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FACULTY Jürgen Rockstroh, MD Professor of Medicine Head of the HIV Outpatient Clinic University of Bonn Bonn, Germany Jürgen Rockstroh, MD, is Professor of Medicine and Head of the HIV Outpatient Clinic at the University of Bonn in Germany. He earned his Doctor of Medicine degree from the Rheinische Friedrich-Wilhelms University of Bonn and completed his residency in the Department of Medicine at the University of Bonn. His department treats the world’s largest cohort of HIV-infected patients with hemophilia. In addition to his clinical practice, Dr Rockstroh is involved in HIV research on antiretroviral therapy (ART), including new drug classes; the course of HIV disease in patients with hemophilia; and HIV and hepatitis co-infection. More recently, he has begun working on the impact of COVID-19 on HIV co-infection. He has been an investigator in multiple clinical trials of ART agents and treatments for HIV, hepatitis co-infection, and COVID-19. From 2007 to 2011 he served as president of the German AIDS Society. Since 2009, he has been a member of the executive committee of the European AIDS Clinical Society (EACS), and from 2011 to 2020 was a member of the governing council of the International AIDS Society. He was chair of the National German AIDS Advisory Panel from 2011 to 2017 and of the EACS coinfection guidelines committee from 2008 to 2017. In 2015,
Professor Rockstroh was elected chair of HIV in Europe (in 2019 renamed as EuroTEST), and in 2019-2020 was president of EACS. The German Society for Infectious Diseases awarded Dr Rockstroh and his co-authors the prize in clinical infectious diseases in 2002 and the national AIDS research prize in 2005. Dr Rockstroh has authored or co-authored more than 700 publications in peerreviewed journals and more than 100 book chapters.
David A. Wohl, MD Professor of Medicine Co-Principal Investigator, Global Infectious Disease Clinical Research Unit Co-Director, Viral Hemorrhagic Fever Clinical Research Group and UNC Project Liberia Institute for Global Health & Infectious Diseases The University of North Carolina at Chapel Hill School of Medicine Chapel Hill, North Carolina Dr Wohl is a Professor of Medicine in the Division of Infectious Diseases at the University of North Carolina (UNC). He is coPrincipal Investigator of the Global UNC Infectious Diseases Clinical Research Unit and Site Leader of its Chapel Hill research site. Dr Wohl is a clinical scientist with a focus on emergent infectious diseases. He has spent more than 20 years leading research into the prevention and treatment of HIV and served 2 terms as a member of the US Department of Health and Human Services Antiretroviral Guidelines Panel. Since 2014, he has been working continuously in Liberia, West Africa, conducting research with survivors of Ebola to learn about chronic complications and sexual transmission of this infection and establishing the UNC Project Liberia research platform at 2 locations in the country. He and his team have extended this work to examine Lassa fever, a viral hemorrhagic fever endemic in West Africa. In 2020, he contributed to the UNC clinical and research response to COVID-19. He is medical director of the UNC Chapel Hill drivethrough testing site, as well as 2 COVID-19 vaccination clinics and
the Chapel Hill COVID-19 monoclonal antibody infusion center. He serves as vice chair of ACTIV-2, an international trial of promising SARS-CoV-2 therapeutics. He has an active clinical practice at UNC and consults on inpatients with COVID-19.
PREAMBLE Target Audience The educational design of this activity addresses the needs of infectious disease and HIV-specialist physicians and other clinicians involved in the care of patients with HIV infection.
Statement of Need/Program Overview
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Though the prevalence of virologic failure (VF) in patients with HIV has decreased as newer antiretroviral (ART) regimens with higher genetic barriers to resistance and reduced toxicity have been approved, VF can still occur. VF may be due to patient, viral, or ART factors, and it is critical that clinicians determine the underlying cause before switching ART regimens so they can work with the patient to select the most appropriate regimen. Resistance will affect selection of subsequent regimens for patients experiencing VF, particularly among those with multidrug resistance (MDR). All patients experiencing VF should undergo resistance testing, and clinicians should engage in shared decision-making when selecting ART regimens, to ensure the patient can be adherent. Heavily treatment-experienced (HTE) patients with MDR have had few options speci cally designed to supplement an optimized background regimen, but these options have expanded over the last several years, and there is hope that this small subset of patients will have even more options in the future. In this eHealth activity, Drs David Wohl and Jürgen Rockstroh discuss evaluation of VF, selection of subsequent regimens for patients experiencing VF, and recently approved and emerging options for HTE patients,
including how to create and simplify salvage regimens for these patients.
Educational Objectives After completing this activity, the participant should be better able to: • Evaluate patient and genotypic causes of virologic failure • Tailor subsequent antiretroviral (ART) regimens according to resistance mutations, adherence, and other patient characteristics • Review mechanisms of action and clinical trial data for newer and emerging options for heavily treatment-experienced (HTE) patients • Incorporate newer therapies into ART regimens for HTE patients
Physician Accreditation Statement This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Global Education Group (Global) and Integritas Communications. Global is accredited by the ACCME to provide continuing medical education for physicians.
Physician Credit Designation Global Education Group designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should
claim only the credit commensurate with the extent of their participation in the activity.
Nurse Practitioner Continuing Education This activity has been planned and implemented in accordance with the Accreditation Standards of the American Association of Nurse Practitioners (AANP) through the joint providership of Global Education Group and Integritas Communications. Global Education Group is accredited by the American Association of Nurse Practitioners as an approved provider of nurse practitioner continuing education. Provider number: 110121. This activity is approved for 1.0 contact hour(s) (which includes 0.3 hour(s) of pharmacology).
Instructions to Receive Credit To receive credit for this activity, participants must complete the preactivity questionnaire, complete and receive a score of 75% on the posttest, and complete the program evaluation.
Global Contact Information For information about the accreditation of this program, please contact Global at 303-395-1782 or cme@globaleducationgroup.com.
Integritas Contact Information For all other questions regarding this monograph, please contact Integritas via email at info@exchangecme.com.
Fee Information & Refund/ Cancellation Policy There is no fee for this educational activity.
Disclosures of Con icts of Interest Global Education Group (Global) adheres to the policies and guidelines, including the Standards for Integrity and Independence in Accredited CE, set forth to providers by the Accreditation Council for Continuing Medical Education (ACCME) and all other professional organizations, as applicable, stating those activities where continuing education credits are awarded must be balanced, independent, objective, and scienti cally rigorous. All persons in a position to control the content of an accredited continuing education program provided by Global are required to disclose all nancial relationships with any ineligible company within the past 24 months to Global. All nancial relationships reported are identi ed as relevant and mitigated by Global in accordance with the Standards for Integrity and Independence in Accredited CE in advance of delivery of the activity to learners. The content of this activity was vetted by Global to assure objectivity and that the activity is free of commercial bias. All relevant nancial relationships have been mitigated.
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The faculty have the following relevant nancial relationships with ineligible companies:
Jürgen Rockstroh, MD Consulting Fee: Abivax, Boehringer Ingelheim, Galapagos, Gilead Sciences, Inc., Janssen, Merck, Theratechnologies, ViiV; Contracted Research: Gilead Sciences, Inc., Merck, ViiV; Honoraria: Gilead Sciences, Inc., Merck, Theratechnologies, ViiV David A. Wohl, MD Consulting Fee: Gilead Sciences, Inc., Janssen, Merck, ViiV; Contracted Research: Gilead Sciences, Inc., Merck, ViiV; Honoraria: Gilead Sciences, Inc., Janssen, Merck, ViiV The planners and managers have the following relevant nancial relationships with ineligible companies: Kristin Delisi, NP
Nothing to disclose
Lindsay Borvansky
Nothing to disclose
Andrea Funk
Nothing to disclose
Liddy Knight
Nothing to disclose
Ashley Cann
Nothing to disclose
Gena Dolson, MS
Nothing to disclose
Jim Kappler, PhD
Nothing to disclose
Disclosure of Unlabeled Use This educational activity may contain discussion of published and/ or investigational uses of agents that are not indicated by the FDA. Global Education Group (Global) and Integritas Communications do not recommend the use of any agent outside of the labeled indications.
