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The challenge of multidrug-resistant HIV: Evolution, testing and promising treatment options


The emergence of resistance: Mechanisms and epidemiology

Multidrug-resistant (MDR) HIV refers to strains of HIV with reduced susceptibility to drugs within all three classes of antiretroviral therapies (ARTs).1 Cases of drug-resistant HIV were identified in the 1990s; between 1996 and 1998 (n = 63, 200), 47.7% of samples collected demonstrated resistance to two or more classes of ARTs and 13.1% were resistant to all three classes.2 Resistance typically develops as a result of selective drug pressure during treatment with a particular regimen.3 It is associated with a decreased susceptibility to ARTs and an increase in mortality.1 Although up to 76% patients develop resistance, estimates vary considerably based on viral load, prior ART exposure, treatment duration and patient adherence.2,4,5 Transmission of multi-drug-resistant strains of HIV is rare.6,7

Rates of transmitted drug-resistant HIV have fluctuated over time.8,9 In the early 2000s, an increase in the prevalence of triple drug-class failure was observed among patients who were treatment exposed and treatment naive.10 From 2000 to 2009, 14% of ART-naive patients with HIV had drug resistance mutations to at least one drug class, 2% had mutations with resistance for two or more classes, and less than 1% had mutations for triple-class resistance.11 In an observational study from 2000 to 2006, 8% of patients with HIV who received prior ART therapy displayed triple-class resistance, with an overall incidence rate of 13 triple-class resistant cases per 1,000 person-years of ART exposure.12 Thankfully, successful use of combined ART and improved treatment options have resulted in the decline of HIV drug resistance.13-15 In 2019, nearly 1.2 million people at least 13 years of age were living with HIV in the United States. In 2020, there were 30,692 new diagnoses among individuals 13 years of age and older, and the rate of viral suppression was 64.6%.16-18

Testing for HIV drug resistance

For newly diagnosed patients, the U.S. Department of Health and Human Services recommends testing for HIV drug resistance at entry into care.19 In ART-naive patients, genotypic testing — which involves testing for the reverse transcriptase and protease genes — is preferred to phenotypic testing. HIV drug-resistance testing is also recommended in patients changing ART regimens who have virologic failure and HIV-RNA levels greater than 200 copies/mL, and in those with suboptimal viral load reduction.19

Unmet needs in the treatment of MDR HIV

Drug-induced and transmitted resistance remains a concern with existing antiretroviral options for the management of HIV,20 especially as MDR HIV is associated with an increase in mortality.1 Additionally, ART regimens are complex, which is their most relevant disadvantage and a barrier to treatment.21 Another major barrier to effective treatment is the side effect (SE) profile of ARTs. SEs include lipodystrophy (disproportionate changes in fat distribution), cardiovascular events, peripheral neuropathy, pancreatitis, bone marrow suppression, myopathy, renal toxicity, osteoporosis, hypersensitivity reactions, nightmares, insomnia, gastrointestinal intolerance, and drug or food interactions.21 Together, these barriers result in variable adherence to daily tablets, which has a strong association with viral load.20,22

In a meta-analysis of data from 84 studies, additional factors that influenced adherence were the human development index (a composite measure based on a country’s average life expectancy, education and standard of living), geo-graphical region, ethnicity, self-identification as a man who has sex with men, injection drug use, participation in methadone maintenance and clinical infection stage.23 Although adherence to treatment is complex, the development of novel agents and preparations with extended-release formulations and reduced toxicities may help address this unmet need in the management of HIV infection.20

Novel agents for MDR HIV

Novel therapies and agents in development offer promise for patients who have limited treatment options to effectively manage their MDR HIV infection.

