinatal Guidelines ). Risk of HIV Acquisition and Transmission Studies have produced conflicting data on the association between hormonal contraception and the risk 50 of acquisition of HIV. Most of the retrospective studies were done in the setting where the partners with HIV were not taking ART. A retrospective secondary analysis of two studies of serodiscordant couples in Africa in which the partner with HIV was not receiving ART found that, compared to women who did not use hormonal contraception, those using hormonal contraception (with the majority of study participants using injectable DMPA) had a two-fold increased risk of acquiring or transmitting HIV. Higher genital HIV RNA concentrations have been found in women with HIV using hormonal contraception than in those not 51 using hormonal contraceptives. Oral contraceptive use was not significantly associated with transmission of HIV; however, the number of women using oral contraceptives in this study was insufficient to adequately assess risk. A World Health Organization expert group reviewed all available evidence regarding hormonal contraception use and HIV transmission to a partner without HIV and recommended that individuals living 52 with HIV can continue to use all existing hormonal contraceptive methods without restriction. Further research is needed to definitively determine whether hormonal contraceptive use is an independent risk factor for acquisition and transmission of HIV, particularly in the setting of ART. Regardless, the potential association of hormonal contraception use and HIV transmission in the absence of ART underscores the importance of ART-induced viral suppression to reduce transmission risk. 53- Intrauterine devices (IUDs) appear to be a safe and effective contraceptive option for individuals with HIV. 55 Although studies have focused primarily on IUDs that do not contain hormones (e.g., copper IUD), several small studies have found that levonorgestrel-releasing IUDs are also safe and not associated with increased 56-58 genital tract shedding of HIV. Pregnancy Clinicians caring for pregnant adults and adolescents with HIV should review the Perinatal Guidelines . The use of combination ARV regimens is recommended for all pregnant persons with HIV, regardless of virologic, immunologic, or clinical parameters, for their own health and to prevent transmission of HIV to the fetus (AI) . Pregnant individuals with HIV should be counseled regarding the known benefits and risks of ARV use during pregnancy to the woman, fetus, and newborn. They should be counseled and strongly encouraged to receive ART for their own health and that of their infants. Open, nonjudgmental, and supportive discussion should be used to encourage them to adhere to care. Prevention of Perinatal Transmission of HIV The use of ART and the resultant reduction of HIV RNA levels decrease the risk of perinatal transmission 59-61 of HIV. The goal of ART is to achieve maximal and sustained viral suppression throughout pregnancy. Long-term follow-up is recommended for all infants who were exposed to ART in utero , regardless of the ). infant’s HIV status (see the Perinatal Guidelines I-23 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

171 Antiretroviral Regimen Considerations Pregnancy should not preclude the use of optimal ARV regimens. As in nonpregnant individuals, genotypic (AIII) resistance testing is recommended for all pregnant persons before ARV initiation and for those with detectable HIV RNA while on ART (AI) . However, ART initiation should not be delayed pending genotypic resistance test results. The ARV regimen can be modified, if necessary, once the resistance test results (BIII) are available . Unique considerations that influence recommendations on the ARVs to use during pregnancy include the following: • Physiologic changes associated with pregnancy that potentially change the PKs of ARV drugs, which may affect ARV dosing at different stages of pregnancy; • Potential ARV-associated adverse effects in pregnancy; • Potential for nonadherence to a particular regimen during pregnancy; and • Potential short-term and long-term ef fects of an ARV drug on the fetus and newborn, which are unknown for many drugs. ART is considered the standard of care for pregnant individuals with HIV, both to treat HIV infection and prevent perinatal transmission of HIV. Clinicians should review the Perinatal Guidelines for ARV recommendations for individuals who have recently received an HIV diagnosis or those who become pregnant while on ART. Based on preliminary data from Botswana that reported neural tube defects in infants born to women who were taking a DTG-based regimen at the time of conception, DTG is currently not recommended for use in those who are pregnant and within 12 weeks post-conception (AII) . Those who are pregnant and at 12 weeks post-conception or later may initiate or continue DTG-based regimens (CIII) . Discontinuing DTG is unlikely to confer any benefit after the neural tube has formed, and medication changes during pregnancy could increase the risk of viremia and perinatal transmission. If maternal HIV RNA is ≥1,000 copies/mL (or unknown) near delivery, IV infusion of ZDV during labor is recommended regardless of the mother’s antepartum regimen and resistance profile and the mode of infant delivery (AI) . Administration of combination ART should continue during labor and before a cesarean delivery (oral medications can be administered with sips of water during this time). Clinicians who are treating pregnant individuals with HIV are strongly encouraged to report cases of prenatal Antiretroviral Pregnancy exposure to ARV drugs (either administered alone or in combinations) to the Registry . The registry collects observational data regarding exposure to Food and Drug Administration- approved ARV drugs during pregnancy to assess potential teratogenicity. Postpartum Management Following delivery, clinical, immunologic, and virologic follow-up should continue as recommended for nonpregnant adults and adolescents. Because maternal ART reduces but does not eliminate the risk of transmission of HIV in breast milk and postnatal transmission can occur despite maternal ART, individuals 62 should be counseled to avoid breastfeeding. Persons with HIV should not premasticate food and feed it to 63 their infants because the practice has been associated with mother-to-child transmission of HIV. ART is currently recommended for all individuals with HIV (AI) ; therefore, maternal ART should be continued after delivery. For more information regarding postpartum management, refer to the Perinatal Guidelines . 64-66 Several studies have demonstrated that adherence to ART may decline in the postpartum period. Clinicians should address ART adherence at each clinic visit postpartum, including an evaluation of specific facilitators of and barriers to adherence. Clinicians may recommend an intervention to improve adherence Adherence to the Continuum of Care (see ). I-24 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

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174 38. Stuart GS, Moses A, Corbett A, et al. Combined oral contraceptives and antiretroviral PK/PD in Malawian women: pharmacokinetics and pharmacodynamics of a combined oral contraceptive and a generic combined formulation J Acquir Immune Defic Syndr antiretroviral in Malawi. . 2011;58(2):e40-43. Available at: http://www.ncbi.nlm.nih.gov/ pubmed/21921726 . Watts DH, et al. Depo-medroxyprogesterone in women on antiretroviral therapy: effective 39. Cohn SE, Park JG, Clin Pharmacol Ther contraception and lack of clinically significant interactions. . 2007;81(2):222-227. Available at: . https://www.ncbi.nlm.nih.gov/pubmed/17192768 Amaral E, Hays M, Viscola MA, Mehta N, Bahamondes L. Pharmacokinetic interactions between depot Nanda K, 40. . 2008;90(4):965-971. Available at: medroxyprogesterone acetate and combination antiretroviral therapy. Fertil Steril . https://www.ncbi.nlm.nih.gov/pubmed/17880953 W atts DH, Park JG, Cohn SE, et al. Safety and tolerability of depot medroxyprogesterone acetate among HIV-infected 41. . 2008;77(2):84-90. Available at: https://www.ncbi.nlm. Contraception women on antiretroviral therapy: ACTG A5093. nih.gov/pubmed/18226670 . Luque AE, Cohn SE, Park JG, et al. Depot medroxyprogesterone acetate in combination with a twice-daily lopinavir- 42. ritonavir-based regimen in HIV-infected women showed effective contraception and a lack of clinically significant interactions, with good safety and tolerability: results of the ACTG 5283 study. Antimicrob Agents Chemother . . http://www.ncbi.nlm.nih.gov/pubmed/25624326 2015;59(4):2094-2101. Available at: Viard JP, Yamgnane A, Karmochkine M, Benachi A. Contraceptive failure of etonogestrel implant in patients Leticee N, 43. treated with antiretrovirals including efavirenz. http://www.ncbi.nlm. Contraception . 2012;85(4):425-427. Available at: . nih.gov/pubmed/22036046 44. -positive woman on antiretroviral therapy McCarty EJ, Keane H, Quinn K, Quah S. Implanon(R) failure in an HIV Int J STD AIDS http://www.ncbi.nlm.nih.gov/ . 2011;22(7):413-414. Available at: resulting in two ectopic pregnancies. pubmed/21729965 . Scarsi KK, Darin KM, Nakalema S, et al. Unintended pregnancies observed with combined use of the levonor 45. gestrel contraceptive implant and efavirenz-based antiretroviral therapy: a three-arm pharmacokinetic evaluation over 48 weeks. Available at: http://www.ncbi.nlm.nih.gov/pubmed/26646680 . Clin Infect Dis . 2016;62(6):675-682. 46. V ieira CS, Bahamondes MV, de Souza RM, et al. Effect of antiretroviral therapy including lopinavir/ritonavir or efavirenz on etonogestrel-releasing implant pharmacokinetics in HIV-positive women. J Acquir Immune Defic Syndr . http://www.ncbi.nlm.nih.gov/pubmed/24798768 . 2014;66(4):378-385. Available at: 47. Chappell CA, Lamorde M, Nakalema S, et al. Efavirenz decreases etonogestrel exposure: a pharmacokinetic evaluation AIDS . 2017;31(14):1965-1972. Available at: https://www.ncbi. . of implantable contraception with antiretroviral therapy . nlm.nih.gov/pubmed/28692531 48. Patel RC, Onono M, Gandhi M, et al. Pregnancy rates in HIV-positive women using contraceptives and efavirenz-based . Lancet HIV . 2015;2(11):e474-482. or nevirapine-based antiretroviral therapy in Kenya: a retrospective cohort study Available at: . http://www.ncbi.nlm.nih.gov/pubmed/26520927 49. Perry SH, Swamy P , Preidis GA, Mwanyumba A, Motsa N, Sarero HN. Implementing the Jadelle implant for women AIDS . living with HIV in a resource-limited setting: concerns for drug interactions leading to unintended pregnancies. 2014;28(5):791-793. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24401645 . . 2012;12(1):2-3. Lancet Infect Dis : an unanswered question. Morrison CS, Nanda K. Hormonal contraception and HIV 50. http://www.ncbi.nlm.nih.gov/pubmed/21975268 . Available at: 51. fron R, Donnell D, Rees H, et al. Use of hormonal contraceptives and risk of HIV-1 transmission: a prospective Hef Lancet Infect Dis . 2012;12(1):19-26. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21975269 . cohort study. orld Health Organization. Hormonal contraceptive methods for women at high risk of HIV and living with HIV: 2014 52. W guidance statment. 2014. Geneva, Switzerland. Available at: http://apps.who.int/iris/bitstream/10665/128537/1/WHO_ RHR_14.24_eng.pdf?ua=1 . 53. A randomized trial of the intrauterine contraceptive device vs hormonal Stringer EM, Kaseba C, Levy J, et al. contraception in women who are infected with the human immunodeficiency virus. Am J Obstet Gynecol . 2007;197(2):144 e141-148. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17689627 . 54. Curtis KM, Nanda K, Kapp N. Safety of hormonal and intrauterine methods of contraception for women with . 2009;23 Suppl 1:S55-67. Available at: HIV/AIDS: a systematic review . AIDS https://www.ncbi.nlm.nih.gov/ pubmed/20081389 . I-27 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

175 55. Centers for Disease Control and Prevention. U.S. medical eligibility criteria for contraceptive use. 2010. Adapted MMWR Morb from: The World Health Organization Medical Eligibility Criteria for Contraceptive Use, 4th edition. . 2010;59(RR04):1-6. Available at: https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5904a1.htm?s_ Mortal Wkly Rep cid=rr5904a1_e . Heikinheimo O, Lehtovirta P , Aho I, Ristola M, Paavonen J. The levonorgestrel-releasing intrauterine system in human 56. . 2011;204(2):126 e121-124. immunodeficiency virus-infected women: a 5-year follow-up study. Am J Obstet Gynecol Available at: http://www.ncbi.nlm.nih.gov/pubmed/21035781 . Lehtovirta P , Paavonen J, Heikinheimo O. Experience with the levonorgestrel-releasing intrauterine system among HIV- 57. Contraception . 2007;75(1):37-39. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17161122 . infected women. 58. Coleman JS, Mwachari C, Balkus J, et al. Ef fect of the levonorgestrel intrauterine device on genital HIV-1 RNA J Acquir Immune Defic shedding among HIV-1-infected women not taking antiretroviral therapy in Nairobi, Kenya. Syndr . 2013;63(2):245-248. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23446496 . , Abrams EJ, Ammann A, et al. Perinatal transmission of human immunodeficiency virus type 1 by pregnant 59. Ioannidis JP J Infect Dis . 2001;183(4):539-545. Available at: https://www.ncbi.nlm. women with RNA virus loads <1000 copies/ml. . nih.gov/pubmed/11170978 60. Mofenson LM, Lambert JS, Stiehm ER, et al. Risk factors for perinatal transmission of human immunodeficiency virus type 1 in women treated with zidovudine. Pediatric AIDS Clinical Trials Group Study 185 Team. N Engl J Med . 1999;341(6):385-393. Available at: https://www.ncbi.nlm.nih.gov/pubmed/10432323 . 61. and the risk Garcia PM, Kalish LA, Pitt J, et al. Maternal levels of plasma human immunodeficiency virus type 1 RNA Women and Infants Transmission Study Group. . 1999;341(6):394-402. Available of perinatal transmission. N Engl J Med at: https://www.ncbi.nlm.nih.gov/pubmed/10432324 . 62. Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission. Recommendations Panel on for the use of antiretroviral drugs in pregnant women with HIV infection and interventions to reduce perinatal HIV transmission in the United States. 2018. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf . 63. AH, Freimanis-Hance L, Dominguez K, et al. Knowledge and practice of prechewing/prewarming food by HIV- Gaur infected women. Pediatrics . 2011;127(5):e1206-1211. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21482608 . 64. AD, Lindsey JC, Shannon M, et al. Adherence to antiretrovirals among US women during and after Bardeguez pregnancy. J Acquir Immune Defic Syndr http://www.ncbi.nlm.nih.gov/ . 2008;48(4):408-417. Available at: pubmed/18614923 . 65. Mellins CA, Chu C, Malee K, et al. Adherence to antiretroviral treatment among pregnant and postpartum HIV -infected women. AIDS Care . 2008;20(8):958-968. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18608073 . 66. Rana AI, Gillani FS, Flanigan TP, Nash BT, Beckwith CG. Follow-up care among HIV-infected pregnant women . 2010;19(10):1863-1867. Available at: in Mississippi. J Womens Health (Larchmt) https://www.ncbi.nlm.nih.gov/ pubmed/20831428 . I-28 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

176 HIV-2 Infection (Last updated April 8, 2015; last reviewed April 8, 2015) Summary of HIV-2 Infection Compared to HIV -1 infection, the clinical course of HIV-2 infection is generally characterized by a longer asymptomatic stage, lower • plasma HIV-2 RNA levels, and lower mortality; however, progression to AIDS does occur. • There have been no randomized trials addressing the question of when to start antiretroviral therapy (ART) or the choice of initial or second-line therapy for HIV-2 infection; thus, the optimal treatment strategy has not been defined. • Although the optimal CD4 T lymphocyte (CD4) cell count threshold for initiating ART in HIV-2 infection is unknown, therapy should be started before there is clinical progression. HIV-2 is intrinsically resistant to non-nucleoside reverse transcriptase inhibitors and to enfuvirtide; thus, these drugs should not be • included in an antiretroviral regimen for a patient living with HIV -2 infection. ART-naive patient who has HIV-2 mono-infection or HIV-1/HIV-2 dual infection and Pending more definitive data on outcomes in an • requires treatment, an initial antiretroviral therapy regimen for these patients should include two nucleoside reverse transcriptase inhibitors plus an HIV-2 active boosted protease inhibitor or integrase strand transfer inhibitors. • A few laboratories now offer quantitative plasma HIV-2 RNA testing for clinical care (see section text). Monitoring of HIV -2 RNA levels, CD4 cell counts, and clinical improvements can be used to assess treatment response, as is • recommended for HIV-1 infection. Resistance-associated viral mutations to nucleoside reverse transcriptase inhibitors, protease inhibitors, and/or integrase strand • transfer inhibitors may develop in patients with HIV -2 while on therapy. However, no validated HIV-2 genotypic or phenotypic antiretroviral resistance assays are available for clinical use. In the event of virologic, immunologic, or clinical failure, second-line treatment should be instituted in consultation with an expert in • HIV-2 management.. HIV-2 infection is endemic in West Africa. Although HIV-2 has had only limited spread outside this area, it should be considered when treating persons of West African origin or in those who have had sexual contact or shared needles with persons of West African origin. The prevalence of HIV-2 infection is also disproportionately high in countries with strong socioeconomic ties to West Africa (e.g., France, Spain, Portugal, and former Portuguese colonies such as Brazil, Angola, Mozambique, and parts of India). Clinical Course of HIV-2 Infection Compared to HIV-1 infection, the clinical course of HIV-2 infection is generally characterized by a longer 1,2 asymptomatic stage, lower plasma HIV-2 viral loads, and lower mortality rate. However, HIV-2 infection can also progress to AIDS over time. Concomitant HIV-1 and HIV-2 infection may occur and should be considered in patients from areas with a high prevalence of HIV-2. Diagnosis of HIV-2 Infection In the appropriate epidemiologic setting, HIV-2 infection should be suspected in patients with clinical conditions suggestive of HIV infection but with atypical serologic results (e.g., a positive screening assay 3 with an indeterminate HIV-1 Western blot. The possibility of HIV-2 infection should also be considered infection but low or in the appropriate epidemiologic setting in patients with serologically confirmed HIV undetectable HIV-1 RNA levels or in those with declining CD4 T lymphocyte (CD4) cell counts despite apparent virologic suppression on antiretroviral therapy (ART). 4 The 2014 Centers for Disease Control and Prevention guidelines for HIV diagnostic testing recommend initial HIV testing using an HIV-1/HIV-2 antigen/antibody combination immunoassay and subsequent testing using an HIV-1/HIV-2 antibody differentiation immunoassay. The Multispot HIV-1/HIV-2 Rapid Test (Bio-Rad Laboratories) is Food and Drug Administration-approved for differentiating HIV-1 from HIV-2 infection. Commercially available HIV-1 viral load assays do not reliably detect or quantify HIV- 5,6 2. Quantitative HIV-2 plasma RNA viral load testing has recently become available for clinical care at the I-29 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

177 7 University of Washington ( http://depts.washington.edu/labweb/AboutLM/Contact.htm and the New York ) https://www.wadsworth.org/programs/id/bloodborne-viruses/clinical-testing/ State Department of Health ( 8 ). hiv-2-nucleic-acid However, it is important to note that approximately one-quarter to one-third of patients with HIV-2 infection who are not on ART will have HIV-2 RNA levels below the limits of detection; some of these patients will have clinical progression and CD4 cell count decline. No validated HIV-2 genotypic or phenotypic antiretroviral (ARV) resistance assays are available for clinical use. Treatment of HIV-2 Infection To date, no randomized trials addressing the question of when to start ART or the choice of initial or second- 9 line therapy for HIV-2 infection have been completed; thus, the optimal treatment strategy has not been defined. Although the optimal CD4 cell count threshold for initiating ART in HIV-2 infection is unknown, therapy should be started before there is clinical progression. 10 HIV-2 is intrinsically resistant to non-nucleoside reverse transcriptase inhibitors (NNRTI) and to enfuvirtide 11 (T-20). Data from in vitro studies suggest that HIV-2 is sensitive to the currently available nucleoside 12,13 reverse transcriptase inhibitors (NRTIs), although with a lower barrier to resistance than HIV-1. Darunavir (DRV), lopinavir (LPV), and saquinavir (SQV) are more active against HIV-2 than other approved 14-17 protease inhibitors (PIs); one of these boosted PIs should be used if a PI-based regimen is used. Other PIs should be avoided because of their lack of ARV activity and high failure rates. The integrase strand transfer inhibitors (INSTIs) raltegravir (RAL), elvitegravir (EVG), and dolutegravir (DTG) have potent activity 18-21 against HIV-2 in vitro . The CCR5 antagonist maraviroc (MVC) appears active against some HIV-2 22 isolates; however, no approved assays to determine HIV-2 co-receptor tropism exist and HIV-2 is known to 23 use many other minor co-receptors in addition to CCR5 and CXCR4. Several small studies suggest poor responses in individuals with HIV-2 infection treated with some ARV regimens, including dual-NRTI regimens; regimens containing NNRTI plus two NRTIs; and some unboosted PI-based regimens including nelfinavir (NFV) or indinavir (IDV) plus zidovudine (ZDV) and lamivudine 9,24-27 (3TC); and atazanavir (ATV)-based regimens. Clinical data on the effectiveness of triple-NRTI regimens 28,29 are conflicting. In general, HIV-2 active, boosted PI-containing regimens have resulted in more favorable 29-31 virologic and immunologic responses than two or three-NRTI-based regimens. However, CD4 cell 31-33 recovery on therapy is generally poorer than that observed for HIV-1. INSTI-based regimens may also 34,35 have favorable treatment responses. A large systematic review of ART for patients with HIV-2 infection 36 (n = 17 studies, 976 patients with HIV-2) was unable to conclude which specific regimens are preferred. Resistance-associated viral mutations to NRTIs, PIs, and/or INSTIs commonly develop in patients with 41,42 24,29,37-41 HIV-2 while on therapy. In one Currently, HIV-2 transmitted drug resistance appears rare. small study, DTG was found to have activity as a second-line INSTI in some patients with HIV-2 who had 43 extensive ARV experience and RAL resistance. Genotypic algorithms used to predict drug resistance in HIV-1 may not be applicable to HIV-2, because pathways and mutational patterns leading to resistance may 13,29,44 differ between the HIV types. Some groups have recommended specific preferred and alternative regimens for initial therapy of HIV -2 45-48 infection; however, currently, there are no controlled trial data to support the effectiveness of the recommended regimens. Pending more definitive data on outcomes in an ART-naive patient who has HIV-2 mono-infection or HIV-1/HIV-2 dual infection and requires treatment, a regimen containing two NRTIs plus an HIV-2 active boosted PI or INSTI should be initiated in individuals with HIV-2 infection. HIV-2 plasma RNA levels, CD4 cell counts, and clinical improvements can be monitored to assess treatment response, as is recommended for HIV-1. Patients who have HIV-2 RNA levels below the limits of detection before therapy should still have HIV-2 plasma RNA monitoring, in addition to CD4 cell count and clinical monitoring. In the event of virologic, immunologic, or clinical failure, second-line treatment should be I-30 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

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180 nih.gov/pubmed/20397306 . Peterson K, Ruelle J, 34. Vekemans M, Siegal FP, Deayton JR, Colebunders R. The role of raltegravir in the treatment of . 2012;17(6):1097-1100. Available at http://www.ncbi.nlm. Antivir Ther HIV-2 infections: evidence from a case series. nih.gov/pubmed/22892365 . Y, Lambert C, Arendt V, Seguin-Devaux C. Virological and immunological outcomes of elvitegravir-based 35. Zheng regimen in a treatment-naive HIV-2-infected patient. . Sep 24 2014;28(15):2329-2331. Available at http://www. AIDS ncbi.nlm.nih.gov/pubmed/25313590 . Ekouevi DK, Tchounga BK, Coffie PA, et al. Antiretroviral therapy response among HIV-2 infected patients: a 36. BMC Infect Dis . 2014;14:461. Available at http://www.ncbi.nlm.nih.gov/pubmed/25154616 . systematic review. 37. Damond F , Matheron S, Peytavin G, et al. Selection of K65R mutation in HIV -2-infected patients receiving tenofovir- containing regimen. Antivir Ther https://www.ncbi.nlm.nih.gov/pubmed/15456096 . . Aug 2004;9(4):635-636. Available at Raugi DN, Smith RA, Ba S, et al. Complex patterns of protease inhibitor resistance among antiretroviral treatment- 38. experienced HIV -2 patients from Senegal: implications for second-line therapy. Antimicrob Agents Chemother . Jun 2013;57(6):2751-2760. Available at http://www.ncbi.nlm.nih.gov/pubmed/23571535 . 39. Charpentier C, Eholie S, Anglaret X, et al. Genotypic resistance profiles of HIV-2-treated patients in West Africa. AIDS . May 15 2014;28(8):1161-1169. Available at http://www.ncbi.nlm.nih.gov/pubmed/24583671 . 40. Charpentier C, Roquebert B, Delelis O, et al. Hot spots of integrase genotypic changes leading to HIV-2 resistance . Mar 2011;55(3):1293-1295. Available at http://www.ncbi.nlm.nih.gov/ . Antimicrob Agents Chemother to raltegravir pubmed/21189351 . -2EU: supporting standardized HIV-2 drug resistance interpretation in 41. Charpentier C, Camacho R, Ruelle J, et al. HIV Europe. Clin Infect Dis . Jun 2013;56(11):1654-1658. Available at http://www.ncbi.nlm.nih.gov/pubmed/23429380 . 42. AIDS Visseaux B, Benard A, et al. Transmitted drug resistance in French HIV-2-infected patients. . Jun 19 Charpentier C, 2013;27(10):1671-1674. Available at . http://www.ncbi.nlm.nih.gov/pubmed/23595155 Visseaux B, et al. Dolutegravir in HIV-2 infected patients with resistant virus to first-line 43. Descamps D, Peytavin G, Clin Infect Dis . Feb 17 2015. Available at http://www.ncbi. integrase inhibitors from the French Named Patient Program. nlm.nih.gov/pubmed/25690598 . 44. Y, Chadwick DR, Breuer J, et al. British HIV Association guidelines for antiretroviral treatment of HIV- Gilleece . Nov 2010;11(10):611-619. Available at https://www.ncbi.nlm.nih.gov/ 2-positive individuals 2010. HIV Med pubmed/20961377 . York State Department of Health AIDS Institute. Human Immunodeficiency Virus Type 2 (HIV-2). 2012. 45. New Available at http://www.hivguidelines.org/wp-content/uploads/2014/01/human-immunodeficiency-virus-type-2-hiv-2- archived-01-27-2014.pdf . 46. orld Health Organization. Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating And Preventing W HIV Infection. 2013. Available at . http://apps.who.int/iris/bitstream/10665/85321/1/9789241505727_eng.pdf 47. Infected Individuals. French HIV-2 Guidelines. Ministry of Health Expert Group on the Medical Management of HIV and Sports;2010. Available at http://www.sante.gouv.fr/IMG/pdf/Rapport_2010_sur_la_prise_en_charge_medicale_des_ personnes_infectees_par_le_VIH_sous_la_direction_du_Pr-_Patrick_Yeni.pdf . 48. orld Health Organization. What ARV regimen to start with in adults adolescents and pregnant women living with HIV- W . 2?. 2013. Available at http://apps.who.int/iris/bitstream/10665/90772/1/WHO_HIV_2013.36_eng.pdf?ua=1 I-33 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

181 (Last updated January 28, 2016; last reviewed January 28, 2016) HIV and the Older Patient Key Considerations When Caring for Older Patients With HIV Antiretroviral therapy (AR T) is recommended for all patients regardless of CD4 T lymphocyte cell count • . ART is especially (AI) important for older patients because they have a greater risk of serious non-AIDS complications and potentially a blunted immunologic response to ART. Adverse drug events from • ART and concomitant drugs may occur more frequently in older patients living with HIV than in younger patients with HIV. Therefore, the bone, kidney, metabolic, cardiovascular, and liver health of older patients should be monitored closely. Polypharmacy is common in older patients with HIV; therefore, there is a greater risk of drug-drug interactions between antiretroviral • drugs and concomitant medications. Potential for drug-drug interactions should be assessed regularly, especially when starting or switching ART and concomitant medications. • HIV experts, primary care providers, and other specialists should work together to optimize the medical care of older patients with HIV with complex comorbidities. • Early diagnosis of HIV and counseling to prevent secondary transmission of HIV remains an important aspect of the care of the older patient with HIV . Rating of Recommendations: A = Strong; B = Moderate; C = Optional Rating of Evidence: I = Data from randomized controlled trials; II = Data from well-designed nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinion Effective antiretroviral therapy (ART) has increased survival in individuals with HIV, resulting in an increasing number of older individuals living with HIV. In the United States, among persons living with HIV at year-end 2013, 42% were age 50 years or older, 6% were age 65 or older, and trends suggest that these 1 proportions will increase steadily. Care of patients with HIV increasingly will involve adults 60 to 80 years of age, a population for which data from clinical trials or pharmacokinetic (PK) studies are very limited. 2 There are several distinct areas of concern regarding the association between age and HIV disease. First, older patients with HIV may suffer from aging-related comorbid illnesses that can complicate the management of HIV infection. Second, HIV disease may affect the biology of aging, possibly resulting in early manifestations of clinical syndromes generally associated with advanced age. Third, reduced mucosal and immunologic defenses (such as postmenopausal atrophic vaginitis) and changes in risk related-behaviors (e.g., decrease in condom use because of less concern about pregnancy or more high-risk sexual activity with increased use of erectile dysfunction drugs) in older adults could lead to increased risk of acquisition and 3,4 transmission of HIV. Finally, because older adults are generally perceived to be at low risk of acquiring HIV, screening for this population remains low. HIV Diagnosis and Prevention in the Older Adult 5 In older adults, failure to consider a diagnosis of HIV likely contributes to later initiation of ART. The Centers for Disease Control and Prevention (CDC) estimates that in 2013, 37% of adults aged 55 years or older at the time of HIV diagnosis met the case definition for AIDS. The comparable CDC estimates are 18% 6 for adults aged 25 to 34 years and 30% for adults aged 35 to 44 years. In one observational cohort, older patients (defined as those ≥35 years of age) appeared to have lower CD4 T lymphocyte (CD4) cell counts at 7 seroconversion, steeper CD4 count decline over time, and tended to present to care with significantly lower 8 CD4 counts. When individuals >50 years of age present with severe illnesses, AIDS-related opportunistic infections (OIs) need to be considered in the differential diagnosis of the illness. Although many older individuals engage in risk behaviors associated with acquisition of HIV, they may see themselves or be perceived by providers as at low risk of infection and, as a result, they are less likely to be 9,10 tested for HIV infection than younger persons. Despite CDC guidelines recommending HIV testing at least I-34 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

182 11 once in individuals aged 13 to 64, and more frequently for those at risk, HIV testing prevalence remains 12 low (<5%) among adults aged 50 to 64, and decreased with increasing age. Clinicians must be attuned to the possibility of HIV infection in older adults, including those older than 64 years of age and especially in those who may engage in high-risk behaviors. Sexual history taking is therefore an important component of general health care for older adults who do not have HIV, together with risk-reduction counseling, and screening for HIV and sexually transmitted infections (STIs), if indicated. Impact of Age on HIV Disease Progression HIV infection presents unique challenges in aging adults and these challenges may be compounded by ART: 13 infection itself is thought to induce immune-phenotypic changes akin to accelerated aging, • HIV but recent laboratory and clinical data provide a more nuanced view of these changes. Some studies have shown that patients with HIV may exhibit chromosomal and immunologic features similar to those 14,15 induced by aging. However, other studies show the immunologic changes to be distinct from age- 16 related changes. In addition, although data on the increased incidence and prevalence of age-associated 17,18 are accumulating, comorbidities in patients with HIV the age of diagnosis for myocardial infection 18,19 and non-AIDS cancers in patients who have HIV and those who do not is the same. • Older patients with HIV have a greater incidence of complications and comorbidities than adults of a similar age who do not have HIV, and may exhibit a frailty phenotype—defined clinically as a decrease 20 in muscle mass, weight, physical strength, energy, and physical activity, although the phenotype is still incompletely characterized in people with HIV. Initiating Antiretroviral Therapy in the Older Patient with HIV section). ART is recommended for all individuals with HIV ( AI ; see Initiation of Antiretroviral Therapy Early treatment may be particularly important in older adults in part because of decreased immune recovery and increased risk of serious non-AIDS events in this population. In a modeling study based on data from an observational cohort, the beneficial effects of early ART were projected to be greatest in the oldest age 21 group (patients between ages 45 and 65 years). No data support a preference for any one of the Panel’s recommended initial ART regimens (see What to Start ) on the basis of patient age. The choice of regimen should instead be informed by a comprehensive review of the patient’s other medical conditions and medications. The What to Start section ( Table 7 ) of these guidelines provides guidance on selecting an antiretroviral regimen based on an older patient’s characteristics and specific clinical conditions (e.g., kidney disease, elevated risk for cardiovascular disease, osteoporosis). In older patients with reduced renal function, dosage adjustment of nucleoside reverse transcriptase inhibitors (NRTIs) may be necessary (see Appendix Table 8 ). In addition, ARV regimen selection may be influenced by potential interaction of antiretroviral medications with drugs used concomitantly to manage comorbidities (see Tables 19a-20b ). Adults age >50 years should be monitored for ART (see effectiveness and safety similarly to other populations with HIV Table 3 ); however, in older patients, special attention should be paid to the greater potential for adverse effects of ART on renal, liver, cardiovascular, metabolic, and bone health (see Table 15 ). HIV, Aging, and Antiretroviral Therapy The efficacy, PKs, adverse effects, and drug interaction potentials of ART in the older adult have not been studied systematically . There is no evidence that the virologic response to ART dif fers in older and younger patients. In a recent observational study, a higher rate of viral suppression was seen in patients >55 years 22 old than in younger patients. However , AR T-associated CD4 cell recovery in older patients is generally 8,23-25 slower and lower in magnitude than in younger patients. This observation suggests that starting ART at a younger age may result in better immunologic response and possibly clinical outcomes. Hepatic metabolism and renal elimination are the major routes of drug clearance, including the clearance of with HIV Guidelines for the Use of Antiretroviral Agents in Adults and Adolescent s 35 I- Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

183 ARV drugs. Both liver and kidney functions decrease with age and may result in impaired drug elimination 26 and increased drug exposure. Most clinical trials have included only a small proportion of participants over 50 years of age, and current ARV dosing recommendations are based on PK and pharmacodynamic data derived from participants with normal organ function. Whether drug accumulation in the older patient may lead to greater incidence and severity of adverse effects than seen in younger patients is unknown. Patients with HIV and aging-associated comorbidities may require additional pharmacologic interventions that can complicate therapeutic management. In addition to taking medications to manage HIV infection and comorbid conditions, many older patients with HIV also are taking medications to relieve discomfort (e.g., pain medications, sedatives) or to manage adverse effects of medications (e.g., anti-emetics). They also may self-medicate with over-the-counter medicines or supplements. In older patients who do not have HIV, 27 polypharmacy is a major cause of iatrogenic complications. Some of these complications may be caused by medication errors (by prescribers or patients), medication nonadherence, additive drug toxicities, and drug-drug interactions. Older patients with HIV are probably at an even greater risk of polypharmacy-related adverse consequences than younger or similarly aged patients with HIV. When evaluating any new clinical complaint or laboratory abnormality in patients with HIV, especially in older patients, clinicians should always consider the possible role of adverse drug reactions from both ARV drugs and other concomitantly administered medications. 28 Drug-drug interactions are common with ART and can be easily overlooked by prescribers. The available drug interaction information on ARV agents is derived primarily from PK studies performed in small numbers of relatively young participants with normal organ function who do not have HIV (see Tables 19a- 20b ). Data from these studies provide clinicians with a basis to assess whether a significant interaction may exist. However, the magnitude of the interaction may be greater in older patients with HIV than in younger patients with HIV. Nonadherence is the most common cause of treatment failure. Complex dosing requirements, high pill burden, inability to access medications because of cost or availability, limited health literacy including misunderstanding of instructions, depression, and neurocognitive impairment are among the key reasons for 32 nonadherence. Although many of these factors associated with nonadherence may be more prevalent in older patients, some studies have shown that older patients with HIV may actually be more adherent to ART 29-31 than younger patients. Clinicians should regularly assess older patients to identify any factors, such as neurocognitive deficits, that may decrease adherence. To facilitate medication adherence, it may be useful to discontinue unnecessary medications, simplify regimens, and recommend evidence-based behavioral approaches including the use of adherence aids such as pillboxes or daily calendars, and support from family members (see ). Adherence to the Continuum of Care Non-AIDS HIV-Related Complications and Other Comorbidities Among persons treated effectively with ART, as AIDS-related morbidity and mortality have decreased, non- 33-35 AIDS conditions constitute an increasing proportion of serious illnesses. Neurocognitive impairment, already a major health problem in aging adults, may be exacerbated by the effect of HIV infection on the 36 brain. In a prospective observational study, neurocognitive impairment was predictive of lower retention in 37 care among older persons. Neurocognitive impairment probably also affects adherence to therapy. Social isolation and depression are also particularly common among older adults with HIV and, in addition to their direct effects on morbidity and mortality, may contribute to poor medication adherence and retention 38,39 40 in care. Heart disease and cancer are the leading causes of death in older Americans. Similarly, non- AIDS events such as heart disease, liver disease, and cancer have emerged as major causes of morbidity and mortality in patients with HIV receiving effective ART. The presence of multiple non-AIDS comorbidities coupled with the immunologic effects of HIV infection may add to the disease burden of aging adults with 41-43 HIV. HIV-specific primary care guidelines have been updated with recommendations for lipid and I-36 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

184 glucose monitoring, evaluation and management of bone health, and management of kidney disease, and are 44-48 available for clinicians caring for older patients with HIV. Switching, Interrupting, and Discontinuing Antiretroviral Therapy in Older Patients Given the greater incidence of comorbidities, non-AIDS complications and frailty among older patients with HIV, switching one or more ARVs in an HIV regimen may be necessary to minimize toxicities and drug-drug interactions. For example, expert guidance now recommends bone density monitoring in men aged ≥50 years and postmenopausal women, and suggests switching from tenofovir disoproxil fumarate or boosted protease 45 inhibitors to other ARVs in older patients at high risk for fragility fractures. Few data exist on the use of ART in severely debilitated patients with chronic, severe, or non-AIDS terminal 49,50 conditions. Withdrawal of ART usually results in rebound viremia and a decline in CD4 cell count. Acute retroviral syndrome after abrupt discontinuation of ART has been reported. In severely debilitated patients, if there are no significant adverse reactions to ART, most clinicians would continue therapy. In cases where ART negatively affects quality of life, the decision to continue therapy should be made together with the patient and/or family members after a discussion on the risks and benefits of continuing or withdrawing ART. Healthcare Utilization, Cost Sharing, and End-of-Life Issues Important issues to discuss with aging patients with HIV are living wills, advance directives, and long-term care planning, including related financial concerns. Out-of-pocket health care expenses (e.g., copayments, deductibles), loss of employment, and other financial-related factors can cause temporary interruptions in treatment, including ART, which should be avoided whenever possible. The increased life expectancy and the higher prevalence of chronic complications in aging populations with HIV can place greater demands upon 51 HIV services. Facilitating a patient’s continued access to insurance can minimize treatment interruptions and reduce the need for other services to manage concomitant chronic disorders. Conclusion HIV disease can be overlooked in aging adults who tend to present with more advanced disease and experience accelerated CD4 loss. HIV induces immune-phenotypic changes that have been compared to accelerated aging. Effective ART has prolonged the life expectancy of patients with HIV, increasing the number of patients >50 years of age living with HIV. However, unique challenges in this population include greater incidence of complications and comorbidities, and some of these complications may be exacerbated or accelerated by long term use of some ARV drugs. Providing comprehensive multidisciplinary medical and psychosocial support to patients and their families (the “Medical Home” concept) is of paramount importance in the aging population. Continued involvement of HIV experts, geriatricians, and other specialists in the care of older patients with HIV is warranted. References Centers for Disease Control and Prevention. HIV Surveillance Report, 2014; vol. 26. 2015. Available at http://www.cdc. 1. . Accessed December 10, 2015. gov/hiv/library/reports/surveillance/ 2. AN. HIV infection, antiretroviral treatment, ageing, and non-AIDS related Deeks SG, Phillips morbidity. BMJ . 2009;338:a3172. Available at http://www.ncbi.nlm.nih.gov/entrez/query. fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19171560 . 3. Levy JA, Ory MG, Crystal S. HIV/AIDS interventions for midlife and older adults: current status and challenges. J Acquir Immune Defic Syndr . Jun 1 2003;33 Suppl 2:S59-67. Available at http://www.ncbi.nlm.nih.gov/entrez/query. fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12853854 . exclusion from sexually transmitted disease risk- 4. Levy BR, Ding L, Lakra D, Kosteas J, Niccolai L. Older persons’ http://www.ncbi.nlm.nih.gov/entrez/ Sex Transm Dis . Aug 2007;34(8):541-544. Available at reduction clinical trials. I-37 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