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The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of any organization associated with this activity. Please refer to the
of cial prescribing information for each product for discussion of approved indications, contraindications, and warnings.
Disclaimer
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Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed in this activity should not be used by clinicians without evaluation of patient conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.
INTRODUCTION The main goal of antiretroviral therapy (ART) regimens to treat patients with HIV is viral suppression. Current ART regimens have led to substantial reductions in morbidity and mortality.1-5 When taken consistently as prescribed, ART can suppress viral load, maintain high CD4 cell counts, prevent transition to AIDS, prolong survival, and reduce risk of transmitting HIV to others.3,6 The introduction of ART regimens with higher ef cacy, higher barriers to resistance, and lower toxicity has resulted in a greater number of patients achieving undetectable levels of HIV RNA.
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However, virologic failure (VF)—de ned as the inability to maintain HIV RNA below a certain threshold—still occurs and can be attributed to several factors, such as drug resistance, suboptimal adherence, or poor drug absorption due to drug-drug or drug-food interactions.7 It is critical that clinicians identify the root cause of initial VF, as this determines next steps in treatment. For individuals with rst-time VF and no multidrug resistance (MDR), the solution may be related to optimizing adherence and tolerability. In heavily treatment-experienced (HTE) patients, subsequent regimen selection is particularly challenging, as these patients frequently have MDR and few remaining ART options.7 Fortunately, advances in therapeutic development have enabled great progress for the treatment of these patients, even those who have resistance to multiple classes of ART agents. This eHealth Source will discuss the evaluation of VF, optimized selection of subsequent treatment for individuals without MDR, novel therapies for HTE patients, and the management of HTE patients who harbor MDR.
References 1.
Lundgren JD, Babiker AG, Gordin F, et al; INSIGHT START Study Group. Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med. 2015;373(9):795-807.
2. TEMPRANO ANRS 12136 Study Group; Danel C, Moh R, et al. A trial of early antiretrovirals and isoniazid preventive therapy in Africa. N Engl J Med. 2015;373(9):808-822. 3. Cohen MS, Chen YQ, McCauley M, et al; HPTN 052 Study Team. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011;365(6):493-505. 4. Kitahata MM, Gange SJ, Abraham AG, et al; NA-ACCORD Investigators. Effect of early versus deferred antiretroviral therapy for HIV on survival. N Engl J Med. 2009;360(18):1815-1826. 5. Reynolds SJ, Makumbi F, Nakigozi G, et al. HIV-1 transmission among HIV-1 discordant couples before and after the introduction of antiretroviral therapy. AIDS. 2011;25(4):473-477. 6. García 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 De c Syndr. 2004;36(2):702-713.
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7. US Department of Health and Human Services. Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV. Accessed April 8, 2022. https:// clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/
CHAPTER 1: EVALUATION OF VIROLOGIC FAILURE Virologic Failure The goal of antiretroviral therapy (ART) is to suppress the plasma HIV RNA below the limits of assay detection.1 Suppressing the viral load prevents the emergence of drug-resistant virus, disease progression, and transmission of HIV to others.2 However, certain patients with HIV will experience virologic failure (VF) on their antiretroviral regimen.1 VF is the inability to achieve and maintain viral suppression below 200 copies/mL of HIV RNA (Figure 1.1).3 In contrast, intermittent blips of low-level viremia (above the limits of assay detection) are generally not associated with subsequent VF.1
Overall rates of VF have declined signi cantly over the last decade thanks to highly potent ART regimens with a high barrier to resistance and low toxicity.4 VF, however, does still exist and can result from a combination of patient, treatment, and viral factors. It is important to identify the cause before adjusting the patient’s ART regimen (Figure 1.2).1,4
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Suboptimal adherence to ART has been associated with VF, emergence of drug resistance, disease progression, morbidity, mortality, and increased healthcare costs. ART regimens have progressively become more convenient and better tolerated, reducing many of the challenges to adherence that led to VF in the past, including high pill burden and dosing frequency, food requirements, pill size, and the presence of treatment-limiting toxicities.1 However, other barriers to optimal adherence persist, such as medication costs, depression or other mental health conditions, substance use disorders, and housing instability or
other de cits in social determinants of health.4 VF can occur with any regimen when dosing is infrequent or when the patient stops the medication. Newer ART regimens recommended as rst line by guidelines panels include those that have a high barrier to resistance, which makes viral resistance to these medications unlikely.1,5 Clinicians should regularly discuss with patients factors that challenge adherence and help them identify preferences regarding their treatment and strategies to improve adherence, if suboptimal.4 Patient self-reporting of ART adherence is the most common method of assessment, though it is possible to include pharmacy records and pill counts to determine adherence as well.1 For most patients with evidence of VF on laboratory testing, however, these methods are not typically necessary. When seeking to determine the causes of VF, pharmacokinetic (PK) causes should be explored, especially in patients for whom suboptimal adherence seems less likely.1 Poor absorption can result from drug-drug interactions (DDIs; eg, tenofovir alafenamide [TAF] administered with carbamazepine or bictegravir [BIC] or dolutegravir [DTG] administered with antacids that contain polyvalent cations) or drug-food interactions (eg, rilpivirine [RPV] administered without a meal).1,5 VF can also result from underlying medical conditions that result in malabsorption (eg, vomiting, diarrhea).1 Therefore, it is important to consider other medical conditions and DDIs that may be causing a PK change.
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Individuals who develop VF may develop drug-resistant mutations to agents with a low genetic barrier to resistance (eg, nonnucleoside reverse transcriptase inhibitors; the rst-generation integrase strand transfer inhibitors [INSTIs] raltegravir and elvitegravir; and the nucleoside reverse transcriptase inhibitors
lamivudine [3TC] and emtricitabine [FTC]).1 On occasion, a patient can have drug-resistant virus detected despite excellent adherence and no DDI or absorption issues; such individuals may have acquired drug-resistant virus when rst infected and prior to treatment initiation (ie, transmitted resistance).4 Testing of all patients for drug resistance prior to treatment initiation is recommended to reduce this risk (though a regimen can be started prior to receiving results and switched later if needed). A higher HIV RNA level at diagnosis may also predispose a patient to developing VF on some ART regimens (eg, RPV + tenofovir/FTC).4 The spectrum of drug resistance in a patient can range from narrow resistance that affects the activity of 1 or 2 drugs (eg, the M184V mutation associated with resistance to 3TC or FTC) to multidrug resistance (MDR) that includes resistance to several drug classes.1,5-7 The risk of developing MDR is much lower than in the past, however, because of more-potent regimens with high barriers to resistance.4 These regimens include the pharmacologically boosted protease inhibitors (darunavir [DRV]/ cobicistat or DRV/ritonavir) or the newer INSTIs (BIC, DTG). Viral resistance is extremely rare in patients experiencing VF on these medications. Therefore, in some cases of VF with these regimens, restart or continued use can be considered once underlying challenges such as adherence, access, DDIs, and absorption are addressed.1,5
Genotype Resistance Testing
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The use of HIV susceptibility testing to guide therapy subsequent to VF leads to better viral suppression and has been associated with improved survival.8,9 As an example, in an observational study of 2699 HIV-infected patients who were eligible for susceptibility testing over a 6-year period, resistance testing was associated