FDA-approved options for MDR HIV infection


Ibalizumab is a humanized IgG4 monoclonal antibody that binds to CD4 that was approved for intravenous administration by the FDA in 2018.24-26 Ibalizumab, in combination with other antiretrovirals, is indicated for the treatment of HIV-1 infection in heavily treatment-experienced adults with MDR HIV-1 infection for whom their current antiretroviral regimen fails.26

FDA approval of ibalizumab was based on results from a phase 3, single-group, open-label clinical trial of 40 adult patients with MDR HIV infection who received a median of 10 previous antiviral therapies (NCT02475629).25 Most patients (83%) treated with ibalizumab had a significant decrease in viral load of at least 0.5 log10 copies/mL on day 14 following the functional monotherapy period (p < .001). At week 25, the end of the maintenance period, patients who received ibalizumab plus an optimized background regimen had a mean reduction in viral load of 1.6 log10 copies/mL from baseline, with 50% and 43% of patients having an HIV-1 RNA level less than 200 copies/mL and less than 50 copies/mL, respectively.

Common SEs associated with ibalizumab were diarrhea, nausea, fatigue, pyrexia, rash and dizziness, and most (87%) were mild or moderate.25 Grade 3 or 4 SEs occurred in 11 patients (28%), and four (10%) had AIDS-defining SEs. Nine patients (23%) had serious SEs. Finally, seven patients had virologic failure and three patients experienced viral rebound.


Fostemsavir, an oral prodrug of an HIV-1 attachment inhibitor,27 was approved for use by the FDA in 2020.28 Fostemsavir is indicated in combination with other antiretrovirals for the treatment of HIV-1 infection in heavily treatment-experienced adults with MDR HIV-1 infection for whom their current antiretroviral regimen fails due to resistance, intolerance or safety considerations.28 An ongoing phase 3 clinical trial (NCT02362503) divided 371 patients with MDR HIV-1 infection into two cohorts.27 Patients in the randomized (3-to-1 ratio) cohort (n = 272) received fostemsavir (functional monotherapy group) or placebo plus their failing regimen for eight days, followed by fostemsavir plus optimized background therapy for the rest of the trial. Patients in the nonrandomized cohort (n = 99) received fostemsavir plus optimized background therapy for the whole trial.

Patients taking fostemsavir in the functional monotherapy group had a greater reduction in HIV-1 RNA levels from baseline compared with placebo (0.79±0.05 log10 vs 0.17±0.08 log10 copies/mL) at day eight, with a significant between-group difference of −0.63 log10 copies/mL in the fostemsavir group (p < .001).27 At week 48, 54% of patients in the randomized cohort and 38% in the nonrandomized cohort achieved virologic suppression (HIV-1 RNA level,
< 40 copies/mL).

Almost all patients (92%) reported SEs and most serious SEs were due to progressive disease.27 A total of 77 (21%) patients had grade 2 to 4 drug-related SEs, which included nausea (4%) and diarrhea (3%). Virologic failure occurred in 18% of patients in the randomized cohort and 46% in the nonrandomized cohort.

Agents in development for MDR HIV infection


Lenacapavir (GS-6207) is an inhibitor of HIV-1 capsid function.29,30 The ongoing phase 3 CAPELLA trial (NCT04150068) is assessing its efficacy and safety in patients with MDR HIV-1 infection.30 The study enrolled 72 patients to a randomized functional monotherapy cohort or a nonrandomized cohort. Significantly more patients who received oral lenacapavir during the functional monotherapy period (15 days) had a reduction from baseline of at least 0.5 log10 copies/mL of HIV-1 RNA than those who received placebo (88% vs 17%; p < .001). At 26 weeks, subcutaneous lenacapavir was associated with a reduction in viral load (<50 copies/mL) in 81% of patients in the randomized cohort and 83% in the nonrandomized cohort.

Overall, seven patients had serious SEs, none of which were related to lenacapavir.30 Drug-related injectionsite reactions (most were grade 1, none were grade 4) were reported in 45 patients. A total of 28% of patients experienced grade 3 or higher laboratory abnormalities. In July 2022, the FDA accepted a new drug application (NDA) resubmission for lenacapavir; a decision on the NDA is expected in late December 2022.31


GSK2838232 is a maturation inhibitor.32 It inhibits formation of the functional capsid p24 by stopping the last cleavage step of the gag capsid-Sp1 polyprotein by HIV protease, resulting in incorrect virion assembly and a viral particle that lacks the ability to cause infection. A phase 2a study of GSK2838232 in combination with cobicistat demonstrated favorable safety and efficacy results, supporting continued development.


