Current Options for Highly Treatment-Experienced People With HIV

The treatment of HIV has dramatically advanced over the past 40 years. Clear data show a decreased occurrence of AIDS and an increased life expectancy.1,2 However, a small percentage of the overall population with HIV cannot achieve treatment goals. People with HIV who are highly treatment-experienced (HTE) may have limited antiretroviral therapy (ART) options due to resistance or tolerability issues. This population may have problems with virologic suppression, immune function, toxicities, and drug–drug interactions. These challenges may lead to an overall decrease in health-related quality of life (HRQOL).3 HTE people with HIV need novel ART options and classes with improved tolerability and no crossresistance to current ART classes.

Transmitted and acquired resistance must be considered in the HIV treatment discussion. In a World Health Organization survey report, there was more than 10% resistance to nevirapine or efavirenz in people with HIV initiating therapy.4 This global prevalence of resistance to the nonnucleoside reverse transcriptase inhibitors emphasizes the need to use ART with long-term efficacy and durability.4 There is also a need to retain these patients in care and encourage adherence. Global access to HIV RNA testing is needed to ensure that ART is effective and to rapidly identify cases of virologic failure.4

Overall resistance rates to 4 ART classes are thought to be low; however, reported prevalence rates to 3 and 4 ART classes are estimated to be 5% to 10% in Europe and less than 3% in North America.1,5 In the United States, approximately 12,000 people with multidrug-resistant HIV need novel agents.2,6 When HIV RNA undetectability cannot be achieved, a secondary goal is to reduce the HIV RNA levels as much as possible and maintain immunologic function.7 Entry inhibitors are second-line agents that prevent HIV-1 cellular entry by binding a cellular target.1 Enfuvirtide (Fuzeon, Genentech) and maraviroc were the first agents in this class; however, there are several disadvantages to these agents, including the route of administration, pill burden, and lower virologic efficacy compared with other ART options.1 The newest agents in the entry inhibitor class are fostemsavir (Rukobia, ViiV) and ibalizumab-uiyk (Trogarzo, Theratechnologies).

Fostemsavir is an HIV-1 attachment inhibitor that binds the gp120 envelope glycoprotein and prevents viral connection to CD4 T cells. The drug was approved in July 2020 and has no apparent cross-resistance to other ART classes.3 Within the same drug class, there is no cross-resistance with ibalizumab-uiyk or maraviroc.8,9 Fostemsavir is dosed as 600-mg tablets orally twice daily without regard to food.1 One concern with twice-daily administration is that nonadherence may have led to virologic failure, and adhering to a twicedaily regimen may be an issue for some people with HIV.6 Common adverse reactions with fostemsavir include nausea, diarrhea, headache, abdominal pain, dyspepsia, fatigue, rash, and sleep disturbances.6 Fostemsavir was studied in people with HIV who failed to respond to their current ART, and this agent also may be used for tolerability issues.10 This drug, combined with optimized background therapy, showed robust and sustained virologic and immunologic responses.11 Patient-reported outcomes from the BRIGHTE trial showed improved HRQOL outcomes.3 These improved outcomes are thought to increase overall adherence to ART, leading to better health outcomes. A case report of the use of fostemsavir to overcome a drug–drug interaction issue also has been published.12

Ibalizumab-uiyk is a long-acting post-attachment inhibitor.13 It is a humanized immunoglobulin G4 (IgG4) monoclonal antibody targeting CD4 receptors of T cells to interfere with the binding of HIV-1 gp120.1 The medication was approved in March 2018 and is given as a twice-monthly parenteral infusion (2,000-mg loading dose, followed by subsequent doses of 800 mg every 2 weeks).2 The most common adverse reactions reported in trials were diarrhea, dizziness, nausea, and rash. Monotherapy with ibalizumab-uiyk is not recommended due to the development of resistance in 1 to 2 weeks.2 The parenteral administration of ibalizumab-uiyk presents logistical barriers to patient care implementation. Adherence may be an issue when clinic visits or home infusions are needed every 2 weeks.2 Missed infusions may lead to resistance.

Several clinical trials reported a decrease in HIV RNA and virologic suppression after therapy with ibalizumab-uiyk.2,14 Pharmacoeconomic studies have reported that ibalizumabuiyk represents a cost-effective and affordable option for HTE people due to an increase in quality-adjusted lifeyears.13,15 Successful treatment of panresistant HIV has been described with ibalizumab-uiyk used as an “induction treatment” followed by an optimized “maintenance treatment.”5 A case report of a switch to ibalizumab as a “bridge therapy” due to a drug–drug interaction with chemotherapy showed an alternative use when other ART options are not available.16