with improved patient survival after controlling for demographics, CD4 cell count, HIV RNA level, and intensity of clinical follow-up.10 Per the US Department of Health and Human Services, HIV drug resistance testing should be conducted in the following ARTexperienced individuals1: • Patients with VF and HIV RNA level >1000 copies/mL and possibly if >500 copies/mL • Patients with suboptimal viral load reduction According to the European AIDS Clinical Society, genotype resistance testing may be performed if HIV RNA is >50 and <200 copies/mL, though VF is likely due to nonadherence; if HIV RNA is >200 copies/mL, the therapeutic decision will depend on resistance testing results.5 Testing to assess for drug resistance is best done while the patient is still on their failing regimen or within the rst 4 weeks after discontinuing treatment. Resistance testing is less accurate if performed while off therapy because levels of the resistant virus may drop in the absence of drug pressure and become harder to detect.1,5
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Genotypic testing is the preferred drug resistance assay for patients with VF while taking their rst or second regimen. These assays can detect mutations in the coding regions for HIV reverse transcriptase, integrase, and protease that have been associated with drug resistance. Genotypic testing is readily available and relatively inexpensive compared with phenotypic assays.8 However, standard genotype tests do not always evaluate for INSTI resistance; thus, if appropriate, it must be speci cally requested.1,8
HIV-1 Proviral DNA Assays Some genotypic resistance assays are designed to analyze HIV-1 proviral DNA located in host cells. These tests can detect drug resistance mutations in proviral HIV DNA archived in peripheral blood mononuclear cells or determine viral tropism.11 Proviral DNA resistance testing may be useful when switching a patient’s ART regimen when the HIV viral load is undetectable and no prior resistance results are available or if low-level viremia is present and a plasma HIV RNA genotypic assay is unlikely to be successful (ie, less than 1000 copies/mL). However, these assays are not as sensitive as the RNA genotype testing and may miss some or all prior resistance mutations that have occurred. As such, ndings from proviral DNA assays must be interpreted within the clinical context and have limited utility in the setting of VF (Video 1.1).1,11
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VIDEO 1.1: Applying HIV Proviral DNA Assays in Practice
Constructing a Cumulative Resistance Pro le Cumulative resistance test results refer to all previous and currently available results from standard genotype, proviral DNA genotype (if available), phenotype, and tropism assays. Once a mutation is detected in a resistance assay, clinicians should consider this mutation to be present moving forward, even if it doesn’t appear on subsequent resistance tests.1 Furthermore, some antiretrovirals may still have partial activity, and it is important to note how a speci c mutation affects drugs within each class and whether there is crossover resistance between classes. Interpretation of ndings is critical before selecting a new ART regimen.1
Key Take-Home Messages • VF is the inability to achieve and maintain viral suppression during treatment with ART. • VF typically results from poor adherence to ART or from DDIs or drug-food interactions that impair absorption, though some patients may have pre-existing (transmitted) drug-resistant virus. • Genotypic testing is best performed while an individual is on treatment. • If drug resistance is present, the goal of treatment for ARTexperienced patients is to establish virologic suppression, with subsequent therapeutic regimens consisting of agents with high potency and ef cacy.
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• The clinical utility of proviral DNA resistance testing has yet to be fully determined.
1.
US Department of Health and Human Services. Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV. Accessed April 8, 2022. https:// clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/
2.
Sunpath H, Hatlen TJ, Naidu KK, et al. Targeting the third '90': introducing the viral load champion. Public Health Action. 2018;8(4):225-231.
3.
Mamo A, Assefa T, Negash W, et al. Virological and immunological antiretroviral treatment failure and predictors among HIV positive adult and adolescent clients in southeast Ethiopia. HIV AIDS (Auckl). 2022;14:73-85.
4.
Cutrell J, Jodlowski T, Bedimo R. The management of treatment-experienced HIV patients (including virologic failure and switches). Ther Adv Infectious Dis. 2020;7:2049936120901395.
5.
European AIDS Clinical Society. EACS Guidelines 2021; v11.0; October 2021. Accessed April 22, 2022. https://www.eacsociety.org/media/ nal2021eacsguidelinesv11.0_oct2021.pdf
6.
Mouradjian MT, Heil EL, Sueng H, Pandit NS. Virologic suppression in patients with a documented M184V/I mutation based on the number of active agents in the antiretroviral regimen. SAGE Open Med. 2020;8:2050312120960570.
7.
Stanford University. HIV Drug Resistance Database. Accessed April 8, 2022. https:// hivdb.stanford.edu/
8.
Günthard HF, Calvez V, Paredes R, et al. Human immunode ciency virus drug resistance: 2018 recommendations of the International Antiviral Society-USA Panel. Clin Infect Dis. 2019;68(2):177-187.
9.
Kantor R, Smeaton L, Vardhanabhuti S, et al; AIDS Clinical Trials Group (ACTG) A5175 Study Team. Pretreatment HIV drug resistance and HIV-1 subtype C are independently associated with virologic failure: results from the multinational PEARLS (ACTG A5175) clinical trial. Clin Infect Dis. 2015;60(10):1541-1549.
10. Palella FJ, Jr., Armon C, Buchacz K, et al; HOPS (HIV Outpatient Study) Investigators. The association of HIV susceptibility testing with survival among HIV-infected patients receiving antiretroviral therapy: a cohort study. Ann Intern Med. 2009;151(2):73-84. 11.
New York State Department of Health AIDS Institute. HIV Resistance Assays. June 2016. Accessed April 11, 2022. https://cdn.hivguidelines.org/wp-content/uploads/ 20200506090926/NYSDOH-AI-HIV-ResistanceAssays_updated_5-5-2020_mbh.pdf
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References
CHAPTER 2: OPTIMIZED SELECTION OF SUBSEQUENT TREATMENT IN PATIENTS WITHOUT MULTIDRUG RESISTANCE Switching ART Regimens vs Optimizing Adherence and Pharmacokinetic Factors
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If virologic failure (VF) in individuals with HIV is con rmed, the clinician must rst evaluate whether the patient is taking their medication correctly. If suboptimal adherence is suspected, barriers to adherence must be assessed and clinicians should determine whether they can be managed.1 For some patients, adherence can be improved with the use of interventions such as pill packs, alarms, or enhanced family or caregiver support.1 However, some individuals have behavioral barriers to adherence (eg, depression, substance use, neurocognitive impairment, low self-esteem, stressful life events, nancial issues, denial, or stigma) that may require more-intensive interventions.1 Once-daily regimens, especially those that are well-tolerated and have low pill burden, are associated with higher rates of adherence and are more convenient for patients (Figure 2.1).2 Furthermore, patients with HIV, especially those who have antiretroviral therapy (ART)
adherence issues, should be placed on regimens with high genetic barriers to resistance (eg, dolutegravir [DTG], bictegravir [BIC], or boosted darunavir [DRV] regimens), when possible.1 In addition to pharmacologic modi cations, settings that incorporate multidisciplinary care (eg, pharmacists, social workers, case managers, psychologists, or substance use disorder providers) may also substantially improve patient adherence to ART.1 Substance use disorder treatment programs are most often not only best suited to addressing substance use disorder but also may offer services that promote adherence, such as directly observed therapy.1
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Before considering whether to switch ART regimens, one must also assess whether VF is due to pharmacokinetic (PK) factors (eg, drug-drug interactions [DDIs] or drug-food interactions) that may impair drug absorption or alter metabolism. These factors should be modi ed when possible.1 For example, the PK-boosting agents ritonavir and cobicistat have the potential for DDIs because they,
like so many drugs, inhibit cytochrome P450–mediated drug metabolism.1,4 Further, administration of proton pump inhibitors with concomitant oral rilpivirine, timing of rilpivirine with H2 receptor agonist dosing, and integrase strand transfer inhibitor (INSTI) dosing with antacids or supplements containing polyvalent cations are also important to consider.1 Clinicians must keep patients’ concomitant medications and comorbid conditions that may be worsened by certain ART regimens top of mind when altering or switching therapies.4,5 Shared decision-making is an important part of determining whether a patient should be switched to another regimen or remain on their current regimen and be counseled on adherence (Video 2.1). This will involve discussing the principles of regimen simpli cation and identifying the causes of VF, as previously discussed.
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VIDEO 2.1: Adherence Counseling vs Switching ART Regimens: How Do You Decide?