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187 36. ance DE, Wadley VG, Crowe MG, Raper JL, Ball KK. Cognitive and everyday functioning in older and younger adults V Clinical Gerontologists . 2011;34(5):413-426. with and without HIV. Jacks A, Wainwright DA, Salazar L, et al. Neurocognitive deficits increase risk of poor retention in care among older 37. AIDS . Aug 24 2015;29(13):1711-1714. Available at http://www.ncbi.nlm. adults with newly diagnosed HIV infection. . nih.gov/pubmed/26372282 , Brennan M, Karpiak SE. Loneliness and HIV-related stigma explain depression 38. Grov C, Golub SA, Parsons JT AIDS Care . May 2010;22(5):630-639. Available at http://www.ncbi.nlm.nih.gov/ among older HIV-positive adults. . pubmed/20401765 39. Kalichman SC, Heckman T, Kochman A, Sikkema K, Bergholte J. Depression and thoughts of suicide among middle- aged and older persons living with HIV-AIDS. Psychiatr Serv . Jul 2000;51(7):903-907. Available at http://www.ncbi. nlm.nih.gov/pubmed/10875956 . AM, King HC. Deaths: Preliminary data for 2009. National Vital Statistics 40. Kochanek KD, Xu J, Murphy SL, Minino Reports . 2011;59(4):1-54. 41. Guaraldi G, Orlando G, Zona S, et al. Premature age-related comorbidities among HIV-infected persons compared with the general population. Clin Infect Dis . Dec 201 1;53(11):1120-1126. Available at http://www.ncbi.nlm.nih.gov/entrez/ query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21998278 . 42. Aging and Premature Age-Related Comorbidities in HIV-Infected Patients: Facts and Capeau J. Premature Hypotheses. Clin Infect Dis . Dec 2011;53(11):1127-1129. Available at http://www.ncbi.nlm.nih.gov/entrez/query. fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21998279 . 43. gerber B, Furrer H, et al. Morbidity and aging in HIV-infected persons: the Swiss HIV cohort Hasse B, Leder Clin Infect Dis study. http://www.ncbi.nlm.nih.gov/entrez/query. . Dec 2011;53(11):1130-1139. Available at fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21998280 . 44. g JA, Gallant JE, Ghanem KG, Emmanuel P, Zingman BS, Horberg MA. Primary care guidelines for the Aber HIV Med icine association of the Infectious Diseases management of persons infected with HIV: 2013 update by the Society of America. . Jan 2014;58(1):e1-34. Available at http://www.ncbi.nlm.nih.gov/pubmed/24235263 . Clin Infect Dis Clin TT, Hoy J, Borderi M, et al. Recommendations for evaluation and management of bone disease in HIV. 45. Brown Infect Dis http://www.ncbi.nlm.nih.gov/pubmed/25609682 . . Apr 15 2015;60(8):1242-1251. Available at 46. Lucas GM, Ross MJ, Stock PG, et al. Clinical practice guideline for the management of chronic kidney disease in : 2014 update by the HIV Med icine Association of the Infectious Diseases Society of America. patients infected with HIV . Nov 1 2014;59(9):e96-138. Available at http://www.ncbi.nlm.nih.gov/pubmed/25234519 . Clin Infect Dis 47. American Academy of HIV Med icine. The HIV and Aging Consensus Project: Recommended treatment strategies for clinicians managing older patients with HIV. 2011. Available at http://www.aahivm.org/Upload_Module/upload/HIV%20 . Accessed January 13, 2016. and%20Aging/Aging%20report%20working%20document%20FINAL.pdf Jacobson TA, Maki KC, Orringer CE, al. e. National lipid association recommendations for patient-centered management 48. of dyslipidemia: part 2. . 2015. J Clin Lipidol 49. A. Chapter 75. In: Berger AM S, JL, Von Roenn JH, ed. Palliative care in HIV/AIDS. In Principles and Practice Selwyn P of Palliative Care and Supportive Oncology 3rd Edition. Philadelphia, PA: Lippincott Williams and Wilkins; 2007:833- 848. V, Krakauer E, et al. Quality HIV Care to the End of life. Clin Infect Dis . Feb 50. Harding R, Simms 15 2011;52(4):553-554; author reply 554. Available at http://www.ncbi.nlm.nih.gov/entrez/query. fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21258107 . 51. A, Morley D, O’Leary AC, Bergin CJ, Horgan M. Determinants of HIV outpatient service utilization: a Brennan http://www.ncbi.nlm.nih.gov/pubmed/24907780 . Jan 2015;19(1):104-119. Available at . systematic review. AIDS Behav I-40 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

188 Considerations for Antiretroviral Use in Patients with Coinfections Hepatitis B/HIV Virus Coinfection (Last updated October 17, 2017; last reviewed October 17, 2017) Panel’s Recommendations Before initiation of antiretroviral therapy (ART), all patients who test positive for hepatitis B surface antigen (HBsAg) should be • . (AIII) using a quantitative assay to determine the level of HBV replication tested for hepatitis B virus (HBV) DNA • Because emtricitabine (FTC), lamivudine (3TC), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF) have , an ART regimen for patients with both HIV and HBV should be include (TAF or TDF) plus activity against both HIV and HBV (3TC or FTC) as the nucleoside reverse transcriptase inhibitor (NRTI) backbone of a fully suppressive antiretroviral (ARV) (AI) regimen . TDF or TAF cannot safely be used, the alternative recommended HBV therapy is entecavir in addition to a fully suppressive • If (BI) . Entecavir has activity against HIV; its use for HBV treatment without ART in patients with dual infection ARV regimen may result in the selection of the M184V mutation that confers HIV resistance to 3TC and FTC. Therefore, entecavir must be used in addition to a fully suppressive ARV regimen when given to patients with HBV/HIV-coinfection (AII) . Peginterferon alfa monotherapy may also be considered in certain patients (CII) . • Other HBV treatment regimens, including adefovir alone or in combination with 3TC or FTC and telbivudine, are not for patients with HBV/HIV coinfection (CII) . recommended • Discontinuation of agents with anti-HBV activity may cause serious hepatocellular damage resulting from reactivation of HBV; patients should be advised against stopping these medications and be carefully monitored during interruptions in HBV treatment (AII) . ART needs to be modified due to HIV virologic failure and the patient has adequate HBV suppression, the ARV drugs • If active against HBV should be continued for HBV treatment in combination with other suitable ARV agents to achieve HIV . (AIII) suppression • HBV reactivation has been observed in persons with HBV infection during interferon-free HCV treatment. For that reason, all patients initiating HCV therapy should be tested for HBV. Persons with HCV/HIV coinfection and active HBV infection ART that includes two agents with anti-HBV activity prior to initiating (determined by a positive HBsAg test) should receive . (AIII) HCV therapy A = Strong; B = Moderate; C = Optional Rating of Recommendations: I = Data from randomized controlled trials; II = Data from well-designed nonrandomized trials or observational Rating of Evidence: cohort studies with long-term clinical outcomes; III = Expert opinion Approximately 5% to 10% of people with HIV in the United States also have chronic hepatitis B virus 1 (HBV) infection. The progression of chronic HBV to cirrhosis, end-stage liver disease, or hepatocellular carcinoma is more rapid in persons with HBV/HIV coinfection than in persons with chronic HBV 2 monoinfection. Conversely, chronic HBV does not substantially alter the progression of HIV infection and does not influence HIV suppression or CD4 T lymphocyte (CD4) cell responses following initiation 3,4 of antiretroviral therapy (ART). However, antiretroviral (ARV) drug toxicities or several liver-associated complications attributed to flares in HBV activity after initiation or discontinuation of dually active ARV 5-7 drugs can affect the treatment of HIV in patients with HBV/HIV coinfection. These complications include the following: • Emtricitabine (FTC), lamivudine (3TC), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (T AF) are ARVs approved to treat HIV that are also active against HBV. Discontinuation of these drugs 8 may potentially cause serious hepatocellular damage resulting from reactivation of HBV. The anti-HBV • drug entecavir has activity against HIV. However, when entecavir is used to treat HBV in patients with HBV/HIV coinfection who are not on ART, the drug may select for the M184V J-1 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

189 mutation that confers HIV resistance to 3TC and FTC. Therefore, when used in patients with HBV/HIV 9 . coinfection, entecavir must be used in addition to a fully suppressive ARV regimen (AII) in patients with HBV/HIV coinfection, • When 3TC is the only active drug used to treat chronic HBV 3TC-resistant HBV emerges in approximately 40% and 90% of patients after 2 and 4 years on 3TC, respectively. Therefore, 3TC or FTC, which is similar to 3TC, should be used in combination with other 10 (AII) anti-HBV drugs . • In patients with HBV/HIV coinfection, immune reconstitution following initiation of treatment for HIV, HBV, or both can be associated with elevated transaminase levels, possibly because HBV-induced liver 11 damage is primarily an immune-mediated disease. • Some ARV agents can increase transaminase levels. The rate and magnitude of these increases are 12-14 higher with HBV/HIV coinfection than with HIV monoinfection. The etiology and consequences of these changes in liver function tests are unclear because the changes may resolve with continued ART. Nevertheless, some experts suspend the suspected agent(s) when the serum alanine transferase (ALT) level increases to 5 to 10 times the upper limit of normal or at a lower threshold if the patient has symptoms of hepatitis. However, increased transaminase levels in persons with HBV/HIV coinfection may indicate hepatitis B e antigen (HBeAg) seroconversion due to immune reconstitution; thus, the cause of the elevations should be investigated before discontinuing medications. In persons with transaminase increases, HBeAg seroconversion should be evaluated by testing for HBeAg and anti-HBe, as well as HBV DNA levels. Recommendations for Patients with HBV/HIV Coinfection • Hepatitis should be evaluated to assess the severity of HBV infection (see All patients with chronic HBV B Virus Infection Guidelines for Prevention and Treatment of Opportunistic Infections in HIV- in the Infected Adults and Adolescents ). Patients with chronic HBV should also be tested for immunity to hepatitis A virus (HAV) infection (anti-HAV antibody total) and, if nonimmune, receive the HAV vaccination. In addition, patients with chronic HBV should be advised to abstain from alcohol and 15 counseled on prevention methods that protect against both HBV and HIV transmission. • Before ART is initiated, all persons who test positive for hepatitis B surface antigen (HBsAg) should be tested for HBV DNA by using a quantitative assay to determine the level of HBV replication (AIII) , and the test should be repeated every 3 to 6 months to ensure effective HBV suppression. The goal of HBV therapy with nucleoside reverse transcriptase inhibitors (NRTIs) is to prevent liver disease complications by sustained suppression of HBV replication. • Since HBV reactivation has been observed in persons with HBV infection during interferon-free HCV 16,17 treatment, persons with HCV/HIV coinfection and active HBV infection (determined by a positive HBsAg test) should receive ART that includes agents with anti-HBV activity (such as [TDF or TAF] plus [FTC or 3TC]) prior to initiating HCV therapy (AIII) . The diagnosis of HBV reactivation should be considered in persons with current HBV infection who experience elevated liver enzymes during or immediately after HCV therapy. Antiretroviral Drugs with Dual Activities against HBV and HIV Among the ARV drugs, 3TC, FTC, TAF, and TDF all have activity against HBV. Entecavir is an HBV nucleoside analog which also has weak HIV activity. TAF is a tenofovir prodrug with HBV activity and potentially less renal and bone toxicities than TDF. The efficacy of TDF versus TAF in patients with HBV monoinfection was evaluated in a randomized controlled trial of HBV treatment-naive and treatment-experienced HBeAg-negative patients. In this study, J-2 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

190 TAF was noninferior to TDF based on the percentage of patients with HBV DNA levels <29 IU/mL at 48 18 = .47). weeks of therapy (94% for TAF vs. 93% for TDF; P TAF was also noninferior to TDF in HBeAg- positive patients with chronic HBV monoinfection with a similar percentage of patients achieving HBV 19 DNA levels <29 IU/mL at 48 weeks of therapy (64% for TAF vs. 67% for TDF; = .25). P In both studies, patients on TAF experienced significantly smaller mean percentage decreases from baseline in hip and spine bone mineral density at 48 weeks than patients receiving TDF. The median change in estimated glomerular 18,19 filtration rate (eGFR) from baseline to 48 weeks also favored TAF. In patients with HBV/HIV coinfection, (TAF or TDF) plus (3TC or FTC) can be considered part of the ARV regimen; entecavir has weak anti-HIV activity and must not be considered part of an ARV regimen. In addition, TDF is fully active for the treatment of persons with known or suspected 3TC-resistant HBV infection, whereas 3TC resistance compromises the activity of entecavir against HBV. Recommended Therapy The combination of (TAF or TDF) plus (3TC or FTC) should be used as the NRTI backbone of an ARV 20-22 . (AII) regimen and for the treatment of both HIV and HBV infection The decision whether to use a TAF- or TDF-containing regimen should be based on an assessment of risk for nephrotoxicity and for acceleration of bone loss. In a switch study in patients with HBV/HIV coinfection, study participants who switched from a primarily TDF-based ART regimen to the fixed-dose combination elvitegravir/cobicistat/tenofovir alafenamide/emtricitabine (EVG/c/TAF/FTC) maintained or achieved HBV suppression, with improved 23 eGFR and bone turnover markers. TAF/FTC-containing regimens currently approved for the treatment of HIV infection are not recommended for use in patients with creatinine clearance (CrCl) <30 mL/min. While data on switching from a TDF-based to a TAF-based ART regimen are limited, the data from the EVG/c/ TAF/FTC switch study suggest that patients with HBV/HIV coinfection can switch to TAF/FTC-containing regimens with a potential reduction in renal and bone toxicity while maintaining HBV suppression. Alternative Therapy If TDF or TAF cannot safely be used, entecavir should be used in addition to a fully suppressive ARV 24 regimen (AII) ; however, entecavir should not be considered as part of the ARV regimen (BII). Because entecavir and 3TC share a partially overlapping pathway to HBV resistance, it is unknown whether the combination of entecavir plus 3TC or FTC will provide greater virologic or clinical benefit than entecavir alone. In persons with known or suspected 3TC-resistant HBV infection, the entecavir dose should be increased from 0.5 mg/day to 1 mg/day. However, entecavir resistance may emerge rapidly in patients with 3TC-resistant HBV infection. Therefore, entecavir should be used with caution in such patients with frequent monitoring (approximately every 3 months) of the HBV DNA level to detect viral breakthrough. Peginterferon alfa monotherapy for up to 48 weeks may also be considered in some patients with HBV/HIV coinfection. However, data on the use of this therapy in persons with HBV/HIV coinfection are limited and, given safety concerns, peginterferon alfa should not be used in persons with HBV/HIV coinfection who have decompensated cirrhosis. HBV Drugs Not Recommended Other HBV treatment regimens include telbivudine used in addition to a fully suppressive ARV regimen, or 20,25,26 adefovir used in combination with 3TC or FTC and a fully suppressive ARV regimen. However, data on these regimens in persons with HBV/HIV coinfection are limited. In addition, these regimens are associated with higher rates of HBV treatment failure and a higher incidence of toxicity when compared to regimens containing TDF, TAF, or entecavir. These toxicities include increased risk of renal disease with adefovir- containing regimens and increased risk of myopathy and neuropathy with telbivudine-containing regimens. Therefore, the Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents does not currently recommend adefovir or telbivudine for patients with HBV/HIV coinfection. J-3 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

191 Changing Antiretroviral Therapy • Need to discontinue ARV medications active against HBV: The patient’s clinical course should be monitored with frequent liver function tests. The use of entecavir to prevent flares can be considered, especially in patients with marginal hepatic reserve such as those with compensated or decompensated 8 cirrhosis. These alternative HBV regimens should only be used in addition to a fully suppressive ARV regimen. Need to change ART because of HIV resistance: If the patient has adequate HBV suppression, the • ARV drugs active against HBV should be continued for HBV treatment in combination with other ARV . (AIII) agents that effectively suppress HIV References 1. , Buchacz K, Moorman AC, Brooks JT. Prevalence of chronic hepatitis B virus infection Spradling PR, Richardson JT J Viral Hepat . Feb 11 2010. Available at https://www.ncbi.nlm. among patients in the HIV Outpatient Study, 1996-2007. nih.gov/pubmed/20158604 . 2. g EC, Skolasky R Jr, et al. HIV-1, hepatitis B virus, and risk of liver-related mortality in the Multicenter Thio CL, Seaber Cohort Study (MACS). Lancet https://www.ncbi.nlm.nih.gov/ . Dec 14 2002;360(9349):1921-1926. Available at . pubmed/12493258 3. A, de Wit S, et al. Hepatitis B and HIV: prevalence, AIDS progression, response to highly active Konopnicki D, Mocroft AIDS antiretroviral therapy and increased mortality in the EuroSIDA cohort. . Mar 24 2005;19(6):593-601. Available at https://www.ncbi.nlm.nih.gov/pubmed/15802978 . 4. Hof fmann CJ, Seaberg EC, Young S, et al. Hepatitis B and long-term HIV outcomes in coinfected HAART recipients. AIDS https://www.ncbi.nlm.nih.gov/pubmed/19550291 . . Sep 10 2009;23(14):1881-1889. Available at , et al. Liver enzyme elevation after lamivudine withdrawal in HIV-hepatitis B virus co- 5. Bellini C, Keiser O, Chave JP infected patients: the Swiss HIV Cohort Study. HIV Med . Jan 2009;10(1):12-18. Available at https://www.ncbi.nlm.nih. gov/pubmed/18795964 . 6. WP, Dore GJ, Duncombe CJ, et al. Risk of severe hepatotoxicity associated with antiretroviral therapy in the HIV- Law . Oct 17 2003;17(15):2191-2199. Available at https://www.ncbi.nlm.nih.gov/ NAT Cohort, Thailand, 1996-2001. AIDS pubmed/14523276 . 7. it FW, Weverling GJ, Weel J, Jurriaans S, Lange JM. Incidence of and risk factors for severe hepatotoxicity associated W J Infect Dis . Jul 1 2002;186(1):23-31. Available at https://www.ncbi.nlm.nih. with antiretroviral combination therapy. . gov/pubmed/12089658 V, Rockstroh J, et al. Frequent hepatitis B virus rebound among HIV-hepatitis B virus-coinfected 8. Dore GJ, Soriano AIDS . Mar 27 2010;24(6):857-865. Available at https://www.ncbi. patients following antiretroviral therapy interruption. . nlm.nih.gov/pubmed/20216301 9. TP, et al. The HBV drug entecavir - effects on HIV-1 replication and resistance. N McMahon MA, Jilek BL, Brennan Engl J Med https://www.ncbi.nlm.nih.gov/pubmed/17582071 . . Jun 21 2007;356(25):2614-2621. Available at Y, Bochet M, Thibault V, et al. Long-term incidence of hepatitis B virus resistance to lamivudine in human 10. Benhamou Hepatology immunodeficiency virus-infected patients. https://www.ncbi.nlm. . Nov 1999;30(5):1302-1306. Available at nih.gov/pubmed/10534354 . 11. Wywiol A, et al. Reactivation of hepatitis B virus replication accompanied by acute hepatitis in Manegold C, Hannoun C, Clin Infect Dis . Jan 2001;32(1):144-148. Available at https://www. patients receiving highly active antiretroviral therapy. ncbi.nlm.nih.gov/pubmed/11118394 . 12. Sulkowski MS, Thomas DL, Chaisson RE, Moore RD. Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. JAMA . Jan 5 2000;283(1):74-80. . Available at https://www.ncbi.nlm.nih.gov/pubmed/10632283 Wit FW, Wertheim-van Dillen PM, et al. Hepatitis B and C virus co-infection and the risk for den Brinker M, 13. J-4 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

192 hepatotoxicity of highly active antiretroviral therapy in HIV-1 infection. AIDS . Dec 22 2000;14(18):2895-2902. https://www.ncbi.nlm.nih.gov/pubmed/11153671 . Available at Neukam K, Mira JA, Collado A, et al. Liver toxicity of current antiretroviral regimens in HIV 14. -infected patients with chronic viral hepatitis in a real-life setting: The HEPAVIR SEG-HEP Cohort. PLoS One . 2016;11(2):e0148104. Available http://www.ncbi.nlm.nih.gov/pubmed/26848975 . at -Infected Adults and Adolescents. Guidelines for the prevention and treatment Panel on Opportunistic Infections in HIV 15. of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Med icine Association of the Infectious Diseases http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf . Society of America. 2016. Available at 16. Bersoff-Matcha SJ, Cao K, Jason M, et al. Hepatitis B virus reactivation associated with direct-acting antiviral therapy for chronic hepatitis C virus: a review of cases reported to the U.S. Food and Drug Administration Adverse Event Reporting System. Ann Intern Med https://www.ncbi.nlm.nih.gov/ . Jun 06 2017;166(11):792-798. Available at . pubmed/28437794 Wang C, Ji D, Chen J, et al. Hepatitis due to reactivation of hepatitis B virus in endemic areas among patients with 17. hepatitis C treated with direct-acting antiviral agents. Clin Gastroenterol Hepatol . Jan 2017;15(1):132-136. Available at https://www.ncbi.nlm.nih.gov/pubmed/27392759 . Buti M, Gane E, Seto WK, et al. A Phase 3 study of tenofovir alafenamide compared with tenofovir disoproxil fumarate 18. in patients with HBeAg-negative, chronic hepatitis B: Week 48 efficacy and safety results. Presented at: EASL International Liver Conference. 2016. Barcelona, Spain. 19. Chan HL Y, Fung S, Seto WK. A Phase 3 study of tenofovir alafenamide compared with tenofovir disoproxil fumarate in patients with HBeAg-positive, chronic hepatitis B: Week 48 efficacy and safety results. Presented at: EASL International Liver Conference. 2016. Barcelona, Spain. 20. Peters MG, Andersen J, Lynch P, et al. Randomized controlled study of tenofovir and adefovir in chronic hepatitis B virus and HIV infection: ACTG A5127. Hepatology https://www.ncbi.nlm.nih. . Nov 2006;44(5):1110-1116. Available at . gov/pubmed/17058225 , Seaberg E, Dore GJ, et al. Combination HBV therapy is linked to greater HBV DNA suppression in a Matthews GV 21. . Aug 24 2009;23(13):1707-1715. Available at cohort of lamivudine-experienced HIV/HBV coinfected individuals. AIDS https://www.ncbi.nlm.nih.gov/pubmed/19584701 . 22. Vries-Sluijs TE, Reijnders JG, Hansen BE, et al. Long-term therapy with tenofovir is effective for patients co-infected de Gastroenterology https://www.ncbi.nlm.nih.gov/pubmed/20801123 . with HIV and HBV. . Aug 26 2010. Available at 23. Gallant J, Brunetta J, Crofoot G, et al. Efficacy and safety of switching to a single-tablet regimen of elvitegravir/ cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/T AF) in HIV-1/hepatitis B coinfected adults. J Acquir Immune Defic Syndr . May 11 2016. Available at http://www.ncbi.nlm.nih.gov/pubmed/27171740 . 24. Pessoa MG, Gazzard B, Huang AK, et al. Efficacy and safety of entecavir for chronic HBV in HIV/HBV coinfected AIDS . Sep 12 2008;22(14):1779-1787. Available at patients receiving lamivudine as part of antiretroviral therapy. https:// www.ncbi.nlm.nih.gov/pubmed/18753861 . Benhamou 25. Y, Bochet M, Thibault V, et al. Safety and efficacy of adefovir dipivoxil in patients co-infected with HIV-1 and lamivudine-resistant hepatitis B virus: an open-label pilot study. . Sep 1 2001;358(9283):718-723. Available at Lancet https://www.ncbi.nlm.nih.gov/pubmed/11551579 . , Valantin MA, Thibault V, et al. Efficacy and safety of adefovir dipivoxil plus pegylated interferon-alpha2a for Ingiliz P 26. the treatment of lamivudine-resistant hepatitis B virus infection in HIV-infected patients. Antivir Ther . 2008;13(7):895- https://www.ncbi.nlm.nih.gov/pubmed/19043923 900. Available at . J-5 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

193 Hepatitis C Virus/HIV Coinfection (Last updated October 25, 2018; last reviewed October 25, 2018) Panel’s Recommendations • . Patients at high risk of HCV infection should All people with HIV should be screened for hepatitis C virus (HCV) infection (AIII) be screened annually and whenever incident HCV infection is suspected (AIII) . • therapy (ART) may slow the progression of liver disease by preserving or restoring immune function and reducing Antiretroviral HIV-related immune activation and inflammation. For most persons with HCV/HIV coinfection, including those with cirrhosis, the benefits of ART outweigh concerns regarding drug-induced liver injury. Therefore, ART should be initiated in all patients with HCV/HIV coinfection, regardless of CD4 T lymphocyte cell count (AI) . • Initial ART regimens that are recommended for most patients with HCV/HIV coinfection are the same as those recommended for individuals without HCV infection. However, when treatment for both HIV and HCV is indicated, the ART and HCV treatment regimens should be selected with special consideration for potential drug-drug interactions and overlapping toxicities (AIII) (see discussion in the text below and in Table 13). , which includes having their liver fibrosis stage • All patients with HCV/HIV coinfection should be evaluated for HCV therapy assessed to inform the length of their therapy and subsequent risk of hepatocellular carcinoma and liver disease complications (AIII) . • Persons with chronic HCV/HIV coinfection should be screened for active and prior hepatitis B virus (HBV) infection by testing for the presence of hepatitis B surface antigen (HBsAg) and antibodies to hepatitis B surface (HBsAb) and core (HBcAb; total . or IgG). Persons who are not immune to HBV infection (HBsAb negative) should receive anti-HBV vaccination (AIII) • HBV reactivation has been observed in persons with HBV infection during HCV treatment with direct-acting antivirals (DAAs). Accordingly , persons with HCV/HIV coinfection and active HBV infection (HBsAg positive) should receive ART that includes (AIII) . two agents with anti-HBV activity prior to initiating HCV therapy A = Strong; B = Moderate; C = Optional Rating of Recommendations: Rating of Evidence: I = Data from randomized controlled trials; II = Data from well-designed nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinion The treatment of hepatitis C virus (HCV) infection is rapidly evolving. Patients with HCV/HIV coinfection treated with all-oral, direct-acting antiviral (DAA) HCV regimens can achieve sustained virologic response 1-3 (HCV cure) at rates comparable to those of patients with HCV mono-infection. This section of the guidelines focuses on hepatic safety and drug-drug interaction issues related to HCV/HIV coinfection and the concomitant use of antiretroviral (ARV) agents and HCV drugs. For specific guidance on HCV treatment, clinicians should refer to the HCV Guidance from the American Association for the Study of Liver Diseases. Among patients with chronic HCV infection, approximately one-third progress to cirrhosis, at a median time 4,5 6-9 of <20 years. The rate of progression increases with older age, alcoholism, male sex, and HIV infection. A meta-analysis found that patients with HCV/HIV coinfection had a three-fold greater risk of progression to 8 cirrhosis or decompensated liver disease than patients with HCV monoinfection. The risk of progression is even greater in patients with HCV/HIV coinfection who have low CD4 T lymphocyte cell counts. Although antiretroviral therapy (ART) appears to slow the rate of HCV disease progression in patients with HCV/ HIV coinfection, several studies have demonstrated that the rate of disease progression continues to exceed 10,11 that observed in patients without HIV infection. Whether HCV infection accelerates HIV progression, as 12 measured by the occurrence of AIDS-related opportunistic infections (OIs) or death, is unclear. With older ARV drugs, persons with chronic HCV co-infection experienced higher rates of hepatotoxicity than those 13,14 seen in persons without HCV. These higher rates have not been observed with the newer ARV agents that are currently in use. Assessment of HCV/HIV Coinfection • All patients with HIV should be screened for HCV infection using sensitive immunoassays licensed for Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV J-6 Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

194 15 the detection of antibodies to HCV in blood. At-risk HCV-seronegative patients should undergo repeat testing annually or as clinically indicated. HCV-seropositive patients should be tested for HCV RNA using a sensitive quantitative assay to confirm the presence of active infection. Patients who test HCV HCV RNA positive should undergo HCV genotyping and liver disease staging as recommended by the Guidance . • Patients with HCV/HIV coinfection should be counseled to avoid consuming alcohol and to use appropriate precautions to prevent transmission of HIV and/or HCV to others. • People with chronic HCV/HIV coinfection should be screened for active and prior hepatitis B virus (HBV) infection by testing for the presence of hepatitis B surface antigen (HBsAg) and antibodies to hepatitis B surface (HBsAb) and core (HBcAb; total or IgG). Persons with evidence of active HBV infection (as determined by the presence of HBsAg) should be • ART that includes agents with anti-HIV and anti-HBV activities further evaluated and treated with . (AIII) • Those who are not immune to HBV infection (HBsAb negative) should receive anti-HBV vaccination. Patients with HCV/HIV coinfection who are susceptible to hepatitis A virus (HAV) should be vaccinated. • All patients with HCV/HIV • coinfection are candidates for curative HCV treatment. Antiretroviral Therapy in HCV/HIV Coinfection When to Start Antiretroviral Therapy Initiation of ART for persons with HCV/HIV coinfection should follow the recommendations for all persons with HIV infection, taking into account the need for concurrent HCV treatment with oral DAA regimens, drug-drug interaction potentials, and the individual’s HBV status. Considerations When Starting Antiretroviral Therapy The same regimens that are recommended for initial treatment of HIV in most ART-naive persons are also recommended for persons with HCV/HIV coinfection. Special considerations for ARV selection in persons with HCV/HIV coinfection include the following: • and HCV treatments are indicated, the ARV regimen should be selected with careful When both HIV consideration of potential drug-drug interactions with the HCV treatment regimen (see Table 13). • coinfection, HBV reactivation has been observed during HCV treatment with In persons with HCV/HBV 16,17 DAAs. Therefore, persons with HCV/HIV coinfection and active HBV infection (HBsAg positive) should receive ART that includes agents with anti-HBV activity (such as tenofovir disoproxil fumarate [TDF] or tenofovir alafenamide plus emtricitabine or lamivudine) prior to initiating HCV therapy (AIII) . • Cirrhotic patients should be evaluated for signs of liver decompensation according to the Child-Turcotte- Pugh classification system. All patients with Child-Pugh class B or C disease should be evaluated by an expert in advanced liver disease and considered for liver transplantation. Furthermore, hepatically metabolized ARV and HCV DAA drugs may be contraindicated or require dose modification in patients with Child-Pugh class B and C disease (see Appendix B, Table 8 ). Hepatotoxicity Drug-induced liver injury (DILI) following the initiation of ART is more common in patients with coinfection HCV/HIV coinfection than in those with HIV mono-infection. Individuals with HCV/HIV J-7 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

195 18 who have advanced liver disease (e.g., cirrhosis, end-stage liver disease) are at greatest risk for DILI. 19 Eradicating HCV infection with treatment may decrease the likelihood of ARV-associated DILI. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels should be monitored 4 to 8 weeks after initiation of ART and at least every 6 to 12 months thereafter, and more often if clinically indicated. Mild to moderate fluctuations in ALT and/or AST levels (<5 times upper limit of normal [ULN]) are typical in individuals with chronic HCV infection. In the absence of signs and/or symptoms of liver disease or increases in bilirubin, these fluctuations do not warrant interruption of ART, but do warrant monitoring to ensure a return to baseline. Patients with significant elevations in ALT and/or AST levels (>5 times ULN), concomitant increase in total bilirubin, and/or concomitant symptoms (weakness, nausea, vomiting) should be carefully evaluated for signs and symptoms of liver insufficiency and for alternative causes of liver injury (e.g., acute HAV or HBV infection, hepatobiliary disease, or alcoholic hepatitis). If these signs and symptoms do not resolve, ART should be discontinued. Concurrent Treatment of HIV and HCV Infections Guidance on the treatment and management of HCV in adults with and without HIV can be found in the HCV Guidance . Several ARV drugs and HCV DAAs have the potential for clinically significant pharmacokinetic drug-drug interactions when used in combination. Prior to starting HCV therapy, the ART regimen may need to be modified to reduce the drug-drug interaction potential. Table 13 below provides recommendations on the concomitant use of selected drugs for treatment of HCV and HIV infection. In patients receiving ART that has been modified to accommodate HCV treatment, HIV RNA should be measured within 2 to 8 weeks after changing HIV therapy to confirm the effectiveness of the new regimen. Clinicians should wait at least 2 weeks after ART modification before initiating an HCV DAA regimen. Clinicians should also wait for at least 2 weeks before resuming the original ART regimen after a patient completes the HCV DAA regimen. The prolonged half-life of some HIV and HCV drugs poses a potential risk of drug-drug interactions if a regimen is resumed soon after ART modification or HCV treatment completion. J-8 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

196 Table 13. Concomitant Use of Selected Antiretroviral Drugs and Hepatitis C Virus Direct-Acting Antiviral Drugs for Treatment of HCV in (page 1 of 4) Adults with HIV The recommendations in this table for concomitant use of selected HIV drugs with FDA-approved HCV DAA drugs are based on available PK interaction data or are predictions based on the known metabolic pathway of the agents. In some cases, there are not enough data to make any recommendations, and these instances are indicated in the table. In all cases where HIV and HCV drugs are used concomitantly, patients should be closely monitored for HIV and HCV virologic efficacy and potential toxicities. As the field of HCV therapy is rapidly evolving, readers should also refer to the latest drug product labels and the HCV Guidance for updated information. Note: included in this table. Please refer to the FDA product labels for information regarding drug not Interactions with FPV, IDV, NFV, and SQV are interactions with these HIV PIs. HCV Direct-Acting Antiviral Agents Coformulated SHOULD NOT BE USED IN THOSE WITH MODERATE TO SEVERE HEPATIC IMPAIRMENT (Cirrhosis classified as Child-Pugh class B or C) NS5B NS5A NS5A Inhibitor/ NS5A Inhibitor/ NS5A Inhibitor/ NS5A/NS5B Inhibitor Inhibitor Selected NS3A/4A Protease NS3A/4A NS3A/4A NS3/4A NS5A/NS5B NS5A/NS5B Inhibitor/ HIV Drugs a Inhibitor plus Protease Inhibitor Protease Protease Inhibitor NS3/4A Protease Inhibitor NS5B Inhibitor Inhibitor Inhibitor Inhibitor Ombitasvir/ Sofosbuvir/ Glecaprevir/ Paritaprevir/ Elbasvir/ Ledipasvir/ Sofosbuvir/ Velpatasvir/ Simeprevir Daclatasvir Sofosbuvir Pibrentasvir Grazoprevir Ritonavir plus Velpatasvir Sofosbuvir Voxilaprevir a Dasabuvir NRTIs 3TC ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ABC ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ FTC ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ TDF ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ Monitor for TDF Monitor for TDF Monitor for TDF toxicity. toxicity. toxicity. TAF ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ PIs b Unboosted ✘ ✘ ✓ ✓ ✓ ✓ ✘ ✘ ✓ ATV J-9 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

197 Table 13. Concomitant Use of Selected Antiretroviral Drugs and Hepatitis C Virus Direct-Acting Antiviral Drugs for Treatment of HCV in (page 2 of 4) Adults with HIV HCV Direct-Acting Antiviral Agents Coformulated SHOULD NOT BE USED IN THOSE WITH MODERATE TO SEVERE HEPATIC IMPAIRMENT (Cirrhosis classified as Child-Pugh class B or C) NS5A NS5B NS5A Inhibitor/ NS5A Inhibitor/ NS5A Inhibitor/ NS5A/NS5B Inhibitor Inhibitor Selected NS3A/4A NS3A/4A Protease NS3A/4A NS3/4A Inhibitor/ NS5A/NS5B NS5A/NS5B HIV Drugs a Inhibitor plus Protease Inhibitor Protease Protease NS3/4A Protease Inhibitor Inhibitor NS5B Inhibitor Inhibitor Inhibitor Inhibitor Ombitasvir/ Sofosbuvir/ Elbasvir/ Glecaprevir/ Paritaprevir/ Ledipasvir/ Sofosbuvir/ Velpatasvir/ Simeprevir Sofosbuvir Daclatasvir Grazoprevir Pibrentasvir Ritonavir plus Velpatasvir Sofosbuvir Voxilaprevir a Dasabuvir PIs , continued c ATV/r or ✘ ✓ ✘ ✘ ✘ ✓ ✓ ATV/c ↓ DCV dose ✓ ✓ to 30 mg/day If a PI/r or PI/c If a PI/r or PI/c DRV/r or ✘ ✘ ✘ ✘ ✓ ✓ ✓ is used with is used with DRV/c If a PI/r is used TDF, ↑ TDF TDF, ↑ TDF with TDF, ↑ TDF concentrations concentrations concentrations. are expected. If are expected. If Monitor for coadministration coadministration TDF-associated is necessary, is necessary, d toxicities. monitor for monitor for Consider TDF-associated TDF-associated monitoring for d d toxicities. toxicities. e hepatotoxicity. LPV/r ✓ ✘ ✘ ✓ ✘ ✘ ✘ TPV/r ? ✘ ✘ ✘ ✘ ✘ ✘ ✘ ✘ NNRTIs DOR ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ If used with TDF, EFV ✓ ✓ ✘ ✘ ✘ ✘ ✘ ✘ monitor for TDF ↑ DCV dose toxicity. to 90 mg/day ETR ✘ ✘ ✘ ✓ ✘ ✘ ✓ ✘ ↑ DCV dose to 90 mg/day J-10 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