Albuvirtide is a long-acting fusion inhibitor.33 In a phase 3 trial (NCT02369965) with 347 participants, most of whom (81.7%) had genotypic resistance to at least one ART, albuvirtide was non-inferior to the standard of care for resistant HIV, with similar safety profiles.


Elsulfavirine, a non-nucleoside reverse transcriptase inhibitor, is a prodrug of the active compound VM-1500A.34 A phase 1 U.S.-based study is recruiting healthy volunteers without HIV infection to assess the safety and tolerability of elsulfavirine (NCT05165550).35

Managed care considerations

The cost of therapy for MDR HIV infection is an important consideration. The monthly average wholesale price for ibalizumab is $12,845 (eight 200-mg vials) and $9,633 (60 tablets of 600 mg each) for fostemsavir.19 Therefore, these drugs come at a high cost per quality-adjusted life-year. However, two cost-effectiveness analyses demonstrated that ibalizumab-containing regimens would substantially improve survival for people with MDR HIV infection, and the overall budget impact would be relatively minor, considering the small number of people for whom such treatment is required.36,37

Although these newer agents are associated with high costs, the development of MDR HIV is multifactorial, and poor patient adherence to ART plays a key role.38 Long-acting ARTs, administered through subcutaneous or intravenous routes, may offer greater adherence and convenience, which could improve patient outcomes.38


While the introduction of combined ARTs helped reduce the occurrence of resistant HIV, there are still people living with MDR HIV infection for whom existing therapies are inadequate. Therefore, it is necessary to develop novel therapies for this group of patients. In the past few years, two novel agents, ibalizumab and fostemsavir, have been approved by the FDA and a third one, lenacapavir, is under review. Additionally, other agents are in development and offer promise.


1. Grover D, Copas A, Green H, et al. UK Collaborative Group on HIV Drug Resistance and UK Collaborative HIV Cohort Study (UK CHIC). What is the risk of mortality following diagnosis of multidrug-resistant HIV-1? J Antimicrob Chemother. 2008;61(3):705-713. doi:10.1093/jac/dkm522

2. Richman DD, Morton SC, Wrin T, et al. The prevalence of antiretroviral drug resistance in the United States. AIDS. 2004;18(10):1393-1401. doi:10.1097/01.aids.0000131310.52526.c7

3. Puertas MC, Ploumidis G, Ploumidis M, et al. Panresistant HIV-1 emergence in the era of integrase strand-transfer inhibitors: a case report. Lancet Microbe. 2020;1(3):e130-e135. doi:10.1016/S2666-5247(20)30006-9

4. Lucas GM, Gallant JE, Moore RD. Relationship between drug resistance and HIV-1 disease progression or death in patients undergoing resistance testing. AIDS. 2004;18(11):1539-1548. doi:10.1097/01.aids.0000131339.68666.1a

5. Harrigan PR, Hogg RS, Dong WWY, et al. Predictors of HIV drug-resistance mutations in a large antiretroviral-naive cohort initiating triple antiretroviral therapy. J Infect Dis. 2005;191(3):339-347. doi:10.1086/427192

6. Raymond S, Piffaut M, Bigot J, et al. Sexual transmission of an extensively drug-resistant HIV-1 strain. Lancet HIV. 2020;7(8):e529-e530. doi:10.1016/S2352-3018(20)30205-8

7. Clutter DS, Jordan MR, Bertagnolio S, Shafer RW. HIV-1 drug resistance and resistance testing. Infect Genet Evol. 2016;46:292-307. doi:10.1016/j.meegid.2016.08.031

8. Little SJ, Holte S, Routy JP, et al. Antiretroviral-drug resistance among patients recently infected with HIV. N Engl J Med. 2002;347(6):385-394. doi:10.1056/NEJMoa013552

9. Grant RM, Hecht FM, Warmerdam M, et al. Time trends in primary HIV-1 drug resistance among recently infected persons. JAMA. 2002;288(2):181-188. doi:10.1001/jama.288.2.181