Matching Resistance Mutations and the Patient’s ART History When Switching Regimens The use of resistance testing has become an integral part of HIV clinical care. The rst clinical description of HIV resistance to an antiretroviral (ARV) agent was published in 1989, when patients taking zidovudine monotherapy accumulated mutations in the reverse transcriptase gene, resulting in a notable increase in drug resistance.6 Since then, HIV variants resistant to every available ARV agent have been identi ed.7 The evolution of drug resistance has signi cant clinical implications for choosing effective ART regimens.1 Although newer regimens have higher barriers to the development of drug resistance, infection with drug-resistant virus is not uncommon, underscoring the recommendation for genotypic resistance testing as part of the initial evaluation of patients with HIV infection (Video 2.2).
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VIDEO 2.2: What Is Transmitted Resistance?
Genotypic resistance assays detect the presence of speci c drug resistance mutations for all ART classes.1 Results are reported as the individual mutations (eg, M184V for lamivudine [3TC] and emtricitabine [FTC] resistance), with comments such as “susceptible,” “possibly resistant,” or “resistant” for each ARV agent.8 Complex mutational patterns can be dif cult to interpret. Fortunately, there are available resources containing comprehensive summaries of HIV-1 drug resistance mutations that are helpful for clinicians. One of them is the Stanford University HIV Drug Resistance Database, which provides useful guidance for interpreting genotypic resistance test results. The Drug Resistance Summary section of this database contains diagrammatic summaries of mutations by drug class and provides interpretation of speci c genotypes that are input by the user (Table 2.1).9
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When choosing a new HIV regimen, it is important to evaluate the patient’s ART history, as well as the results of previous and current genotype drug resistance tests to determine which agents are likely to be fully or partially active (Table 2.2 and Figure 2.2).1 The goal with all new regimens is to achieve and maintain viral suppression. The expected potency of the new therapies is crucial for predicting virologic ef cacy.1 To prevent VF with the new ART regimen, the US Department of Health and Human Services (DHHS) Antiretroviral Guidelines Panel stipulates that the regimen include 2 fully active ART drugs if at least 1 has a high resistance barrier. The
European AIDS Clinical Society (EACS) recommends the use of at least 2, but preferably 3, active drugs.10 If 1 of these newly selected agents is fully active, they can be combined with 2 nucleoside reverse transcriptase inhibitors (NRTIs) provided at least 1 of those is also fully active.1 Alternatively, if both a second-generation INSTI and boosted protease inhibitor (PI) are predicted to be fully active, they can be utilized in combination and be highly effective in individuals with VF (without the use of an NRTI). The DHHS states that if no fully active agent with a high resistance barrier is available, the clinician should prescribe 3 fully active agents.1
EACS guidelines state that if the patient has only limited NRTI mutations, the new regimen can include 2 NRTIs (3TC or FTC plus another NRTI) and 1 active boosted PI or BIC or DTG.10 In 2 randomized studies, which together evaluated more than 1000 patients, individuals failing an initial regimen that included an NRTI backbone plus a non-nucleoside reverse transcriptase inhibitor (NNRTI) were switched to a new regimen consisting of boosted lopinavir plus either 2 or 3 NRTIs.12-14 Approximately 80% of these patients were able to achieve a viral load <400 copies/mL, regardless of which regimen they received, and in 1 study, approximately 75% had a viral load <50 copies/mL.13 Virologic suppression was achieved among individuals receiving the NRTI regimen even when no fully active NRTIs were included in the regimen.12,13,15
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The DAWNING study in patients failing an initial NNRTI plus 2 NRTIs found that DTG had superior ef cacy to boosted lopinavir when used in combination with 2 NRTIs, at least 1 of which was fully active. Patients did not have evidence of resistance to PIs or
INSTIs. At 24 weeks, signi cantly more patients who received DTG had virologic suppression (82% vs 69%). Furthermore, those who received DTG were less likely to have VF (6 patients vs 18 patients), which was de ned as a viral load >400 copies/mL on 2 occasions.16 BIC is available only as a combination pill and has a high barrier to resistance. Although EACS has named it as a possible subsequent regimen for patients experiencing VF with their rst regimen, the DHHS has not yet (as of June 2022) gone to the same lengths.1,10 There is, however, evidence for its utility in patients experiencing VF. For example, a real-world cohort study found that patients who were not virally suppressed and experienced VF while taking PIs or NNRTIs were able to achieve and maintain virologic suppression after switching to BIC/tenofovir alafenamide (TAF)/FTC.17 Similarly, another real-world cohort found that BIC/TAF/FTC showed high rates of virologic suppression, including in patients with 3TC/FTC resistance mutations.18
Key Take-Home Messages • Patients with VF should rst be assessed for adherence, DDIs, absorption issues, or drug-food interactions prior to switching regimens. • When selecting a new regimen, it is essential to assess the patient’s ART history, as well as the ndings of previous and current genotype drug resistance tests, to determine which agents are likely to be fully or partially active.
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• National guidelines contain recommendations to aid in selecting subsequent regimens for patients experiencing VF with drugresistant virus.
1.
US Department of Health and Human Services. Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV. Accessed April 8, 2022. https:// clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/
2. Nachega JB, Parienti J-J, 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. 2014;58(9):1297-1307. 3. US Department of Health and Human Services. HIV/AIDS glossary. Accessed April 11, 2022. https://clinicalinfo.hiv.gov/en/glossary 4. Saag MS, Gandhi RT, Hoy JF, et al. Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2020 recommendations of the International Antiviral Society– USA panel. JAMA. 2020;324(16):1651-1669. 5. Arribas JR, Thompson M, Sax PE, et al. Brief Report: Randomized, double-blind comparison of tenofovir alafenamide (TAF) vs tenofovir disoproxil fumarate (TDF), each coformulated with elvitegravir, cobicistat, and emtricitabine (E/C/F) for initial HIV-1 treatment: week 144 results. J Acquir Immune De c Syndr. 2017;75(2):211-218. 6. Larder BA, Darby G, Richman DD. HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science. 1989;243(4899):1731-1734. 7. World Health Organization. HIV drug resistance. Accessed April 11, 2022. https:// www.who.int/news-room/fact-sheets/detail/hiv-drug-resistance 8. Hirsch MS, Günthard HF, Schapiro JM, et al. Antiretroviral drug resistance testing in adult HIV-1 infection: 2008 recommendations of an International AIDS Society-USA panel. Clin Infect Dis. 2008;47(2):266-285. 9. Stanford University Health Plans. HIV Drug Resistance Database. Accessed April 8, 2022. https://hivdb.stanford.edu/ 10. European AIDS Clinical Society. EACS Guidelines 2021; v11.0; October 2021. Accessed April 22, 2022. https://www.eacsociety.org/media/ nal2021eacsguidelinesv11.0_oct2021.pdf 11. Cutrell J, Jodlowski T, Bedimo R. The management of treatment-experienced HIV patients (including virologic failure and switches). Ther Adv Infectious Dis. 2020;7:2049936120901395. 12. Boyd MA, Kumarasamy N, Moore CL, et al; SECOND-LINE Study Group. Ritonavirboosted lopinavir plus nucleoside or nucleotide reverse transcriptase inhibitors versus ritonavir-boosted lopinavir plus raltegravir for treatment of HIV-1 infection in adults with virological failure of a standard rst-line ART regimen (SECOND-LINE): a randomised, open-label, non-inferiority study. Lancet. 2013;381(9883):2091-2099.
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13. Paton NI, Kityo C, Hoppe A, et al; EARNEST Trial Team. Assessment of second-line antiretroviral regimens for HIV therapy in Africa. N Engl J Med. 2014;371(3):234-247.