198 Table 13. Concomitant Use of Selected Antiretroviral Drugs and Hepatitis C Virus Direct-Acting Antiviral Drugs for Treatment of HCV in Adults with HIV (page 3 of 4) HCV Direct-Acting Antiviral Agents Coformulated SHOULD NOT BE USED IN THOSE WITH MODERATE TO SEVERE HEPATIC IMPAIRMENT (Cirrhosis classified as Child-Pugh class B or C) NS5B NS5A NS5A Inhibitor/ NS5A Inhibitor/ NS5A Inhibitor/ NS5A/NS5B Inhibitor Inhibitor Selected NS3A/4A NS3A/4A Protease NS3A/4A NS3/4A NS5A/NS5B NS5A/NS5B Inhibitor/ HIV Drugs a Inhibitor plus Protease Inhibitor Protease Protease Inhibitor NS3/4A Protease Inhibitor NS5B Inhibitor Inhibitor Inhibitor Inhibitor Ombitasvir/ Sofosbuvir/ Glecaprevir/ Paritaprevir/ Elbasvir/ Sofosbuvir/ Ledipasvir/ Velpatasvir/ Daclatasvir Simeprevir Sofosbuvir Grazoprevir Pibrentasvir Ritonavir plus Velpatasvir Sofosbuvir Voxilaprevir a Dasabuvir NNRTIs , continued NVP ✓ ✘ ✘ ✓ ✓ ✘ ✘ ✘ ✘ If used with TDF, ↑ DCV dose to 90 mg/day monitor for TDF toxicity. RPV ✓ ✓ ✓ ✓ ✓ ✓ ✘ ✓ INSTIs BIC/TAF/FTC ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ DTG ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ If used with TDF, monitor for TDF toxicity. EVG/c/TDF/ ✘ ✓ ✘ ✘ ✓ ✘ ✓ ✓ ✓ FTC If used with TDF, ↓ DCV dose If used with TDF, If used with TDF, monitor for TDF monitor for TDF monitor for TDF to 30 mg/day toxicity. Consider toxicity. toxicity. Consider monitoring for monitoring for f e hepatotoxicity. hepatotoxicity. EVG/c/TAF/ ✓ ✘ ✘ ✘ ✓ ✓ ✓ ✓ ✓ FTC Consider Consider ↓ DCV dose monitoring for monitoring for to 30 mg/day e f hepatotoxicity. hepatotoxicity. RAL ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ CCR5 Antagonist MVC ✘ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ J-11 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

199 Table 13. Concomitant Use of Selected Antiretroviral Drugs and Hepatitis C Virus Direct-Acting Antiviral Drugs for Treatment of HCV in (page 4 of 4) Adults with HIV a Dasabuvir must be prescribed with ombitasvir/paritaprevir/RTV. b Reduce ATV dose to 300 mg and instruct the patient to take it in the morning at same time as ombitasvir/paritaprevir/RTV plus dasabuvir. If RTV cannot be used, choose an alternative HCV regimen. c This HCV regimen contains R TV. If ATV is part of the ARV regimen, prescribe ATV 300 mg without COBI or RTV. It should be taken in the morning at the same time as ombitasvir/ paritaprevir/RTV plus dasabuvir. Resume RTV or COBI regimen when HCV therapy is completed. d Consider using an alternative HCV treatment or ARV regimen to avoid increases in TDF exposure. If co-administration is necessary, monitor patient for TDF-associated adverse reactions. e V oxilaprevir exposures can increase when it is coadministered with pharmacologically boosted DRV or EVG. Until more safety data in clinical settings becomes available, patients who are receiving voxilaprevir and pharmacologically boosted DRV or EVG should be monitored for hepatotoxicity. f Glecaprevir exposures can increase when it is coadministered with EVG/c. Until more safety data in clinical settings becomes available, patients who are receiving glecaprevir and EVG/c should be monitored for hepatotoxicity . Key to Symbols: = ARV agents that can be used concomitantly ✓ ✘ = ARV agents not recommended ? = data limited or not available on pharmacokinetic interactions with ARV drug ↑ = increase ↓ = decrease Key to Acronyms: 3TC = lamivudine; ABC = abacavir; ARV = antiretroviral; ATV = atazanavir; ATV/c = atazanavir/cobicistat; ATV/r = atazanavir/ritonavir; BIC = bictegravir; COBI = cobicistat; DAA = direct-acting antiviral agents; DCV = daclatasvir; DOR = doravirine; DRV = darunavir; DRV/c = darunavir/cobicistat; DRV/r = darunavir/ritonavir; DTG = dolutegravir; DSV = Food and Drug Administration; EVG/c = elvitegravir/cobicistat; FPV = fosamprenavir; FTC = emtricitabine; HCV = dasabuvir; EFV = efavirenz; ETR = etravirine; EVG = elvitegravir; FDA TI = non-nucleoside reverse transcriptase inhibitor; NRTI = hepatitis C virus; IDV = indinavir; INSTI = integrase strand transfer inhibitor; LPV/r = lopinavir/ritonavir; MVC = maraviroc; NNR = nucleoside reverse transcriptase inhibitor; NVP = nevirapine; PI = protease inhibitor; PI/c = protease inhibitor/cobicistat; PI/r = protease inhibitor/ritonavir; PK = pharmacokinetic; RAL = raltegravir; RPV = rilpivirine; RTV = ritonavir; SQV = saquinavir; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; TPV/r = tipranavir/ritonavir J-12 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

200 References 1. Naggie S, Cooper C, Saag M, et al. Ledipasvir and sofosbuvir fo r HCV in patients coinfected with HIV-1. N Engl J Med . vailable at: https://www.ncbi.nlm.nih.gov/pubmed/26196665 2015;373(8):705-713. A . Rockstroh JK, Nelson M, Katlama C, et al. Efficacy and safety of 2. grazoprevir (MK-5172) and elbasvir (MK-8742) in patients Lancet HIV . with hepatitis C virus and HIV co-infection (C-EDGE CO-INFECTION): a non-randomised, open-label trial. 2015;2(8):e319-327. A https://www.ncbi.nlm.nih.gov/pubmed/26423374 . vailable at: Sogni P All-oral direct-acting antiviral regimens in HIV/hepatitis C virus-coinfected patients 3. , Gilbert C, Lacombe K, et al. e prospective ANRS CO13-HEPAVIH cohort. Clin Infect Dis . with cirrhosis are efficient and safe: real-life results from th vailable at: . 2016;63(6):763-770. A https://www.ncbi.nlm.nih.gov/pubmed/27317796 Alter MJ, Mar golis HS, Krawczynski K, et al. The natural history of community-acquired hepatitis C in the United States. 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Available at: https://www.ncbi.nlm.nih.gov/pubmed/11462196 . Clin Infect Dis Thein HH, -infected individuals and the impact 9. Yi Q, Dore GJ, Krahn MD. Natural history of hepatitis C virus infection in HIV of HIV in the era of highly active antiretroviral therapy: a meta-analysis. AIDS . 2008;22(15):1979-1991. Available at: https:// www.ncbi.nlm.nih.gov/pubmed/18784461 . W eber R, Sabin CA, Friis-Moller N, et al. Liver-related deaths in persons infected with the human immunodeficiency virus: the 10. D:A:D study. . Arch Intern Med . 2006;166(15):1632-1641. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16908797 Kitahata MM, Gange SJ, N Engl 11. Abraham AG, et al. Effect of early versus deferred antiretroviral therapy for HIV on survival. J Med https://www.ncbi.nlm.nih.gov/pubmed/19339714 . . 2009;360(18):1815-1826. Available at: Greub G, Leder d immune recovery during antiretroviral therapy gerber B, Battegay M, et al. 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201 Tuberculosis/HIV Coinfection (Last updated July 14, 2016; last reviewed July 14, 2016) Panel’s Recommendations • Selection of a tuberculosis (TB)-preventive treatment for individuals living with HIV and coinfected with latent tuberculosis infection (L TBI) should be based on the individual’s antiretroviral therapy (ART) regimen as noted below: Any • (AII) . ART regimen can be used when isoniazid alone is used for LTBI treatment • Only efavirenz (EFV)- or raltegravir (RAL)-based regimens (in combination with either abacavir/lamivudine [ABC/3TC] or tenofovir . disoproxil fumarate/emtricitabine [TDF/FTC]) can be used with once-weekly isoniazid plus rifapentine (AIII) • If rifampin or rifabutin is used to treat L TBI, clinicians should review Tables 19a through 19e to assess the potential for interactions among different antiretroviral (ARV) drugs and the rifamycins . (BIII) • All patients with both HIV and active TB who are not on ART should be started on ART as described below: 3 : Initiate ART as soon as possible, but within 2 weeks of starting TB treatment In patients with CD4 counts <50 cells/mm (AI) . • 3 In patients with CD4 counts ≥50 cells/mm • Initiate ART within 8 weeks of starting TB treatment (AIII) . : In all pregnant women with HIV Initiate ART as early as feasible, for treatment of maternal HIV infection and to prevent mother- • : . (AIII) to-child transmission (MTCT) of HIV In patients with tuberculous meningitis: Caution should be exercised when initiating ART early, as high rates of adverse • (AI) . events and deaths have been reported in a randomized trial • TB treatment regimens and should be included for patients with both HIV and active TB, Rifamycins are critical components of unless precluded because of TB resistance or toxicity. However, rifamycins have a considerable potential for drug-drug interactions. Clinicians should review to assess the potential for interactions among different ARV drugs and the Tables 19a through 19e (BIII) . rifamycins A = Strong; B = Moderate; C = Optional Rating of Recommendations: I = Data from randomized controlled trials; II = Data from well-designed nonrandomized trials or observational Rating of Evidence: cohort studies with long-term clinical outcomes; III = Expert opinion Management of Latent Tuberculosis Infection in HIV-Infected Patients According to the World Health Organization (WHO), approximately one-third of the world’s population is 1 infected with tuberculosis (TB), with a 5% to 10% lifetime risk of progressing to active disease. People with HIV who are coinfected with TB have a much higher risk of developing active TB than individuals who do 2 not have HIV, and this risk increases as immune deficiency worsens. Anti-Tuberculosis Therapy as Preventive Tuberculosis Treatment Many clinical trials have demonstrated that treatment for latent tuberculosis infection (L TBI) reduces risk of 3 active TB in people with HIV, especially those with a positive tuberculin skin test. After active TB disease has been excluded, the Centers for Disease Control and Prevention (CDC) recommends one of the following ): regimens for LTBI treatment ( http://www.cdc.gov/tb/topic/treatment/ltbi.htm • Isoniazid (INH) daily or twice weekly for 9 months • INH plus rifapentine once weekly for 12 weeks • Rifampin (or rifabutin) daily for 4 months TBI to prevent active TB. It can be For more than 30 years, INH has been the cornerstone of treatment for L coadminstered with any antiretroviral (ARV) regimen and is safe to use in pregnant women. The combination of INH and rifapentine administered weekly for 12 weeks as directly observed therapy (DOT) is another treatment option for LTBI. In the PREVENT TB study, rifapentine plus INH for 12 weeks was as safe and 4 effective as 9 months of INH alone in preventing TB in patients with HIV who were not on ART. There was no difference in TB incidence in 1,148 South African adults with HIV who were randomized to receive rifapentine plus INH weekly for 12 weeks, rifampin plus INH twice weekly for 12 weeks, INH daily for 6 5 months, or continuous INH therapy. Although rifapentine induces cytochrome P (CYP) 450 isoenzymes and J-14 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

202 can potentially cause significant drug-drug interactions, there are now pharmacokinetic (PK) data supporting 6 7 its use with efavirenz (EFV) . Rifampin or rifabutin for 4 months may also be and raltegravir (RAL) (AIII) considered for LTBI treatment, but clinicians should pay careful attention to potential drug-drug interactions Tables 19a through 19e ). with specific ARV drugs (see If a patient with HIV is a contact of an individual with drug-resistant TB, the options for LTBI treatment should be modified. In this setting, consultation with a TB expert is advised. Antiretroviral Therapy’s Effect in Preventing Active Tuberculosis Accumulating evidence also suggests that ART can prevent active TB. The TEMPRANO study conducted in Côte d’Ivoire randomized 2,056 participants with HIV who did not meet WHO criteria for ART initiation to one of four study arms: deferred ART (until WHO criteria were met); deferred ART plus INH preventive 8 therapy (IPT); early ART; or early ART plus IPT. Among participants with CD4 T lymphocyte (CD4) 3 counts >500 cells/mm , starting ART immediately reduced the risk of death and serious HIV-related illness, including TB, by 44% (2.8 vs. 4.9 severe events per 100 person-years with immediate and deferred ART, respectively; P = .0002). Six months of IPT independently reduced the risk of severe HIV morbidity by 35% (3.0 vs. 4.7 severe events per 100 person years with IPT and no IPT, respectively; P = .005) with no overall increased risk of other adverse events. In the START study, 4,685 participants with CD4 counts 3 >500 cells/mm were randomized to receive immediate ART or ART deferred until their CD4 count dropped 3 to 350 cells/mm or until they developed a clinical condition that required ART. TB was one of the three most common clinical events, occurring in 14% of participants in the immediate initiation group and 20% 9 of participants in the deferred initiation group. Collectively, these two large randomized studies showed that early initiation of ART (with or without IPT) reduced active TB, particularly in countries with high prevalence of HIV/TB coinfection. Antiretroviral Therapy for Patients with HIV and Active Tuberculosis Active pulmonary or extrapulmonary TB disease requires prompt initiation of TB treatment. The treatment of active TB disease in patients with HIV should follow the general principles guiding treatment for individuals without HIV. The Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected 10 Adults and Adolescents ( Adult and Adolescent OI Guidelines ) include a more complete discussion of the diagnosis and treatment of TB disease in patients with HIV. All patients with HIV/TB disease should be treated with ART (AI) . Important issues related to the use of ART in patients with active TB disease include: • When to start ART; • ARV agents; Significant PK drug-drug interactions between anti-TB and ARV and anti-TB drug use; and • The additive toxicities associated with concomitant • The development of TB-associated immune reconstitution inflammatory syndrome (IRIS) after ART initiation. Tuberculosis Diagnosed While Patient is Receiving Antiretroviral Therapy When TB is diagnosed in a patient receiving ART, the ARV regimen should be assessed with particular attention to potential PK interactions between ARVs and TB drugs (discussed below). The patient’s ARV regimen may need to be modified to permit use of the optimal TB treatment regimen (see Tables 19a through 19e for dosing recommendations). Therapy Yet Receiving Antiretr uberculosis Diagnosed in a Patient Not oviral T In patients not taking ART at the time of TB diagnosis, delaying ART initiation for an extended period 15 +- Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV may Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

203 result in further immune decline with increased risk of new opportunistic diseases and death, especially in patients with advanced HIV disease. Several randomized controlled trials have attempted to address the optimal timing of ART initiation in the setting of active TB disease. The results of these trials have caused a paradigm shift favoring earlier ART initiation in patients with TB. The timing of ART in specific patient populations is discussed below. 3 Patients with CD4 count <50 cells/mm : Three large randomized clinical trials in patients with HIV/TB disease, conducted in Africa and Asia, all convincingly showed that early ART in those with CD4 counts <50 3 11-14 cell/mm In these studies, early ART was defined as starting significantly reduced AIDS events or deaths. ART within 2 weeks and at no later than 4 weeks after initiation of TB therapy. In all three studies, IRIS was more common in patients initiating ART earlier than in patients starting ART later, but the syndrome was infrequently associated with mortality. Collectively these three trials support initiation of ART within the first 3 2 weeks of TB treatment in patients with CD4 cell counts <50 cells/mm (AI) . 3 Patients with CD4 counts ≥50 cells/mm : In the three studies mentioned above, there was no survival 3 benefit for patients with CD4 count ≥50 cells/mm who initiated ART at <2 weeks versus later (8 to 12 weeks) after beginning TB treatment. ART should not be delayed until TB treatment is completed, as this 11 strategy was associated with higher mortality in the SAPiT-1 study. Importantly, none of the studies demonstrated harm from earlier ART initiation, and there are many well-documented benefits from ART in people with HIV regardless of TB coinfection. It is unlikely that more trials will be conducted to specifically 3 inform the decision on when to start ART in patients with TB and CD4 counts over 50 cells/mm . However, given the growing body of evidence supporting early ART in general and lack of data showing any harm in patients with TB coinfection, the the Panel recommends ART initiation within 8 weeks of starting TB 3 treatment for those with ≥50 cells/mm . (AIII) Patients with drug-resistant TB: Mortality rates in patients with multidrug-resistant (MDR) or extensively 15 drug-resistant (XDR) TB and HIV are very high. Retrospective case control studies and case series 16,17 provide growing evidence of better outcomes associated with receipt of ART in such patients, but the optimal timing for initiation of ART is unknown. Management of patients with HIV and drug-resistant TB is (BIII) . complex, and expert consultation is encouraged TB meningitis is often associated with severe complications and a high Patients with TB meningitis: mortality rate. In a study conducted in Vietnam, patients were randomized to immediate ART or to ART deferred 2 months after initiation of TB treatment. A significantly higher rate of severe (Grade 4) adverse events was seen in patients who received immediate ART than in those with deferred therapy (80.3% vs. 18 P = 0.04). 69.1% for early and deferred ART, respectively; Therefore, caution should be exercised when (AI) . initiating ART early in patients with TB meningitis Pregnant patients: All pregnant women with HIV and active TB should be started on ART as early as feasible, both for treatment of maternal HIV infection and to prevent perinatal transmission of HIV (AIII) . The choice of ART should be based on efficacy and safety in pregnancy and should take into account potential drug-drug interactions between ARVs and rifamycins (see Perinatal Guidelines for more detailed 19 discussions). Drug Interaction Considerations Rifamycins are a crucial component of TB treatment regimens. However, they are associated with a considerable potential for PK drug interactions. Rifampin is a potent inducer of the hepatic CYP 450 (mostly 3A and 2C subfamilies), P-glycoprotein (P-gp), and uridine diphosphate glucuronosyltransferase (UGT) 1A1 enzymes. Rifabutin and rifapentine are CYP 3A4 substrates and inducers. As potent enzyme inducers, ARV drug exposure. The the rifamycins can accelerate drug metabolism, resulting in significant reduction in ARV drugs most affected by CYP induction include all protease inhibitors (PIs), non-nucleoside reverse J-16 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

204 transcriptase inhibitors (NNRTIs), the integrase strand transfer inhibitors (INSTIs) elvitegravir (EVG) and the CCR5 antagonist maraviroc (MVC). Additionally, UGT1A1 induction may hasten the metabolism of TIs) and the INSTIs dolutegravir (DTG) and RAL. Most nucleos(t)ide reverse transcriptase inhibitors (NR the fusion inhibitor enfuvirtide are not expected to have significant drug interactions with the rifamycins. As a P-gp substrate, tenofovir alafenamide (TAF)’s drug exposure may be reduced by rifamycins; therefore, 20 concomitant administration of TAF and a rifamycin is not recommended at this time. Tables 19a through outline the magnitude of these interactions and provide dosing recommendations when rifamycins and 19e selected ARV drugs are used concomitantly. As a potent enzyme inducer, rifampin use leads to significant reduction in ARV drug exposure; therefore, use of rifampin is not recommended for patients receiving PIs (boosted or unboosted), EVG, etravirine (ETR), rilpivirine (RPV), or TAF. Increased ARV doses are needed when rifampin is used with DTG, RAL, or MVC. In contrast to its effect on other ARV drugs, rifampin only leads to modest reduction in EFV 21,22 concentrations. Several observational studies suggest that good virologic, immunologic, and clinical 23,24 outcomes may be achieved with standard doses of EFV. Even though the current EFV label recommends 25 increasing the EFV dose from 600 mg to 800 mg once daily in patients weighing >50 kg, this dosage increase is generally not necessary. Rifabutin, a weaker CYP3A4 enzyme inducer, is an alternative to rifampin, especially in patients receiving PI- or INSTI-based ARV regimens. Because rifabutin is a substrate of the CYP 450 enzyme system, its metabolism may be affected by NNRTIs or PIs. Therefore, rifabutin dosage adjustment is generally recommended (see Tables 19a through 19e for dosing recommendations). Rifapentine is a long-acting rifamycin which can be given once weekly with INH to treat latent TB 27 26 infection. Once-daily rifapentine is a more potent inducer than daily rifampin therapy. The impact of once weekly dosing of rifapentine on the PKs of most ARV drugs has not been systematically explored. 28 Once-daily rifapentine did not affect the oral clearance of EFV in individuals with HIV and has minimal 6 impact on EFV exposure when given once weekly, whereas once-weekly rifapentine led to increase instead 7 of decrease in RAL drug exposure in healthy volunteers. Pending additional PK data on the effect of rifapentine on other ARV drugs, once-weekly INH plus rifapentine for LTBI treatment should only be given to patients receiving either an EFV- or RAL- based regimen (AIII) . After selecting the ARV drugs and rifamycin to use, clinicians should determine the appropriate dose of each, and should closely monitor the patients to assure good control of both TB and HIV infections. Suboptimal HIV suppression or suboptimal response to TB treatment should prompt assessment of drug adherence, adequacy of drug exposure (consider therapeutic drug monitoring [TDM]), or presence of acquired HIV or TB drug resistance. Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome IRIS is a clinical condition caused by ART-induced restoration of pathogen-specific immune responses to opportunistic infections such as TB, resulting in either the deterioration of a treated infection (paradoxical IRIS) or a new presentation of a previously subclinical infection (unmasking IRIS). TB-associated IRIS (TB- IRIS) has been reported in 8% to more than 40% of patients starting ART after TB is diagnosed, although the 29,30 incidence depends on the definition of IRIS and the intensity of monitoring. Predictors of IRIS include 3 a baseline CD4 count <50 cells/mm ; higher on-ART CD4 counts; high pre-ART and lower on-ART HIV viral loads; severity of TB disease, especially high pathogen burden; and a less than 30-day interval between 24,31-33 initiation of TB and HIV treatments. Most IRIS in HIV/TB disease occurs within 3 months of the start of ART. Manifestations of unmasking TB-IRIS are characterized by their marked inflammatory nature, such as high fever, respiratory distress, lymphadenitis, abscesses, and sepsis syndrome. Manifestations of paradoxical TB- J-17 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

205 IRIS include fevers, new or worsening lymphadenopathy, new or worsening pulmonary infiltrates, enlarging pleural effusions, and new or enlarging tuberculomas. IRIS ranges from mild to severe to life-threatening. Patients with mild or moderately severe IRIS can be managed symptomatically or treated with nonsteroidal inflammatory agents. Patients with more severe IRIS can be treated successfully with corticosteroids, although data on the optimal dose, duration of therapy, and 34 overall safety and efficacy are limited. In the presence of IRIS, neither TB therapy nor ART should be . (AIII) stopped because both therapies are necessary for the long-term health of the patient References orld Health Organization. 1. . 2015. Available at http://apps.who.int/iris/ W Global Tuberculosis Report 2015 . bitstream/10665/191102/1/9789241565059_eng.pdf?ua=1 Lawn SD, Harries AD, Williams BG, et al. Antiretroviral therapy and the control of HIV-associated tuberculosis. 2. http://www.ncbi.nlm.nih.gov/ Will ART do it? Int J Tuberc Lung Dis . May 2011;15(5):571-581. Available at . pubmed/21756508 Akolo C, Cochrane Adetifa I, Shepperd S, Volmink J. Treatment of latent tuberculosis infection in HIV infected persons. 3. http://www.ncbi.nlm.nih.gov/pubmed/20091503 . . 2010(1):CD000171. Available at Database Syst Rev Sterling TR, Scott NA, Miro JM, et al. Three months of weekly rifapentine plus isoniazid for treatment of 4. AIDS . Mar 17 2016. Available at Mycobacterium tuberculosis infection in HIV co-infected persons. http://www.ncbi. . nlm.nih.gov/pubmed/26990624 infection. N Martinson NA, Barnes GL, Moulton LH, et al. New regimens to prevent tuberculosis in adults with HIV 5. Engl J Med . Jul 7 201 . http://www.ncbi.nlm.nih.gov/pubmed/21732833 1;365(1):11-20. Available at Farenc C, Doroumian S, Cantalloube C, et al. Rifapentine Once-W eekly Dosing Effect on Efavirenz Emtricitabine and 6. Tenofovir PKs. 21st Conference on Retroviruses and Opportunistic Infections; 2014; Boston, MA. W einer M, Egelund EF, Engle M, et al. Pharmacokinetic interaction of rifapentine and raltegravir in healthy volunteers. J 7. . Apr 2014;69(4):1079-1085. Available at http://www.ncbi.nlm.nih.gov/pubmed/24343893 . Antimicrob Chemother TEMPRANO ANRS Study Group, Danel C, Moh R, et al. A Trial of Early Antiretrovirals and Isoniazid Preventive 8. Therapy in Africa. N Engl J Med http://www.ncbi.nlm.nih.gov/ . Aug 27 2015;373(9):808-822. Available at . pubmed/26193126 INSIGHT START Study Group, Lundgren JD, Babiker AG, et al. Initiation of Antiretroviral Therapy in Early 9. N Engl J Med http://www.ncbi.nlm.nih.gov/ Asymptomatic HIV Infection. . Aug 27 2015;373(9):795-807. Available at pubmed/26192873 . Panel on Opportunistic Infections in HIV -Infected Adults and Adolescents. Guidelines for the prevention and treatment 10. of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the icine Association of the Infectious Diseases HIV Med http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf Society of America. Available at . Accessed June 22, 2016. Abdool Karim SS, Naidoo K, Grobler 11. A, et al. Timing of initiation of antiretroviral drugs during tuberculosis therapy. N Engl J Med . Feb 25 2010;362(8):697-706. Available at http://www.ncbi.nlm.nih.gov/entrez/query. fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20181971 . Abdool Karim SS, Naidoo K, Grobler A, et al. Integration of antiretroviral therapy with tuberculosis treatment. 12. N Engl J Med . Oct 20 201 http://www.ncbi.nlm.nih.gov/entrez/query. 1;365(16):1492-1501. Available at . fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=22010915 Blanc FX, Sok T, Laureillard D, et al. Earlier versus later start of antiretroviral therapy in HIV-infected adults with 13. tuberculosis. N Engl J Med . Oct 20 2011;365(16):1471-1481. Available at http://www.ncbi.nlm.nih.gov/entrez/query. fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=22010913 . Havlir DV 14. , Kendall MA, Ive P, et al. Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. N Engl J Med . Oct 20 2011;365(16):1482-1491. Available at http://www.ncbi.nlm.nih.gov/entrez/query. fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=22010914 . Gandhi NR, Shah NS, Andrews JR, et al. HIV coinfection in multidrug- and extensively drug-resistant tuberculosis 15. . Jan 1 2010;181(1):80-86. Available at results in high early mortality. Am J Respir Crit Care Med http://www.ncbi.nlm. nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19833824 . J-18 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

206 16. A, et al. Early treatment outcomes and HIV status of patients with extensively drug-resistant Dheda K, Shean K, Zumla Lancet . May 22 2010;375(9728):1798-1807. Available at tuberculosis in South Africa: a retrospective cohort study. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20488525 . 17. Pietersen E, Ignatius E, Streicher EM, et al. Long-term outcomes of patients with extensively drug-resistant tuberculosis Lancet in South http://www.ncbi.nlm.nih.gov/ Africa: a cohort study. . Apr 5 2014;383(9924):1230-1239. Available at . pubmed/24439237 18. orok ME, Yen NT, Chau TT, et al. Timing of initiation of antiretroviral therapy in human immunodeficiency virus T (HIV)—associated tuberculous meningitis. . Jun 2011;52(11):1374-1383. Available at http://www.ncbi. Clin Infect Dis . nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21596680 19. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf . http://www.gilead.com/~/media/files/pdfs/ Gilead Sciences. Descovy Product Label . Foster City, CA. 2016. Available at 20. medicines/hiv/descovy/descovy_pi.pdf?la=en . , Ruiz-Valderas R, Viciana P, et al. Pharmacokinetic interactions between efavirenz and rifampicin in 21. Lopez-Cortes LF Clin Pharmacokinet . 2002;41(9):681-690. Available at http://www.ncbi.nlm.nih. HIV-infected patients with tuberculosis. . gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12126459 22. Luetkemeyer AF, Rosenkranz SL, Lu D, et al. Relationship between weight, efavirenz exposure, and virologic suppression in HIV-infected patients on rifampin-based tuberculosis treatment in the AIDS Clinical Trials Group A5221 STRIDE Study. Clin Infect Dis . Aug 2013;57(4):586-593. Available at http://www.ncbi.nlm.nih.gov/pubmed/23592830 . 23. Friedland G, Khoo S, Jack C, Lalloo U. Administration of efavirenz (600 mg/day) with rifampicin results . J in highly variable levels but excellent clinical outcomes in patients treated for tuberculosis and HIV Antimicrob Chemother . Dec 2006;58(6):1299-1302. Available at http://www.ncbi.nlm.nih.gov/entrez/query. fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17032686 . 24. W, Kiertiburanakul S, Sungkanuparph S, et al. Efavirenz 600 mg/day versus efavirenz 800 mg/day in HIV- Manosuthi infected patients with tuberculosis receiving rifampicin: 48 weeks results. AIDS . Jan 2 2006;20(1):131-132. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16327334 . Sustiva Product Label . 2015. Available at http://www.accessdata.fda.gov/drugsatfda_docs/ 25. Bristol-Myers Squibb. . label/2010/021360s024lbl.pdf 26. Centers for Disease Control and Prevention. Recommendations for use of an isoniazid-rifapentine regimen with MMWR Morb Mortal Wkly Rep . Dec 9 direct observation to treat latent Mycobacterium tuberculosis infection. 1;60(48):1650-1653. Available at http://www.ncbi.nlm.nih.gov/pubmed/22157884 . 201 Dooley KE, Bliven-Sizemore EE, Weiner M, et al. Safety and pharmacokinetics of escalating daily doses of the 27. antituberculosis drug rifapentine in healthy volunteers. Clin Pharmacol Ther . May 2012;91(5):881-888. Available at . http://www.ncbi.nlm.nih.gov/pubmed/22472995 AT, Bao Y, Swindells S, et al. Efavirenz Pharmacokinetics and Pharmacodynamics in HIV-Infected Persons Podany 28. Receiving Rifapentine and Isoniazid for Tuberculosis Prevention. . Oct 15 2015;61(8):1322-1327. Clin Infect Dis Available at http://www.ncbi.nlm.nih.gov/pubmed/26082504 . 29. , et al. Tuberculosis-associated immune reconstitution inflammatory syndrome: case Meintjes G, Lawn SD, Scano F definitions for use in resource-limited settings. http://www.ncbi. Lancet Infect Dis . Aug 2008;8(8):516-523. Available at . nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18652998 , Easterbrook PJ. Validation of a published case definition for tuberculosis-associated immune 30. Haddow LJ, Moosa MY AIDS . Jan 2 2010;24(1):103-108. Available at http://www.ncbi.nlm.nih.gov/ reconstitution inflammatory syndrome. . entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19926965 31. Michailidis C, Pozniak AL, Mandalia S, Basnayake S, Nelson MR, Gazzard BG. Clinical characteristics of IRIS and tuberculosis. Antivir Ther . 2005;10(3):417-422. 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207 www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17255740 . Meintjes G, 34. Wilkinson RJ, Morroni C, et al. Randomized placebo-controlled trial of prednisone for paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome. AIDS . Sep 24 2010;24(15):2381-2390. Available http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20808204 at . J-20 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

208 Limitations to Treatment Safety and Efficacy Adherence to the Continuum of Care (Last reviewed October 17, 2017) Key Summary of Adherence to the Continuum of Care Linkage-to-care and adherence to both antiretroviral therapy (ART) and clinic appointments should be regularly assessed. • s barriers to adherence to ART and appointments should be assessed before initiation of ART and regularly thereafter. An individual’ • Patients with ART adherence problems should be placed on regimens with high genetic barriers to resistance, such as dolutegravir • (DTG) or boosted darunavir (DRV). Side effects, out-of-pocket costs, convenience, and patient preferences also need to be considered. • Patients having difficulties with adherence to appointments or ART should be approached in a constructive, collaborative, nonjudgmental, and problem-solving manner. • The approach to improved adherence should be tailored to each person’ s needs (or barriers to care). Approaches could include, but are not limited to: Changing • ART to simplify dosing or reduce side effects • ART and appointments Finding resources to assist with treatment costs to maintain uninterrupted access to both Allowing flexible appointment scheduling • • Assisting with transportation, or • Linking patients to counseling to overcome stigma, substance use, or depression. Multidisciplinary approaches to find solutions to • ART and appointment adherence problems are often necessary, including collaboration with social work and case management (to the extent available). The clinician’s role is to help the patient understand the importance of adherence to the continuum of care and reveal barriers to adherence, and link the patient to resources to overcome those barriers. A summary of best practice interventions to improve linkage, retention, and adherence can be found at a Centers for Disease Control • and Prevention compendium ( https://www ). .cdc.gov/hiv/research/interventionresearch/compendium/index.html Introduction Treatment adherence includes initiating care with an HIV provider (linkage to care), regularly attending appointments (retention in care), and adherence to antiretroviral therapy (ART). The concept of a “continuum of care” has been used to describe the process of HIV testing, linkage to HIV care, initiation of ART, 1-3 adherence to treatment, retention in care, and virologic suppression. The U.S. Centers for Disease Control and Prevention (CDC) estimates that HIV has not yet been diagnosed in about 13% of the people living with HIV in the United States. After receiving an HIV diagnosis, about 75% of individuals are linked to care within 30 days. However, only 57% of persons who receive an HIV diagnosis are retained in HIV care. It is estimated that only approximately 55% of persons with diagnosed HIV are virally suppressed because of 4 poor linkage to care and retention in care. The data for adolescents and young adults are even more sobering: only 51% of youth living with HIV receive a diagnosis, 68% are linked to care within 1 month, and 55% are retained in care. As a result, adolescents and young adults had the lowest rate of viral suppression among all 5 age groups, at only 44%. Outcomes along the continuum also vary by geographic region and other population 4 characteristics, such as sex, race/ethnicity, and HIV risk factors. To achieve optimal clinical outcomes and to realize the potential public health benefit of treatment as prevention, adherence to each step in the continuum 6 of care is critical. It is also important to realize that retention and adherence are not static states. Life events, changes in insurance status, comorbid conditions and health system changes can cause people to shift back and forth on the continuum. Knowledgeable providers and high-quality system processes are vital in promoting rapid linkage and sustained retention in care and adherence to ART. This section provides guidance on linking patients to care, assessing and improving retention in care, and assessing and improving adherence to ART. The CDC maintains a compendium of evidence-based K-1 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

209 and evidence-informed interventions to improve linkage, retention, and adherence ( https://www.cdc.gov/ ). In addition, a number of other groups and hiv/research/interventionresearch/compendium/index.html 6,7 organizations have provided guidance for improving adherence to the steps in the care continuum. Linkage to Care Receiving a diagnosis of HIV infection can be traumatic and linkage to care efforts must be delivered with sensitivity and persistence. The time from diagnosis to linkage to care can be affected by many factors, including insufficient socioeconomic resources, active substance use, mental health problems, stigma, and 8-12 disease severity (symptomatic HIV is associated with more successful linkage). In the United States, youth, people who use injection drugs, and black/African American persons have lower rates of linkage to 4 care. Some health system-associated factors have also been associated with linkage success or failure. Co- 11 location of testing and treatment services and active linkage services (e.g., assisting the patient in setting up appointments, maintaining an active relationship with the patient until linkage is completed, and providing 13-15 linkage case management services) bolster linkage to care. Conversely, passive linkage (e.g., only providing names and contact information for treatment centers) is associated with lower linkage to care. Monitoring Linkage to Care Linking to HIV care after a new diagnosis of HIV infection is defined as completing an outpatient appointment with a clinical provider who has the skills and ability to treat HIV infection, including prescribing ART. Patients should be linked to care as soon as possible after diagnosis with HIV, preferably within 30 days. Monitoring linkage is a critical responsibility so that interventions can ef fectively reach persons who are not linked to care. If the facilities that diagnose and treat an individual are the same or share the same electronic medical record system, it is relatively straightforward to monitor linkage to care. Monitoring linkage for persons whose HIV is diagnosed outside the treatment provider’s healthcare system is difficult and generally is the responsibility of the diagnosing provider/entity and the public health authority . However, once a patient makes contact with the treating clinical system, he or she should be engaged in linkage efforts and monitored for successful linkage to and retention in HIV care. Improving Linkage to Care Strategies to improve linkage to care are summarized in Table 14 . Linkage efforts should include immediate 13 referral to care at diagnosis, appointment reminders, and outreach efforts if needed. The only intervention shown to increase linkage to care in a randomized trial conducted in the United States is the Anti-Retroviral 14 Treatment and Access to Services (ARTAS) intervention. ARTAS is a strength-based intervention which aims to facilitate linkage to and retention in care for persons with recently diagnosed HIV. The ARTAS intervention was tested in four cities and enrolled a diverse group of persons. The participants in the ARTAS intervention trial were randomized to either an intervention arm or a control arm. Participants randomized to the control arm received information about HIV and care resources and a referral to a local HIV Med ical provider. Each participant in the intervention arm worked with an ARTAS interventionist for five sessions, 90 days, or until linkage—whichever came first. The interventionist helped the participant to identify and use his or her strengths, abilities, and skills to link to HIV care, and linked the participant to community resources. Linkage to care, defined as completing at least one visit with an HIV clinician within the first 6 months, was greater among the ARTAS participants than the control participants (78% vs. 60%, adjusted RR = 1.36, P < 0.001). Furthermore, a greater percentage of ARTAS participants were retained in care, defined as visiting an HIV clinician at least once in each of the first two 6-month blocks after enrollment (64% vs. 49% for ARTAS and control participants, respectively; adjusted RR = 1.41, P = 0.006). ARTAS has been 15 replicated in a community-based study. https:// CDC supports free training in the ARTAS intervention ( effectiveinterventions.cdc.gov/en/HighImpactPrevention/PublicHealthStrategies/ARTAS.aspx ). Other studies support the importance of post-test counseling to educate, motivate, and present positive messages about K-2 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