Another novel therapy is lenacapavir (Gilead) in the newest ART class of capsid inhibitors, which works by disrupting the functioning of the HIV capsid across multiple steps in the viral life cycle.17 Lenacapavir is an investigational agent and can be administered orally, either daily or weekly, and subcutaneously up to every 6 months.17 It is being investigated in both HTE and treatment-naive people with HIV. No overlapping resistance with other classes or preexisting resistance mechanisms is known; however, emergent resistance during treatment has been reported.17,18 Results from the CAPELLA and CALIBRATE studies reported a rapid reduction in HIV RNA and no serious adverse events.17 After submission to the FDA, the manufacturer received a complete response letter in March 2022 detailing chemistry, manufacturing, and controls concerns relating to the compatibility of lenacapavir with the proposed borosilicate glass vial.19 Gilead is working with the FDA to resolve the issues.19

Transmitted and acquired resistance leading to virologic failure remain a global issue in the treatment of HIV. Recently approved agents represent a step forward toward virologic control for all people with HIV, including those who are HTE. However, there is still a need for more options in novel classes to overcome resistance, tolerability, and drug–drug interaction issues.

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2. Chahine EB, Durham SH. Ibalizumab: the first monoclonal antibody for the treatment of HIV-1 infection. Ann Pharmacother. 2021;55(2):230-239.

3. Anderson SJ, Murray M, Cella D, et al. Patientreported outcomes in the phase III BRIGHTE trial of the HIV-1 attachment inhibitor prodrug fostemsavir in heavily treatment-experienced individuals. Patient. 2022;15(1):131-143.

4. World Health Organization. HIV drug resistance. November 22, 2021. Accessed April 26, 2022. https://www.who.int/news-room/ fact-sheets/detail/hiv-drug-resistance

5. Canetti D, Muccini C, Spagnuolo V, et al. Achieving virological control in panresistant HIV-1 infection: a case series.

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6. Chahine EB. Fostemsavir: the first oral attachment inhibitor for treatment of HIV-1 infection.

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7. Department of Health and Human Services.

Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of

Antiretroviral Agents in Adults and Adolescents

With HIV. Updated January 20, 2022. Accessed

April 26, 2022. https://bit.ly/38ybb0p-IDSE

8. Muccini C, Canetti D, Castagna A, et al. Efficacy and safety profile of fostemsavir for the

treatment of people with human immunodeficiency virus-1 (HIV-1): current evidence and place in therapy. Drug Des Devel Ther. 2022;16:297-304. 9. Rose R, Gartland M, Li Z, et al. Clinical evidence for a lack of cross-resistance between temsavir and ibalizumab or maraviroc. AIDS. 2022;36(1):11-18. 10. Hiryak K, Koren DE. Fostemsavir: a novel attachment inhibitor for patients with multidrug-resistant HIV-1 infection.

Ann Pharmacother. 2021;55(6):792-797. 11. Ackerman P, Thompson M, Molina JM, et al. Long-term efficacy and safety of fostemsavir among subgroups of heavily treatment-experienced adults with HIV-1. AIDS. 2021;35(7):1061-1072. 12. Pecora Fulco P, Nixon D, Gomes DC. Novel use of fostemsavir for 2 multidrug-resistant persons with human immunodeficiency virus.

Ann Pharmacother. 2022;56(4):501-502. 13. Brogan AJ, Talbird SE, Davis AE, et al. The cost-effectiveness and budget impact of ibalizumab-uiyk for adults with multidrug-resistant

HIV-1 infection in the United States. Pharmacoeconomics. 2021;39(4):421-432. 14. Gathe JC, Hardwicke RL, Garcia F, et al. Efficacy, pharmacokinetics, and safety over 48 weeks with ibalizumab-based therapy in treatment-experienced adults infected with HIV-1: a phase 2a study. J Acquir Immune Defic Syndr. 2021;86(4):482-489. 15. Millham LRI, Scott JA, Sax PE, et al. Clinical and economic impact of ibalizumab for people with multidrug-resistant HIV in the

United States. J Acquir Immune Defic Syndr. 2020;83(2):148-156. 16. Dickter JK, Martin AL, Ho S, et al. Ibalizumabuiyk as a bridge therapy for a patient with drug-resistant HIV-1 infection receiving chemotherapy: a case report. J Clin Pharm Ther. 2021;46($):1185-1187. 17. Dvory-Sobol H, Shaik N, Callebaut C, et al.

Lenacapavir: A first-in-class HIV-1 capsid inhibitor. Curr Opin HIV AIDS. 2022;17(1):15-21. 18. Margot N, Vanderveen L, Naik V, et al. Phenotypic resistance to lenacapavir and monotherapy efficacy in a proof-of-concept clinical study. J Antimicrob Chemother. 2022;77(4):989-995. 19. Gilead receives complete response letter from

U.S. FDA for investigational lenacapavir due to vial compatibility issues [press release]. Business Wire; March 1, 2022. Accessed April 26, 2022. https://bwnews.pr/3yWvaAi

PharmD, MSc, BCIDP, AAHIVP, FCCP, is an associate professor, College of Pharmacy, Midwestern University, in Downers Grove, Illinois.