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References
14. La Rosa AM, Harrison LJ, Taiwo B, et al; ACTG A5273 Study Group. Raltegravir in second-line antiretroviral therapy in resource-limited settings (SELECT): a randomised, phase 3, non-inferiority study. Lancet HIV. 2016;3(6):e247-258. 15. Paton NI, Kityo C, Thompson J, et al; Europe Africa Research Network for Evaluation of Second-line Therapy (EARNEST) Trial Team. Nucleoside reverse-transcriptase inhibitor cross-resistance and outcomes from second-line antiretroviral therapy in the public health approach: an observational analysis within the randomised, open-label, EARNEST trial. Lancet HIV. 2017;4(8):e341-e348. 16. Aboud M, Kaplan R, Lombaard J, et al. Dolutegravir versus ritonavir-boosted lopinavir both with dual nucleoside reverse transcriptase inhibitor therapy in adults with HIV-1 infection in whom rst-line therapy has failed (DAWNING): an open-label, noninferiority, phase 3b trial. Lancet Infect Dis. 2019;19(3):253-264. 17. Chang H-M, Chou P-Y, Chou C-H, Tsai H-C. Outcomes after switching to BIC/FTC/TAF in patients with virological failure to protease inhibitors or non-nucleoside reverse transcriptase inhibitors: a real-world cohort study. Infect Drug Resist. 2021;14:4877-4886.
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18. Ambrosioni J, Rojas Liévano J, Berrocal L, et al. Real-life experience with bictegravir/ emtricitabine/tenofovir alafenamide in a large reference clinical centre. J Antimicrob Chemother. 2022;77(4):1133-1139.
CHAPTER 3: NOVEL MECHANISMS OF ACTION PROVIDING NEW OPTIONS FOR HEAVILY TREATMENTEXPERIENCED PATIENTS: CLINICAL TRIAL DATA Scienti c Response to Clinical Needs
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Currently, antiretroviral therapy (ART) regimens are much less likely to result in highly resistant HIV compared with older regimens that were less potent (Figure 3.1).1 A recent study found that patients with HIV who entered care between 2009 and 2011 had an 80% lower risk of limited treatment options compared with those entering care between 2006 and 2008. Furthermore, a signi cant increase was noted in undetectable HIV viral load among individuals ever classi ed as having limited treatment options (<30% in 2001 to >80% in 2011).1 Similarly, a study in Switzerland found that the prevalence of 3-class resistance decreased from 9% in 1999 to 4.4% in 2013 and remained below 0.4% among patients who initiated ART after 2006.2 Despite advances in development of ART regimens over the years, a very small subset
of patients (<1%) still experiences virologic failure (VF), with development of multidrug resistance (MDR) (Video 3.1).
VIDEO 3.1: Treatment Options for Patients With MDR
Historic ART Options for HTE Patients
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Until a few years ago, only a few ART regimens were speci cally developed for heavily treatment-experienced (HTE) people with
MDR. Data demonstrate that, historically, patients with limited treatment options struggled to become virally suppressed, though recently these patients have become able to achieve roughly the same levels of viral suppression as patients with VF who still have remaining treatment options.1 Treatment options typically consisted of a complex regimen, with high pill burden, created from any and all remaining options, including older antiretrovirals (ARVs) that were rarely used; this occasionally included enfuvirtide, which needs to be injected twice daily and is associated with signi cant injection site reactions.3
Novel ART Mechanisms of Action, Evidence to Date, and Potential Indications for Use Long-Acting ART New strategies are now available to meet the challenge of HTE patients, with ARVs offering, in some cases, novel mechanisms of action.4
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In March 2018, the US Food and Drug Administration (FDA) approved ibalizumab (IBA) for the treatment of HIV-1 infection in combination with other ARVs in HTE adults with MDR who are failing their current ART regimen.5 It was subsequently approved by the European Medicines Agency (EMA) in 2019. This agent is a recombinant humanized monoclonal antibody (mAb) that blocks HIV-1 from infecting CD4+ T cells by binding to domain 2 of CD4+ cell receptors, leading to a conformational change that blocks the interaction of gp120 and HIV co-receptors. IBA is administered intravenously as a 2-g single dose, followed by a maintenance dose of 800 mg every 14 days thereafter.5
The approval was based on the phase 3 TMB-301 study, which included 40 HTE study participants with MDR HIV.6 All study participants had an HIV-1 RNA viral load of more than 1000 copies/ mL for 8 weeks before screening. Individuals were required to have received ART for at least 6 months before screening, with documented genotypic or phenotypic resistance to at least 1 drug in at least 3 classes. Moreover, patients continued their previous regimen before the initiation of an optimized background regimen that included at least 1 fully active agent.6 After 24 weeks of treatment with IBA, the mean reduction in viral load was 1.6 log10 HIV RNA copies/mL, and 55% had a reduction of more than 1.0 log10.6 Data showed that 43% of patients were virally suppressed (<50 copies/mL) at week 25, which increased to 59% at week 48 (Figure 3.2). Encouragingly, the study achieved its primary endpoint, with 83% of IBA-treated individuals showing at least a 0.5-log10 decrease in HIV-1 RNA copy number by day 14 (P<0.001). The most common adverse events (AEs) associated with the drug were diarrhea, dizziness, rash, and nausea.6
In April 2022, the manufacturer announced that commercialization of IBA will cease in certain European countries beginning late October 2022 due to failed price negotiations. The manufacturer is
searching for another commercial partner to ensure that IBA will be available to patients who are currently receiving it or are eligible in the future.7 Another long-acting agent, lenacapavir (LEN), has also shown promise as a treatment option for HIV; this therapeutic is given subcutaneously (SQ) every 6 months. LEN is a rst-in-class capsid inhibitor that disrupts the HIV capsid during multiple stages of the viral life cycle, preventing HIV from multiplying.8
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CAPELLA was a double-blind placebo-controlled phase 2/3 study that consisted of 36 HTE patients with HIV who were failing their current regimen and who had documented resistance to 2 or more agents from 3 or more of the major ARV classes. In the trial, 24 participants were randomly assigned to oral LEN plus their failing regimen for 2 weeks, whereas placebo was added for the other 12 participants.9,10 The primary endpoint was the percentage of individuals achieving a decline of at least 0.5 log10 copies/mL by day 15 of the study. Another 36 patients who showed a decline in viral load of ≥0.5 log10 copies/mL or a viral load of <400 copies/mL during the screening period were assigned to oral LEN plus an optimized background regimen for 2 weeks (nonrandomized cohort).9,10 At baseline, the median viral load across all patients was 4.5 log10 copies/mL. In the randomized LEN treatment arm, 88% (21 of 24) of patients met the primary endpoint compared with 17% (2 of 12) of patients in the placebo arm. The mean change in viral load was signi cantly greater in the treatment arm (1.93 log10 copies/mL) compared with the placebo arm (−0.29 log10 copies/mL; P<0.0001).10 On day 15, patients in the treatment arm and those in the nonrandomized cohort received an injection of LEN SQ and patients in the placebo arm began a 2-week oral leadin with LEN, followed by an injection together with an optimized background regimen. Treatment with LEN SQ led to high rates of
virologic suppression at week 26 in the randomized and nonrandomized cohorts (Figure 3.3). The most common AEs reported with LEN (7%-8%) included diarrhea, nausea, cough, headache, pyrexia, and urinary tract infection, none of which led to discontinuation of the study drug.9
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More recently presented ndings from the CAPELLA trial showed that 83% of the patients from the randomized cohort receiving LEN SQ in combination with an optimized background regimen had an undetectable viral load (<50 copies/mL) at week 52.11 Subgroup analyses also investigated the effect on viral suppression of baseline CD4 count and HIV RNA and the number of active ARVs in the optimized background regimen (Figure 3.4).12 LEN resistance occurred in 4 patients through week 26, but none thereafter.11 All 4 individuals had either no fully active drugs in the optimized background regimen or harbored inadequate adherence to the optimized background regimen.
A new drug application was submitted to the FDA and EMA in 2021 for HTE patients with MDR, and in April 2022 the FDA issued a complete response letter regarding manufacturing concerns; the manufacturing company plans to provide the FDA with a comprehensive plan and compelling data for use of a different vial type.13 In May 2022, the FDA released the hold it had placed on clinical trials of LEN. LEN is still under review with the EMA (as of May 2022).