210 16 17 peer support, living with HIV, and engaging with the patient at the clinic in advance of the visit with the 18 19 provider. Financial incentives did not increase linkage to care within 90 days in a large randomized trial. Retention in Care 20,21 Poor retention in HIV care is associated with greater risk of death. Poor retention is more common in persons who are substance users, have serious mental health problems, have unmet socioeconomic needs (e.g., housing, food, or transportation), lack financial resources or health insurance, have schedules that 22-25 complicate adherence, have been recently incarcerated, or face stigma. At the provider and health system level, low trust in providers and a poor patient-provider relationship have been associated with 26-28 lower retention, as has lower satisfaction with the clinic experience. Availability of appointments and timeliness of appointments (i.e., long delay from the request for an appointment to the appointment’s date) and scheduling convenience are also factors. Monitoring Retention in Care 6 Retention in care should be routinely monitored. There are various ways to measure retention, including measures based on attended visits over a defined period of time (constancy measures), and measures based 29 30 on missed visits. Both approaches are valid and independently predict survival. Missed visits and a prolonged time since last visit are relatively easy to measure and should trigger efforts to retain or re-engage a person in care. Constancy measures (e.g., at least two visits that are at least 90 days apart over 1 year, or at least one visit every 6 months over the last 2 years), can be used as clinic quality assurance measures. Improving Retention in Care . The Retention through Enhanced Strategies to improve retention in care are summarized in Table 14 Personal Contact (REPC) intervention was tested in a randomized trial in six clinics in the United States. The intervention relied on personal contact by an interventionist with at-risk patients. It included a brief face- to-face meeting upon returning to care and at each clinic visit and three types of phone calls: to check on patients between visits, as appointment reminders just before visits, and to attempt to reschedule missed visits. REPC resulted in small but significant improvements in retention in care, including in racial/ethnic minority 31 populations and persons with detectable plasma HIV RNA. In-clinic opioid replacement therapy helps opioid 32 users remain in care. An intervention using the electronic medical record to alert providers when patients 33 had suboptimal follow-up or high viral loads also improved retention in care. On the other hand, in two randomized trials involving out-of-care, hospitalized patients with HIV, peer counselors and patient navigators 34,35 did not improve relinkage to care after hospital discharge. Data from nonrandomized studies support: • Clinic-wide marketing (e.g., posters, brochures, and customer service training of patient-facing staff) to 36 promote attending scheduled visits and provide patients a welcoming and courteous experience, 37 • Stepped case management and social and outreach services, and • “Data to Care” approaches which use clinic and public health data to reach out-of-care persons and re-engage them into care (see https://effectiveinterventions.cdc.gov/en/highimpactprevention/ 38-40 publichealthstrategies/DatatoCare.aspx ). However, the effectiveness of “data to care” interventions is variable and privacy concerns must be adequately addressed. Overall, these data support the concept that all clinic personnel, from the facilities staff to nurses to providers, play important roles in supporting retention in care by providing the optimal patient care experience, constructively affirming attendance rather than criticizing non-attendance, and collaboratively 27,31,36 problem solving with patients to overcome barriers to care. Flexible appointment schedules, expanded clinic hours, and copay and other financial or insurance assistance such as that provided by the R yan White program will also provide patients with uninterrupted access to clinical care. Guidelines regarding linkage K-3 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

211 6,7 and retention have been published. CDC maintains a compendium of evidence-based and evidence- https://www.cdc.gov/hiv/research/interventionresearch/compendium/index.html informed interventions ( ). The use of financial incentives or rewards to promote retention in care has been studied. A large study At baseline, 45% of the patients were randomized clinic sites to financial incentives or standard-of-care. retained in care in these clinics. The relative increase in the proportion of participants retained in care was 9% higher in clinics offering incentives than in standard-of-care clinics. Viral suppression also improved 4% 19 at financial incentive clinics, from a baseline of 62%. In another large, randomized study of persons out- of-care and hospitalized, financial incentives plus patient navigation did not lead to sustained improvement 34 in retention or viral load suppression over that achieved with standard care. The use of financial incentives therefore remains experimental and cannot be recommended for routine care at this time. Adherence to Antiretroviral Therapy Adherence to ART can be influenced by a number of factors, including the patient’s social situation and 41 clinical condition, the prescribed regimen, and the patient-provider relationship. Poor adherence is often a consequence of one or more behavioral, structural, and psychosocial barriers (e.g., depression and other mental illnesses, neurocognitive impairment, low health literacy, low levels of social support, stressful life events, busy or unstructured daily routines, active substance use, homelessness, poverty, nondisclosure of HIV 42-44 serostatus, denial, stigma, and inconsistent access to medications due to financial and insurance status). Characteristics of one or more components of the prescribed regimen can affect adherence. Once-daily 45 regimens, including those with low pill burden (even if not one pill once daily), without a food requirement, 46,47 and few side effects or toxicities, are associated with higher levels of adherence. Single-tablet regimens (STR) that include all antiretrovirals in one pill taken once daily are easier for people to use. However, data to support or refute the superiority of a STR versus a once-daily multi-tablet regimen (MTR), as might be required for the use of some soon-to-be-available generic-based antiretroviral (ARV) regimens, are limited. There are demonstrated beneficial effects on virologic suppression in switch studies, in which persons on 48 MTR are randomized to stay on MTR or switch to STR. Whether an STR is beneficial in treatment-naive patients is not known, with at least one large observational cohort study showing benefit of once-daily STR 47,49 versus once-daily MTR, but only when switches for simplification of MTR were considered failures. Comparisons of these regimens are hampered since not all drugs and classes are available as STR. Characteristics of the clinical setting can also have important structural influences on the success or failure of medication adherence. Settings that provide comprehensive multidisciplinary care (e.g., by case managers, pharmacists, social workers, and mental health and substance abuse providers) support patients’ complex needs, including their medication adherence-related needs. Drug abuse treatment programs are often best suited to address substance use and may offer services that promote adherence, such as directly observed therapy (DOT). Monitoring Adherence to Antiretroviral Therapy Adherence to ART should be assessed and addressed in a constructive and nonjudgmental manner at every visit. Given the potency of contemporary ART, a detectable viral load identified during chronic care for a patient with stable access to ART is most likely the result of poor adherence. Patient self-report, the most frequently used method for evaluating medication adherence, remains a useful tool. Carefully assessed patient 50,51 self-report of high-level adherence to ART has been associated with favorable viral load responses. Patient admission of suboptimal adherence is highly correlated with poor therapeutic response. The reliability of self-report often depends on how the clinician elicits the information. It is most reliable when ascertained in a simple, nonjudgmental, routine, and structured format that normalizes less-than-perfect adherence and minimizes socially desirable responses. To allow patients to disclose lapses in adherence, some experts suggest inquiring about the number of missed doses during a defined time period. For example, for a patient with a K-4 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

212 detectable viral load, a provider might state, “I know it is difficult to take medicine every day. Most people miss doses at least sometimes. Thinking about the last 2 weeks, how many times have you missed doses? Please give me a rough estimate so I can help you take the best care of yourself.” Other research supports 52,53 simply asking patients to rate their adherence during the last 4 weeks on a 5- or 6-point Likert scale. Other measures of adherence include pharmacy records and pill counts. Pharmacy records can be valuable when medications are obtained exclusively from a single source. Because pill counts can be altered by patients, are labor intensive, and can be perceived as confrontational, they are generally not used in routine care. Other methods of assessing adherence include the use of therapeutic drug monitoring and electronic measurement devices (e.g., Medication Event Monitoring System [MEMS] bottle caps and dispensing systems). However, these methods are costly and are generally reserved for research settings. Improving Adherence to Antiretroviral Therapy Strategies to improve adherence to ART are summarized in Table 14 . Just as they support retention in care, 51,54-56 all health care team members play integral roles in successful ART adherence programs. An increasing number of interventions have proven effective in improving adherence to ART (for descriptions of the interventions, see http://www.cdc.gov/hiv/research/interventionresearch/compendium/ma/index.html ). The many options can be customized to suit a range of needs and settings. It is important that each new patient receives and understands basic information about HIV infection, including the goals of therapy (achieving and maintaining viral suppression, which will decrease HIV- associated complications and prevent transmission), the prescribed regimen (including dosing schedule and potential side effects), the importance of adherence to ART, and the potential for the development of drug resistance as a consequence of suboptimal adherence. Patients must also be positively motivated to initiate therapy, which can be assessed by simply asking patients if they want to start treatment for HIV infection. Clinicians should assist patients in identifying facilitating factors and potential barriers to adherence, and develop multidisciplinary plans to attempt to overcome those barriers. Processes for obtaining medications and refills should be clearly described. Transportation to pharmacy and to clinic visits should be assessed with linkage to appropriate services as needed. Plans to ensure uninterrupted access to ART via insurance, copay assistance, pharmaceutical company assistance programs, or AIDS Drug Assistance Programs (ADAP), for example, should be made and reviewed with the patient. Much of this ef fort to inform, motivate, and reduce barriers can be achieved by support staff, and can be accomplished concomitant with, 57-60 or even after, starting therapy. While delaying the initiation of ART is rarely indicated, some patients may not be comfortable starting treatment. Patients expressing reluctance to initiate ART should be engaged in counseling to understand and overcome barriers to ART initiation. Although homelessness, substance use, and mental health problems are associated with poorer adherence, they are not predictive enough at the individual level to warrant withholding or delaying therapy given the simplicity, potency, and tolerability of contemporary ART. Rapid ART initiation at the time of HIV diagnosis has been pursued as a strategy to increase viral load suppression and retention in care, but safety data, data on intermediate or long-term outcomes, and data from randomized controlled trials conducted in high-resource settings are currently 57-60 lacking. For more details, see Initiation of Antiretroviral Therapy . 61,62 The first principle of successful treatment is to design a plan to which the patient can commit. It is important to consider the patient’s daily schedule; tolerance of pill number, size, and frequency; and any issues affecting absorption (e.g., use of acid-reducing therapy and food requirements). With the patient’s input, a medication choice and administration schedule should be tailored to his or her daily activities. Clinicians should explain to patients that their first regimen is usually the best option for a simple regimen that affords long-term treatment success. Establishing a trusting patient-provider relationship and maintaining good communication will help to improve adherence and long-term outcomes. Medication taking can also be enhanced using medication reminder aids. There is strongest evidence for text messaging, but pill box 63-67 monitors, pill boxes, and alarms may also improve adherence. K-5 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

213 Positive reinforcement can greatly help patients maintain high levels of adherence. This technique to foster adherence includes informing patients of their low or suppressed viral load and increases in CD4 T 68-70 lymphocyte cell counts. Motivational interviewing has also been used with some success. Other effective interventions include nurse home visits, a five-session group intervention, and couples- or family-based interventions. Interventions involving several approaches are generally more successful than single-strategy interventions, and interventions based on cognitive behavioral therapy and supporter interventions have been 71 shown to improve viral suppression. Problem-solving approaches that vary in intensity and culturally tailored 70,72,73 approaches also are promising. To maintain high levels of adherence in some patients, it is important to provide substance abuse therapy and to strengthen social support. DOT has been effective in providing ART to 74 75 active drug users but not to patients in a general clinic population or in home-based settings with partners 76 responsible for DOT. The use of incentives or rewards to promote adherence has been studied, and they have 19 been shown to improve adherence in one study. However, the durability and feasibility of financial incentives 34,77,78 are not known at this time, hence rewards for adherence are not generally recommended. Conclusion Even armed with accurate information about a patient’s adherence and barriers to ART and appointment adherence, clinicians often fail to engage patients in a productive conversation and instead simply tell patients to be adherent and offer warnings about what might ensue with continued poor adherence. This approach fails to acknowledge a patient’s barriers to adherence, fails to provide the patient with actionable information, erodes rather than builds the patient-provider relationship, and has been demonstrated to not 79,80 improve adherence. At the same time, however, many of the interventions shown to improve adherence are difficult to implement in routine care. Nonetheless, effective lessons from this body of research can be applied to routine care to improve linkage to care, adherence to ART, and adherence to appointments. These lessons include the following: • ART and appointments. Regularly assess adherence to • Engage a patient who is struggling with adherence at any step on the care continuum with a constructive, collaborative, nonjudgmental, and problem-solving approach rather than reprimanding them or lecturing them on the importance of adherence. • Elicit an individual’s barriers to adherence, which may include personal barriers (e.g., substance use, housing instability, stigma, lack of transportation), clinic barriers (e.g., limited clinic hours, processes that make it more difficult to obtain prescriptions or schedule appointments), and system barriers (e.g., copays, prior approvals, processes that complicate maintaining pharmacy benefits or obtaining refills). • ailor approaches to improve adherence to an individual’s needs and barriers, for example, by changing T ART to simplify dosing or reduce side effects, finding resources to assist with copays or other out-of- Table 14 ) to maintain an uninterrupted supply of ART and access to clinicians, or pocket costs (see linking patients to counseling to overcome stigma, substance use, or depression. • ART adherence problems on regimens with high genetic barriers to Place patients with apparent resistance, such as dolutegravir or boosted-darunavir regimens. When selecting the regimen, consider possible side effects, out-of-pocket costs, convenience, and patient preferences since the only regimen that will work is the one the patient can obtain and is willing and able to take. • Understand that multidisciplinary approaches and time to understand and address barriers are needed in many situations, and that the clinician’s role is to help the patient to understand the importance of adherence to the continuum of care and reveal any barriers to adherence, and link the patient to resources to overcome those barriers. K-6 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

214 Table 14. Strategies to Improve Linkage to Care, Retention in Care, Adherence to Appointments, and (page 1 of 2) Adherence to Antiretroviral Therapy Strategies Examples Provide an accessible, trustworthy, Care providers, nurses, social workers, case managers, pharmacists, and medication • nonjudgmental multidisciplinary health managers. care team. • Strengthen early linkage to care and Encourage health care team participation in linkage to and retention in care. retention in care. • Use ARTAS training (if available). Evaluate patient’s knowledge s current knowledge base in mind, provide information about HIV, Keeping the patient’ • about HIV infection, prevention, including the natural history of the disease, HIV viral load and CD4 count and expected clinical outcomes according to these parameters, therapeutic and prevention consequences and treatment and, based on this assessment, provide HIV-related of poor adherence, and importance of staying in HIV care. information. Assess patient’s cognitive competence and impairment. • Identify facilitators, potential barriers to adherence, and necessary medication • Assess behavioral and psychosocial challenges, including depression, mental illnesses, management skills both before starting levels of social support, levels of alcohol consumption and current substance use, ART and on an ongoing basis. nondisclosure of HIV serostatus, and stigma. • Identify and address language and literacy barriers. • Assess beliefs, perceptions, and expectations about taking ART (e.g., impact on health, side effects, disclosure issues, consequences of poor adherence). Ask about medication-taking skills and foreseeable challenges with adherence (e.g., past • difficulty keeping appointments, adverse effects from previous medications, issues managing other chronic medications, need for medication reminders and organizers). • Assess structural issues, including unstable housing, lack of income, unpredictable daily schedule, lack of prescription drug coverage, lack of continuous access to medications, transportation problems. Provide needed resources. Provide or refer for mental health and/or substance abuse treatment. • Provide resources to obtain prescription drug coverage (e.g., Common Patient Assistance • http://bit.ly/CommonPAPForm ; Pharmaceutical Company HIV Program Application (CPAPA): http://bit.ly/1XIahvN Patient Assistance Programs and Cost-Sharing Assistance Programs: • Provide resources about stable housing, social support, transportation assistance, and . income and food security Review potential side ef fects, dosing frequency, pill burden, storage requirements, food • Involve the patient in ARV regimen selection. requirements, and consequences of poor adherence. Assess daily activities and tailor regimen to predictable and routine daily events. • Consider preferential use of PI/r-based or DTG-based ART if poor adherence is anticipated. • • Consider use of STR formulations. fect adherence and access to medications. • Assess if cost/copayment for drugs will af Assess adherence at every clinic visit. • Monitor viral load as a strong biologic measure of adherence. • Use a simple behavioral rating scale or self-reported assessment. • Employ a structured format that normalizes or assumes less-than-perfect adherence and minimizes socially desirable or “white-coat adherence” responses. • Ensure that other members of the health care team also assess and support adherence. Use positive reinforcement to foster • Inform patients of low or nondetectable levels of HIV viral load and increases in CD4 cell adherence success. counts. • Thank patients for attending their appointments. K-7 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

215 Table 14. Strategies to Improve Linkage to Care, Retention in Care, Adherence to Appointments, and (page 2 of 2) Adherence to Antiretroviral Therapy Examples Strategies • Failure to understand dosing instructions. Identify the type of and reasons for poor adherence and target ways to • Complexity of regimen (e.g., pill burden, size, dosing schedule, food requirements, improve adherence. polypharmacy). Pill aversion or pill fatigue. • Adverse effects. • Inadequate understanding of drug resistance and its relationship to adherence. • • Patient is unaware of appointments or appointments are not scheduled with proper patient input. Cost-related issues (copays for medications or visits, missed work time). • . • Depression, drug and alcohol use, homelessness, poverty Stigma of taking pills or attending HIV • -related appointments. Nondisclosure of status leading to missed doses, refills, or appointments. • Select from among available ef fective https://www.cdc.gov/hiv/research/interventionresearch/compendium/index.html for a See • adherence and retention interventions. summary of best practice interventions to improve linkage, retention, and adherence. Use adherence-related tools to complement education and counseling interventions (e.g., text • messaging, pill box monitors, pill boxes, alarms). Use community resources to support adherence (e.g., visiting nurses, community workers, • , peer advocates, transportation assistance). family • Use patient prescription assistance programs (see above, under “Provide needed resources”). • Use motivational interviews. Provide outreach for patients who drop out of care • Use peer or paraprofessional treatment navigators. • Recognize positive clinical outcomes resulting from better adherence. • • in persons in substance use treatment (if feasible). Arrange for DOT • Enhance clinic support and structures to promote linkage and retention (reminder calls, flexible scheduling, open access, active referrals, and improved patient satisfaction). Record and follow up on missed visits. Systematically monitor retention in • care. ART = antiretroviral therapy; ARTAS = Anti-Retroviral Treatment and Access to Services; ARV = antiretroviral; CD4 = Key to Acronyms: CD4 T lymphocyte; DOT = directly observed therapy; DTG = dolutegravir; PI/r = ritonavir-boosted protease inhibitor; STR = single tablet regimen References 1. Gardner EM, McLees MP , Steiner JF, Del Rio C, Burman WJ. The spectrum of engagement in HIV care and its relevance to test-and-treat strategies for prevention of HIV infection. . Mar 15 2011;52(6):793-800. Clin Infect Dis Available at . https://www.ncbi.nlm.nih.gov/pubmed/21367734 2. Greenber g AE, Hader SL, Masur H, Young AT, Skillicorn J, Dieffenbach CW. Fighting HIV/AIDS in Washington, D.C. . Nov-Dec 2009;28(6):1677-1687. Available at https://www.ncbi.nlm.nih.gov/pubmed/19887408 . Health Aff Giordano TP, Suarez-Almazor ME, Grimes RM. The population effectiveness of highly active antiretroviral therapy: 3. Curr HIV/AIDS Rep . Nov 2005;2(4):177-183. Available at https://www.ncbi.nlm.nih.gov/ are good drugs good enough? pubmed/16343375 . 4. Centers for Disease Control and Prevention. Monitoring selected national HIV prevention and care objectives by using HIV . 2016;21(No. surveillance data—United States and 6 dependent areas, 2014. HIV Surveillance Supplemental Report https://www.cdc.gov/hiv/pdf/library/reports/surveillance/cdc-hiv-surveillance-supplemental-report- 4). Available at K-8 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

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221 Adverse Effects of Antiretroviral Agents (Last updated October 25, 2018; last reviewed October 25, 2018) Adverse effects have been reported with all ARV drugs and, in the earlier era of combination ART, adverse effects were among the most common reasons for switching or discontinuing therapy and for medication 1 nonadherence. Fortunately, newer ARV regimens are associated with fewer serious and intolerable adverse effects than regimens used in the past. Generally, less than 10% of ART-naive patients enrolled in randomized trials experience treatment-limiting adverse events. However, the long-term complications of ART can be underestimated, because most clinical trials use highly specific inclusion criteria when enrolling participants and the duration of participant follow-up is relatively short. As ART is now recommended for all patients regardless of CD4 cell count, and because therapy must be continued indefinitely , the focus of patient management has evolved from identifying and managing early ARV-related toxicities to individualizing therapy to avoid long-term adverse effects, including diabetes, accelerated vascular disease, kidney dysfunction, and bone loss. To achieve sustained viral suppression over a lifetime, both long-term and short-term ART toxicities must be anticipated and overcome. The clinician must consider potential adverse effects when selecting an ARV regimen, as well as the individual patient’s comorbidities, concomitant medications, and prior history of drug intolerances. Several factors may predispose individuals to adverse effects of ARV medications, such as: • Concomitant use of medications with overlapping and additive toxicities. • Comorbid conditions that increase the risk of or exacerbate adverse effects. For example, underlying 2,3 liver disease from alcohol use, co-infection with viral hepatitis, and/or liver steatosis may increase the risk of hepatotoxicity when drugs such as efavirenz (EFV) or protease inhibitors are used; psychiatric disorders may be exacerbated by EFV , rilpivirine, and, infrequently, by integrase strand transfer 4,5 inhibitors; and borderline or mild renal dysfunction increases the risk of nephrotoxicity from tenofovir disoproxil fumarate (TDF). • Drug-drug interactions that may increase toxicities of ARV drugs or concomitant medications. 6,7 • Genetic factors that predispose patients to abacavir (ABC) hypersensitivity reaction, EFV 8,9 10 neuropsychiatric toxicity and QTc prolongation, and atazanavir (ATV)-associated hyperbilirubinemia. Information on the adverse effects of ARVs is outlined in several tables in the guidelines. Table 15 provides clinicians with a list of the most common and/or severe ARV-associated adverse events for each drug class. Appendix B, Tables 1–6 . The most common adverse effects of individual ARV agents are summarized in K-14 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

222 Table 15. Common and/or Severe Adverse Effects Associated with Antiretroviral Therapy (page 1 of 5) “N/A” indicates either that there are no reported cases for that particular side effect or that data for that specific ARV drug class are not available. Appendix B See for additional information listed by drug. Drug Class Adverse Effect PIs INSTIs EIs NRTIs NNRTIs N/A N/A Spontaneous bleeding, hematuria in N/A N/A Bleeding Events hemophilia TPV: Intracranial hemorrhage is associated with CNS lesions, trauma, alcohol abuse, hypertension, coagulopathy, anticoagulant or antiplatelet agents, and the use of vitamin E supplements. Bone Density N/A TDF: Associated with greater Effects loss of BMD than other NRTIs. Osteomalacia may be associated with renal tubulopathy and urine Decreases in BMD observed after the initiation of any ART regimen. phosphate wasting. TAF : Associated with smaller declines in BMD than those seen with TDF. Bone Marrow : Anemia, neutropenia N/A N/A N/A N/A ZDV Suppression Cardiac N/A N/A N/A RPV, EFV: QTc prolongation SQV/r, ATV/r, and LPV/r: PR Conduction prolongation. Risk factors include pre- Effects existing heart disease and the use of other medications. SQV/r: QT prolongation. Obtain ECG before administering SQV. Cardiovascular ABC and ddI: Associated with N/A DRV, FPV, IDV, and LPV/r: Associated N/A N/A Disease an increased risk of MI in with cardiovascular events in some some cohort studies. Absolute cohorts risk greatest in patients with traditional CVD risk factors. Cholelithiasis N/A N/A N/A N/A : Cholelithiasis and kidney stones ATV may present concurrently. Median onset is 42 months. K-15 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

223 (page 2 of 5) Table 15. Common and/or Severe Adverse Effects Associated with Antiretroviral Therapy Drug Class Adverse Effect NRTIs PIs EIs INSTIs NNRTIs Diabetes Mellitus ZDV, d4T, and ddI N/A Reported for some (IDV, LPV/r), but not N/A N/A and Insulin all, PIs. Resistance Dyslipidemia d4T > ZDV > ABC : ↑ TG and LDL N/A : ↑ TG, ↑ LDL, ↑ HDL EVG/c : ↑ TG, ↑ All RTV- or COBI-Boosted PIs : ↑ TG, ↑ LDL, ↑ HDL EFV LDL, ↑ HDL : ↑ TG, ↑ LDL, ↑ HDL (no TAF LPV/r and FPV/r > DRV/r and ATV/r: change in TC:HDL ratio) ↑ TG TDF has been associated with lower lipid levels than ABC or TA F. Gastrointestinal ddI and ZDV > Other NRTIs: N/A GI intolerance (e.g., diarrhea, nausea, IBA: 8% of EVG/c: Nausea and Effects vomiting) patients reported diarrhea Nausea and vomiting diarrhea in a study ddI: Pancreatitis NFV and LPV/r > DRV/r and ATV/r: of 40 people. Diarrhea Hepatic Effects N/A All PIs: Drug-induced hepatitis and EFV: Most cases relate to an MVC: Reported with most NRTIs. hepatic decompensation have been increase in transaminases. Hepatotoxicity with ZDV, d4T, and ddI: Steatosis reported; greatest frequency occurs or without rash or Fulminant hepatitis leading to with TPV/r. HSRs reported. death or hepatic failure requiring ddI: Prolonged exposure linked to transplantation have been noncirrhotic portal hypertension TPV/r: Contraindicated in patients with reported. and esophageal varices. hepatic insufficiency (Child Pugh class NVP: Severe hepatotoxicity B or C). When TAF, TDF, 3TC, and FTC associated with skin rash or are Withdrawn in Patients with : Jaundice due to indirect IDV and ATV hypersensitivity. A 2-week NVP HBV/HIV Coinfection or When hyperbilirubinemia dose escalation may reduce risk. : HBV Resistance Develops Risk is greater for women with Patients with HBV/HIV coinfection pre-NVP CD4 counts >250 cells/ may develop severe hepatic 3 mm and men with pre-NVP CD4 flares. 3 . counts >400 cells/mm be used for never NVP should post-exposure prophylaxis. are not EFV and NVP recommended in patients with hepatic insufficiency (Child-Pugh class B or C). K-16 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

224 Table 15. Common and/or Severe Adverse Effects Associated with Antiretroviral Therapy (page 3 of 5) Drug Class Adverse Effect NRTIs NNRTIs PIs INSTIs EIs N/A NVP : HSR reported when ABC: Contraindicated if patient : Hypersensitivity syndrome MVC : HSR Hypersensitivity RAL RAL is given with other reported as part of hepatotoxicity and rash Reaction is HLA-B*5701 positive. of a syndrome drugs also known to cause that may be accompanied by Median onset for HSR is 9 days; Excluding fever, general malaise, fatigue, related to HSRs. All ARVs should be rash alone or 90% of reactions occur within first myalgias, arthralgias, blisters, stopped if HSR occurs. hepatotoxicity. 6 weeks of treatment. Stevens-Johnson oral lesions, conjunctivitis, facial syndrome DTG : Reported in <1% edema, eosinophilia, renal HSR Symptoms (in Order of of patients in clinical dysfunction, granulocytopenia, or Descending Frequency): Fever, development program lymphadenopathy. rash, malaise, nausea, headache, myalgia, chills, diarrhea, vomiting, Risk is greater for ARV-naive abdominal pain, dyspnea, women with pre-NVP CD4 counts arthralgia, and respiratory 3 >250 cells/mm and men with pre- symptoms 3 . NVP CD4 counts >400 cells/mm Overall, risk is higher for women Symptoms worsen with than men. continuation of ABC. A 2-week dose escalation of NVP Patients should not be reduces risk. rechallenged with ABC if HSR is suspected, regardless of their HLA-B*5701 status. Lactic Acidosis N/A Reported with NRTIs, Especially N/A N/A N/A d4T, ZDV, and ddI: Insidious onset with GI prodrome, weight loss, and fatigue. May rapidly progress with tachycardia, tachypnea, jaundice, weakness, mental status changes, pancreatitis, and organ failure. Mortality high if serum lactate >10 mmol/L. Women and obese patients at increased risk. Lipodystrophy N/A Lipoatrophy: d4T > ZDV. More likely when NRTIs are Lipohypertrophy: Trunk fat increase observed with EFV-, PI-, and RAL-containing regimens; however, coadministered with EFV than causal relationship has not been established. with an RTV-boosted PI. K-17 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

225 Table 15. Common and/or Severe Adverse Effects Associated with Antiretroviral Therapy (page 4 of 5) Drug Class Adverse Effect NRTIs NNRTIs PIs INSTIs EIs N/A ZDV: Myopathy Myopathy/ N/A N/A RAL and DTG : ↑ CPK, rhabdomyolysis, and Elevated Creatine myopathy or myositis have Phosphokinase been reported. Nervous System/ N/A All INSTIs: Insomnia, N/A d4T > ddI: Peripheral neuropathy Neuropsychiatric Events: EFV > Psychiatric (can be irreversible) RPV, DOR > ETR depression, and suicidality Effects have been reported with EFV: Somnolence, insomnia, d4T: Associated with rapidly INSTI use, primarily in abnormal dreams, dizziness, progressive, ascending patients with pre-existing neuromuscular weakness impaired concentration, psychiatric conditions. depression, psychosis, and resembling Guillain-Barré suicidal ideation. Symptoms syndrome (rare) usually subside or diminish after 2–4 weeks. Bedtime dosing may reduce symptoms. Risk factors include presence of psychiatric illness, concomitant use of agents with neuropsychiatric effects, and increased EFV concentrations because of genetic factors or increased absorption with food. An association between EFV and suicidal ideation, suicide, and attempted suicide was found in a retrospective analysis of comparative trials. RPV: Depression, suicidality, sleep disturbances DOR: Sleep disorders and disturbances, dizziness, altered sensorium; depression and suicidality/self-harm Rash MVC, IBA ATV, DRV, FPV, LPV/r, and TPV All INSTIs FTC : Hyperpigmentation All NNRTIs K-18 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

226 Table 15. Common and/or Severe Adverse Effects Associated with Antiretroviral Therapy (page 5 of 5) Drug Class Adverse Effect PIs EIs NRTIs NNRTIs INSTIs RPV: Inhibits Cr secretion ATV and LPV/r: Associated with Renal Effects/ IBA: SCr : ↑ SCr, proteinuria, DTG, COBI (as a Boosting TDF Agent for EVG), and BIC: abnormalities hypophosphatemia, urinary increased risk of chronic kidney without reducing renal glomerular Urolithiasis disease in a large cohort study. phosphate wasting, glycosuria, Inhibits Cr secretion without ≥Grade 3 reported function. hypokalemia, and non-anion gap reducing renal glomerular in 10% of trial : ↑ SCr, pyuria, renal atrophy, or IDV function metabolic acidosis. Concurrent participants. hydronephrosis use of TDF with COBI- or RTV- containing regimens appears to : Stone or crystal formation. IDV, ATV increase risk. Adequate hydration may reduce risk. TAF : Less impact on renal COBI (as a Boosting Agent for DRV biomarkers and lower rates of or ATV): Inhibits Cr secretion without proteinuria than TDF. reducing renal glomerular function. Some reported cases for ddI and Stevens-Johnson N/A RAL Some reported cases for FPV, DRV, NVP > DLV, EFV, ETR, RPV Syndrome/ IDV, LPV/r, and ATV. ZDV. Toxic Epidermal Necrosis Key to Acronyms: 3TC = lamivudine; ABC = abacavir; ART= antiretroviral therapy; ARV = antiretroviral; ATV = atazanavir; ATV/r = atazanavir/ritonavir; BIC = bictegravir; BMD = bone mineral density; CD4 = CD4 T lymphocyte; Cr = creatinine; CNS = central nervous system; COBI = cobicistat; CPK = creatine phosphokinase; CVD = cardiovascular disease; d4T = stavudine; ddI = didanosine; DLV = delavirdine; DOR = doravirine; DRV = darunavir; DRV/r = darunavir/ritonavir; DTG = dolutegravir; ECG = electrocardiogram; EFV = efavirenz; EI = entry inhibitor; ETR = etravirine; EVG = elvitegravir; EVG/c = elvitegravir/cobicistat; FPV = fosamprenavir; FPV/r = fosamprenavir/ritonavir; FTC = emtricitabine; GI = gastrointestinal; HBV = IBA = ibalizumab; IDV = indinavir; INSTI = integrase strand transfer inhibitor; LDL = low-density lipoprotein; hepatitis B virus; HDL = high-density lipoprotein; HSR = hypersensitivity reaction; LPV/r = lopinavir/ritonavir; MI = myocardial infarction; MVC = maraviroc; NFV = nelfinavir; NNR TI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; NVP = nevirapine; PI = protease inhibitor; RAL = raltegravir; RPV = rilpivirine; RTV = ritonavir; SCr = serum creatinine; SQV = saquinavir; SQV/r = saquinavir/ritonavir; TAF = tenofovir alafenamide; TC = total cholesterol; TDF = tenofovir disoproxil fumarate; TG = triglycerides; TPV = tipranavir; TPV/r = tipranavir/ritonavir; ZDV = zidovudine K-19 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

227 Switching Antiretroviral Therapy Due to Adverse Effects Some patients experience treatment-limiting toxicities associated with ART. In these cases, ART must be modified. ART-associated adverse events can range from acute and potentially life-threatening to chronic and insidious. Serious life-threatening events (e.g., hypersensitivity reaction due to ABC, symptomatic hepatotoxicity, or severe cutaneous reactions) require the immediate discontinuation of all ARV drugs and re-initiation of an alternative regimen without overlapping toxicity. Toxicities that are not life-threatening (e.g., urolithiasis with ATV or renal tubulopathy with TDF) can usually be managed by substituting another ARV agent for the presumed causative agent without interrupting ART. Other chronic, non–life-threatening adverse events (e.g., dyslipidemia) can be addressed either by switching the potentially causative agent for another agent or by managing the adverse event with additional pharmacological or nonpharmacological interventions. Management strategies must be individualized for each patient. Switching from an effective ARV regimen (or agent) to a new regimen (or agent) must be done carefully and only when the potential benefits of the change outweigh the potential complications of altering treatment. The fundamental principle of regimen switching is to maintain viral suppression. When selecting a new agent or regimen, providers should be aware that resistance mutations are archived in HIV reservoirs, regardless of when the mutations were identified by genotypic resistance testing. Even if resistance mutations are absent from subsequent resistance test results, they may reappear under selective drug pressure. It is critical that providers review the following information before implementing any treatment switch: • The patient’ s medical and complete ARV history, including prior virologic responses to ART; • All previous resistance test results; Viral tropism (if MVC is being considered); • • HLA-B*5701 status (if ABC is being considered); Comorbidities; • • s pregnancy status, ability to use effective contraceptives, and desire for pregnancy (if DTG The patient’ is being considered for patients of child-bearing potential); HBV status, since patients with evidence of chronic HBV infection should not discontinue TDF or TAF • unless a regimen contains another agent that is active against HBV; • Adherence history; • Prior intolerances to any ARVs; and • Concomitant medications and supplements, taking into consideration any potential drug interactions with ARVs. patient’s willingness to accept new requirements for food or dosing must also be assessed. In some cases, A medication costs may also be a factor to consider before switching treatment. Signs and symptoms of comorbidities, adverse effects of concomitant medications, or HIV itself may mimic adverse effects caused by ART. Therefore, clinicians should investigate all potential causes for an adverse event. In the case of a severe adverse event, it may be necessary to discontinue or switch ARVs pending the outcome of such an investigation. For the first few months after an ART switch, the patient should be closely monitored for any new adverse events. The patient’s viral load should also be monitored to assure continued viral suppression. Table 16 lists several major ART-associated adverse events and the options for appropriate switches between agents in an ARV regimen. The table focuses on the ARVs most commonly used in the United States and lists substitutions that are supported by ARV switch studies, the findings of comparative ARV trials and observational cohort studies, or expert opinion. Switching agents in a successful ARV regimen should be done carefully and only when the potential benefits of the change outweigh the potential complications of altering treatment. K-20 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

228 Table 16. Antiretroviral Therapy-Associated Adverse Events That Can Be Managed with Substitution of Alternative Antiretroviral Agent (page 1 of 3) ARV Agent(s) or Drug Class Comments Adverse Event Switch to Switch from b a TAF or ABC TDF Bone Density Declines in BMD have been observed upon Effects initiation of most ART regimens. Switching NRTI-sparing regimens or from TDF to alternative ARV agents has been regimens using only 3TC or shown to increase bone density, but the clinical FTC as the NRTI may be significance of this increase remains uncertain. considered, if appropriate. TAF is associated with smaller declines in BMD than TDF, and patients show improvement in BMD upon switching to TAF. The long-term impact of TAF on patients with osteopenia or osteoporosis is unknown; close clinical monitoring is recommended in this setting. b ZDV TDF, TAF, or ABC Bone Marrow ZDV has been associated with neutropenia and Suppression macrocytic anemia. Cardiac High EFV and RPV exposures may cause QT A PI- or INSTI-based regimen EFV, RPV prolongation. QTc Interval Prolongation Consider switching from EFV- or RPV-based regimens if patient is taking other medications with known risk of Torsades de Pointes, or in patients at higher risk of Torsades de Pointes. Cardiovascular ABC use has been associated with CV disease TDF, TAF, FTC, or 3TC ABC Events and cardiac events in some, but not all, observational studies. Myocardial infarction, ischemic TDF has been associated with lower lipid levels than TAF. stroke RTV- or COBI-boosted PI RAL, DTG, BIC, or RPV RAL, DTG, BIC, and RPV have less effect on regimens, EFV, EVG/c lipids than RTV- or COBI-boosted PI regimens, EFV, and EVG/c. Large observation cohorts have found an association between some PIs (DRV, FPV, IDV, LPV/r) and an increased risk of CV events. However, this association has not been seen with ATV. Further study is needed. ETR, PI/c, or PI/r EFV, RPV Central Nervous In most patients, EFV-related CNS effects subside within 4 weeks after initiation of the System, INSTIs may be used, but drug. Persistent or intolerable effects should Neuropsychiatric monitoring is recommended Side Effects prompt substitution of EFV. (see Comments column). Dizziness, suicidal INSTIs are associated with insomnia. ideation, abnormal Depression and suicidality have been dreams, depression infrequently reported with INSTI use, primarily in patients with pre-existing psychiatric conditions. Dyslipidemia RTV- or COBI-boosted RAL, DTG, BIC, or RPV Elevated TG and LDL levels are more common regimens, and EFV with LPV/r and FPV/r than with other RTV- Hypertriglyceridemia boosted PIs. Improvements in TG and LDL (with or without levels have been observed with switch from elevated LDL level) c LPV/r to ATV or ATV/r. K-21 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

229 Table 16. Antiretroviral Therapy-Associated Adverse Events That Can Be Managed with Substitution (page 2 of 3) of Alternative Antiretroviral Agent ARV Agent(s) or Drug Class Comments Adverse Event Switch to Switch from GI intolerance is common with boosted PIs LPV/r Gastrointestinal ATV/c, ATV/r, DRV/c, DRV/r, and is linked to the total dose of RTV. More GI Effects RAL, DTG, BIC, or EVG/c toxicity is seen with LPV/r than with ATV/r or Nausea, diarrhea DRV/r. GI effects are often transient and do not warrant substitution unless they are persistent and intolerable. Other RTV- or COBI-boosted RAL, DTG, BIC, or NNRTIs In a trial of treatment-naive patients, rates of regimens diarrhea and nausea were similar for EVG/c/ TDF/FTC and ATV/r plus TDF/FTC. Hypersensitivity ABC TDF or TAF Never rechallenge with ABC following a Reaction suspected HSR, regardless of the patient’s HLA-B*5701 status. NVP, EFV, ETR, RPV Non-NNRTI ART Risk of HSR with NVP is higher for women and those with high CD4 cell counts. DTG, RAL Non-INSTI ART Reactions to NVP, ETR, RAL, DTG, and MVC may be accompanied by elevated liver Suitable alternative ART MVC transaminases. LPV/r, FPV/r INSTI, NNRTI Insulin Resistance Results of switch studies have been inconsistent. Studies in HIV-negative patients suggest a direct causal effect of LPV/r (and IDV) on insulin resistance. However, traditional risk factors may be stronger risk factors for insulin resistance than the use of any PI. Increases in unconjugated bilirubin are ATV, ATV/c, ATV/r DRV/c, DRV/r, INSTI, or Jaundice and Icterus common with ATV and generally do not require NNRTI modification of therapy unless resultant symptoms are distressing to the patient. b TDF, TAF, or ABC Lipoatrophy d4T, ZDV Peripheral lipoatrophy is associated with prior thymidine analog (d4T and ZDV) use. Subcutaneous fat Switching from these ARVs prevents worsening wasting of limbs, lipoatrophy, but fat recovery is typically slow face, buttocks (may take years) and incomplete. Lipohypertrophy Accumulation of visceral, truncal, dorsocervical, and breast fat has been observed during ART, particularly during use of older PI-based regimens (e.g., IDV), but whether ART directly causes fat accumulation remains unclear. There is no clinical evidence that switching to another first line regimen will reverse weight or visceral fat gain. Rash NNRTIs (especially NVP and PI- or INSTI-based regimen Mild rashes that develop after initiation EFV) of NNRTIs other than NVP rarely require treatment switch. When serious rash develops due to any NNRTI, switch to another drug class. Mild rashes following DRV/r use may resolve ATV/c, ATV/r, or another drug DRV/c, DRV/r class (e.g., INSTI) without modification of therapy. For more severe reactions, change to an alternative boosted PI or an agent from another drug class. K-22 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

230 Table 16. Antiretroviral Therapy-Associated Adverse Events That Can Be Managed with Substitution (page 3 of 3) of Alternative Antiretroviral Agent ARV Agent(s) or Drug Class Adverse Event Comments Switch from Switch to a b ABC, Renal Effects TDF TAF (for patients with TDF may cause tubulopathy. CrCl >30 mL/min), NRTI- Switching from TDF to TAF is associated Including proximal sparing regimens, or regimens with improvement in proteinuria and renal renal tubulopathy using only 3TC or FTC as the biomarkers. The long-term impact of TAF and elevated NRTI may be considered if on patients with pre-existing renal disease, creatinine appropriate. including overt proximal tubulopathy, is unknown, and close clinical monitoring is recommended in this setting. ATV/c, ATV/r, LPV/r DTG, BIC, RAL, or NNRTI COBI, DTG, BIC, and, to a lesser extent, RPV, can increase SCr through inhibition of creatinine secretion. This effect does not affect glomerular filtration. However, assess patient for renal dysfunction if SCr increases by >0.4 mg/dL. Stones ATV, ATV/c, ATV/r DRV/c, DRV/r, INSTI, or This switch should be made if the clinician NNRTI believes ATV is the cause of the stones. Nephrolithiasis and cholelithiasis a In patients with chronic active HBV infection, another agent that is active against HBV should be substituted for TDF. b ABC should be used only in patients known to be HLA-B*5701 negative. c TDF reduces ATV levels; therefore, unboosted ATV should not be coadministered with TDF. Key to Acronyms: 3TC = lamivudine; ABC = abacavir; ART = antiretroviral therapy; ARV = antiretroviral; ATV = atazanavir; ATV/c = atazanavir/cobicistat; ATV/r = atazanavir/ritonavir; BIC = bictegravir; BMD = bone mineral density; CD4 = CD4 T lymphocyte; CNS = central nervous system; COBI = cobicistat; CrCl = creatine clearance; CV = cardiovascular; d4T = stavudine; DOR = doravirine; DRV = darunavir; DRV/c = darunavir/cobicistat; DRV/r = darunavir/ritonavir; DTG = dolutegravir; EFV = efavirenz; ETR = etravirine; EVG/c = elvitegravir/cobicistat; FPV = fosamprenavir; FPV/r = fosamprenavir/ritonavir; FTC = emtricitabine; GI = gastrointestinal; HBV = hepatitis B virus; HSR = hypersensitivity reaction; IDV = indinavir; INSTI = integrase strand transfer inhibitor; LDL = low-density lipoprotein; LPV/r = lopinavir/ritonavir; MVC = maraviroc; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; NVP = nevirapine; PI = protease inhibitor; PI/c = protease inhibitor/cobicistat; PI/r = protease inhibitor/ritonavir; RAL = raltegravir; RPV = rilpivirine; RTV = ritonavir; SCr = serum creatinine; TAF = tenofovir alafenamide; TC = total cholesterol; TDF = tenofovir disoproxil fumarate; TG = triglycerides; ZDV = zidovudine References 1. T regimen in an O’Brien ME, Clark RA, Besch CL, et al. Patterns and correlates of discontinuation of the initial HAAR J urban outpatient cohort. https://www.ncbi.nlm.nih.gov/ . 2003;34(4):407-414. Available at: Acquir Immune Defic Syndr . pubmed/14615659 den Brinker M, Wit FW, Wertheim-van Dillen PM, et al. Hepatitis B and C virus co-infection and the risk for 2. AIDS . 2000;14(18):2895-2902. Available at: hepatotoxicity of highly active antiretroviral therapy in HIV-1 infection. https://www.ncbi.nlm.nih.gov/pubmed/11153671 . , Clevenbergh P, et al. Hepatitis B or hepatitis C virus infection is a risk factor for severe hepatic Saves M, Raffi F 3. cytolysis after initiation of a protease inhibitor-containing antiretroviral regimen in human immunodeficiency virus- . 2000;44(12):3451-3455. Available at: infected patients. The APROCO Study Group. Antimicrob Agents Chemother . https://www.ncbi.nlm.nih.gov/pubmed/11083658 Harris M, Larsen G, Montaner JS. Exacerbation of depression associated with starting raltegravir: a report of four cases. 4. https://www.ncbi.nlm.nih.gov/pubmed/18753871 . AIDS . 2008;22(14):1890-1892. Available at: 5. Kheloufi F , Allemand J, Mokhtari S, Default A. Psychiatric disorders after starting dolutegravir: report of four cases. . https://www.ncbi.nlm.nih.gov/pubmed/26372287 . 2015;29(13):1723-1725. Available at: AIDS K-23 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

231 6. Mallal S, Phillips E, Carosi G, et al. HLA-B*5701 screening for hypersensitivity to abacavir . N Engl J Med . 2008;358(6):568-579. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18256392 . 7. Saag M, Balu R, Phillips E, et al. High sensitivity of human leukocyte antigen-b*5701 as a marker for immunologically confirmed abacavir hypersensitivity in white and black patients. Clin Infect Dis . 2008;46(7):1 111-1118. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18444831 . 8. Gounden V, van Niekerk C, Snyman T, George JA. Presence of the CYP2B6 516G> T polymorphism, increased plasma efavirenz concentrations and early neuropsychiatric side effects in South African HIV-infected patients. . AIDS Res Ther . http://www.ncbi.nlm.nih.gov/pubmed/20723261 2010;7:32. Available at: Abdelhady AM, Shugg T, Thong N, et al. Efavirenz inhibits the human ether-a-go-go related current (hERG) and 9. J Cardiovasc Electrophysiol . 2016;27(10):1206-1213. induces QT interval prolongation in CYP2B6*6*6 allele carriers. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27333947 . 10. Rodriguez-Novoa S, Martin-Carbonero L, Barreiro P, et al. Genetic factors influencing atazanavir plasma concentrations http://www.ncbi.nlm.nih.gov/ and the risk of severe hyperbilirubinemia. AIDS . 2007;21(1):41-46. Available at: . pubmed/17148966 K-24 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

232 Cost Considerations and Antiretroviral Therapy (Last updated July 14, 2016; last reviewed July 14, 2016) Although antiretroviral therapy (ART) is expensive (see Table 16 below), the cost-effectiveness of ART has 1 2,3 been demonstrated in analyses of older and newer regimens, as well as for treatment-experienced patients 4 with drug-resistant HIV. Given the recommendations for immediate initiation of lifelong treatment and the increasing number of patients taking ART, the Panel now introduces cost-related issues pertaining to medication adherence and cost-containment strategies, as discussed below. Costs as They Relate to Adherence from a Patient Perspective Cost sharing: Cost sharing is where the patient is responsible for some of the medication cost burden (usually accomplished via copayments, coinsurance, or deductibles); these costs are often higher for branded medications than for generic medications. In one comprehensive review, increased patient cost sharing resulted in decreased medical adherence and more frequent drug discontinuation; for patients with chronic 5 diseases, increased cost sharing was also associated with increased use of the medical system. Conversely, copayment reductions, such as those that might be used to incentivize prescribing of generic drugs, 6 have been associated with improved adherence in patients with chronic diseases. Whereas cost sharing disproportionately affects low-income patients, resources (e.g., the Ryan White AIDS Drug Assistance Program [ADAP]) are available to assist eligible patients with copays and deductibles. Given the clear association between out-of-pocket costs for patients with chronic diseases and the ability of those patients to pay for and adhere to medications, clinicians should minimize patients’ out-of-pocket drug-related expenses whenever possible. As a cost-containment strategy, some programs require that clinicians obtain prior Prior authorizations: authorizations or permission before prescribing newer or more costly treatments rather than older or less expensive drugs. Although there are data demonstrating that prior authorizations do reduce spending, several studies have also shown that prior authorizations result in fewer prescriptions filled and increased 7-9 nonadherence. Prior authorizations in HIV care specifically have been reported to cost over $40 each in 10 provider personnel time (a hidden cost) and have substantially reduced timely access to medications. The impact of the availability of generic antiretroviral (ARV) drugs on selection of ART in Generic ART: the United States is unknown. Because U.S. patent laws currently limit the coformulation of some generic alternatives to branded drugs, generic options may result in increased pill burden. To the extent that pill burden, rather than drug frequency, results in reduced adherence, generic ART could lead to decreased 11,12 costs but at the potential expense of worsening virologic suppression rates and poorer clinical outcomes. Furthermore, prescribing the individual, less-expensive generic components of a branded coformulated product rather than the branded product itself could, under some insurance plans, lead to higher copays—an out-of-pocket cost increase that may reduce medication adherence. Potential Cost Containment Strategies from a Societal Perspective Given resource constraints, it is important to maximize the use of resources without sacrificing clinical outcomes. Evidence-based revisions to these guidelines recommend tailored laboratory monitoring for patients with long-term virologic suppression on ART as one possible way to provide overall cost savings. Data suggest that continued CD4 monitoring yields no clinical benefit for patients whose viral loads 13 3 are suppressed and whose CD4 counts exceed 200 cells/mm after 48 weeks of therapy. A reduction in laboratory use from biannual to annual CD4 monitoring could save ~$10 million per year in the United 14 States ). Although this is a small proportion of the overall costs associated with Laboratory Monitoring (see HIV care, such a strategy could reduce patients’ personal expenses if they have deductibles for laboratory tests. The present and future availability of generic formulations of certain ARV drugs, despite the potential caveats of increased pill burden and reduced adherence, offers other money-saving possibilities on a much K-25 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

233 greater scale. One analysis suggests the possibility of saving approximately $900 million nationally in the first year of switching from a branded fixed-dose combination product to a three-pill regimen containing 3 generic efavirenz. In summary, understanding HIV and ART related-costs in the United States is complicated because of the wide variability in medical coverage, accessibility, and expenses across regions, insurance plans, and pharmacies. In an effort to retain excellent clinical outcomes in an environment of cost-containment strategies, providers should remain informed of current insurance and payment structures, ART costs (see Table 16 below for estimates of drugs’ average wholesale prices), discounts among preferred pharmacies, and available generic ART options. Providers should work with patients and their case managers and social workers to understand their patients’ particular pharmacy benefit plans and potential financial barriers to filling their prescriptions. Additionally, providers should familiarize themselves with ARV affordability resources (such as ADAP and pharmaceutical company patient assistance programs for patients who qualify) and refer patients to such assistance if needed. K-26 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

234 Table 17. Monthly Average Prices of Commonly Used Antiretroviral Drugs , 2018; last reviewed October 25, 2018) (Last updated November 26 (page 1 of 5) Prescription drug pricing in the United States involves complex systems of negotiations, rebates, discounts, and reimbursement rates. Much of the information used to determine drug prices is confidential, and prices can vary depending on the purchaser, the type of public or private insurance flation can trigger additional rebates for coverage in use, and the number of generic competitors. In addition, price increases that exceed rates of in Medicaid and 340B Drug Discount Program entities. Table 17 includes three benchmark prices, rounded to the nearest dollar , for commonly used a antiretroviral (ARV) drugs as a general reference for he alth care providers when considering the cost of HIV treatment. Health care providers should contact patients’ pharmacies or payors regarding actual prices, comparative cost savings, and related formulary restrictions. Wholesale acquisition cost (WAC) is the list price published by manufacturers for prescription drugs or biologics sold to wholesalers. The WAC price approximates what retail pharmacies pay wholesalers for single-source (e.g., brand-name) drugs. There is a range of WAC prices for generic ARVs, as these are multiple-source products with variable list prices. With increasing competition, actual transactional prices of generic drugs Average wholesale price (AWP) has historically been used as the basis for setting among wholesalers and pharmacies decrease substantially. public (e.g., Medicaid) and private (e.g., commercial insurer) reimbursement rates for pharmacies. Neither W AWP include variable price AC nor Veterans’ concessions along supply and payment chains, including discounts and rebates to wholesalers, pharmacies, federal purchasers (e.g., the Administration), pharmacy benefit managers, commercial insurers, Medicaid, 340B pharmacies, and AIDS Drug Assistance Programs. The availability of these discounts and rebates depends on product demand, market competition, and WAC price increases set by manufacturers. Maximum prices are assigned to generic products with three or more therapeutically and pharmaceutically equivalent products, as determined Administration. by the Food and Drug federal upper limit (FUL) . Federal Medicaid will reimburse state This federally established price is the Medicaid programs up to this limit for multiple-source drugs (plus the dispensing fee); commercial insurers set their own reimbursement upper limits with pharmacies. Whereas WACs and AWPs are generally set annually, FULs are adjusted monthly, particularly for multiple-source drugs with fluctuating pharmacy acquisition costs. In the table below, the FUL for a drug is described as “pending” if a generic drug currently lacks the competition required to trigger a FUL. ARV Drug FUL AWP WAC Tablets, Capsules, or Strength, Formulation b b c (Monthly) (Generic and Brand Names) (As of 9/1/2018) (Monthly) mLs per Month Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Abacavir Generic • 60 tablets $150 to $482 $579 to $603 $44 300 mg tablet • Ziagen 300 mg tablet 60 tablets $559 $670 Emtricitabine Emtriva 200 mg capsules 30 capsules $537 $644 N/A • Lamivudine • Generic 300 mg tablet 30 tablets $75 to $343 $429 to $430 $83 $499 $416 30 tablets • Epivir 300 mg tablet K-27 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

235 Table 17. Monthly Average Prices of Commonly Used Antiretroviral Drugs (Last updated November 26, 2018; last reviewed October 25, 2018) (page 2 of 5) ARV Drug AWP WAC FUL Tablets, Capsules, or Strength, Formulation c b b (Monthly) (Monthly) (As of 9/1/2018) (Generic and Brand Names) mLs per Month Nucleoside Reverse Transcriptase Inhibitors (NRTIs) , continued Tenofovir Disoproxil Fumarate • $58 to $922 $110 to $1,216 Pending Generic 300 mg tablet 30 tablets iread 300 mg tablet 30 tablets $1,140 $1,368 • V Zidovudine 300 mg tablet $36 to $54 $54 to $365 $13 • Generic 60 tablets NRTI Combination Products Abacavir/Lamivudine 600 mg/300 mg tablets 30 tablets $185 to $1,116 $1,395 $356 • Generic 600 mg/300 mg tablets 30 tablets $1,292 • Epzicom $1,550 Tenofovir Alafenamide/Emtricitabine 25 mg/200 mg tablet 30 tablets $1,676 Descovy N/A • $2,011 Tenofovir Disoproxil Fumarate/Emtricitabine T ruvada 300 mg/200 mg tablet 30 tablets $1,676 $2,011 N/A • Tenofovir Disoproxil Fumarate/Lamivudine 30 tablets $1,005 $1,207 N/A • Cimduo 300 mg/300 mg tablet Zidovudine/Lamivudine Generic 60 tablets $134 to $578 $878 to $932 $47 300 mg/150 mg tablet • 300 mg/150 mg tablet 60 tablets $901 • Combivir $1,082 Abacavir Sulfate/Zidovudine/Lamivudine Generic 300 mg/300 mg/150 mg tablet 60 tablets $1,391 $1,738 Pending • T rizivir 300 mg/300 mg/150 mg tablet 60 tablets $1,610 $1,932 • Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Efavirenz • Generic 600 mg tablet 30 tablets $894 $1,118 Pending Sustiva 600 mg tablet 30 tablets $981 $1,177 • Doravirine N/A 100 mg tablet 30 tablets $1,380 $1,656 Pifeltro • K-28 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

236 Table 17. Monthly Average Prices of Commonly Used Antiretroviral Drugs (Last updated November 26, 2018; last reviewed October 25, 2018) (page 3 of 5) AWP ARV Drug WAC FUL Tablets, Capsules, or Strength, Formulation c b b (Monthly) (Monthly) (As of 9/1/2018) (Generic and Brand Names) mLs per Month Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) , continued Etravirine • $1,296 $1,523 N/A Intelence 200 mg tablet 60 tablets Nevirapine 200 mg tablet 60 tablets $10 to $45 $648 to $651 $37 Generic • iramune 200 mg tablet • $855 $1,026 V 60 tablets Generic XR 30 tablets $246 to $565 $678 to $706 • 400 mg tablet $231 Viramune XR 30 tablets $793 $951 400 mg tablet • Rilpivirine 25 mg tablet 30 tablets $1043 $1,252 • Edurant N/A Protease Inhibitors (PIs) Atazanavir 200 mg capsule 60 capsules $1,580 to $1,668 Pending • Generic $878 to $1,264 Reyataz 200 mg capsule 60 capsules $1,463 $1,756 • Generic $870 to $1,252 $1,565 to $1,652 • 300 mg capsule 30 capsules Pending Reyataz 30 capsules $1,449 $1,739 • 300 mg capsule Atazanavir/Cobicistat 300/150 mg tablet 30 tablets $1,605 $1,927 N/A • Evotaz Darunavir 60 tablets $1,581 $1,897 N/A Prezista • 600 mg tablet 800 mg tablet 30 tablets $1,581 $1,897 N/A • Prezista Prezista 100 mg/mL suspension 200 mL $878 $1,054 N/A • Darunavir/Cobicistat 800 mg/150 mg tablet 30 tablets $1,806 $2,168 N/A Prezcobix • Lopinavir/Ritonavir Kaletra 200 mg/50 mg tablet 120 tablets $1,024 $1,229 N/A • Tipranavir N/A 250 mg capsule 120 capsules $1,578 $1,894 Aptivus • K-29 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

237 Table 17. Monthly Average Prices of Commonly Used Antiretroviral Drugs (Last updated November 26, 2018; last reviewed October 25, 2018) (page 4 of 5) WAC ARV Drug AWP FUL Tablets, Capsules, or Strength, Formulation b b c (Monthly) (As of 9/1/2018) (Generic and Brand Names) (Monthly) mLs per Month Integrase Strand Transfer Inhibitors (INSTIs) Dolutegravir ivicay 50 mg tablet 30 tablets $1,658 $1,989 N/A T • ivicay 50 mg tablet 60 tablets $3,315 $3,978 N/A • T Raltegravir Isentress 60 tablets $1,500 $1,800 N/A • 400 mg tablet 600 mg tablet $1,500 $1,800 N/A Isentress HD 60 tablets • Fusion Inhibitor Enfuvirtide 90 mg injection kit 60 doses (1 kit) $3,586 $4,303 • Fuzeon N/A CCR5 Antagonist Maraviroc 150 mg tablet 60 tablets $1,813 N/A • Selzentry $1,511 Selzentry 300 mg tablet 60 tablets $1,511 $1,813 N/A • Selzentry $3,022 $3,626 N/A • 300 mg tablet 120 tablets CD4-Directed Post-Attachment Inhibitor Ibalizumab-uiyk rogarzo 200 mg vials 8 vials $9,080 $10,896 • N/A T Coformulated Combination Products as Single Tablet Regimens Bictegravir/Tenofovir Alafenamide/Emtricitabine N/A 30 tablets $2,946 $3,535 Biktarvy • 50 mg/25 mg/200 mg Darunavir/Cobicistat/Tenofovir Alafenamide/Emtricitabine • Symtuza $3,482 $4,178 N/A 600 mg/150 mg/10 mg/200 mg 30 tablets Dolutegravir/Abacavir/Lamivudine $3,366 riumeq 50 mg/600 mg/300 mg tablet 30 tablets $2,805 N/A T • Dolutegravir/Rilpivirine Juluca 50 mg/25 mg 30 tablets $2,579 $3,095 N/A • Doravirine/Tenofovir Disoproxil Fumarate/Lamivudine N/A 100 mg/300 mg/300 mg 30 tablets $2,100 $2,520 Delstrigo • K-30 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

238 Table 17. Monthly (Last updated November 26, 2018; last reviewed October 25, 2018) Average Prices of Commonly Used Antiretroviral Drugs (page 5 of 5) WAC AWP ARV Drug FUL Tablets, Capsules, or Strength, Formulation b b c (Monthly) (As of 9/1/2018) (Monthly) (Generic and Brand Names) mLs per Month , continued Coformulated Combination Products as Single Tablet Regimens Efavirenz/Tenofovir Disoproxil Fumarate/Emtricitabine N/A $3,269 $2,724 30 tablets 600 mg/300 mg/200 mg tablet Atripla • Efavirenz/Tenofovir Disoproxil Fumarate/Lamivudine 600 mg/300 mg/ 30 0 mg tablet N/A Symfi 30 tablets $1,634 $1,961 • 0 mg tablet 30 400 mg/300 mg/ 30 tablets • $1,961 $1,634 Symfi Lo N/A Elvitegravir/Cobicistat/Tenofovir Alafenamide/Emtricitabine $3,535 N/A • Genvoya 150 mg/150 mg/10 mg/200 mg tablet 30 tablets $2,946 Elvitegravir/Cobicistat/Tenofovir Disoproxil Fumarate/ Emtricitabine 150 mg/150 mg/300 mg/200 mg tablet $3,708 N/A 30 tablets $3,090 Stribild • Rilpivirine/Tenofovir Alafenamide/Emtricitabine N/A • 30 tablets $2,681 $3,217 Odefsey 25 mg/25 mg/200 mg tablet Rilpivirine/Tenofovir Disoproxil Fumarate/Emtricitabine $2,681 N/A 30 tablets • Complera 25 mg/300 mg/200 mg tablet $3,217 Pharmacokinetic Enhancers (Boosters) Cobicistat $264 N/A 30 tablets 150 mg tablet Tybost • $219 Ritonavir $222 $278 Pending • Generic 100 mg tablet 30 tablets $257 30 tablets 100 mg tablet Norvir • $309 a The following less commonly used ARV drugs are not included in this table: delavirdine, didanosine, fosamprenavir, indinavir, nelfinavir, saquinavir, and stavudine. b Source: IBM Watson Health. Micromedex Red Book [database]. 2018 . Available at: https://www.micromedexsolutions.com c Source: Medicare & Medicaid Services. Federal Upper Limits—September 2018 [database]. 2018 September 1. Available at: https://www.medicaid.gov/medicaid/prescription-drugs/ pharmacy-pricing/index.html . K-31 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

239 References 1. Freedber g KA, Losina E, Weinstein MC, et al. The cost effectiveness of combination antiretroviral therapy for HIV N Engl J Med https://www.ncbi.nlm.nih.gov/pubmed/11248160 . disease. . Mar 15 2001;344(11):824-831. Available at 2. Mauskopf J, Brogan AJ, Talbird SE, Martin S. Cost-effectiveness of combination therapy with etravirine in treatment- AIDS . Jan 28 2012;26(3):355-364. Available at http://www.ncbi.nlm.nih.gov/ experienced adults with HIV-1 infection. pubmed/22089378 . alensky RP, Sax PE, Nakamura YM, et al. Economic savings versus health losses: the cost-effectiveness of generic 3. W antiretroviral therapy in the United States. . Jan 15 2013;158(2):84-92. Available at http://www.ncbi.nlm. Ann Intern Med nih.gov/pubmed/23318310 . 4. Bayoumi AM, Barnett PG, Joyce VR, et al. Cost-effectiveness of newer antiretroviral drugs in treatment-experienced patients with multidrug-resistant HIV disease. J Acquir Immune Defic Syndr . Dec 1 2013;64(4):382-391. Available at . http://www.ncbi.nlm.nih.gov/pubmed/24129369 Goldman DP , Joyce GF, Zheng Y. Prescription drug cost sharing: associations with medication and medical utilization 5. JAMA . Jul 4 2007;298(1):61-69. Available at http://www.ncbi.nlm.nih.gov/pubmed/17609491 . and spending and health. 6. Maciejewski ML, Farley JF , Parker J, Wansink D. Copayment reductions generate greater medication adherence in targeted patients. . Nov 2010;29(11):2002-2008. Available at http://www.ncbi.nlm.nih.gov/pubmed/21041739 . Health Aff 7. Abdelgawad T, Egbuonu-Davis L. Preferred drug lists and Medicaid prescriptions. Pharmacoeconomics . 2006;24 Suppl 3:55-63. Available at http://www.ncbi.nlm.nih.gov/pubmed/17266388 . 8. . 2006;24 Ridley DB, Axelsen KJ. Impact of Medicaid preferred drug lists on therapeutic adherence. Pharmacoeconomics Suppl 3:65-78. Available at http://www.ncbi.nlm.nih.gov/pubmed/17266389 . W ilson J, Axelsen K, Tang S. Medicaid prescription drug access restrictions: exploring the effect on patient persistence 9. with hypertension medications. http://www.ncbi.nlm.nih. Am J Manag Care . Jan 2005;11 Spec No:SP27-34. Available at . gov/pubmed/15700907 Raper JL, Willig JH, Lin HY, et al. Uncompensated medical provider costs associated with prior authorization for 10. Clin Infect Dis http://www.ncbi.nlm. . Sep 15 2010;51(6):718-724. Available at prescription medications in an HIV clinic. nih.gov/pubmed/20695800 . Hanna DB, Hessol NA, Golub ET , et al. Increase in Single-Tablet Regimen Use and Associated Improvements in 11. Adherence-Related Outcomes in Hiv-Infected Women. J Acquir Immune Defic Syndr . Dec 8 2013. Available at http:// www.ncbi.nlm.nih.gov/pubmed/24326606 . 12. Nachega JB, Parienti JJ, Uthman OA, et al. Lower pill burden and once-daily antiretroviral treatment regimens for HIV infection: A meta-analysis of randomized controlled trials. Clin Infect Dis . May 2014;58(9):1297-1307. Available at https://www.ncbi.nlm.nih.gov/pubmed/24457345 . 13. Girard PM, Nelson M, Mohammed P , Hill A, van Delft Y, Moecklinghoff C. Can we stop CD4+ testing in patients with HIV-1 RNA suppression on antiretroviral treatment? AIDS . Nov 13 2013;27(17):2759-2763. Available at http://www. ncbi.nlm.nih.gov/pubmed/23842127 . 14. Hyle EP , Sax PE, Walensky RP. Potential savings by reduced CD4 monitoring in stable patients with HIV receiving http://www.ncbi.nlm.nih.gov/ antiretroviral therapy. JAMA Intern Med . Oct 14 2013;173(18):1746-1748. Available at . pubmed/23978894 K-32 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

240 Drug-Drug Interactions (Last updated October 25, 2018; last reviewed October 25, 2018) Pharmacokinetic (PK) drug-drug interactions between antiretroviral (ARV) drugs and concomitant medications are common and may lead to increased or decreased drug exposure. In some instances, changes in drug exposure may increase toxicities or affect therapeutic responses. When prescribing or switching one or more drugs in an ARV regimen, clinicians must consider the potential for drug-drug interactions—both those affecting ARVs and those affecting the other drugs a patient is taking. A thorough review of concomitant medications in consultation with an expert in ARV pharmacology can help in designing a regimen that minimizes undesirable interactions. Recommendations for managing a particular drug interaction may differ depending on whether a new ARV is being initiated in a patient on a stable concomitant medication or a new concomitant medication is being initiated in a patient on a stable ARV regimen. The magnitude and significance of interactions are difficult to predict when several drugs with competing metabolic pathways are prescribed concomitantly. When it is necessary to prescribe interacting drugs, clinicians should be vigilant in monitoring for therapeutic efficacy and/or concentration-related toxicities. Mechanisms of Pharmacokinetic Interactions PK interactions may occur during absorption, metabolism, or elimination of the ARV and/or the interacting drugs. The most common mechanisms of interactions are described below and listed for each ARV drug in Table 18. Pharmacokinetic Interactions Affecting Drug Absorption The extent of oral absorption of drugs can be affected by the following mechanisms: • Acid-reducing agents, such as proton pump inhibitors, H2 antagonists, or antacids, can reduce the ARV drugs that require gastric acidity for optimal absorption (i.e., atazanavir [ATV] and absorption of rilpivirine [RPV]). • Products that contain polyvalent cations, such as supplements, iron products, or antacids that contain aluminum, calcium, or magnesium, can bind to integrase strand transfer inhibitors (INSTIs) and reduce absorption of these ARV agents. • Drugs that induce or inhibit the enzyme cytochrome P450 3A4 (CYP3A4) or efflux transporter p-glycoprotein in the intestines may reduce or promote the absorption of other drugs. Pharmacokinetic Interactions Affecting Hepatic Metabolism Two major enzyme systems are most frequently responsible for clinically significant drug interactions. • The cytochrome P450 enzyme system is responsible for the metabolism of many drugs, including the non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), the CCR5 antagonist maraviroc (MVC), and the INSTI elvitegravir (EVG). CYP3A4 is the most common enzyme responsible for drug metabolism, though multiple enzymes may be involved in the metabolism of a drug. ARV drugs and concomitant medications may be inducers, inhibitors, and/or substrates of these enzymes. The uridine diphosphate glucuronosyltransferase (UGT) 1A1 enzyme is the primary enzyme responsible • for the metabolism of the INSTIs dolutegravir (DTG) and raltegravir (RAL). Drugs that induce or inhibit the UGT enzyme can affect the PKs of these INSTIs. Pharmacokinetic Enhancers (Boosters) PK enhancing is a strategy used to increase exposure of an ARV by concomitantly administering a drug that inhibits the enzymes that metabolize the ARV. Currently, two agents are used as PK enhancers: ritonavir L-1 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

241 (RTV) and cobicistat (COBI). Both of these drugs are potent inhibitors of the CYP3A4 enzyme, resulting in higher systemic exposures of the coadministered ARV that is metabolized by this pathway. Importantly, RTV and COBI have different effects on other CYP- or UGT-metabolizing enzymes and drug transporters. Complex or unknown mechanisms of PK-based interactions preclude extrapolation of RTV drug interactions to certain COBI interactions, such as interactions with warfarin, phenytoin, voriconazole, oral contraceptives, and certain HMG-CoA reductase inhibitors (or statins). Other Mechanisms of Pharmacokinetic Interactions Knowledge of drug transporters is evolving, elucidating additional drug interaction mechanisms. For example, DTG decreases the renal clearance of metformin by inhibiting organic cation transporters in renal tubular cells. Similar transporters aid hepatic, renal, and biliary clearance of drugs and may be susceptible to drug interactions. ARVs and concomitant medications may be inducers, inhibitors, and/or substrates of these drug transporters. Tables 19a through 20b provide information on known or suspected drug interactions between ARV agents and commonly prescribed medications based on published PK data or information from product labels. The tables provide general guidance on drugs that should not be coadministered and recommendations for dose modifications or alternative therapy. Role of Therapeutic Drug Monitoring in Managing Drug-Drug Interactions Therapeutic drug monitoring (TDM) can guide the dosing of certain medications by using measured drug TDM concentrations to improve the likelihood of desired therapeutic and safety outcomes. Drugs suitable for are characterized by a known exposure-response relationship and a therapeutic range of concentrations. The therapeutic range is a range of concentrations established through clinical investigations that are associated with a greater likelihood of achieving the desired therapeutic response and/or reducing the frequency of drug- associated adverse reactions. When concomitant use of an ARV drug and another medication is likely to result in a clinically important PK drug-drug interaction, the first step is to assess whether there are other , equally effective treatment options that can be used in order to avoid the interaction. If that is not possible, TDM may be useful in assessing whether a dose adjustment is needed. Assays for some ARV drug concentrations are commercially available; however, it may take 1 week or longer for the results to be reported. When interpreting the results, clinicians should take into account the patient’s medication adherence, the timing of last dose and blood draw, and the time elapsed since coadministration of the interacting drug combination. If needed, a specialist in ARV clinical pharmacology should be consulted when interpreting the results and deciding what actions to take. If a dose adjustment is needed, it is necessary to repeat TDM after the adjusted drug reaches steady state in order to assure appropriate dosing. TDM information should not be used alone; it must be integrated with other clinical information, including virologic responses and signs and symptoms of drug toxicities, to assure safe and effective therapy. L-2 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

242 Table 18. Mechanisms of Antiretroviral-Associated Drug Interactions (Last updated October 25, 2018; last reviewed October 25, 2018) (page 1 of 2) PK interactions may occur during absorption, metabolism, or elimination of the ARV and/or the interacting drugs. This table does not include a comprehensive list of all possible mechanisms of interactions for individual ARV drugs (e.g., transporters); however, the table lists the most common mechanisms of known interactions and focuses on absorption and CYP- and UGT1A1-mediated interactions. N/A indicates that there are no clinically relevant interactions by these mechanisms. Note: Identified mechanisms are specific to individual ARV drugs and not combinations of ARV drugs. Enzymes That Metabolize or are Induced or Other Mechanisms That May Affect Oral ARV Absorption of ARV Drugs Inhibited by ARV Drugs Mechanisms Drugs of Known by Drug CYP CYP Increasing CYP Cationic P-glyco- Drug UGT1A1 Class Substrate protein Inhibitor Chelation Inducer Gastric pH Interactions INSTIs N/A Concentration Inhibitor of renal Substrate BIC N/A 3A4 N/A Substrate decreased transporters by products OCT2 and MATE1 that contain polyvalent Inhibitor of renal Substrate DTG N/A Substrate 3A4 (minor) N/A N/A cations (e.g., transporters Ca, Mg, Al, Fe, OCT2 and Zn) MATE1 EVG N/A N/A N/A 2C9 Substrate N/A 3A4 RAL N/A N/A N/A N/A N/A Substrate N/A PK Enhancers (Boosters) COBI N/A N/A Inhibitor 3A4 3A4, 2D6 N/A N/A N/A N/A RTV N/A Substrate, N/A 3A4, 2D6 3A4, 2D6 1A2, 2B6, Inducer 2C8, 2C9, inhibitor 2C19 PIs Note: When PIs are coadministered with PK enhancers (boosters), the pharmacologic properties of both agents should be considered when assessing potential drug interactions. 3A4 N/A Substrate, ATV Concentration OATP inhibitor 3A4 N/A Inhibitor decreased inducer, inhibitor N/A N/A DRV Substrate, 3A4 2C9 N/A OATP inhibitor 3A4 inducer 3A4 Concentration FPV N/A Substrate, N/A N/A 3A4 N/A decreased by inhibitor H2 antagonist LPV N/A N/A Substrate 3A4 3A4 N/A N/A OATP inhibitor SQV Substrate, 3A4 3A4 N/A N/A OATP inhibitor N/A N/A inhibitor N/A N/A Substrate, 3A4 2D6 3A4, 1A2, OATP inhibitor N/A TPV 2C19 inducer NNRTIs N/A N/A N/A N/A 3A4, 3A5 N/A N/A DOR N/A EFV N/A N/A N/A 2B6 3A4 N/A N/A 3A4, 2B6, (primary), 2C19 2A6, 3A4 L-3 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

243 Table 18. Mechanisms of Antiretroviral-Associated Drug Interactions (Last updated October 25, (page 2 of 2) 2018; last reviewed October 25, 2018) Mechanisms That May Affect Oral Other Enzymes That Metabolize or are Induced or ARV Absorption of ARV Drugs Mechanisms Inhibited by ARV Drugs Drugs of Known by Drug CYP CYP Increasing CYP Cationic P-glyco- Drug UGT1A1 Class Chelation protein Gastric pH Substrate Inhibitor Inducer Interactions NNRTIs , continued ETR N/A N/A 3A4, 2C9, 2C9, 2C19 3A4 N/A N/A N/A 2C19 NVP N/A N/A N/A 3A4, 2B6 N/A 3A4, 2B6 N/A N/A N/A RPV N/A N/A N/A 3A4 Concentration N/A N/A decreased NRTIs N/A Substrate N/A ABC Alcohol N/A N/A N/A N/A dehydrogenase substrate FTC N/A N/A N/A N/A N/A N/A N/A N/A 3TC N/A N/A N/A N/A N/A N/A N/A N/A N/A TAF N/A N/A Substrate N/A N/A N/A OATP substrate N/A TDF Substrate N/A N/A N/A N/A Competition N/A of active renal tubular secretion ZDV N/A N/A N/A N/A N/A N/A N/A Glucuronidation CCR5 Antagonist N/A N/A N/A MVC N/A N/A Substrate 3A4 N/A Fusion Inhibitor N/A N/A N/A N/A N/A N/A N/A T-20 N/A 3TC = lamivudine; ABC = abacavir; Al = aluminum; ARV = antiretroviral; ATV = atazanavir; BIC = bictegravir; Ca Key to Acronyms: = calcium; COBI = cobicistat; CYP = cytochrome P; DOR = doravirine; DRV = darunavir; DTG = dolutegravir; EFV = efavirenz; ETR = etravirine; EVG = elvitegravir; Fe = iron; FPV = fosamprenavir; FTC = emtricitabine; INSTI = integrase strand transfer inhibitor; LPV = lopinavir; MATE = multidrug and toxin extrusion transporter; Mg = magnesium; MVC = maraviroc; NNRTI = non-nucleoside reverse transcriptase inhibitors; NRTI = nucleoside reverse transcriptase inhibitors; NVP = nevirapine; OCT2 = organic cation transporter 2; OATP = organic anion-transporting polypeptide; PK = pharmacokinetic; PI = protease inhibitor; RAL = raltegravir; RPV = rilpivirine; RTV = ritonavir; SQV = saquinavir; T-20 = enfuvirtide; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; TPV = tipranavir; UGT = uridine diphosphate glucuronosyltransferase; ZDV = zidovudine; Zn = zinc L-4 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