Short-Acting ART In July 2020, the FDA approved fostemsavir (FTR) for the treatment of HIV-1 infection, in combination with other ARVs, in HTE adults with MDR HIV-1 infection failing their current ART regimen.14 It
was approved by the EMA in February 2021. FTR is hydrolyzed to the active moiety, temsavir, which is a gp120 attachment inhibitor.14 Temsavir binds to the HIV-1 envelope protein gp120 subunit and selectively inhibits the interaction between the virus and cellular CD4 receptors, preventing host cell attachment.14 In addition, temsavir can inhibit gp120-dependent post-attachment steps required for viral entry into host cells. This agent is administered orally as a 600-mg dose, twice daily, in combination with other ARVs.14
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The approval was supported by ef cacy and safety ndings in the BRIGHTE trial involving 371 HTE adults with continued high viral load (≥400 copies/mL).15 The randomized cohort included 272 patients who each had at least 1 but no more than 2 fully active ARV agents to include as part of an optimized background regimen with FTR.15 More than 80% had been exposed to ≥5 different HIV treatment regimens prior to the trial and 86% had a history of AIDS.15 In the randomized trial arm, all patients received open-label FTR after the initial 8 days of treatment with FTR 600 mg or placebo twice daily plus the failing background regimen. More than half of the randomized intent-to-treat exposed population achieved an HIV viral load <40 copies/mL at 48 weeks and the ef cacy of FTR was maintained through week 96 (Figure 3.5).15,16 In a separate nonrandomized cohort of 99 patients who had no fully active drugs available at baseline and were treated with FTR 600 mg twice daily plus an optimized ART regimen, 38% had an HIV viral load <40 copies/mL at 48 weeks.15 AEs led to the discontinuation of FTR in 7% of patients.15
Islatravir is an investigational rst-in-class nucleoside reverse transcriptase translocation inhibitor. This agent inhibits reverse transcriptase by multiple mechanisms, including reverse transcriptase translocation inhibition and delayed chain termination, through viral DNA structural changes.17 Studies of islatravir plus doravirine as HIV treatment in HTE patients have been placed on hold by the FDA (current as of May 2022) because of reports of decreases in total lymphocyte and CD4 counts in some patients receiving this therapy.18
Key Take-Home Messages • Due to the increased potency of ART regimens, VF with resistance is signi cantly less prevalent now compared with the early 2000s. • New and emerging long-acting ART regimens include the mAb IBA (which has been approved by the FDA and EMA), and the capsid inhibitor LEN (currently resolving manufacturing concerns regarding the vials used to administer the agent).
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• FTR is a short-acting ART regimen for use in HTE patients.
References 1.
Bajema KL, Nance RM, Delaney JAC, et al; Centers for AIDS Research Clinical Network of Integrated Systems (CNICS). Substantial decline in heavily treated therapyexperienced persons with HIV with limited antiretroviral treatment options. AIDS. 2020;34(14):2051-2059.
2. Scherrer AU, von Wyl V, Yang W-L, et al. Emergence of acquired HIV-1 drug resistance almost stopped in Switzerland: a 15-year prospective cohort analysis. Clin Infect Dis. 2016;62(10):1310-1317. 3. US Department of Health and Human Services. Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV. Accessed April 8, 2022. https:// clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/ 4. Cambou MC, Landovitz RJ. Novel antiretroviral agents. Curr HIV/AIDS Rep. 2020;17(2):118-124. 5. Trogarzo. Prescribing information. Thera Technologies; 2021. Accessed April 11, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761065s011lbl.pdf 6. Emu B, Fessel J, Schrader S, et al. Phase 3 study of ibalizumab for multidrug-resistant HIV-1. N Engl J Med. 2018;379(7):645-654. 7. TaiMed receives from Theratechnologies noti cation of returning commercialization rights for Trogarzo in European territory. News release. TaiMed Biologics. April 27, 2022. Accessed May 4, 2022. http://www.taimedbiologics.com/news/info/104 8. Dvory-Sobol H, Shaik N, Callebaut C, Rhee MS. Lenacapavir: a rst-in-class HIV-1 capsid inhibitor. Curr Opin HIV AIDS. 2022;17(1):15-21. 9. Molina J, Segal-Maurer S, Stellbrink HJ, et al. Ef cacy and safety of long-acting subcutaneous lenacapavir in phase 2/3 in heavily treatment-experienced people with HIV: week 26 results (CAPELLA study). Presented at: International AIDS Society; July 18-21, 2021; virtual conference. 10. Segal-Maurer S, Castagna A, Berhe M, et al. Potent antiviral activity of lenacapavir in phase 2/3 in heavily ART-experienced PWH. Presented at: Conference on Retroviruses and Opportunistic Infections; March 6, 11, 2021; virtual conference. 11. Ogbuagu O, Segal-Maurer S, Brinson C, et al. Long-acting lenacapavir in people with multidrug resistant HIV-1: week 52 results. Presented at: Conference on Retroviruses and Opportunistic Infections; February 12-16, 2022; virtual conference. 12. Stellbrink HJ, deJesus E, Segal-Maurer S, et al. Subgroup ef cacy analyses of longacting subcutaneous lenacapavir in phase 2/3 in heavily treatment-experienced people with HIV (CAPELLA study). Presented at: European AIDS Clinical Society; October 27-30, 2021; London, United Kingdom.
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13. Gilead receives complete response letter from U.S. FDA for investigational lenacapavir due to vial compatibility issues. News release. Business Wire. March 1, 2022. Accessed April 11, 2022. https://www.gilead.com/news-and-press/press-room/press-
releases/2022/3/gilead-receives-complete-response-letter-from-us-fda-forinvestigational-lenacapavir-due-to-vial-compatibility-issues 14. Rukobia. Prescribing information. Viiv; 2020. Accessed April 11, 2022. https:// www.accessdata.fda.gov/drugsatfda_docs/label/2020/212950s000lbl.pdf 15. Kozal M, Aberg J, Pialoux G, et al; BRIGHTE Trial Team. Fostemsavir in adults with multidrug-resistant HIV-1 infection. N Engl J Med. 2020;382(13):1232-1243. 16. Lataillade M, Lalezari JP, Kozal M, et al. Safety and ef cacy of the HIV-1 attachment inhibitor prodrug fostemsavir in heavily treatment-experienced individuals: week 96 results of the phase 3 BRIGHTE study. Lancet HIV. 2020;7(11):e740-e751. 17. Bleasby K, Houle R, Hafey M, et al. Islatravir is not expected to be a victim or perpetrator of drug-drug interactions via major drug-metabolizing enzymes or transporters. Viruses. 2021;13(8):1566.
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18. Merck announces clinical holds on studies evaluating islatravir for the treatment and prevention of HIV-1 infection. News release. Business Wire. December 13, 2021. Accessed April 11, 2022. https://www.merck.com/news/merck-announces-clinicalholds-on-studies-evaluating-islatravir-for-the-treatment-and-prevention-of-hiv-1infection/
CHAPTER 4: MANAGING HTE PATIENTS WITH MULTIDRUG RESISTANCE Identifying and Evaluating Viable ART Options for HTE Patients With HIV The presence of resistant virus is determined through the results of genotypic resistance tests and antiretroviral therapy (ART) treatment history. The selection of HIV therapy in the context of multidrug resistance (MDR) can be challenging and should generally be undertaken in consultation with an HIV specialist.1 Table 4.1 lists the recommended ART options by the US Department of Health and Human Services and European AIDS Clinical Society.