244 Table 19a. Drug Interactions Between Protease Inhibitors and Other Drugs (Last updated October 25, 2018; last reviewed October 25, 2018) (page 1 of 19) This table provides known or predicted information regarding PK interactions between PIs and non-ARV drugs. When information is available, interactions for PK-boosted (with either RTV or COBI) and unboosted ATV are listed separately. The term “All PIs” refers to both unboosted ATV and PIs boosted with either RTV or COBI, except the PIs noted below. For interactions between ARV agents and for dosing recommendations, , 20a , and 20b refer to Tables 19c . Recommendations for managing a particular drug interaction may differ depending on whether a new ARV drug is being initiated in a patient on a stable concomitant medication or if a new concomitant medication is being initiated in a patient on a stable ARV regimen. The magnitude and significance of drug interactions are difficult to predict when several drugs with competing metabolic pathways are prescribed concomitantly . FPV, IDV, NFV, and SQV are not included in this table. Please refer to the FDA product labels for Note: FPV, IDV, NFV, and SQV for information regarding drug interactions with these PIs. Effect on PI and/ Concomitant PI Dosing Recommendations and Clinical Comments or Concomitant Drug Drug Concentrations Alpha-Adrenergic Antagonists for Benign Prostatic Hyperplasia All PIs Alfuzosin Contraindicated. ↑ alfuzosin expected Doxazosin All PIs ↑ doxazosin possible Initiate doxazosin at lowest dose and titrate while monitoring for clinical response/toxicity. Dose reduction may be necessary. Tamsulosin All PIs ↑ tamsulosin expected Coadministration is not recommended. If coadministered, monitor for tamsulosin toxicities. Terazosin All PIs ↔ or ↑ terazosin possible Initiate terazosin at lowest dose and titrate while monitoring for clinical response/toxicity. Dose reduction may be necessary. Silodosin ↑ silodosin expected Contraindicated. All PIs Acid Reducers Give ATV at least 2 hours before or 1–2 hours after antacids or ATV, ATV/c, Antacids When given simultaneously, ↓ ATV expected ATV/r buffered medications. TPV/r TPV AUC ↓ 27% Give TPV at least 2 hours before or 1 hour after antacids. H2 Receptor H2 receptor antagonist single dose should not exceed a dose ATV ↓ ATV (unboosted) Antagonists equivalent to famotidine 20 mg, and the total daily dose should not exceed a dose equivalent to famotidine 20 mg BID in PI-naive patients. Unboosted ATV plus famotidine should not be used in combination in PI-experienced patients. Give ATV at least 2 hours before and at least 10 hours after the H2 receptor antagonist. ATV/c, ATV/r ↓ ATV H2 receptor antagonist dose should not exceed a dose equivalent to famotidine 40 mg BID in ART-naive patients or famotidine 20 mg BID in ART-experienced patients. Give ATV 300 mg plus (COBI 150 mg or RTV 100 mg) simultaneously with and/or ≥10 hours after the dose of H2 receptor antagonist. If using TDF and H2 receptor antagonist in ART-experienced patients, use ATV 400 mg plus (COBI 150 mg or RTV 100 mg). ↔ demonstrated or expected No dose adjustment necessary. DRV/c, DRV/r, LPV/r L-5 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

245 Table 19a. Drug Interactions Between Protease Inhibitors and Other Drugs (Last updated October (page 2 of 19) 25, 2018; last reviewed October 25, 2018) Effect on PI and/ Concomitant PI or Concomitant Drug Dosing Recommendations and Clinical Comments Drug Concentrations , continued Acid Reducers ATV ↓ ATV PPIs are not recommended in patients receiving unboosted PPIs In these patients, consider alternative acid-reducing agents, (unboosted) AT V. RTV or COBI boosting, or alternative PIs. ATV/c, ATV/r ↓ ATV PPIs should not exceed a dose equivalent to omeprazole 20 mg daily in PI-naive patients. PPIs should be administered at least 12 hours before ATV/c or ATV/r. PPIs are not recommended in PI-experienced patients. DRV/c, LPV/r ↔ expected No dose adjustment necessary. DRV/r No dose adjustment necessary. If there is a lack of symptomatic Omeprazole AUC ↓ 42% relief, increase dose to no more than omeprazole 40 mg daily. Omeprazole AUC ↓ 70% Coadministration is not recommended. TPV/r If coadministration is necessary, dose increases of omeprazole may be considered based on clinical response. Anticoagulants and Antiplatelets Apixaban ↑ apixaban expected PI/c, PI/r Coadministration is not recommended in patients who require apixaban 2.5 mg twice daily. In patients who require apixaban 5 mg or 10 mg twice daily, reduce apixaban dose by 50%. Betrixaban ATV/c, ATV/r, ↑ betrixaban expected Administer an initial single dose of betrixaban 80 mg followed by LPV/r betrixaban 40 mg once daily. DRV/c, DRV/r ↔ betrixaban expected No dose adjustment necessary. TPV/r No data No dosing recommendations available at this time. Consider alternative ARV or warfarin. Dabigatran ↑ dabigatran expected ATV/c, ATV/r, Dabigatran dosing recommendation depends on indication and renal function. Refer to dabigatran dosing instructions for LPV/r With COBI 150 mg Alone: concomitant use with P-gp inhibitors in dabigatran prescribing 10% to Dabigatran AUC ↑ 1 • information. 127% DRV/c, DRV/r No dose adjustment necessary. ↔ dabigatran expected TPV/r No dosing recommendations available at this time. Consider No data alternative ARV or warfarin. Edoxaban ↑ edoxaban expected Stroke Prevention in Nonvalvular Atrial Fibrillation Indication: ATV/c, ATV/r, LPV/r • No dose adjustment necessary. Deep Venous Thrombosis and Pulmonary Embolism Indication: • Administer edoxaban 30 mg once daily ↔ edoxaban expected No dose adjustment necessary. DRV/r DRV/c, TPV/r No data No dosing recommendations available at this time. Consider alternative ARV or warfarin. Rivaroxaban PI/c, PI/r ↑ rivaroxaban expected Coadministration is not recommended. Ticagrelor ↑ ticagrelor expected Coadministration is not recommended. All PIs Vorapaxar All PIs ↑ vorapaxar expected Coadministration is not recommended. L-6 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

246 Table 19a. Drug Interactions Between Protease Inhibitors and Other Drugs (Last updated October 25, (page 3 of 19) 2018; last reviewed October 25, 2018) Effect on PI and/ Concomitant PI or Concomitant Drug Dosing Recommendations and Clinical Comments Drug Concentrations Anticoagulants and Antiplatelets , continued ↓ warfarin possible Monitor INR closely when stopping or starting PI/c and adjust Warfarin PI/r warfarin dose accordingly. If switching between RTV and COBI, No data PI/c the effect of COBI on warfarin is not expected to be equivalent to RTV’s effect on warfarin. Anticonvulsants Carbamazepine May ↓ PI levels substantially Do not coadminister. Consider alternative anticonvulsant or ATV A RV. (unboosted) Consider alternative anticonvulsant or monitor levels of both ↑ carbamazepine possible ATV/r, LPV/r, TPV/r drugs and assess virologic response. Do not coadminister with TPV/r ↑ carbamazepine AUC LPV/r once daily. 26% May ↓ PI levels substantially Carbamazepine AUC ↑ 45% DRV/r Monitor anticonvulsant level and adjust dose accordingly. DRV: no significant change PI/c ↑ carbamazepine possible Contraindicated. ↓ cobicistat expected ↓ PI levels expected Eslicarbazepine, ↓ PI possible Consider alternative anticonvulsant or ARV. If coadministration is All PIs necessary, monitor for virologic response. Consider monitoring Oxcarbazepine anticonvulsant and PI concentration. Ethosuximide ↑ ethosuximide possible Clinically monitor for ethosuximide toxicities. All PIs ATV No dose adjustment necessary. Lamotrigine Lamotrigine: no effect (unboosted) ATV/r Lamotrigine AUC ↓ 32% A dose increase of lamotrigine may be needed; consider monitoring lamotrigine concentration or consider alternative Lamotrigine AUC ↓ 50% LPV/r anticonvulsant. LPV: no significant change DRV/r, TPV/r ↓ lamotrigine possible PI/c No data Monitor anticonvulsant level and adjust dose accordingly. Phenobarbital PI/c ↓ cobicistat expected Contraindicated. ↓ PI levels expected Consider alternative anticonvulsant or monitor levels of both ATV May ↓ PI levels substantially (unboosted), drugs and assess virologic response. PI/r Do not coadminister with LPV/r once daily or unboosted ATV. L-7 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

247 Table 19a. Drug Interactions Between Protease Inhibitors and Other Drugs (Last updated October 25, (page 4 of 19) 2018; last reviewed October 25, 2018) Effect on PI and/ Concomitant PI or Concomitant Drug Dosing Recommendations and Clinical Comments Drug Concentrations , continued Anticonvulsants Consider alternative anticonvulsant or May ↓ PI levels substantially Do not coadminister. Phenytoin ATV ATV/r. (unboosted) ATV/r, DRV/r, ↓ phenytoin possible Consider alternative anticonvulsant or monitor levels of both drugs and assess virologic response. TPV/r ↓ PI possible LPV/r Phenytoin AUC ↓ 31% Consider alternative anticonvulsant or monitor levels of both drugs and assess virologic response. LPV/r AUC ↓ 33% Do not coadminister with LPV/r once daily. ↓ cobicistat expected Contraindicated. PI/c ↓ PI levels expected Valproic Acid PI/c, PI/r ↓ or ↔VPA possible Monitor VPA levels and virologic response. Monitor for LPV- related toxicities. (VPA) LPV AUC ↑ 75% Antidepressants, Anxiolytics, and Antipsychotics (also see Sedative/Hypnotics section below) Aripiprazole PI/c, PI/r ↑ aripiprazole expected Administer 25% of the usual aripiprazole dose. Titrate dose based on clinical monitoring for efficacy/toxicity. Refer to aripiprazole label for doses to use in patients who have major depressive disorder or who are known to be CYP2D6 poor metabolizers. ATV ↑ aripiprazole expected Administer 50% of the usual aripiprazole dose. Titrate based on clinical monitoring for efficacy/toxicity. Refer to aripiprazole label (unboosted) for doses to use in patients who have major depressive disorder or who are known to be CYP2D6 poor metabolizers. PI/c, PI/r Brexpiprazole Administer 25% of the usual brexpiprazole dose. Titrate based on ↑ brexpiprazole expected clinical monitoring for efficacy/toxicity. Refer to brexpiprazole label for doses to use in patients who have major depressive disorder or who are known to be CYP2D6 poor metabolizers. ATV ↑ brexpiprazole expected Administer 50% of the usual brexpiprazole dose. Titrate based on (unboosted) clinical monitoring for efficacy/toxicity. Refer to brexpiprazole label for doses to use in patients who have major depressive disorder or who are known to be CYP2D6 poor metabolizers. Bupropion LPV/r Bupropion AUC ↓ 57% Titrate bupropion dose based on clinical response. TPV/r Bupropion AUC ↓ 46% ATV/r, DRV/r ↓ bupropion possible PI/c ↔ bupropion expected No dose adjustment necessary. Buspirone All PIs ↑ buspirone expected Use a low dose of buspirone with caution and titrate buspirone dose based on clinical response. L-8 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

248 Table 19a. Drug Interactions Between Protease Inhibitors and Other Drugs (Last updated October 25, (page 5 of 19) 2018; last reviewed October 25, 2018) Effect on PI and/ Concomitant PI or Concomitant Drug Dosing Recommendations and Clinical Comments Drug Concentrations , continued Antidepressants, Anxiolytics, and Antipsychotics (also see Sedative/Hypnotics section below) All PIs ↑ cariprazine expected Starting Cariprazine in a Patient Already Receiving a PI: Cariprazine • Administer cariprazine 1.5 mg on Day 1 and Day 3, with no dose given on Day 2. From Day 4 onward, administer cariprazine 1.5 mg daily. Dose can be increased to a maximum dose of cariprazine 3 mg daily. If the PI is withdrawn, cariprazine dose may need to be increased. Starting a PI in a Patient Already Receiving Cariprazine: • For patients receiving cariprazine 3 mg or cariprazine 6 mg daily, reduce dose by half. For patients taking cariprazine 4.5 mg daily, the dose should be reduced to cariprazine 1.5 mg or cariprazine 3 mg daily. For patients taking cariprazine 1.5 mg daily , change to cariprazine 1.5 mg every other day. If PI is withdrawn, cariprazine dose may need to be increased. All PIs Fluvoxamine ↑ fluvoxamine possible Titrate fluvoxamine dose based on clinical response. ↑ lurasidone expected Contraindicated. PI/c, PI/r Lurasidone ↑ lurasidone expected Consider alternative therapy. If coadministration is necessary, ATV (unboosted) reduce lurasidone dose by 50%. Pimavanserin ↑ pimavanserin expected Reduce dose from pimavanserin 34 mg daily to pimavanserin 17 All PIs mg daily. Pimozide All PIs ↑ pimozide expected Contraindicated. Quetiapine All PIs ↑ quetiapine expected Starting Quetiapine in a Patient Receiving a PI: • Start quetiapine at the lowest dose and titrate up as needed. Monitor for quetiapine ef fectiveness and adverse effects. Starting a PI in a Patient Receiving a Stable Dose of Quetiapine: Reduce quetiapine dose to 1/6 of the original dose. Closely • monitor for quetiapine ef fectiveness and adverse effects. Trazodone RTV 200 mg BID (for 2 days) ↑ Use lowest dose of trazodone and monitor for CNS and CV All PIs adverse effects. trazodone AUC 240% Tricyclic Use lowest possible TCA dose and titrate based on clinical ↑ TCA expected All PIs Antidepressants assessment and/or drug levels. (TCA) Amitriptyline, desipramine, doxepin, imipramine, nortriptyline ↑ antipsychotic possible Titrate antipsychotic dose using the lowest initial dose, or adjust Other PI/c, PI/r maintenance dose accordingly. Monitor for toxicities. Antipsychotics (CYP3A4 and/or CYP2D6 substrates) Other Selective Titrate SSRI dose based on clinical response. Paroxetine AUC ↓ 39% DRV/r Serotonin Sertraline AUC ↓ 49% Reuptake Inhibitors No data ATV/r, LPV/r, (SSRIs) TPV/r (e.g., citalopram, escitalopram, PI/c Effects unknown Titrate SSRI dose using the lowest available initial or fluoxetine, maintenance dose. paroxetine, sertraline) L-9 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

249 Table 19a. Drug Interactions Between Protease Inhibitors and Other Drugs (Last updated October 25, (page 6 of 19) 2018; last reviewed October 25, 2018) Effect on PI and/ Concomitant PI Dosing Recommendations and Clinical Comments or Concomitant Drug Drug Concentrations Antifungals PI/c, ATV/r, Fluconazole No significant effect observed or No dose adjustment necessary. expected DRV/r, LPV/r Fluconazole >200 mg daily is not recommended. If high-dose TPV/r TPV AUC ↑ 50% fluconazole is indicated, consider alternative ARV. LPV/r Isavuconazole If coadministered, consider monitoring isavuconazole Isavuconazole AUC ↑ 96% concentrations and toxicities and assessing virologic response. LPV AUC ↓ 27% RTV AUC ↓ 31% All PIs except ↑ isavuconazole possible If coadministered, consider monitoring isavuconazole concentrations LPV/r and toxicities. Monitor for PI toxicity and virologic response. ↑ or ↓ PI possible Itraconazole ↑ itraconazole possible All PIs Consider monitoring itraconazole level to guide dose adjustments. Doses >200 mg/day with PI/r, ATV/c, or are not recommended ↑ PI possible DRV/c unless dosing is guided by itraconazole levels. Posaconazole ATV/r ATV AUC ↑ 146% If coadministered, monitor for PI adverse effects. Consider monitoring for posaconazole concentrations and toxicities. ↑ posaconazole possible ATV ATV AUC ↑ 268% ↑ posaconazole possible ATV/c, DRV/c, ↑ PI possible DRV/r, LPV/r, ↑ posaconazole possible TPV/r Voriconazole ATV Monitor for toxicities. ↑ voriconazole possible (unboosted) ↑ PI possible All PI/r Do not coadminister voriconazole and RTV or COBI unless RTV 100 mg BID ↓ voriconazole benefit outweighs risk. If coadministered, consider monitoring AUC 39% voriconazole concentration and adjust dose accordingly. PI/c Effect on voriconazole unknown Antihyperglycemics Canagliflozin PI/r ↓ canagliflozin expected If a patient is already tolerating canagliflozin 100 mg daily, has 2 an eGFR >60 mL/min/1.73m , and requires additional glycemic control, consider increasing dose to canagliflozin 300 mg daily. PI/c ↓ canagliflozin possible If used in combination, monitor glycemic control. All PIs ↑ saxagliptin expected Limit saxagliptin dose to 2.5 mg once daily Saxagliptin Dapagliflozin/ All PIs ↑ saxagliptin expected Do not coadminister , as this coformulated drug contains 5 mg of Saxagliptin saxagliptin. Antimalarials DRV/r Artemether AUC ↓ 16% Artemether/ Clinical significance unknown. If used, monitor closely for Lumefantrine antimalarial efficacy and lumefantrine toxicity. a DHA AUC ↓ 18% Lumefantrine AUC ↑ 2.5-fold DRV/c ↑ lumefantrine expected Effect on artemether unknown LPV/r Artemether AUC ↓ 40% DHA AUC ↓ 17% Lumefantrine AUC ↑ 470% L-10 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

250 Table 19a. Drug Interactions Between Protease Inhibitors and Other Drugs (Last updated October 25, (page 7 of 19) 2018; last reviewed October 25, 2018) Effect on PI and/ Concomitant PI or Concomitant Drug Dosing Recommendations and Clinical Comments Drug Concentrations Antimalarials , continued LPV/r Dihydroartemisinin AUC ↓ 49% Artesunate/ Clinical significance unknown. If used, monitor closely for Mefloquine antimalarial efficacy. Mefloquine AUC ↓ 28% ↔ LPV ATV/r, LPV/r Atovaquone/ With ATV/r: No dose recommendation. Consider alternative drug for malaria Proguanil prophylaxis, if possible. Atovaquone AUC ↓ 46% • • Proguanil AUC ↓ 41% With LPV/r: • Atovaquone AUC ↓ 74% • Proguanil AUC ↓ 38% RTV Mefloquine With RTV 200 mg BID: Use with caution. Effect on exposure of RTV-boosted PIs is unknown. • RTV AUC ↓ 31%, C ↓ 43% min ↔ mefloquine Antimycobacterials (for treatment of Mycobacterium tuberculosis and nontuberculosis mycobacterial infections) All PIs Bedaquiline With LPV/r: Clinical significance unknown. Use with caution if benefit outweighs the risk and monitor for QTc prolongation and liver • Bedaquiline AUC ↑ 1.9-fold function tests. With Other PI/r, ATV/c, or DRV/c: • ↑ bedaquiline possible Clarithromycin ATV Clarithromycin AUC ↑ 94% May cause QTc prolongation. Reduce clarithromycin dose by (unboosted) 50%. Consider alternative therapy (e.g., azithromycin). All PIs Consider alternative macrolide (e.g., azithromycin). ↑ clarithromycin expected Monitor for clarithromycin-related toxicities or consider an DRV/r ↑ clarithromycin AUC 57% alternative macrolide (e.g., azithromycin). LPV/r ↑ clarithromycin expected Reduce clarithromycin dose by 50% in patients with CrCl 30−60 RTV 500 mg BID ↑ clarithromycin mL/min. 77% Reduce clarithromycin dose by 75% in patients with CrCl <30 mL/ TPV/r ↑ clarithromycin 19% min. Clarithromycin ↑ TPV 66% L-11 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

251 Table 19a. Drug Interactions Between Protease Inhibitors and Other Drugs (Last updated October 25, (page 8 of 19) 2018; last reviewed October 25, 2018) Effect on PI and/ Concomitant or Concomitant Drug PI Dosing Recommendations and Clinical Comments Drug Concentrations Mycobacterium tuberculosis , continued Antimycobacterials (for treatment of and nontuberculosis mycobacterial infections) ↑ rifabutin AUC expected Rifabutin Rifabutin 150 mg once daily or 300 mg three times a week. ATV (unboosted) Monitor for antimycobacterial activity and consider therapeutic ATV/r Compared with Rifabutin (300 drug monitoring. mg Once Daily) Alone, Rifabutin PK data reported in this table are results from healthy volunteer (150 mg Once Daily) plus ATV/r: studies. Lower rifabutin exposure has been reported in patients • Rifabutin AUC ↑ 110% and with HIV than in healthy study participants. metabolite AUC ↑ 2,101% DRV/r Compared with Rifabutin (300 mg Once Daily) Alone, Rifabutin (150 mg Every Other Day) plus DRV/r: • Rifabutin AUC ↔ and metabolite AUC ↑ 881% LPV/r Compared with Rifabutin (300 mg daily) Alone, Rifabutin (150 mg Once Daily) plus LPV/r: Rifabutin AUC ↑ 203% and • metabolite AUC ↑ 375% Rifabutin AUC ↑ 190% and TPV/r metabolite AUC ↑ 1,971% PI/c ↑ rifabutin expected Rifampin All PIs ↓ PI concentration by >75% Contraindicated. Additional RTV does not overcome this interaction and may increase hepatotoxicity. Additional COBI is not recommended. Consider rifabutin if a rifamycin is indicated. All PIs Do not coadminister. Rifapentine ↓ PI expected Antipneumocystis and Antitoxoplasmosis Drug Atovaquone ATV/r ↔ atovaquone No dose adjustment necessary. Cardiac Medications Amiodarone ↑ both amiodarone and PI Contraindicated. TPV/r possible All PIs except ↑ both amiodarone and PI Use with caution. Monitor for amiodarone toxicity and consider TPV/r possible ECG and amiodarone drug levels. Antiarrhythmics Consider alternative antiarrhythmics or ARV. If coadministered, ↑ antiarrhythmic possible ATV (e.g., disopyramide, monitor for antiarrhythmic toxicities. (unboosted) dofetilide, lidocaine, PI/c, PI/r ↑ antiarrhythmic possible Do not coadminister. Consider alternative antiarrhythmics or mexiletine, ARV. propafenone) Dronedarone ATV Do not coadminister. ↑ dronedarone possible (unboosted) ↑ dronedarone expected Contraindicated. PI/c, PI/r Flecanide All PIs except Do not coadminister. ↑ flecainide possible TPV/r TPV/r ↑ flecanide expected Contraindicated. L-12 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

252 Table 19a. Drug Interactions Between Protease Inhibitors and Other Drugs (Last updated October 25, (page 9 of 19) 2018; last reviewed October 25, 2018) Effect on PI and/ Concomitant PI or Concomitant Drug Dosing Recommendations and Clinical Comments Drug Concentrations , continued Cardiac Medications All PIs except ↑ propafenone possible Do not coadminister. Propafenone TPV/r Contraindicated. TPV/r ↑ propafenone expected ↑ quinidine possible Do not coadminister. All PIs except Quinidine TPV/r TPV/r ↑ quinidine expected Contraindicated. Beta-Blockers May need to decrease beta-blocker dose; adjust dose based on All PIs ↑ beta-blockers possible (e.g., carvedilol, clinical response. metoprolol, timolol) Consider using beta-blockers that are not metabolized by CYP450 enzymes (e.g., atenolol, labetalol, nadolol, sotalol). All PIs LPV/r ↑ bosentan 48-fold (Day Bosentan Do not coadminister bosentan and unboosted ATV. 4) and 5-fold (Day 10) In Patients on a PI (Other than Unboosted ATV) >10 Days: ↓ ATV expected • Start bosentan at 62.5 mg once daily or every other day. In Patients on Bosentan who Require a PI (Other than Unboosted ATV): • Stop bosentan ≥36 hours before PI initiation and restart bosentan 10 days after PI initiation at 62.5 mg once daily or . every other day When Switching Between COBI and RTV: • Maintain same bosentan dose. Calcium Channel ↑ dihydropyridine possible Use with caution. Titrate CCB dose and monitor closely. ECG All PIs monitoring is recommended when CCB is used with ATV. Blockers (CCBs), ↑ verapamil possible Except Diltiazem RTV (200 mg BID) ↑ digoxin Digoxin Use with caution. Monitor digoxin levels. Digoxin dose may need PI/c , PI/r AUC 29% and ↑ half-life 43% to be decreased. Titrate initial digoxin dose. DRV/r ↑ digoxin AUC 36% 41% and COBI ↑ digoxin C max ↔ AUC ATV/c, Decrease diltiazem dose by 50%. ECG monitoring is Unboosted ATV ↑ diltiazem AUC Diltiazem 125% ATV/r, ATV recommended. (unboosted) Greater ↑ likely with ATV/c or ATV/r DRV/c, DRV/r, ↑ diltiazem possible Use with caution. Adjust diltiazem according to clinical response and toxicities. LPV/r, TPV/r Eplerenone PI/c, PI/r ↑ eplerenone expected Contraindicated. Ranolazine ATV Do not coadminister. ↑ ranolazine possible (unboosted) ↑ ranolazine expected Contraindicated. PI/c, PI/r Ivabradine All PIs ↑ ivabradine expected Contraindicated. L-13 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

253 Table 19a. Drug Interactions Between Protease Inhibitors and Other Drugs (Last updated October 25, (page 10 of 19) 2018; last reviewed October 25, 2018) Effect on PI and/ Concomitant Dosing Recommendations and Clinical Comments or Concomitant Drug PI Drug Concentrations Corticosteroids No dose adjustment necessary. Beclomethasone DRV/r ↔ 17-BMP (active metabolite) AUC Inhaled or intranasal RTV 100 mg BID ↑ 17-BMP AUC 2-fold No dose adjustment necessary. All PIs except ↔ expected DRV/r s Budesonide, ↑ glucocorticoids possible Coadministration can result in adrenal insufficiency and Cushing’ All PIs syndrome. Ciclesonide, Do not coadminister unless potential benefits of RTV 100 mg BID ↑ fluticasone inhaled or intranasal corticosteroid outweigh the risks of Fluticasone, AUC 350-fold Mometasone adverse effects associated with corticosteroids. Consider an alternative corticosteroid (e.g., beclomethasone). Inhaled or intranasal All PIs ↑ glucocorticoids possible Betamethasone, Coadministration can result in adrenal insufficiency and Cushing’ s Do not coadminister unless potential benefits of Budesonide syndrome. ↓ PI possible Systemic systemic corticosteroid outweigh the risks of adverse effects associated with systemic corticosteroids. ↑ glucocorticoids possible Dexamethasone Consider alternative corticosteroid for long-term use. If All PIs Systemic coadministration is necessary, monitor virologic response to ART. ↓ PI possible Prednisone, LPV/r ↑ prednisolone AUC 31% Coadministration may be considered if the potential benefits Prednisolone outweigh the risks of adverse effects associated with systemic ↑ prednisolone possible All PIs Systemic corticosteroids. If coadministered, monitor for adrenal insufficiency, Cushing’s syndrome, and other corticosteroid- associated toxicities. Coadministration can result in adrenal Do not coadminister. Betamethasone, All PIs ↑ glucocorticoids expected insufficiency and Cushing’s syndrome. Methylpred- nisolone, Triamcinolone Local injections, including intra- articular, epidural, or intra-orbital Hepatitis C Direct-Acting Antiviral Agents Daclatasvir ATV/c, ATV/r ↑ daclatasvir Decrease daclatasvir dose to 30 mg once daily. ATV No dose adjustment necessary. ↔ daclatasvir (unboosted), DRV/c, DRV/r, LPV/r No data TPV/r No dosing recommendations available at this time. , should be ATV without COBI or additional RTV Dasabuvir plus ATV 300 mg alone, ↔ ATV (unboosted) Paritaprevir/ given in the morning with dasabuvir plus paritaprevir/ombitasvir/ RT V. Ombitasvir/RTV DRV ↓ 43% to 48% Do not coadminister. DRV C min LPV/r Paritaprevir AUC ↑ 117% Do not coadminister. ATV/c, DRV/c, No data Do not coadminister. TPV/r L-14 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

254 Table 19a. Drug Interactions Between Protease Inhibitors and Other Drugs (Last updated October 25, (page 11 of 19) 2018; last reviewed October 25, 2018) Effect on PI and/ Concomitant PI or Concomitant Drug Dosing Recommendations and Clinical Comments Drug Concentrations Hepatitis C Direct-Acting Antiviral Agents , continued ATV/r Elbasvir/ Elbasvir AUC ↑ 4.8-fold Contraindicated. Grazoprevir Grazoprevir AUC ↑ 10.6-fold May increase the risk of ALT elevations due to a significant increase in grazoprevir plasma concentrations caused by ATV ↔ by elbasvir OATP1B1/3 inhibition. ATV AUC ↑ 43% by grazoprevir Elbasvir AUC ↑ 66% DRV/r Grazoprevir AUC ↑ 7.5-fold ↔ DRV Elbasvir AUC ↑ 3.7-fold LPV/r Grazoprevir AUC ↑ 12.9-fold ↔ LPV ATV ↑ grazoprevir expected (unboosted), ATV/c, DRV/c, TPV/r Glecaprevir/ ATV When Given with ATV/r 300/100 Contraindicated. (unboosted), Pibrentasvir mg Once Daily: ATV/c, ATV/r • Glecaprevir AUC ↑ 6.5-fold • Pibrentasvir AUC ↑ 64% DRV/c, DRV/r When Given with DRV/r 800/100 Do not coadminister. mg Once Daily: • Glecaprevir AUC ↑ 5-fold • ↔ pibrentasvir LPV/r Glecaprevir AUC ↑ 4-fold Do not coadminister. Pibrentasvir ↑ 2.5-fold ↑ glecaprevir and pibrentasvir TPV/r Do not coadminister. expected Ledipasvir/ ATV/r ATV AUC ↑ 33% No dose adjustment necessary. Sofosbuvir Coadministration of ledipasvir/sofosbuvir with TDF and a Ledipasvir AUC ↑ 113% PI/r results in increased exposure to TDF. The safety of the ↔ sofosbuvir increased TDF exposure has not been established. Consider ↔ DRV expected DRV/r alternative HCV or ARV drugs to avoid increased TDF toxicities. If coadministration is necessary, monitor for TDF-associated ↔ ledipasvir/sofosbuvir adverse reactions. ATV ↔ expected (unboosted), ATV/c, DRV/c, LPV/r TPV/r ↓ ledipasvir and sofosbuvir Do not coadminister. expected L-15 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

255 Table 19a. Drug Interactions Between Protease Inhibitors and Other Drugs (Last updated October 25, (page 12 of 19) 2018; last reviewed October 25, 2018) Effect on PI and/ Concomitant PI or Concomitant Drug Dosing Recommendations and Clinical Comments Drug Concentrations Hepatitis C Direct-Acting Antiviral Agents , continued Simeprevir All PIs Do not coadminister. Compared with Simeprevir 150 mg Alone, Simeprevir 50 mg plus DRV/r 800 mg/100 mg Daily: • Simeprevir AUC ↑ 159% RTV 100 mg BID ↑ simeprevir AUC 618% TPV/r ↓ sofosbuvir expected Do not coadminister. Sofosbuvir Sofosbuvir/ ATV/r ↔ ATV/r No dose adjustment necessary. Velpatasvir ↔ sofosbuvir Velpatasvir AUC ↑ 2.4-fold No dose adjustment necessary. ↔ DRV/r DRV/r Sofosbuvir AUC ↓ 28% ↔ velpatasvir ATV ↔ sofosbuvir and velpatasvir No dose adjustment necessary. (unboosted), expected ATV/c, DRV/c, LPV/r TPV/r ↓ sofosbuvir expected Do not coadminister. ↓ velpatasvir expected Sofosbuvir/ ATV When Given with ATV/r: Do not coadminister. (unboosted), Velpatasvir/ • Voxilaprevir AUC ↑ 4.3-fold Voxilaprevir ATV/c, ATV/r • Velpatasvir AUC ↑ 93% • Sofosbuvir AUC ↑ 40% LPV/r ↑ voxilaprevir expected Do not coadminister. DRV/c , DRV/r When Given with DRV/r: No dose adjustment needed. • Voxilaprevir AUC ↑ 2.4-fold • ↔ DRV/r, velpatasvir, and sofosbuvir Do not coadminister. ↓ sofosbuvir expected TPV/r ↓ velpatasvir expected Effect on voxilaprevir is unknown. Herbal Products St. John’s Wort All PIs ↓ PI expected Contraindicated. L-16 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

256 Table 19a. Drug Interactions Between Protease Inhibitors and Other Drugs (Last updated October 25, (page 13 of 19) 2018; last reviewed October 25, 2018) Effect on PI and/ Concomitant or Concomitant Drug Dosing Recommendations and Clinical Comments PI Drug Concentrations Hormonal Therapies Hormonal ATV Prescribe oral contraceptive that contains no more than 30 mcg of Ethinyl estradiol AUC ↑ 48% b ethinyl estradiol (unboosted) Contraceptives or recommend alternative contraceptive method. Norethindrone AUC ↑ 110% Oral Oral contraceptives containing less than 25 mcg of ethinyl estradiol or progestins other than norethindrone or norgestimate have not been studied. Ethinyl estradiol AUC ↓ 19% and ATV/r Oral contraceptive should contain at least 35 mcg of ethinyl c ↓ 37% C estradiol. min Norgestimate ↑ 85% Oral contraceptives containing progestins other than norethindrone or norgestimate have not been studied. Norethindrone AUC ↑ 51% and C ↑ 67% min ATV/c Contraindicated with drospirenone-containing hormonal Drospirenone AUC ↑ 2.3-fold contraceptive due to potential for hyperkalemia. Consider Ethinyl estradiol AUC ↓ 22% alternative or additional contraceptive method or alternative ARV drug. DRV/c Drospirenone AUC ↑ 1.6-fold Clinical monitoring is recommended due to the potential for hyperkalemia. Consider alternative or additional contraceptive Ethinyl estradiol AUC ↓ 30% method or alternative ARV. DRV/r, LPV/r, Ethinyl estradiol AUC ↓ 37% to Consider alternative or additional contraceptive method or TPV/r alternative ARV drug. 55% Norethindrone AUC ↓ 14% to 34% With TPV/r: • ↔ norethindrone AUC No dose adjustment necessary. Depot MPA MPA AUC ↑ 46% LPV/r Injectable No significant change in C min Etonogestrel- Use standard dose. Etonogestrel AUC ↑ 52% and LPV/r ↑ 34% Releasing C min Subdermal Implant No data Consider alternative or additional contraceptive method or All other PIs alternative ARV drug. Etonogestrel/ Ethinyl estradiol AUC ↓ 26% ATV/r Use standard dose. Ethinyl Estradiol Etonogestrel AUC ↑ 79% Vaginal Ring Transdermal LPV/r ↔ LPV Use standard dose. Ethinyl Estradiol/ Ethinyl estradiol AUC ↓ 45%, Norelgestromin norelgestromin AUC ↑ 83% All other PIs No data Consider alternative or additional contraceptive method or alternative ARV drug. L-17 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

257 Table 19a. Drug Interactions Between Protease Inhibitors and Other Drugs (Last updated October 25, (page 14 of 19) 2018; last reviewed October 25, 2018) Effect on PI and/ Concomitant or Concomitant Drug PI Dosing Recommendations and Clinical Comments Drug Concentrations , continued Hormonal Therapies ↓ estrogen possible with Adjust estrogen dosage as needed based on clinical effects. All PIs Menopausal estradiol or conjugated estrogen Hormone (equine and synthetic) Replacement Therapy (HRT) ↑ drospirenone possible Adjust progestin/progesterone dosage as needed based on All PIs clinical effects. Because drospirenone is prescribed as a lower ↑ medroxyprogesterone dose for menopausal HRT than the products used for hormonal contraceptives, it is not contraindicated with ATV/c products. ↑ micronized progesterone See Hormonal Contraceptives for other progestin-PI interactions ↓ estradiol possible Adjust estradiol dosage as needed based on clinical effects and Gender-Affirming All PIs Hormone Therapy endogenous hormone concentrations. ↔ finasteride, goserelin, All PIs No dose adjustment necessary. leuprolide acetate, and spironolactone expected ↑ dutasteride possible Adjust dutasteride dosage as needed based on clinical effects All PIs and endogenous hormone concentrations. ↓ testosterone possible Adjust testosterone dosage as needed based on clinical effects All PIs and endogenous hormone concentrations. HMG-CoA Reductase Inhibitors Atorvastatin ATV ↑ atorvastatin possible Titrate atorvastatin dose carefully and use lowest dose necessary (unboosted), while monitoring for toxicities. ATV/r Coadministration is not recommended. Atorvastatin AUC ↑ 9.2-fold, ATV/c ↑ 18.9-fold C max Titrate atorvastatin dose carefully and use the lowest dose DRV/r plus atorvastatin 10 mg DRV/r necessary while monitoring for toxicities. Do not exceed 20 mg similar to atorvastatin 40 mg administered alone atorvastatin daily. Titrate atorvastatin dose carefully and use lowest dose necessary DRV/c Atorvastatin AUC ↑ 3.9-fold, C ↑ 4.2-fold while monitoring for toxicities. Do not exceed 20 mg atorvastatin max daily. Atorvastatin AUC ↑ 5.9-fold, LPV/r Titrate atorvastatin dose carefully and use lowest dose necessary C ↑ 4.7-fold while monitoring for toxicities. Do not exceed 20 mg atorvastatin max daily. Do not coadminister. Atorvastatin AUC ↑ 9.4-fold, TPV/r C ↑ 8.6-fold max Significant ↑ lovastatin expected Contraindicated. Lovastatin All PIs No dose adjustment necessary. ATV ↑ pitavastatin AUC 31% Pitavastatin All PIs ↑ 60% and C max ↔ ATV DRV/r ↓ pitavastatin AUC 26% ↔ DRV/r LPV/r ↓ pitavastatin AUC 20% ↔ LPV L-18 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

258 Table 19a. Drug Interactions Between Protease Inhibitors and Other Drugs (Last updated October 25, (page 15 of 19) 2018; last reviewed October 25, 2018) Effect on PI and/ Concomitant PI Dosing Recommendations and Clinical Comments or Concomitant Drug Drug Concentrations , continued HMG-CoA Reductase Inhibitors ATV/c, ATV/r No data Titrate pravastatin dose carefully while monitoring for toxicities. Pravastatin DRV/c, DRV/r With DRV/r: itrate pravastatin dose carefully while monitoring for toxicities. T Pravastatin AUC ↑ 81% • following single dose of pravastatin • Pravastatin AUC ↑ 23% at steady state Pravastatin AUC ↑ 33% No dose adjustment necessary. LPV/r ATV/r Rosuvastatin AUC ↑ 3-fold, Titrate rosuvastatin dose carefully and use lowest dose necessary Rosuvastatin C while monitoring for toxicities. Do not exceed rosuvastatin 10 mg ↑ 7-fold max daily. ATV/c Rosuvastatin AUC ↑ 3.4-fold, C ↑ 10.6-fold max DRV/c Rosuvastatin AUC ↑ 1.9-fold, Titrate rosuvastatin dose carefully and use the lowest dose ↑ 3.8-fold necessary while monitoring for toxicities. Do not exceed C max rosuvastatin 20 mg daily. DRV/r Rosuvastatin AUC ↑ 48%, C Titrate rosuvastatin dose carefully and use the lowest necessary max ↑ 2.4-fold dose while monitoring for toxicities. Rosuvastatin AUC ↑ 2.1-fold, Titrate rosuvastatin dose carefully and use the lowest necessary LPV/r C ↑ 4.7-fold dose. Do not exceed rosuvastatin 10 mg daily. max TPV/r Rosuvastatin AUC ↑ 26%, C No dose adjustment necessary. max ↑ 2.2-fold Significant ↑ simvastatin Contraindicated. All PIs Simvastatin expected Immunosuppressants Initiate with an adjusted dose of immunosuppressant to account All PIs ↑ immunosuppressant expected Cyclosporine, Everolimus, for potential increased concentrations of the immunosuppressant Sirolimus, and monitor for toxicities. Therapeutic drug monitoring of Tacrolimus immunosuppressant is recommended. Consult with specialist as necessary. L-19 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

259 Table 19a. Drug Interactions Between Protease Inhibitors and Other Drugs (Last updated October 25, (page 16 of 19) 2018; last reviewed October 25, 2018) Effect on PI and/ Concomitant PI or Concomitant Drug Dosing Recommendations and Clinical Comments Drug Concentrations Narcotics and Treatment for Opioid Dependence Buprenorphine AUC ↑ 93% Buprenorphine ATV Do not coadminister. (unboosted) Sublingual, buccal, d Norbuprenorphine AUC ↑ 76% or implant ↓ ATV possible ATV/r Buprenorphine AUC ↑ 66% Monitor for sedation and other signs or symptoms of over- medication. Buprenorphine dose reduction may be necessary. It d Norbuprenorphine AUC ↑ 105% may be necessary to remove implant and treat with a formulation that permits dose adjustments. No significant effect on DRV/r No dose adjustment necessary. Clinical monitoring is buprenorphine recommended. When transferring buprenorphine from transmucosal delivery to implantation, monitor to ensure d Norbuprenorphine AUC ↑ 46% buprenorphine effect is adequate and not excessive. ↑ 71% and C min LPV/r No significant effect No significant effect on TPV/r Consider monitoring TPV level. When transferring buprenorphine buprenorphine from transmucosal delivery to implantation, monitor to ensure buprenorphine effect is adequate and not excessive. d Norbuprenorphine , AUC, C max ↓ 80% and C min ↓ 19% to 40% TPV C min Titrate buprenorphine dose using the lowest initial dose. PI/c Effects unknown Dose adjustment of buprenorphine may be needed. It may be necessary to remove implant and treat with a formulation that permits dose adjustments. Clinical monitoring is recommended. ↑ fentanyl possible Clinical monitoring is recommended, including for potentially fatal Fentanyl All PIs respiratory depression. ATV Methadone No significant effect No dose adjustment necessary. (unboosted) PI/c Effects unknown Titrate methadone dose using the lowest feasible initial dose. Dose adjustment of methadone may be needed. Clinical monitoring is recommended. All PI/r ATV/r and DRV/r ↓ Opioid withdrawal is unlikely but may occur. Dosage adjustment e R-methadone AUC 16% to 18% of methadone is not usually required, but monitor for opioid withdrawal and increase methadone dose as clinically indicated. LPV/r ↓ methadone AUC 26% to 53% e TPV/r ↓ R-methadone AUC 48% Oxycodone All PIs Oxycodone AUC ↑ 2.6-fold with Monitor for opioid-related adverse effects. Oxycodone dose LPV/r reduction may be necessary. Tramadol All PIs ↑ tramadol possible Tramadol dose reduction may be necessary. Monitor for tramadol toxicities and clinical response. L-20 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

260 Table 19a. Drug Interactions Between Protease Inhibitors and Other Drugs (Last updated October 25, (page 17 of 19) 2018; last reviewed October 25, 2018) Effect on PI and/ Concomitant PI Dosing Recommendations and Clinical Comments or Concomitant Drug Drug Concentrations PDE5 Inhibitors All PIs except RTV (600 mg BID for 5 days) Avanafil Coadministration is not recommended. unboosted ATV ↑ avanafil AUC 13-fold and ↑ 2.4-fold C max No data Avanafil dose should not exceed 50 mg once every 24 hours. ATV (unboosted) All PIs DRV/r plus sildenafil 25 mg Sildenafil For Treatment of Erectile Dysfunction: similar to sildenafil 100 mg alone • Start with sildenafil 25 mg every 48 hours and monitor for adverse ef fects of sildenafil. RTV 500 mg BID ↑ sildenafil AUC 1,000% For Treatment of PAH: • Contraindicated. Tadalafil RTV 200 mg BID ↑ tadalafil AUC All PIs For Treatment of Erectile Dysfunction: 124% Start with tadalafil 5-mg dose and do not exceed a single dose • of tadalafil 10 mg every 72 hours. Monitor for adverse effects of TPV/r (1st dose) ↑ tadalafil AUC tadalafil. 133% For Treatment of PAH No significant effect on TPV/r steady state In Patients on a PI >7 Days: Start with tadalafil 20 mg once daily and increase to tadalafil 40 • . mg once daily based on tolerability In Patients on Tadalafil who Require a PI: Stop tadalafil ≥24 hours before PI initiation. Seven days after • PI initiation, restart tadalafil at 20 mg once daily and increase to tadalafil 40 mg once daily based on tolerability . In Patients Switching between COBI and RTV: • Maintain tadalafil dose. For Treatment of Benign Prostatic Hyperplasia: • Maximum recommended daily dose is tadalafil 2.5 mg per day. Vardenafil All PIs RTV 600 mg BID ↑ vardenafil Start with vardenafil 2.5 mg every 72 hours and monitor for AUC 49-fold adverse effects of vardenafil. Sedative/Hypnotics Alprazolam, Consider alternative benzodiazepines, such as lorazepam, ↑ benzodiazepine possible All PIs oxazepam, or temazepam. Clonazepam, RTV (200 mg BID for 2 days) ↑ Diazepam alprazolam half-life 222% and ↑ AUC 248% Lorazepam, All PIs No data These benzodiazepines are metabolized via non-CYP450 pathways; thus, there is less interaction potential than with other Oxazepam, Temazepam benzodiazepines. Midazolam ↑ midazolam expected All PIs Oral midazolam is contraindicated with PIs. Parenteral midazolam can be used with caution when given as a single dose in a monitored situation for procedural sedation. Suvorexant All PIs ↑ suvorexant expected Coadministration is not recommended. L-21 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

261 Table 19a. Drug Interactions Between Protease Inhibitors and Other Drugs (Last updated October 25, (page 18 of 19) 2018; last reviewed October 25, 2018) Effect on PI and/ Concomitant PI or Concomitant Drug Dosing Recommendations and Clinical Comments Drug Concentrations , continued Sedative/Hypnotics All PIs ↑ triazolam expected Contraindicated. Triazolam RTV (200 mg BID) ↑ triazolam half-life 1,200% and AUC 2,000% PI/c, PI/r ↑ zolpidem possible Initiate zolpidem at a low dose. Dose reduction may be Zolpidem necessary. Miscellaneous Drugs All PIs ↑ calcifediol possible Calcifediol Dose adjustment of calcifediol may be required, and serum 25-hydroxyvitamin D, intact PTH, and serum calcium concentrations should be closely monitored. Cisapride ↑ cisapride expected Contraindicated. All PIs Colchicine All PIs RTV 100 mg BID ↑ colchicine For Treatment of Gout Flares: AUC 296% and C 184% max • Administer a single dose of colchicine 0.6 mg, followed by colchicine 0.3 mg 1 hour later. Do not repeat dose for at least 3 Significant ↑ colchicine expected days. with all PIs, with or without COBI or RTV For Prophylaxis of Gout Flares: • Administer colchicine 0.3 mg once daily or every other day. For Treatment of Familial Mediterranean Fever: Do not exceed colchicine 0.6 mg once daily or colchicine 0.3 mg • BID. Do not coadminister in patients with hepatic or renal impairment. All PIs ↑ dronabinol possible Monitor for increased dronabinol-related adverse reactions. Dronabinol All PIs ↑ eluxadoline expected Administer eluxadoline at a dose of 75 mg twice daily and monitor Eluxadoline fects. for eluxadoline-related adverse ef All PIs ↓ PI expected Contraindicated. Enzalutamide All PIs ↑ dihydroergotamine, Contraindicated. Ergot Derivatives ergotamine, methylergonovine expected Flibanserin ↑ flibanserin expected Contraindicated. All PIs Irinotecan ATV ↑ irinotecan expected Contraindicated. (unboosted), ATV/c, ATV/r Mitotane All PIs ↓ PI expected Contraindicated. Salmeterol All PIs ↑ salmeterol possible Do not coadminister because of potential increased risk of salmeterol-associated CV events. L-22 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

262 Table 19a. Drug Interactions Between Protease Inhibitors and Other Drugs (Last updated October 25, (page 19 of 19) 2018; last reviewed October 25, 2018) a DHA is an active metabolite of artemether. b The following products contain no more than 30 mcg of ethinyl estradiol combined with norethindrone or norgestimate (generic formulations may also be available): Lo Minastrin Fe; Lo Loestrin Fe; Loestrin 1/20, 1.5/30; Loestrin Fe 1/20, 1.5/30; Loestrin 24 Fe; Minastrin 24 Fe; Ortho Tri-Cyclen Lo. c The following products contain at least 35 mcg of ethinyl estradiol combined with norethindrone or norgestimate (generic formulations may also be available): Brevicon; Femcon Fe; Modicon; Norinyl 1/35; Ortho-Cyclen; Ortho-Novum 1/35, 7/7/7; Ortho Tri-Cyclen; Ovcon 35; Tri-Norinyl. d Norbuprenorphine is an active metabolite of buprenorphine. e R-methadone is the active form of methadone. Key to Symbols: ↑ = increase ↓ = decrease ↔ = no change Key to Acronyms: 17-BMP = beclomethasone 17-monopropionate; ALT = alanine aminotransferase; ART = antiretroviral therapy; ARV = antiretroviral; ATV = atazanavir; ATV/c = atazanavir/cobicistat; ATV/r = atazanavir/ritonavir; AUC = area under the curve; BID = twice daily; C = minimum plasma concentration; CNS = central nervous system; COBI = cobicistat; = maximum plasma concentration; C min max CrCl = creatinine clearance; CV = cardiovascular; CYP = cytochrome P; DHA = dihydroartemisinin; DRV = darunavir; DRV/c = darunavir/ cobicistat; DRV/r = darunavir/ritonavir; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; FPV = fosamprenavir; HCV = hepatitis C virus; HRT = hormone replacement therapy; IDV = indinavir; INR = international normalized ratio; LPV = lopinavir; LPV/r = lopinavir/ritonavir; MPA = medroxyprogesterone acetate; NFV = nelfinavir; OATP = organic anion-transporting polypeptide; PAH = pulmonary arterial hypertension; PDE5 = Phosphodiesterase Type 5; PI = protease inhibitor; PI/c = protease inhibitor/cobicistat; PI/r = protease inhibitor/ritonavir; PK = pharmacokinetic; PPI = proton pump inhibitor; PTH = parathyroid hormone; QTc = QT corrected for heart rate; RTV = ritonavir; SQV = saquinavir; TDF = tenofovir disoproxil fumarate; TPV = tipranavir; TPV/r = tipranavir/ritonavir L-23 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

263 Table 19b. Drug Interactions Between Non-Nucleoside Reverse Transcriptase Inhibitors and Other Drugs (Last updated October 25, 2018; last reviewed October 25, 2018) (page 1 of 10 ) This table provides information relating to PK interactions between NNRTIs and non-ARV drugs. For Tables 20a , and 20b , 19c interactions between ARV agents and for dosing recommendations, refer to . Recommendations for managing a particular drug interaction may differ depending on whether a new ARV drug is being initiated in a patient on a stable concomitant medication or if a new concomitant medication is being initiated in a patient on a stable ARV regimen. The magnitude and significance of drug interactions are . difficult to predict when several drugs with competing metabolic pathways are prescribed concomitantly Note: DLV is not included in this table. Please refer to the DLV FDA package insert for information V. regarding drug interactions. The term “All NNRTIs” in this table refers to all NNRTIs except for DL Effect on NNRTI and/ Concomitant a Drug Class/ NNRTI or Concomitant Drug Dosing Recommendations and Clinical Comments Name Concentrations Acid Reducers Antacids ↓ RPV expected when given Give antacids at least 2 hours before or at least 4 hours RPV after RPV. simultaneously H2 Receptor ↓ RPV Give H2 receptor antagonists at least 12 hours before or RPV Antagonists at least 4 hours after RPV. PPIs RPV Contraindicated. Do not coadminister . With Omeprazole 20 mg Daily: RPV AUC ↓ 40% and C ↓ • min 33% Alpha-Adrenergic Antagonists for Benign Prostatic Hyperplasia Alfuzosin, Consider alternative therapy. If coadministration is EFV, ETR, NVP ↓ alpha antagonist expected Doxazosin, necessary, monitor for therapeutic effectiveness of alpha Silodosin antagonist. Tamsulosin EFV, ETR, NVP ↓ tamsulosin expected Monitor for therapeutic effectiveness of tamsulosin after 2 to 4 weeks of dosing. May need to increase to tamsulosin 0.8 mg once daily for patients who fail to respond to the 0.4 mg dose. Anticoagulants/Antiplatelets EFV, ETR, NVP ↓ apixaban possible Consider alternative therapy. Apixaban All NNRTIs ↔ betrixaban expected No dose adjustment necessary. Betrixaban Clopidogrel EFV, ETR ↓ activation of clopidogrel possible ETR may prevent metabolism of clopidogrel (inactive) to its active metabolite. Avoid coadministration, if possible. DOR, NVP, RPV No dose adjustment necessary. ↔ clopidogrel expected All NNRTIs Dabigatran No dose adjustment necessary. ↔ dabigatran expected Edoxaban All NNRTIs ↔ edoxaban expected No dose adjustment necessary. Prasugrel All NNRTIs ↔ prasugrel expected No dose adjustment necessary. Rivaroxaban EFV, ETR, NVP ↓ rivaroxaban possible Consider alternative therapy. Ticagrelor EFV, ETR, NVP ↓ ticagrelor expected Consider alternative therapy. Monitor INR and adjust warfarin dose accordingly. ↑ or ↓ warfarin possible EFV, ETR, NVP Warfarin L-24 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

264 Table 19b. Drug Interactions Between Non-Nucleoside Reverse Transcriptase Inhibitors and Other ) Drugs (Last updated October 25, 2018; last reviewed October 25, 2018) (page 2 of 10 Effect on NNRTI and/ Concomitant a Drug Class/ or Concomitant Drug Dosing Recommendations and Clinical Comments NNRTI Name Concentrations Anticonvulsants Carbamazepine, EFV Carbamazepine plus EFV: Monitor anticonvulsant and EFV concentrations or, if Phenobarbital, possible, use alternative anticonvulsant to those listed. Carbamazepine AUC ↓ 27% • Phenytoin EFV AUC ↓ 36% • : Phenytoin plus EFV • ↓ EFV • ↓ phenytoin possible Do not coadminister . Consider alternative anticonvulsant. ETR ↓ anticonvulsant and ETR possible ↓ anticonvulsant and NVP possible Monitor anticonvulsant and NVP concentrations and NVP virologic responses or consider alternative anticonvulsant. ↓ Contraindicated. Do not coadminister. Consider DOR, RPV NNRTI possible alternative anticonvulsant. ↓ NNRTI possible Monitor virologic outcomes and consider monitoring Eslicarbazepine All NNRTIs plasma concentrations of ARVs, or consider alternative anticonvulsant or ARV drug. Oxcarbazepine DOR, RPV ↓ NNRTI possible Contraindicated. Do not coadminister. Consider alternative anticonvulsant. Ethosuximide, Monitor seizure control and plasma concentrations of ↓ anticonvulsant possible ETR, EFV Lacosamide, anticonvulsants (when available). Tiagabine, Zonisamide, ↓ lamotrigine possible Lamotrigine EFV Monitor seizure control and plasma concentrations of lamotrigine. Antidepressants Bupropion AUC ↓ 55% Titrate bupropion dose based on clinical response. Bupropion EFV, NVP ↓ bupropion possible Citalopram, ↓ antidepressant possible Titrate antidepressant dose based on clinical response. EFV, ETR, NVP Escitalopram All NNRTIs ↔ antidepressant expected No dose adjustment necessary. Fluoxetine, Fluvoxamine EFV, ETR ↔ paroxetine observed with EFV No dose adjustment necessary. Paroxetine or ETR DOR, NVP, RPV ↔ expected with No dose adjustment necessary. DOR, NVP or RPV EFV, ETR, NVP Nefazodone ↓ nefazodone expected Monitor the antidepressant effect and titrate dose as necessary. Monitor for ARV-related adverse events. ↑ NNRTI possible ↑ NNRTI possible Monitor for ARV-related adverse events. DOR, RPV EFV Titrate sertraline dose based on clinical response. Sertraline AUC ↓ 39% Sertraline EFV, ETR, NVP ↓ trazodone possible Monitor the therapeutic effect of trazodone and titrate Trazodone dose as necessary. L-25 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

265 Table 19b. Drug Interactions Between Non-Nucleoside Reverse Transcriptase Inhibitors and Other ) Drugs (Last updated October 25, 2018; last reviewed October 25, 2018) (page 3 of 10 Effect on NNRTI and/ Concomitant a NNRTI or Concomitant Drug Dosing Recommendations and Clinical Comments Drug Class/ Name Concentrations Antifungals ↔ fluconazole or EFV EFV Fluconazole No dose adjustment necessary. ETR ETR AUC ↑ 86% No dose adjustment necessary. Use with caution. Increased risk of hepatotoxicity possible with this NVP AUC ↑ 110% NVP combination. Monitor NVP toxicity or use alternative ARV agent. DOR,RPV ↑ NNRTI possible No dose adjustment necessary. ↓ isavuconazole possible Dose adjustments for isavuconazole may be necessary. Isavuconazole EFV, ETR, NVP Consider monitoring isavuconazole concentration and antifungal response. NNRTI possible No dose adjustment necessary. DOR, RPV ↑ Itraconazole and OH-itraconazole Itraconazole EFV Failure to achieve therapeutic itraconazole concentrations AUC, C ↓ 35% to has been reported. Avoid this combination if possible. , and C min max 44% If coadministered, closely monitor itraconazole concentration and adjust dose accordingly. ETR Dose adjustments for itraconazole may be necessary. ↓ itraconazole possible Monitor itraconazole level and antifungal response. ↑ ETR possible NVP Itraconazole AUC ↓ 61% Avoid this combination if possible. If coadministered, monitor itraconazole concentration and adjust dose ↑ NVP possible accordingly. DOR, RPV No dose adjustment necessary. ↑ NNRTI possible Posaconazole AUC ↓ 50% Posaconazole EFV Avoid concomitant use unless the benefit outweighs the risk. If coadministered, monitor posaconazole ↔ EFV concentration and adjust dose accordingly. DOR, ETR, NVP, ↑ NNRTI possible Monitor for NNRTI toxicities. RPV Voriconazole AUC ↓ 77% Voriconazole EFV Contraindicated at standard doses. EFV AUC ↑ 44% Dose Adjustment: • Voriconazole 400 mg BID, EFV 300 mg daily ETR ↔ V oriconazole AUC No dose adjustment necessary. ETR AUC ↑ 36% ↓ voriconazole possible NVP Monitor for toxicity and antifungal response and/or voriconazole concentration. ↑ NVP possible DOR, RPV NNRTI possible No dose adjustment necessary. ↑ Antihyperglycemics No dose adjustment necessary. Canagliflozin, All NNRTIs ↔ antihyperglycemic expected Dapagliflozin, Empagliflozin, Sitagliptin EFV, ETR, NVP ↓ antihyperglycemic possible Monitor glycemic control. Linagliptin, Saxagliptin L-26 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

266 Table 19b. Drug Interactions Between Non-Nucleoside Reverse Transcriptase Inhibitors and Other ) Drugs (Last updated October 25, 2018; last reviewed October 25, 2018) (page 4 of 10 Effect on NNRTI and/ Concomitant a NNRTI or Concomitant Drug Dosing Recommendations and Clinical Comments Drug Class/ Name Concentrations Antimalarials EFV Consider alternative ARV or antimalarial drug. If used in Artemether/ Artemether AUC ↓ 79% combination, monitor closely for antimalarial efficacy. Lumefantrine DHA AUC ↓ 75% Lumefantrine AUC ↓ 56% Artemether AUC ↓ 38% Clinical significance of the reduced antimalarial drug ETR concentrations unknown. If used in combination with ↔ DHA AUC ETR, monitor for antimalarial efficacy. ↔ Lumefantrine AUC ↔ ETR AUC NVP Clinical significance unknown. If used, monitor closely for Artemether AUC ↓ 67% to 72% . antimalarial efficacy and lumefantrine toxicity DHA: Study results are conflicting. DHA • AUC ↓ 37% in one study , no difference in another. Lumefantrine: Study results are conflicting. • Lumefantrine AUC ↓ 25% to 58% in 2 studies but ↑ 56% in another. EFV Atovaquone/ No dose recommendation. Consider alternative drug for Atovaquone AUC ↓ 75% malaria prophylaxis, if possible. Proguanil Proguanil AUC ↓ 43% Antimycobacterials EFV, ETR ↓ bedaquiline possible Do not coadminister. Bedaquiline ↔ bedaquiline AUC NVP No dose adjustment necessary. Clarithromycin AUC ↓ 39% Clarithromycin Monitor for effectiveness or consider alternative agent, EFV such as azithromycin, for MAC prophylaxis and treatment. ETR Clarithromycin AUC ↓ 39% Consider alternative agent, such as azithromycin, for MAC prophylaxis and treatment. ETR AUC ↑ 42% NVP Monitor for effectiveness or use alternative agent, such Clarithromycin AUC ↓ 31% as azithromycin, for MAC prophylaxis and treatment. NVP AUC ↑ 26% RPV ↔ clarithromycin expected Consider alternative macrolide, such as azithromycin, for MAC prophylaxis and treatment. ↑ RPV possible Rifabutin DOR AUC ↓ 50% Increase DOR dose to 100 mg twice daily. No dose DOR adjustment for rifabutin. EFV Rifabutin ↓ 38% Dose: Rifabutin 450–600 mg/day; or • • Rifabutin 600 mg 3 times/week if EFV is not coadministered with a PI. ↔ Rifabutin and metabolite AUC Do not coadminister ETR plus PI/r with rifabutin. ETR ETR AUC ↓ 37% Use rifabutin 300 mg once daily if ETR is administered without PI/r L-27 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

267 Table 19b. Drug Interactions Between Non-Nucleoside Reverse Transcriptase Inhibitors and Other ) Drugs (Last updated October 25, 2018; last reviewed October 25, 2018) (page 5 of 10 Concomitant Effect on NNRTI and/ a or Concomitant Drug Dosing Recommendations and Clinical Comments NNRTI Drug Class/ Concentrations Name , continued Antimycobacterials NVP Rifabutin , Rifabutin AUC ↑ 17% and No dose adjustment necessary. Use with caution. metabolite AUC ↑ 24% continued ↓ 16% NVP C min RPV Rifabutin plus RPV 50 mg Once Increase RPV dose to 50 mg once daily. No dose adjustment for rifabutin. Daily Compared to RPV 25 mg Once Daily Alone: • ↔ RPV AUC and C min Rifampin DOR AUC ↓ 88% Contraindicated. DOR EFV EFV AUC ↓ 26% Do not use EFV 400 mg with rifampin. Maintain EFV dose at 600 mg once daily and monitor for virologic response. Do not coadminister. ETR Significant ↓ ETR possible Do not coadminister. NVP ↓ 20% to 58% NVP RPV RPV AUC ↓ 80% Contraindicated. Rifapentine EFV ↔ EFV concentrations No dose adjustment necessary. ↓ NNRTI possible Do not coadminister. ETR, NVP ↓ DOR, RPV NNRTI expected Contradindicated. Antipneumocystis and Antitoxoplasmosis Drugs EFV Consider alternative agent for PCP or toxoplasmosis Atovaquone Atovaquone AUC ↓ 44% to 47% treatment or use alternative ARV drug. If used in combination, monitor therapeutic efficacy of atovaquone. Antipsychotics ↓ aripiprazole expected Monitor effectiveness of antipsychotic. Consider Aripiprazole EFV, ETR, NVP doubling usual dose of aripiprazole over 1–2 weeks. Refer to aripiprazole prescribing information for dosing recommendations. Brexpiprazole EFV, ETR, NVP ↓ brexpiprazole expected Monitor effectiveness of antipsychotic. Consider doubling the usual dose of brexpiprazole and making further adjustments based on clinical response. Refer to brexpiprazole prescribing information. EFV, ETR, NVP ↓ cariprazine and ↑ or ↓ active Cariprazine Coadministration is not recommended. metabolite possible Olanzapine ↓ olanzapine possible Monitor effect of olanzapine. EFV DOR, ETR, NVP, ↔ olanzapine expected No dose adjustment necessary. RPV Pimozide ↓ pimozide possible Monitor therapeutic effectiveness of pimozide EFV, ETR, NVP EFV, ETR, NVP ↓ antipsychotic possible Monitor effect of antipsychotic. Lurasidone, Pimavanserin, Quetiapine, Thioridazine L-28 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

268 Table 19b. Drug Interactions Between Non-Nucleoside Reverse Transcriptase Inhibitors and Other ) Drugs (Last updated October 25, 2018; last reviewed October 25, 2018) (page 6 of 10 Effect on NNRTI and/ Concomitant a NNRTI or Concomitant Drug Dosing Recommendations and Clinical Comments Drug Class/ Name Concentrations Benzodiazepines ↓ alprazolam possible EFV, ETR, NVP Alprazolam Monitor for therapeutic effectiveness of alprazolam. Monitor for therapeutic effectiveness of diazepam. Diazepam EFV, NVP ↓ diazepam possible ↑ diazepam possible ETR Decreased dose of diazepam may be necessary. Monitor for diazepam toxicity. Lorazepam EFV ↔ lorazepam AUC No dose adjustment necessary. ETR, NVP ↔ lorazepam expected EFV Midazolam Monitor therapeutic effectiveness and toxicity of ↑ or ↓ midazolam possible midazolam. Midazolam AUC ↓ 31% Monitor therapeutic effectiveness of midazolam. ETR Midazolam active metabolite C max ↑ 57% NVP ↓ midazolam possible Monitor therapeutic effectiveness of midazolam. Triazolam ↓ triazolam possible Monitor therapeutic effectiveness of triazolam. EFV, ETR, NVP Cardiac Medications Dihydropyridine EFV, ETR, NVP ↓ CCBs possible Titrate CCB dose based on clinical response. CCBs Diltiazem, EFV Diltiazem AUC ↓ 69% Titrate diltiazem or verapamil dose based on clinical response. Verapamil ↓ verapamil possible ETR, NVP ↓ diltiazem or verapamil possible Corticosteroids Dexamethasone DOR, EFV, ETR, ↓ NNRTI possible Consider alternative corticosteroid for long-term use. If NVP dexamethasone is used with NNRTI, monitor virologic response. RPV Significant ↓ RPV possible Contraindicated with more than a single dose of dexamethasone. Hepatitis C Direct-Acting Antiviral Agents Daclatasvir EFV, ETR, NVP The recommended dose is daclatasvir 90 mg once daily. Daclatasvir 120 mg Once Daily plus EFV 600 mg Daily Compared with Daclatasvir 60 mg Alone: Daclatasvir C ↓ 17%, AUC ↑ • min 37% No dose adjustment necessary. DOR, RPV No data Dasabuvir plus DOR ↑ DOR possible No dose adjustment necessary. Paritaprevir/ EFV No data Contraindicated. Ombitasivir/RTV ETR, NVP Do not coadminister. ↓ DAAs possible RPV AUC ↑ 150% to 225% Do not coadminister, due to potential for QT interval RPV prolongation with higher concentrations of RPV. L-29 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

269 Table 19b. Drug Interactions Between Non-Nucleoside Reverse Transcriptase Inhibitors and Other Drugs (Last updated October 25, 2018; last reviewed October 25, 2018) (page 7 ) of 10 Effect on NNRTI and/ Concomitant a Dosing Recommendations and Clinical Comments Drug Class/ NNRTI or Concomitant Drug Name Concentrations Hepatitis C Direct-Acting Antiviral Agents , continued Elbasvir AUC ↓ 54% EFV Elbasvir/ Contraindicated. Grazoprevir Grazoprevir AUC ↓ 83% EFV ↔ by grazoprevir EFV ↔ AUC by elbasvir ETR, NVP Do not coadminister. ↓ elbasvir and grazoprevir expected No dose adjustment necessary. ↔ Elbasvir, grazoprevir DOR, RPV ↔ DOR, RPV Glecaprevir/ DOR ↑ DOR expected No dose adjustment necessary. Pibrentasvir Do not coadminister. EFV ↓ glecaprevir and pibrentasvir expected ETR , NVP ↓ glecaprevir and pibrentasvir possible No dose adjustment necessary. RPV ↔ glecaprevir, pibrentasvir RPV AUC ↑ 84% , and C Ledipasvir AUC, C EFV Ledipasvir/ No dose adjustment necessary. min max ↓ 34% Sofosbuvir ↔ sofosbuvir ETR, NVP No significant effect expected ↔ Ledipasvir, sofosbuvir DOR, RPV ↔ DOR, RPV Simeprevir No significant effect expected. DOR No dose adjustment necessary. EFV ↓ Simeprevir AUC ↓ 71%, C Do not coadminister. min 91% ↔ EFV ETR, NVP ↓ simeprevir expected Do not coadminister. ↔ simeprevir and RPV RPV No dose adjustment necessary. ↓ Velpatasvir AUC ↓ 43%, C EFV Sofosbuvir/ Do not coadminister. max ↓ 47% 37% and C Velpatasvir min ETR, NVP ↓ velpatasvir expected Do not coadminister. DOR, RPV No significant effect expected No dose adjustment necessary. EFV ↓ Sofosbuvir/ Velpatasvir AUC ↓ 43% , C Do not coadminister. max ↓ 47% 37%, and C Velpatasvir/ min Voxilaprevir ↓ voxilaprevir expected ETR, NVP ↓ voxilaprevir expected Do not coadminister. ↓ velpatasvir expected No dose adjustment necessary. No signficant effect expected DOR, RPV L-30 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

270 Table 19b. Drug Interactions Between Non-Nucleoside Reverse Transcriptase Inhibitors and Other Drugs (Last updated October 25, 2018; last reviewed October 25, 2018) (page 8 ) of 10 Concomitant Effect on NNRTI and/ a NNRTI Dosing Recommendations and Clinical Comments Drug Class/ or Concomitant Drug Name Concentrations Herbal Products St. John’s Wort Do not coadminister. EFV, ETR, NVP ↓ EFV, ETR, and NVP expected DOR, RPV ↓ NNRTI expected Contraindicated. Hormonal Therapies Hormonal EFV ↔ Ethinyl estradiol Use alternative or additional contraceptive methods. , Contraceptives Etonogestrel (metabolite of oral Oral ↓ 61% desogestrel) C min Levonorgestrel (metabolite of oral norgestimate) AUC ↓ 83% Norelgestromin (metabolite of oral norgestimate) AUC ↓ 64% No dose adjustment necessary. ETR Ethinyl estradiol AUC ↑ 22% No significant effect on norethindrone Ethinyl estradiol AUC ↓ 29%, C NVP Based on clinical data demonstrating no change in min ↓ 58% effectiveness, no dose adjustment necessary. Norethindrone AUC ↓ 18% Etonogestrel (metabolite of oral desogestrel) C ↓ 22% min RPV ↔ Ethinyl estradiol No dose adjustment necessary. ↔ Norethinodrone No dose adjustment necessary. ↔ Ethinyl estradiol DOR ↔ Levonorgestrel EFV, NVP No dose adjustment necessary. Depot Medroxy- DMPA: no significant change progesterone Acetate (MPA) Injectable EFV Etonogestrel- Use alternative or additional contraceptive methods. Etonogestrel AUC ↓ 63% to 82% Releasing Etonogestrel: no significant change No dose adjustment necessary. NVP Subdermal Implant EFV Ethinyl estradiol (intravaginal ring) Use alternative or additional contraceptive methods. Etonogestrel/ AUC ↓ 56% Ethinyl Estradiol Vaginal Ring Etonogestrel (intravaginal ring) AUC ↓ 81% EFV Use alternative or additional contraceptive methods. Levonorestrel- Levonorgestrel AUC ↓ 47% Releasing Unintended pregnancies were observed in women who Subdermal used EFV and levonorgestrel implant concomitantly. Implant NVP No dose adjustment necessary. Levonorgestrel AUC ↑ 35% EFV Levonorgestrel AUC ↓ 58% Effectiveness of emergency postcoital contraception may Levonorgestrel be diminished. For emergency contraception L-31 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

271 Table 19b. Drug Interactions Between Non-Nucleoside Reverse Transcriptase Inhibitors and Other Drugs (Last updated October 25, 2018; last reviewed October 25, 2018) (page 9 ) of 10 Concomitant Effect on NNRTI and/ a Dosing Recommendations and Clinical Comments NNRTI or Concomitant Drug Drug Class/ Concentrations Name , continued Hormonal Therapies ↓ estrogen possible with estradiol EFV, ETR, NVP Menopausal Monitor menopausal symptoms. Titrate to the dose of or conjugated estrogen (equine Hormone hormonal therapy that achieves menopausal symptom Replacement and synthetic) relief. Therapy ↓ medroxyprogesterone possible ↓ micronized progesterone possible ↓ drospirenone possible See Hormonal Contraceptives for other progestin-NNRTI interactions EFV, ETR, NVP ↓ estradiol possible Gender-Affirming Monitor feminizing effects of estrogen and antiandrogen Hormone therapy and titrate dosing as necessary to achieve ↔ goserelin, leuprolide acetate, therapeutic goals. Therapy and spironolactone expected ↓ dutasteride and finasteride possible EFV, ETR, NVP Monitor masculinizing effects of testosterone and titrate ↓ testosterone possible testosterone dose as necessary to achieve therapeutic goals. HMG-CoA Reductase Inhibitors EFV, ETR Atorvastatin AUC ↓ 32% to 43% Atorvastatin Adjust atorvastatin dose according to lipid response, but do not exceed the maximum recommended dose. NVP ↓ atorvastatin possible Adjust atorvastatin dose according to lipid response, but do not exceed the maximum recommended dose. No dose adjustment necessary. DOR, RPV ↔ atorvastatin AUC Fluvastatin Dose adjustments for fluvastatin may be necessary. EFV, ETR ↑ fluvastatin possible Monitor for fluvastatin toxicity. Simvastatin AUC ↓ 68% EFV Lovastatin, Adjust simvastatin dose according to lipid response, but Simvastatin do not exceed the maximum recommended dose. If EFV Simvastatin active metabolite AUC is used with a PI/r, simvastatin and lovastatin should be ↓ 60% avoided. ↓ lovastatin possible ETR, NVP Adjust lovastatin or simvastatin dose according to lipid responses but do not exceed the maximum ↓ simvastatin possible recommended dose. If ETR or NVP is used with a PI/r, simvastatin and lovastatin should be avoided. No dose adjustment necessary. Pitavastatin EFV ↔ pitavastatin AUC No dose adjustment necessary. DOR, ETR, NVP, ↔ pitavastatin expected RPV Adjust statin dose according to lipid responses, but do not EFV Pravastatin Pravastatin AUC ↓ 44% exceed the maximum recommended dose. ↓ pravastatin possible ETR No dose adjustment necessary. Rosuvastatin EFV, ETR, NVP ↔ rosuvastatin expected L-32 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