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When identifying subsequent regimens for heavily treatmentexperienced (HTE) patients who have virologic failure (VF), it is important to note that adding a single antiretroviral (ARV) drug is not recommended; it is unlikely the patient will become virally suppressed and may instead develop resistance to all drugs in the regimen.1,2 Salvage regimens for HTE patients may include partially active drugs, such as nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors, and second-generation integrase strand transfer inhibitors (INSTIs). Use of salvage regimens may result in the need for increased dosing of ART with high barrier to resistance.1 Fostemsavir (FTR) and ibalizumab (IBA) should be considered when patients develop resistance to at least 3 classes of ARVs.1,2 Lenacapavir (LEN), a rst-in-class capsid inhibitor, has
shown promise in clinical trials, but the US Food and Drug Administration (FDA) recently issued a complete response letter regarding manufacturing issues, as discussed in Chapter 3, though the clinical trial hold has been lifted.3-5
Providing Simpli cation Options for Patients Suppressed on Complex Salvage Regimens
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The primary objective of simplifying regimens is to maintain viral suppression.1 Achieving viral suppression in HTE patients is quite challenging, and the decision to alter a regimen is not done lightly. Simplifying treatment in these patients can be dif cult because of limited treatment options and differences in resistance mutations for each patient. Simpli cation and switching may be desired by the patient and clinician for many reasons: adverse events (AEs), pill burden, new or worsening medical comorbidities, drug-drug interactions (DDIs), or drug-food interactions (Video 4.1).1,2,6 For example, NRTIs frequently have little activity in HTE patients and can increase AEs, DDIs, and cost, making their removal from a regimen a desirable outcome. The VERITAS trial was conducted in HTE patients with MDR who were virally suppressed on a regimen of at least 4 ARVs (including 1 inactive NRTI). Patients who had the inactive NRTI removed at baseline were able to maintain viral suppression for 48 weeks.7 On the other hand, keeping lamivudine (3TC) or emtricitabine (FTC) to maintain selective pressure and the signature M184V mutation can be useful, as M184V-containing viruses are impaired in replication tness.8,9
VIDEO 4.1: Simplifying Salvage Regimens: Patient Case Discussion Though challenging, there is hope for reducing pill burden in HTE patients. Multiple studies have shown that when HTE patients, both those who were and were not virally suppressed, were switched to a combination of dolutegravir (DTG) and boosted darunavir (DRV), they were able to maintain viral suppression.10-12 Likewise, a trial of elvitegravir/cobicistat/tenofovir alafenamide/FTC plus DRV has been shown to be superior to continuation on current salvage regimen. This trial was conducted in patients who had resistance to at least 2 ART classes but no INSTI resistance and no history of Q151M or T69 insertion.13 Particularly in an aging HIV patient population, the need arises to create (if possible) a new regimen for HTE patients that does not include a booster such as ritonavir or cobicistat because of numerous DDIs in this patient population, which tends to have increasing comorbidities and polypharmacy. In patients with no integrase resistance, the combination of a second-generation INSTI (ie, DTG) together with a second-generation non-nucleoside reverse transcriptase inhibitor (eg, etravirine or doravirine) that usually is fully active even in the
presence of K103N (the signature mutation for efavirenz failure), with or without 3TC, represents a highly effective treatment option.14,15 If simpli cation or switching is considered in individuals with suppressed viral loads who are on salvage regimens, it is critical to account for the patient’s resistance and ART history. If the patient has multiple prior ARV failures or a history of multiple prior ART regimens, the use of proviral DNA genotypic testing may be useful in addition to genotypic RNA testing. Proviral DNA testing may not detect all of a patient’s drug-resistance mutations or may identify mutations that appear to be inconsistent with a patient’s response to treatment; thus, the ndings must be interpreted with caution.1
Expanding Shared Decision-Making
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An essential strategy of improving care, adherence, and viral suppression in patients with HIV involves the implementation of shared decision-making. Shared decision-making is an approach in which clinicians and patients share the best available evidence when faced with the task of making decisions, and patients are supported to consider all options and express informed preferences (Figure 4.1).16,17
Should a clinician and HTE patient decide to switch regimens to include a newer ARV, the patient must be educated on and consider options such as FTR and IBA (and potentially LEN in the future), and part of this consideration must involve route of administration. FTR is given orally twice daily whereas IBA is given intravenously every 2 weeks.18,19 Not only must the clinician and patient decide whether it is preferable to have a higher pill burden with FTR or undergo frequent visits to receive IBA, the patient must ensure that he or she has reliable transportation and time to receive IBA in clinic, and the clinic must have infusion space and staff. If approved, LEN will offer improved convenience, requiring only twice-annual subcutaneous injections; the clinic must consider necessary storage areas and ensure they have staff to administer the drug and monitor patients following the injection, if required. Clinicians should also engage in shared decision-making when assessing whether to simplify a salvage regimen in a virally suppressed patient, a complex process with multiple factors.
Key Take-Home Messages • To determine new regimens for HTE patients, clinicians must consider the type of failing regimen, genetic resistance, and the goal of the new regimen. • Before switching, clinicians should review resistance and history of VF to ensure the new regimen will maintain virologic suppression. • There are options speci cally indicated for HTE patients with MDR (ie, FTR and IBA, and LEN, if approved).
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• Shared decision-making is often associated with better outcomes for HTE patients with HIV, such as improved ART adherence rates.
Modern ART regimens often achieve a very high level of virologic success; as a result, rates of VF, particularly rates in patients with limited treatment options, have dramatically declined in recent years. Although decreasing in prevalence, VF still exists in a proportion of patients with HIV, creating signi cant challenges for clinicians. As there is no single approach to successfully managing VF, clinicians must be prepared to individualize treatment, often in consultation with colleagues, for HTE patients with MDR. Individualizing treatment includes assessing reasons for VF, optimizing selection of subsequent treatment regimens after VF, staying up to date on the latest clinical trial data and regulatory body approvals for HIV treatment, deciding whether to simplify salvage regimens, and incorporating a shared decision-making model.
References 1.
US Department of Health and Human Services. Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV. Accessed April 8, 2022. https:// clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/
2. European AIDS Clinical Society. EACS Guidelines 2021; v11.0; October 2021. Accessed April 22, 2022. https://www.eacsociety.org/media/ nal2021eacsguidelinesv11.0_oct2021.pdf 3. Gilead receives complete response letter from U.S. FDA for investigational lenacapavir due to vial compatibility issues. News release. Business Wire. March 1, 2022. Accessed April 11, 2022. https://www.gilead.com/news-and-press/press-room/pressreleases/2022/3/gilead-receives-complete-response-letter-from-us-fda-forinvestigational-lenacapavir-due-to-vial-compatibility-issues 4. Molina J, Segal-Maurer S, Stellbrink HJ, et al. Ef cacy and safety of long-acting subcutaneous lenacapavir in phase 2/3 in heavily treatment-experienced people with HIV: week 26 results (CAPELLA study). Presented at: International AIDS Society; July 18-21, 2021; virtual conference.
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5. Ogbuagu O, Segal-Maurer S, Brinson C, et al. Long-acting lenacapavir in people with multidrug resistant HIV-1: week 52 results. Presented at: Conference on Retroviruses and Opportunistic Infections; February 12-16, 2022; virtual conference.
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Conclusion
6. Orkin C, Cahn P, Castagna A, et al. Opening the door on entry inhibitors in HIV: rede ning the use of entry inhibitors in heavily treatment experienced and treatmentlimited individuals living with HIV. HIV Med. 2022. [Epub ahead of print]. 7. Trottier B, Longpré D, Dion H, et al. Removing inactive NRTIs in a salvage regimen is safe, maintains virological suppression and reduces treatment costs: 96 weeks post VERITAS study. J Int AIDS Soc. 2014;17(4 suppl 3):19815. 8. Wei X, Liang C, Götte M, Wainberg MA. The M184V mutation in HIV-1 reverse transcriptase reduces the restoration of wild-type replication by attenuated viruses. AIDS. 2002;16(18):2391-2398. 9. Castagna A, Danise A, Menzo S, et al. Lamivudine monotherapy in HIV-1-infected patients harbouring a lamivudine-resistant virus: a randomized pilot study (E-184V study). AIDS. 2006;20(6):795-803. 10. Vizcarra P, Fontecha M, Monsalvo M, Vivancos MJ, Rojo A, Casado JL. Ef cacy and safety of dolutegravir plus boosted-darunavir dual therapy among highly treatmentexperienced patients. Antivir Ther. 2019;24(6):467-471. 11. Capetti AF, De Socio GV, Cossu MV, et al. Durability of dolutegravir plus boosted darunavir as salvage or simpli cation of salvage regimens in HIV-1 infected, highly treatment-experienced subjects. HIV Clin Trials. 2018;19(6):242-248. 12. Hawkins KL, Montague BT, Rowan SE, et al. Boosted darunavir and dolutegravir dual therapy among a cohort of highly treatment-experienced individuals. Antivir Ther. 2019;24(7):513-519. 13. Huhn GD, Tebas P, Gallant J, et al. A randomized, open-label trial to evaluate switching to elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide plus darunavir in treatment-experienced HIV-1-Infected adults. J Acquir Immune De c Syndr. 2017;74(2):193-200. 14. Mazzitelli M, Sasset L, Leoni D, Putaggio C, Cattelan AM. Real life use of dolutegravir doravirine dual regimen in experienced elderly PLWH with multiple comorbidities and on polypharmacy: a retrospective analysis. Medicine (Baltimore). 2021;100(52):e28488. 15. Seybold U, Gottwald F, Fibseca J, Bogner, JR. The DoDo experience: an alternative 2DR of doravirine and dolutegravir. Presented at: Deutsch-Österreichischer AIDSKongress; March 25-27, 2021; virtual conference. 16. University of Utah Health Plans. Shared decision making. Accessed April 12, 2022. https://uhealthplan.utah.edu/quality-improvement/shared-decision-making.php 17. Sewell WC, Solleveld P, Seidman D, Dehlendorf C, Marcus JL, Krakower DS. Patient-led decision-making for HIV preexposure prophylaxis. Curr HIV/AIDS Rep. 2021;18(1):48-56. 18. Trogarzo. Prescribing information. Thera Technologies; 2021. Accessed April 11, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761065s011lbl.pdf
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19. Rukobia. Prescribing information. Viiv; 2020. Accessed April 11, 2022. https:// www.accessdata.fda.gov/drugsatfda_docs/label/2020/212950s000lbl.pdf
CLINICAL RESOURCE CENTER™ CLINICAL PRACTICE GUIDELINES EACS Guidelines 2021; v11.0; October 2021. European AIDS Clinical Society. https://www.eacsociety.org/media/ nal2021eacsguidelinesv11.0_oct2021.pdf
Human immunode ciency virus drug resistance: 2018 recommendations of the International Antiviral SocietyUSA Panel. Günthard HF, Calvez V, Paredes R, et al. Clin Infect Dis. 2019;68(2):177-187. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321850/
Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV. US Department of Health and Human Services. https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/
CLINICIAN RESOURCES HIV resistance assays. New York State Department of Health AIDS Institute.
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https://cdn.hivguidelines.org/wp-content/uploads/20200506090926/NYSDOHAI-HIV-Resistance-Assays_updated_5-5-2020_mbh.pdf
HIV Drug Resistance Database. Stanford University. https://hivdb.stanford.edu/
HIV drug resistance. World Health Organization. https://www.who.int/news-room/fact-sheets/detail/hiv-drug-resistance
PATIENT AND CAREGIVER RESOURCES AIDSMap Resources. NAM Publications. https://www.aidsmap.com/about-hiv
Resources for persons living with HIV. Centers for Disease Control and Prevention. https://www.cdc.gov/hiv/basics/livingwithhiv/resources.html
HIV resources. National Institutes of Health. https://www.oar.nih.gov/hiv-resources/public
SUGGESTED READINGS Dolutegravir versus ritonavir-boosted lopinavir both with dual nucleoside reverse transcriptase inhibitor therapy in adults with HIV-1 infection in whom rst-line therapy has failed (DAWNING): an open-label, non-inferiority, phase 3b trial. Aboud M, Kaplan R, Lombaard J, et al. Lancet Infect Dis. 2019;19(3):253-264. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(19)30036-2/ fulltext
Real-life experience with bictegravir/emtricitabine/ tenofovir alafenamide in a large reference clinical centre. Ambrosioni J, Rojas Liévano J, Berrocal L, et al. J Antimicrob Chemother. 2022;77(4):1133-1139. https://academic.oup.com/jac/article-abstract/77/4/1133/6510932
Substantial decline in heavily treated therapyexperienced persons with HIV with limited antiretroviral treatment options. Bajema KL, Nance RM, Delaney JAC, et al; Centers for AIDS Research Clinical Network of Integrated Systems (CNICS). AIDS. 2020;34(14):2051-2059.
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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606534/
Ritonavir-boosted lopinavir plus nucleoside or nucleotide reverse transcriptase inhibitors versus ritonavir-boosted lopinavir plus raltegravir for treatment of HIV-1 infection in adults with virological failure of a standard rst-line ART regimen (SECOND-LINE): a randomised, open-label, non-inferiority study. Boyd MA, Kumarasamy N, Moore CL, et al; SECOND-LINE Study Group. Lancet. 2013;381(9883):2091-2099. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)61164-2/ fulltext
The management of treatment-experienced HIV patients (including virologic failure and switches). Cutrell J, Jodlowski T, Bedimo R. Ther Adv Infectious Dis. 2020;7:2049936120901395. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974747/
Lenacapavir: a rst-in-class HIV-1 capsid inhibitor. Dvory-Sobol H, Shaik N, Callebaut C, Rhee MS. Curr Opin HIV AIDS. 2022;17(1):15-21. https://journals.lww.com/co-hivandaids/Fulltext/2022/01000/ Lenacapavir__a_ rst_in_class_HIV_1_capsid.4.aspx
Phase 3 study of ibalizumab for multidrug-resistant HIV-1. Emu B, Fessel J, Schrader S, et al. N Engl J Med. 2018;379(7):645-654.
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https://www.nejm.org/doi/full/10.1056/nejmoa1711460
Safety and ef cacy of the HIV-1 attachment inhibitor prodrug fostemsavir in heavily treatment-experienced individuals: week 96 results of the phase 3 BRIGHTE study. Lataillade M, Lalezari JP, Kozal M, et al. Lancet HIV. 2020;7(11):e740e751. https://www.thelancet.com/journals/lanhiv/article/PIIS2352-3018(20)30240X/fulltext
Real life use of dolutegravir doravirine dual regimen in experienced elderly PLWH with multiple comorbidities and on polypharmacy: a retrospective analysis. Mazzitelli M, Sasset L, Leoni D, Putaggio C, Cattelan AM. Medicine (Baltimore). 2021;100(52):e28488. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8718210/
Long-acting lenacapavir in people with multidrug resistant HIV-1: week 52 results. Ogbuagu O, Segal-Maurer S, Brinson C, et al. Presented at: Conference on Retroviruses and Opportunistic Infections; February 12-16, 2022; virtual conference. Abstract 491. https://www.croiconference.org/abstract/long-acting-lenacapavir-in-peoplewith-multidrug-resistant-hiv-1-week-52-results/
Potent antiviral activity of lenacapavir in phase 2/3 in heavily ART-experienced PWH. Segal-Maurer S, Castagna A, Berhe M, et al. Conference on Retroviruses and Opportunistic Infections; March 6-10, 2021; virtual conference. Abstract 127.
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https://www.croiconference.org/abstract/potent-antiviral-activity-oflenacapavir-in-phase-2-3-in-heavily-art-experienced-pwh/
The M184V mutation in HIV-1 reverse transcriptase reduces the restoration of wild-type replication by attenuated viruses. Wei X, Liang C, Götte M, Wainberg MA. AIDS. 2002;16(18):2391-2398. https://journals.lww.com/aidsonline/Fulltext/2002/12060/ The_M184V_mutation_in_HIV_1_reverse_transcriptase.3.aspx
Ef cacy and safety of dolutegravir plus boosteddarunavir dual therapy among highly treatmentexperienced patients. Vizcarra P, Fontecha M, Monsalvo M, Vivancos MJ, Rojo A, Casado JL. Antivir Ther. 2019;24(6):467-471.
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https://journals.sagepub.com/doi/10.3851/IMP3319
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