272 Table 19b. Drug Interactions Between Non-Nucleoside Reverse Transcriptase Inhibitors and Other 10 Drugs (Last updated October 25, 2018; last reviewed October 25, 2018) (page ) 10 of Effect on NNRTI and/ Concomitant a Dosing Recommendations and Clinical Comments or Concomitant Drug Drug Class/ NNRTI Name Concentrations Immunosuppressants Cyclosporine, ↓ immunosuppressant possible Increase in immunosuppressant dose may be necessary. EFV, ETR, NVP Therapeutic drug monitoring of immunosuppressant is Everolimus, recommended. Consult with specialist as necessary. Sirolimus, Tacrolimus Narcotics/Treatments for Opioid Dependence Buprenorphine EFV Buprenorphine AUC ↓ 50% No dose adjustment recommended; monitor for Sublingual or withdrawal symptoms. b Norbuprenorphine AUC ↓ 71% buccal No dose adjustment necessary. Buprenorphine AUC ↓ 25% ETR No significant effect No dose adjustment necessary. NVP EFV, ETR, NVP No data Clinical monitoring is recommended if NNRTI is initiated Buprenorphine Implant after insertion of buprenorphine implant. Methadone EFV Methadone AUC ↓ 52% Opioid withdrawal common; increased methadone dose often necessary. No dose adjustment necessary. No significant effect DOR, ETR Opioid withdrawal is common; increased methadone Methadone AUC ↓ 37% to 51% NVP dose is often necessary. No significant effect on NVP c RPV R-methadone AUC ↓ 16% No dose adjustment necessary, but monitor for withdrawal symptoms. PDE5 Inhibitors Sildenafil DOR, RPV ↔ sildenafil expected No dose adjustment necessary. ETR Sildenafil AUC ↓ 57% May need to titrate sildenafil dose based on clinical effect. ↓ sildenafil possible EFV, NVP Tadalafil EFV, ETR, NVP ↓ tadalafil possible May need to titrate tadalafil dose based on clinical effect. RPV ↔ tadalafil No dose adjustment necessary. May need to increase PDE5 inhibitor dose based on Avanafil, EFV, ETR, NVP ↓ PDE5 inhibitor possible Vardenafil clinical effect. Miscellaneous Drugs Contraindicated. Enzalutamide All NNRTIs ↓ NNRTI expected Mitotane ↓ NNRTI expected All NNRTIs Contraindicated. a Approved dose for RPV is 25 mg once daily. Most PK interaction studies were performed using 75 mg to 150 mg per dose. b Norbuprenorphine is an active metabolite of buprenorphine. c R-methadone is the active form of methadone. Key to Symbols: ↑ = increase ↓ = decrease ↔ = no change Key to Acronyms: ARV = antiretroviral; AUC = area under the curve; BID = twice daily; CCB = calcium channel blocker; C = maximum max plasma concentration; C = minimum plasma concentration; DAA = direct-acting antiviral; DHA = dihydroartemisinin; DMPA = depot min medroxyprogesterone acetate; DOR = doravirine; EFV = efavirenz; ETR = etravirine; HMG-CoA = hydroxy-methylglutaryl-coenzyme A; INR = international normalized ratio; MAC = Mycobacterium avium complex; NNRTI = non-nucleoside reverse transcriptase inhibitor; NVP = Pneumocystis jirovecii nevirapine; OH-itraconazole = active metabolite of itraconazole; PCP = pneumonia; PDE5 = phosphodiesterase type 5; PI = protease inhibitor; PI/r = protease inhibitor/ritonavir; PK = pharmacokinetic; PPI = proton pump inhibitor; RPV = rilpivirine; R TV = ritonavir L-33 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

273 Table 19c. Drug Interactions Between Nucleoside Reverse Transcriptase Inhibitors and Other Drugs (Including Antiretroviral Agents) (Last updated October 25, 2018; last reviewed October 25, 2018) (page 1 of 3) Recommendations for managing a particular drug interaction may differ depending on whether a new ARV drug is being initiated in a patient on a stable concomitant medication or whether a new concomitant medication is being initiated in a patient on a stable ARV regimen. The magnitude and significance of drug interactions are difficult to predict when several drugs with competing metabolic pathways are prescribed concomitantly. Note: Interactions associated with ddI and d4T are not included in this table. Please refer to FDA product labels for information regarding interactions between ddI or d4T and other concomitant drugs. Concomitant Drug Class/ Effect on NRTI and/or Concomitant Dosage Recommendations and Clinical NRTI Name Drug Concentrations Comments Cytomegalovirus and Hepatitis B Antivirals No data Adefovir Do not coadminister. Serum concentrations of TDF TDF and/or other renally eliminated drugs may increase. Ganciclovir, TAF , TDF No data Serum concentrations of ganciclovir and/or TFV Valganciclovir may increase. Monitor for dose-related toxicities. ZDV Potential increase in hematologic toxicities. No significant effect Hepatitis C Antiviral Agents Glecaprevir/Pibrentasvir TAF, TDF No significant effect No dose adjustment necessary. Ledipasvir/Sofosbuvir, TAF No dose adjustment. No significant effect Sofosbuvir/Velpatasvir, TDF Ledipasvir ↑ TFV AUC 40% to 98% No dose adjustment necessary. Sofosbuvir/Velpatasvir/ when TDF is given with RPV and EFV The safety of increased TFV exposure when Voxilaprevir ledipasvir/sofosbuvir is coadministered with TDF Further ↑ TFV possible if TDF is given with PIs plus a PI/r or PI/c has not been established. Consider alternative HCV or ARV drugs to avoid increased TFV toxicities. Consider using TAF in patients at risk of TDF- associated adverse events. If TDF is used in these patients, monitor for TDF toxicity. Coadministration of ledipasvir/sofosbuvir with EVG/c/TDF/FTC is not recommended. Ribavirin TDF With Sofosbuvir 400 mg: No dose adjustment necessary. • ↔ TFV AUC ZDV Avoid coadministration if possible, or closely Ribavirin inhibits phosphorylation of ZDV. monitor HIV virologic response and possible hematologic toxicities. INSTIs DTG TAF ↔ TAF AUC No dose adjustment necessary. TDF ↔ TDF AUC No dose adjustment necessary. ↔ DTG AUC RAL TDF RAL AUC ↑ 49% No dose adjustment necessary. Narcotics/Treatment for Opioid Dependence No dose adjustment necessary. 3TC, No significant effect Buprenorphine TDF, TAF, ZDV L-34 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

274 Table 19c. Drug Interactions Between Nucleoside Reverse Transcriptase Inhibitors and Other Drugs (Including Antiretroviral Agents) (Last updated October 25, 2018; last reviewed October 25, 2018) (page 2 of 3) Concomitant Drug Class/ Dosage Recommendations and Clinical Effect on NRTI and/or Concomitant NRTI Name Drug Concentrations Comments , continued Narcotics/Treatment for Opioid Dependence ABC Methadone clearance ↑ 22% No dose adjustment necessary. Methadone Monitor for ZDV-related adverse effects. ZDV ZDV AUC ↑ 29% to 43% Other ZDV ZDV AUC ↑ 31% Monitor for ZDV-related adverse effects. Atovaquone Anticonvulsants TAF Coadministration is not recommended. With Carbamazepine: Carbamazepine, • TAF AUC ↓ 55% oxcarbazepine, ↓ TAF possible with other phenobarbital, phenytoin anticonvulsants Antimycobacterial TAF TAF AUC ↓ 55% Coadministration is not recommended. Rrifampin TFV-DP (intracellular active moiety) AUC ↓ 36% TAF plus Rifampin Compared with TDF Alone: • -DP (intracellular active moiety) TFV AUC ↑ 4.2-fold With Twice-Daily TAF 25 mg Compared with Once-Daily TAF without Rifampin: • TAF AUC ↓ 14% -DP (intracellular active moiety) • TFV AUC ↓ 24% TDF ↔ AUC TFV No dose adjustment necessary. Rifabutin, Rifapentine TAF Coadministration is not recommended. ↓ TAF possible TAF Coadministration is not recommended. St. John’s Wort ↓ TAF possible PIs (HIV) ATV (Unboosted), ATV/c, TAF TAF 10 mg with ATV/r: No dose adjustment (use TAF 25 mg). ATV/r T • AF AUC ↑ 91% TAF 10 mg with ATV/c: • T AF AUC ↑ 75% TDF With ATV (Unboosted): Avoid concomitant use without RTV or COBI. ↓ 23% • TV AUC ↓ 25% and C A min Dose: with RTV than to 40% (higher C min • A TV 300 mg daily plus (RTV 100 mg or COBI 150 without RTV) mg) daily when coadministered with TDF 300 mg TFV AUC ↑ 24% to 37% daily • If using TDF and H2 receptor antagonist in an AR T-experienced patient, use ATV 400 mg daily plus (RTV 100 mg or COBI 150 mg) daily Monitor for TDF-associated toxicity. ZDV With ATV (Unboosted): Clinical significance unknown. ZDV C ↓ 30% and ↔ ZDV AUC • min L-35 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

275 Table 19c. Drug Interactions Between Nucleoside Reverse Transcriptase Inhibitors and Other Drugs (Including Antiretroviral Agents) (Last updated October 25, 2018; last reviewed October 25, 2018) (page 3 of 3) Concomitant Drug Class/ Dosage Recommendations and Clinical Effect on NRTI and/or Concomitant NRTI Name Comments Drug Concentrations PIs (HIV) , continued DRV/c TAF No dose adjustment necessary. TAF 25 mg with DRV/c: • ↔ TAF ↑ TDF possible Monitor for TDF-associated toxicity. TDF DRV/r TAF TAF 10 mg with DRV/r: No dose adjustment necessary. ↔ • TAF TFV AUC ↑ 22% and C ↑ 37% Clinical significance unknown. Monitor for TDF- TDF min associated toxicity. TAF LPV/r No dose adjustment necessary. TAF 10 mg with DRV/r: • T AF AUC ↑ 47% TDF ↔ LPV/r AUC Clinical significance unknown. Monitor for TDF- associated toxicity. TFV AUC ↑ 32% ABC ABC AUC ↓ 35% to 44% Appropriate doses for this combination have not TPV/r been established. TAF ↓ TAF expected Coadministration is not recommended. ↔ TDF AUC TDF No dose adjustment necessary. ↓ TPV AUC ↓ 9% to 18% and C min 12% to 21% ZDV ZDV AUC ↓ 31% to 42% Appropriate doses for this combination have not been established. ↔ TPV AUC Key to Symbols: ↑ = increase ↓ = decrease ↔ = no change Key to Acronyms: 3TC = lamivudine; ABC = abacavir; ART = antiretroviral therapy; ARV = antiretroviral; ATV = atazanavir; ATV/c = atazanavir/cobicistat; ATV/r = atazanavir/ritonavir; AUC = area under the curve; C = minimum plasma concentration; COBI = cobicistat; min d4T = stavudine; ddI = didanosine; DRV/c = darunavir/cobicistat; DRV/r = darunavir/ritonavir; DTG = dolutegravir; EFV = efavirenz; EVG = elvitegravir; FDA = Food and Drug Administration; FTC = emtricitabine; HCV = hepatitis C virus; INSTI = integrase strand transfer inhibitors; LPV/r = lopinavir/ritonavir; NRTI = nucleoside reverse transcriptase inhibitor; PI = protease inhibitor; PI/c = protease inhibitor/ cobicistat; PI/r = protease inhibitor/ritonavir; RAL = raltegravir; RPV = rilpivirine; RTV = ritonavir; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; TFV = tenofovir; TFV-DP = tenofovir diphosphate; TPV/r = tipranavir/ritonavir; ZDV = zidovudine L-36 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

276 Table 19d. Drug Interactions Between Integrase Strand Transfer Inhibitors and Other Drugs (Last updated October 25, 2018; last reviewed October 25, 2018) (page 1 of 15) This table provides information on known or predicted PK interactions between INSTIs (BIC, DTG, EVG, or RAL) and non-ARV drugs. EVG is always coadministered with COBI. Recommendations for managing a particular drug interaction may differ depending on whether a new ARV drug is being initiated in a patient on a stable concomitant medication or whether a new concomitant medication is being initiated in a patient on a stable ARV regimen. The magnitude and significance of drug interactions are difficult to predict when several drugs with competing metabolic pathways are prescribed concomitantly. Concomitant Drug Effect on INSTI or Concomitant Drug Dosing Recommendations and Clinical INSTI Class/Name Comments Concentrations Alpha-Adrenergic Antagonists for Benign Prostatic Hyperplasia Alfuzosin BIC, DTG, RAL ↔ expected No dose adjustment necessary. EVG/c ↑ alfuzosin expected Contraindicated. Doxazosin BIC, DTG, RAL ↔ expected No dose adjustment necessary. EVG/c Initiate doxazosin at lowest dose and titrate ↑ doxazosin possible while monitoring for clinical response/toxicity. Dose reduction may be necessary. Tamsulosin BIC, DTG, RAL ↔ expected No dose adjustment necessary. EVG/c ↑ tamsulosin expected Coadministration is not recommended. If coadministered, monitor for tamsulosin toxicities. Terazosin BIC, DTG, RAL ↔ expected No dose adjustment necessary. ↑ terazosin possible EVG/c Initiate terazosin at lowest dose and titrate while monitoring for clinical response/toxicity. Dose reduction may be necessary. BIC, DTG, RAL ↔ expected No dose adjustment necessary. Silodosin EVG/c ↑ silodosin expected Contraindicated. Acid Reducers Al, Mg, With Antacids Containing Al/Mg or Ca: ↔ BIC AUC if antacid is given 2 hours after BIC +/- BIC and under fasting conditions • BIC can be taken under fasting conditions at Ca-Containing least 2 hours before antacids containing Al/ BIC AUC ↓ 79% if given simultaneously with Antacids Mg or Ca. antacid Please refer to the Do not coadminister BIC simultaneously with, or BIC AUC ↓ 52% if antacid is given 2 hours Miscellaneous Drugs 2 hours after, antacids containing Al/Mg or Ca. before BIC section of this table for recommendations Give DTG at least 2 hours before or at least DTG DTG AUC ↓ 74% if given simultaneously with on use with other 6 hours after antacids containing polyvalent antacid polyvalent cation cations. DTG AUC ↓ 26% if given 2 hours before products (e.g., Fe, antacid Ca supplements, multivitamins). Separate EVG/c/TDF/FTC and antacid EVG/c EVG AUC ↓ 40% to 50% if given administration by >2 hours. simultaneously with antacid EVG AUC ↓ 15% to 20% if given 2 hours before or after antacid; ↔ with 4-hour interval L-37 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

277 Table 19d. Drug Interactions Between Integrase Strand Transfer Inhibitors and Other Drugs (Last (page 2 of 15) updated October 25, 2018; last reviewed October 25, 2018) Concomitant Drug Effect on INSTI or Concomitant Drug Dosing Recommendations and Clinical INSTI Class/Name Comments Concentrations , continued Acid Reducers RAL Al, Mg, Do not coadminister RAL and Al-Mg Al/Mg Hydroxide Antacid: +/- Use alternative acid hydroxide antacids. • RAL C ↓ 49% to 63% min Ca-Containing reducing agent. Antacid: CaCO , continued Antacids 3 Antacids: With CaCO 3 • RAL (400 mg BID) C ↓ 32% Please refer to the min Do not 1200 mg once daily: RAL • Miscellaneous Drugs RAL (1200 mg once daily) C ↓ 48% to • min coadminister. section of this table 57% • RAL 400 mg BID: No dose adjustment or for recommendations separation necessary. on use with other polyvalent cation products (e.g., Fe, Ca supplements, multivitamins). H2-Receptor BIC, DTG, No significant effect No dose adjustment necessary. Antagonists EVG/c RAL RAL AUC ↑ 44% and C No dose adjustment necessary. ↑ 60% max PPIs No significant effect BIC, DTG, No dose adjustment necessary. EVG/c ↑ 24% No dose adjustment necessary. RAL AUC ↑ 37% and C RAL min Anticoagulants and Antiplatelets Apixaban BIC, DTG, RAL ↔ expected No dose adjustment necessary. ↑ apixaban expected EVG/c In Patients Requiring Apixaban 2.5 mg Twice Daily: • Coadministration is not recommended. In Patients Requiring Apixaban 5 mg or 10 mg Twice Daily: • Reduce apixaban dose by 50%. Betrixaban ↔ expected BIC, DTG, RAL No dose adjustment necessary. EVG/c ↑ betrixaban expected Administer initial single dose of betrixaban 80 mg, followed by betrixaban 40 mg once daily. Dabigatran BIC, DTG, RAL ↔ expected No dose adjustment necessary. EVG/c ↑ dabigatran expected Dabigatran dosing recommendation depends on indication and renal function. Refer to Dabigatran AUC ↑ 110% to 127% with COBI dabigatran prescribing information for dosing 150 mg alone instruction when used with P-gp inhibitors. Edoxaban BIC, DTG, RAL No dose adjustment necessary. ↔ expected EVG/c ↔ or ↑ edoxaban expected For Stroke Prevention in Nonvalvular Atrial Fibrillation: • No dose adjustment necessary. For Deep Venous Thrombosis and Pulmonary Embolism: • Administer edoxaban 30 mg once daily. Rivaroxaban BIC, DTG, RAL ↔ expected No dose adjustment necessary. EVG/c ↑ rivaroxaban expected Coadministration is not recommended. L-38 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

278 Table 19d. Drug Interactions Between Integrase Strand Transfer Inhibitors and Other Drugs (Last (page 3 of 15) updated October 25, 2018; last reviewed October 25, 2018) Concomitant Drug Dosing Recommendations and Clinical Effect on INSTI or Concomitant Drug INSTI Class/Name Concentrations Comments Anticoagulants and Antiplatelets , continued Ticagrelor No dose adjustment necessary. BIC, DTG, RAL ↔ expected Coadministration is not recommended. ↑ ticagrelor expected EVG/c Vorapaxar ↔ expected No dose adjustment necessary. BIC, DTG, RAL ↑ vorapaxar expected Coadministration is not recommended. EVG/c Warfarin ↔ expected No dose adjustment necessary. BIC, DTG, RAL ↑ or ↓ warfarin possible EVG/c Monitor INR and adjust warfarin dose accordingly. Anticonvulsants Carbamazepine BIC ↓ BIC possible Consider using an alternative anticonvulsant or A RV. DTG DTG AUC ↓ 49% Increase DTG dose to 50 mg BID in treatment- naive or treatment-experienced, INSTI-naive patients. Use alternative anticonvulsant for INSTI- experienced patients with known or suspected INSTI resistance. EVG/c Carbamazepine AUC ↑ 43% Contraindicated. EVG AUC ↓ 69% and C ↓ >99% min ↓ COBI expected RAL ↓ or ↔ RAL possible Coadministration is not recommended. All INSTIs Consider using an alternative anticonvulsant or Eslicarbazepine ↓ INSTI possible A RV. ↓ COBI possible Ethosuximide BIC, DTG, RAL ↔ expected No dose adjustment necessary. EVG/c Clinically monitor for ethosuximide toxicities. ↑ ethosuximide possible Lamotrigine BIC, DTG, RAL ↔ expected No dose adjustment necessary. EVG/c No data Monitor anticonvulsant level and adjust dose accordingly. Oxcarbazepine All INSTIs ↓ INSTI possible Consider using an alternative anticonvulsant or A RV. ↓ COBI possible Phenobarbital BIC Coadministration is not recommended. ↓ BIC possible Phenytoin DTG ↓ DTG possible Coadministration is not recommended. EVG/c ↓ EVG/c expected Contraindicated. RAL Coadministration is not recommended. ↓ or ↔ RAL possible Valproic Acid All INSTIs No data Monitor valproic acid concentration and virologic response. L-39 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

279 Table 19d. Drug Interactions Between Integrase Strand Transfer Inhibitors and Other Drugs (Last (page 4 of 15) updated October 25, 2018; last reviewed October 25, 2018) Concomitant Drug Dosing Recommendations and Clinical Effect on INSTI or Concomitant Drug INSTI Class/Name Comments Concentrations Antidepressants/Anxiolytics/Antipsychotics Also see Sedative/Hypnotics section below. ↔ expected No dose adjustment necessary. Aripiprazole BIC, DTG, RAL ↑ aripiprazole expected EVG/c Administer 25% of the usual aripiprazole dose. Titrate based on clinical monitoring for efficacy and toxicity. Refer to aripiprazole label for dosing recommendations in patients who are known to be CYP2D6 poor metabolizers or who have major depressive disorder. BIC, DTG, RAL Brexpiprazole No dose adjustment necessary. ↔ expected EVG/c Administer 25% of the usual brexpiprazole ↑ brexpiprazole expected dose. Titrate based on clinical monitoring for efficacy/toxicity. Refer to brexpiprazole label for dosing recommendations in patients who are known to be CYP2D6 poor metabolizers or who have major depressive disorder. BIC, DTG, RAL ↔ expected No dose adjustment necessary. Bupropion ↑ bupropion possible Titrate bupropion dose based on clinical EVG/c response. Buspirone BIC, DTG, RAL ↔ expected No dose adjustment necessary. EVG/c ↑ buspirone possible Initiate buspirone at a low dose. Dose reduction may be necessary. Cariprazine ↔ expected No dose adjustment necessary. BIC, DTG, RAL Starting Cariprazine in a Patient Already on EVG/c ↑ cariprazine expected EVG/c: Administer cariprazine 1.5 mg on Day 1 and • Day 3, with no dose given on Day 2. • From Day 4 onward, administer 1.5 mg daily . Can be increased to a maximum dose of 3 mg daily. If EVG/c is withdrawn, cariprazine dose may • need to be increased. Starting EVG/c in a Patient Already on Cariprazine: For patients receiving cariprazine 3 mg or 6 mg • daily , reduce cariprazine dose by half. For patients taking cariprazine 4.5 mg daily , the • dose should be reduced to 1.5 mg or 3 mg daily. • For patients taking cariprazine 1.5 mg daily , change to 1.5 mg every other day. • If EVG/c is withdrawn, cariprazine dose may need to be increased. L-40 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

280 Table 19d. Drug Interactions Between Integrase Strand Transfer Inhibitors and Other Drugs (Last (page 5 of 15) updated October 25, 2018; last reviewed October 25, 2018) Concomitant Drug Dosing Recommendations and Clinical Effect on INSTI or Concomitant Drug INSTI Class/Name Comments Concentrations Antidepressants/Anxiolytics/Antipsychotics , continued Also see Sedative/Hypnotics section below. Fluvoxamine BIC, DTG, RAL ↔ expected No dose adjustment necessary. EVG/c ↑ or ↓ EVG possible Consider alternative antidepressant or ARV. Lurasidone BIC, DTG, RAL ↔ expected No dose adjustment necessary. EVG/c ↑ lurasidone expected Contraindicated. BIC, DTG, RAL ↔ expected Standard doses. Pimavanserin ↑ pimavanserin expected EVG/c Reduce pimavanserin dose by 50%. Titrate dose based on efficacy and toxicity. Pimozide ↔ expected No dose adjustment necessary. BIC, DTG, RAL EVG/c ↑ pimozide expected Contraindicated. Quetiapine ↔ expected No dose adjustment necessary. BIC, DTG, RAL ↑ quetiapine AUC expected EVG/c Initiation of Quetiapine in a Patient Receiving EVG/c: Start quetiapine at the lowest dose and titrate • up as needed. Monitor for quetiapine efficacy and adverse effects. Initiation of EVG/c in a Patient Receiving a Stable Dose of Quetiapine: • Reduce quetiapine dose to 1/6 of the original dose, and closely monitor for quetiapine efficacy and adverse ef fects. SSRIs EVG/c ↔ EVG No dose adjustment necessary. Citalopram, ↔ sertraline escitalopram, ↑ other SSRI possible Initiate with lowest dose of SSRI and titrate fluoxetine, paroxetine, dose carefully based on antidepressant sertraline response. BIC, DTG, RAL BIC, DTG, RAL expected No dose adjustment necessary. ↔ ↔ SSRI expected TCAs No dose adjustment necessary. ↔ expected BIC, DTG, RAL Amitriptyline, EVG/c Desipramine AUC ↑ 65% Initiate with lowest dose of TCA and titrate dose desipramine, carefully. doxepin, imipramine, ↑ TCA expected Initiate with lowest dose of TCA and titrate dose nortriptyline carefully based on antidepressant response and/or drug levels. Trazodone BIC, DTG, RAL ↔ expected No dose adjustment necessary. EVG/c Initiate with lowest dose of trazodone and titrate ↑ trazodone possible dose carefully. Other EVG/c ↑ antipsychotic possible Initiate antipsychotic at a low dose. Decrease in Antipsychotics antipsychotic dose may be necessary. (CYP3A4 and/or CYP2D6 substrates) L-41 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

281 Table 19d. Drug Interactions Between Integrase Strand Transfer Inhibitors and Other Drugs (Last (page 6 of 15) updated October 25, 2018; last reviewed October 25, 2018) Concomitant Drug Dosing Recommendations and Clinical Effect on INSTI or Concomitant Drug INSTI Class/Name Concentrations Comments Antifungals Isavuconazole BIC No dose adjustment necessary. ↑ BIC possible EVG/c ↑ isavuconazole expected If coadministered, consider monitoring isavuconazole concentrations and assess ↑ EVG and COBI possible virologic response. Itraconazole BIC ↑ BIC expected No dose adjustment necessary. No dose adjustment necessary. ↔ expected DTG, RAL EVG/c Consider monitoring itraconazole level to guide ↑ itraconazole expected dosage adjustments. High itraconazole doses ↑ EVG and COBI possible (>200 mg/day) are not recommended unless dose is guided by itraconazole levels. Posaconazole BIC No dose adjustment necessary. ↑ BIC expected ↔ expected DTG, RAL No dose adjustment necessary. EVG/c ↑ EVG and COBI possible If coadministered, monitor posaconazole concentrations. ↑ posaconazole possible Voriconazole ↑ BIC possible No dose adjustment necessary. BIC DTG, RAL ↔ expected No dose adjustment necessary. ↑ voriconazole expected EVG/c Do not coadminister voriconazole and COBI unless benefit outweighs risk. ↑ EVG and COBI possible If coadministered, consider monitoring voriconazole concentrations and adjust dose accordingly. Antihyperglycemics Metformin BIC Metformin AUC ↑ 39% Monitor for metformin adverse effects. DTG DTG 50 mg Once Daily plus Metformin 500 Start metformin at lowest dose and titrate based mg BID: on glycemic control. Monitor for metformin adverse effects. ↑ 66% • Metformin AUC ↑ 79% and C max When starting/stopping DTG in patients on DTG 50 mg BID plus Metformin 500 mg BID: metformin, dose adjustment of metformin may AUC ↑ 2.4-fold and C Metformin ↑ 2-fold • max be necessary to maintain optimal glycemic control and/or minimize adverse effects of metformin. ↔ expected No dose adjustment necessary. RAL Saxagliptin BIC, DTG, RAL No dose adjustment necessary. ↔ expected EVG/c ↑ saxagliptin expected Limit saxagliptin dose to 2.5 mg once daily. Dapagliflozin/ BIC, DTG, RAL No dose adjustment necessary. ↔ expected Saxagliptin ↑ saxagliptin expected Do not coadminister , as this coformulated EVG/c drug contains 5 mg of saxagliptin. Antimycobacterials Clarithromycin BIC, DTG, RAL ↔ expected No dose adjustment necessary. EVG/c ↑ clarithromycin possible : CrCl 50−60 mL/min • Reduce clarithromycin dose by 50% ↑ COBI possible : CrCl <50 mL/min • EVG/c is not recommended. L-42 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

282 Table 19d. Drug Interactions Between Integrase Strand Transfer Inhibitors and Other Drugs (Last (page 7 of 15) updated October 25, 2018; last reviewed October 25, 2018) Concomitant Drug Effect on INSTI or Concomitant Drug Dosing Recommendations and Clinical INSTI Class/Name Comments Concentrations Antimycobacterials , continued Rifabutin Rifabutin (300 mg Once Daily): BIC Do not coadminister. ↓ 56% • BIC AUC ↓ 38% and C min DTG Rifabutin (300 mg Once Daily): No dose adjustment necessary. AUC ↔ and C • ↓ 30% DTG min EVG/c Rifabutin 150 mg Every Other Day with EVG/c Do not coadminister. Once Daily Compared to Rifabutin 300 mg Once Daily Alone: ↔ rifabutin AUC • 25-O-desacetyl-rifabutin AUC ↑ 625% • EVG AUC ↓ 21% and C • ↓ 67% min RAL ↓ 20% No dose adjustment necessary. RAL AUC ↑ 19% and C min Rifampin BIC Contraindicated. BIC AUC ↓ 75% DTG Rifampin with DTG 50 mg BID Compared to Dose: DTG 50 mg BID Alone: DTG 50 mg BID (instead of 50 mg once daily) • DTG for patients without suspected or documented AUC ↓ 54% and C • ↓ 72% min INSTI mutation. Rifampin with DTG 50 mg BID Compared to Alternative to rifampin should be used in DTG 50 mg Once Daily Alone: patients with certain suspected or documented DTG • ↑ 22% AUC ↑ 33% and C min INSTI-associated resistance substitutions. Consider using rifabutin. Significant ↓ EVG and COBI expected EVG/c Contraindicated. RAL RAL 400 mg: Dose: RAL RAL ↓ 61% • 800 mg BID, instead of 400 mg BID AUC ↓ 40% and C • min Do not coadminister RAL 1200 mg once Rifampin with RAL 800 mg BID Compared to daily with rifampin. RAL 400 mg BID Alone: ↓ 53% AUC ↑ 27% and C RAL • min Monitor closely for virologic response or consider using rifabutin as an alternative rifamycin. Rifapentine Do not coadminister. Significant ↓ BIC, DTG, EVG, and COBI BIC, DTG, EVG/c expected RAL Rifapentine 900 mg Once Weekly: For once-weekly rifapentine, use standard RAL 400 mg BID doses. RAL AUC ↑ 71% and C ↓ 12% • min Do not coadminister with once-daily Rifapentine 600 mg Once Daily: rifapentine. • ↓ 41% C RAL min L-43 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

283 Table 19d. Drug Interactions Between Integrase Strand Transfer Inhibitors and Other Drugs (Last (page 8 of 15) updated October 25, 2018; last reviewed October 25, 2018) Concomitant Drug Dosing Recommendations and Clinical Effect on INSTI or Concomitant Drug INSTI Class/Name Concentrations Comments Cardiac Medications Antiarrhythmics No dose adjustment necessary. ↔ expected for the listed antiarrhythmics, BIC, DTG except for disopyramide Amiodarone, Coadminister with caution. Clinical monitoring is bepridil, digoxin, recommended. ↑ disopyramide possible disopyramide, RAL ↔ expected for the listed antiarrhythmics No dose adjustment necessary. dronedarone, ↑ antiarrhythmics possible Use antiarrhythmics with caution. TDM, if EVG/c flecainide, systemic available, is recommended for antiarrhythmics. lidocaine, mexilitine, Digoxin C ↑ 41% and no significant max propafenone, change in AUC quinidine Bosentan Standard doses. BIC, DTG ↓ BIC, DTG possible No dose adjustment necessary. ↔ expected RAL ↑ bosentan possible EVG/c In Patients on EVG/c ≥10 Days : • Start bosentan at 62.5 mg once daily or every other day based on individual tolerability. In Patients on Bosentan Who Require EVG/c: Stop bosentan ≥36 hours before EVG/c • initiation. At least 10 days after initiation of EVG/c, resume bosentan at 62.5 mg once daily or every other day based on individual tolerability . Beta-blockers ↔ expected No dose adjustment necessary. BIC, DTG, RAL (e.g., metoprolol, EVG/c ↑ beta-blockers possible Beta-blocker dose may need to be decreased; timolol) adjust dose based on clinical response. Consider using beta-blockers that are not metabolized by CYP450 enzymes (e.g., atenolol, labetalol, nadolol, sotalol). CCBs BIC ↑ BIC possible with diltiazem No dose adjustment necessary. ↔ expected for all other CCBs ↔ expected No dose adjustment necessary. DTG, RAL ↑ CCBs possible EVG/c Coadminister with caution. Titrate CCB dose and monitor for CCB efficacy and toxicities. Table 19a for diltiazem plus ATV/r Refer to recommendations. Dofetilide BIC, DTG ↑ dofetilide expected Contraindicated. RAL ↔ expected No dose adjustment necessary. ↑ dofetilide possible EVG/c Do not coadminister. Eplerenone ↔ expected BIC, DTG, RAL No dose adjustment necessary. EVG/c ↑ eplerenone expected Contraindicated. Ranolazine BIC, DTG, RAL ↔ expected No dose adjustment necessary. EVG/c Contraindicated. ↑ ranolazine expected Ivabradine BIC, DTG, RAL ↔ expected No dose adjustment necessary. EVG/c ↑ ivabradine expected Contraindicated. L-44 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

284 Table 19d. Drug Interactions Between Integrase Strand Transfer Inhibitors and Other Drugs (Last (page 9 of 15) updated October 25, 2018; last reviewed October 25, 2018) Concomitant Drug Dosing Recommendations and Clinical Effect on INSTI or Concomitant Drug INSTI Class/Name Comments Concentrations Corticosteroids Beclomethasone BIC, DTG, ↔ expected No dose adjustment necessary. Inhaled or intranasal EVG/c, RAL Budesonide, No dose adjustment necessary. BIC, DTG, RAL ↔ expected Ciclesonide, EVG/c ↑ glucocorticoid possible Coadministration can result in adrenal Fluticasone, insufficiency and Cushing’s syndrome. Mometasone Do not coadminister unless potential Inhaled or intranasal benefits of inhaled or intranasal corticosteroid outweigh the risks of systemic corticosteroid adverse effects. Consider an alternative corticosteroid (e.g., beclomethasone). Betamethasone, BIC, DTG, RAL ↔ expected No dose adjustment necessary. Budesonide EVG/c ↑ glucocorticoids possible Coadministration can result in adrenal Systemic insufficiency and Cushing’s syndrome. Do not ↓ EVG possible coadminister unless potential benefits of systemic budesonide outweigh the risks of systemic corticosteroid adverse effects. Dexamethasone BIC Consider an alternative corticosteroid for ↓ BIC possible Systemic long-term use or an alternative ARV. If coadministration is necessary, monitor virologic response to ART. DTG, RAL ↔ expected No dose adjustment necessary. EVG/c ↓ EVG and COBI possible Consider an alternative corticosteroid for long- term use or alternative ART. If coadministration is necessary, monitor virologic response to ART. Prednisone, BIC, DTG, RAL ↔ expected No dose adjustment necessary. Prednisolone EVG/c ↑ prednisolone possible Coadministration may be considered if Systemic the potential benefits outweigh the risks of systemic corticosteroid adverse effects. If coadministered, monitor for adrenal insufficiency and Cushing’s syndrome. Betamethasone, No dose adjustment necessary. ↔ expected BIC, DTG, RAL Methylprednisolone, EVG/c Coadministration may Do not coadminister. ↑ glucocorticoids expected Prednisolone, result in adrenal insufficiency and Cushing’s Triamcinolone syndrome. Local injections, including intra- articular, epidural, or intra-orbital Hepatitis C Direct Acting Antivirals DTG ↔ daclatasvir No dose adjustment necessary. Daclatasvir EVG/c ↑ daclatasvir Decrease daclastavir dose to 30 mg once daily. BIC, RAL No data No dose adjustment necessary. Dasabuvir plus BIC, DTG No data No dose adjustment necessary. Ombitasvir/ No data EVG/c Do not coadminister. Paritaprevir/RTV RAL RAL AUC ↑ 134% No dose adjustment necessary. L-45 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

285 Table 19d. Drug Interactions Between Integrase Strand Transfer Inhibitors and Other Drugs (Last (page 10 of 15) updated October 25, 2018; last reviewed October 25, 2018) Concomitant Drug Dosing Recommendations and Clinical Effect on INSTI or Concomitant Drug INSTI Class/Name Comments Concentrations Hepatitis C Direct Acting Antivirals , continued Elbasvir/Grazoprevir No dose adjustment necessary. BIC ↔ BIC expected ↔ elbasvir No dose adjustment necessary. DTG ↔ grazoprevir ↔ DTG EVG/c ↑ elbasvir and ↑ grazoprevir expected Coadministration is not recommended. ↔ elbasvir No dose adjustment necessary. RAL ↔ grazoprevir ↔ RAL with elbasvir RAL AUC ↑ 43% with grazoprevir Glecaprevir/ ↔ BIC expected No dose adjustment necessary. BIC Pibrentasvir DTG, RAL No significant effect No dose adjustment necessary. Glecaprevir AUC ↑ 3-fold EVG/c No dose adjustment necessary. Pibrentasvir AUC ↑ 57% EVG AUC ↑ 47% Ledipasvir/ EVG/c/TDF/ ↑ TDF and ↑ ledipasvir expected Do not coadminister. Sofosbuvir FTC EVG/c/TAF/ No dose adjustment necessary. ↔ EVG/c/TAF/FTC expected FTC BIC, DTG, RAL ↔ DTG or RAL No dose adjustment necessary. Simeprevir No dose adjustment necessary. BIC, DTG, RAL ↔ expected ↑ simeprevir expected EVG/c Coadministration is not recommended. No dose adjustment necessary. ↔ expected Sofosbuvir All INSTIs All INSTIs ↔ expected No dose adjustment necessary. Sofosbuvir/ Velpatasvir EVG/c Sofosbuvir/ When Given with Sofosbuvir/Velpatasvir/ No dose adjustment necessary. Velpatasvir/ Voxilaprevir (400 mg/100 mg/100 mg) plus Voxilaprevir Voxilaprevir 100 mg: • Sofosbuvir AUC ↑ 22% ↔ velpatasvir • • V oxilaprevir AUC ↑ 2-fold ↔ expected No dose adjustment necessary. BIC, DTG, RAL Herbal Products St. John’s Wort BIC, DTG ↓ BIC and DTG possible Do not coadminister. EVG/c ↓ EVG and COBI possible Contraindicated. L-46 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Downloaded from https://aidsinfo.nih.gov/guidelines on 5/7/2019

286 Table 19d. Drug Interactions Between Integrase Strand Transfer Inhibitors and Other Drugs (Last updated October 25, 2018; last reviewed October 25, 2018) (page 11 of 15) Concomitant Drug Effect on INSTI or Concomitant Drug Dosing Recommendations and Clinical INSTI Class/Name Concentrations Comments Hormonal Therapies ↔ ethinyl estradiol, norgestimate, and DTG Hormonal BIC, DTG, RAL No dose adjustment necessary. Contraceptives or RAL Oral Norgestimate AUC, C , and C EVG/c ↑ >2-fold The effects of increases in progestin max min (norgestimate) are not fully known and can ↓ 44% Ethinyl estradiol AUC ↓ 25% and C min include insulin resistance, dyslipidemia, acne, and venous thrombosis. Weigh the risks and benefits of the drug and consider using an alternative contraceptive method. ↑ drospirenone possible Clinical monitoring is recommended, due to the potential for hyperkalemia. No drug-drug interaction studies have been All INSTIs Hormonal No data Contraceptives conducted with INSTIs and non-oral routes of hormone administration. It is unclear if oral Non-oral drug-drug interaction data can be extrapolated beyond oral routes of administration. Menopausal No dose adjustment necessary. BIC, DTG, RAL With Estradiol or Conjugated Estrogen (Equine Hormone and Synthetic): Replacement • ↔ estrogen expected Therapy ↔ drospirenone, medroxyprogesterone, or micronized progesterone expected EVG/c Adjust estrogen and progestin dose as needed expected ↓ estrogen based on clinical effects. ↑ drospirenone possible ↑ oral medroxyprogesterone possible ↑ oral micronized progesterone possible Gender-Affirming BIC, DTG, RAL ↔ estrogen expected No dose adjustment necess