10. Mocroft A, Ledergerber B, Viard JP, et al; EuroSIDA Study Group. Time to virological failure of 3 classes of antiretrovirals after initiation of highly active antiretroviral therapy: results from the EuroSIDA study group. J Infect Dis. 2004;190(11):1947-1956. doi:10.1086/425424

11. Ross LL, Shortino D, Shaefer MS. Changes from 2000 to 2009 in the prevalence of HIV-1 containing drug resistance-associated mutations from antiretroviral therapy-naive, HIV-1-infected patients in the United States. AIDS Res Hum Retroviruses. 2018;34(8):672-679. doi:10.1089/AID.2017.0295

12. Napravnik S, Keys JR, Quinlivan EB, Wohl DA, Mikeal OV, Eron JJ Jr. Triple-class antiretroviral drug resistance: risk and predictors among HIV-1-infected patients. AIDS. 2007;21(7):825-834. doi:10.1097/QAD.0b013e32805e8764

13. 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. doi:10.1093/cid/ciw128

14. Davy-Mendez T, Eron JJ, Brunet L, Zakharova O, Dennis AM, Napravnik S. New antiretroviral agent use affects prevalence of HIV drug resistance in clinical care populations. AIDS. 2018;32(17):2593-2603. doi:10.1097/QAD.0000000000001990

15. Armenia D, Di Carlo D, Flandre P, et al. HIV MDR is still a relevant issue despite its dramatic drop over the years. J Antimicrob Chemother. 2020;75(5):1301-1310. doi:10.1093/jac/dkz554

16. Centers for Disease Control and Prevention. Estimated HIV incidence and prevalence in the United States, 2015-2019. HIV Surveillance Supplemental Report 2021;26(No. 1). Published May 2021. Accessed November 9, 2022. https://www.cdc.gov/hiv/pdf/library/reports/surveillance/cdc-hiv-surveil-lance-supplemental-report-vol-26-1.pdf

17. Centers for Disease Control and Prevention. HIV Surveillance Report, 2020; vol. 33. http://www.cdc.gov/hiv/library/reports/hiv-surveillance.html. Published May 2022. Accessed November 9, 2022. https://www.cdc.gov/hiv/pdf/library/reports/surveillance/cdc-hiv-surveillance-report-2020-updated-vol-33.pdf

18. Centers for Disease Control and Prevention. Monitoring selected national HIV prevention and care objectives by using HIV surveillance data—United States and 6 dependent areas, 2020. HIV Surveillance Supplemental Report 2022;27(No. 3). Revised edition. Published August 2022. Accessed November 9, 2022. https://www.cdc.gov/hiv/pdf/library/reports/surveillance/cdc-hiv-surveillance-supplemental-report-vol-27-3.pdf

19. 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. Updated September 21, 2022. Accessed November 9, 2022. https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/adult-adolescent-arv/guidelines-adult-adolescent-arv.pdf

20. Cambou MC, Landovitz RJ. Novel antiretroviral agents. Curr HIV/AIDS Rep. 2020;17(2):118-124. doi:10.1007/s11904-020-00486-2

21. Iacob SA, Iacob DG, Jugulete G. Improving the adherence to antiretroviral therapy, a difficult but essential task for a successful HIV treatment-clinical points of view and practical considerations. Front Pharmacol. 2017;8:831. doi:10.3389/fphar.2017.00831

22. Bangsberg DR, Hecht FM, Charlebois ED, et al. Adherence to protease inhibitors, HIV-1 viral load, and development of drug resistance in an indigent population. AIDS. 2000;14(4):357-366. doi:10.1097/00002030-200003100-00008

23. Ortego C, Huedo-Medina TB, Llorca J, et al. Adherence to highly active antiretroviral therapy (HAART): a meta-analysis. AIDS Behav. 2011;15(7):1381-1396. doi:10.1007/s10461-011-9942-x

24. Reimann KA, Lin W, Bixler S, et al. A humanized form of a CD4-specific monoclonal antibody exhibits decreased antigenicity and prolonged plasma half-life in rhesus monkeys while retaining its unique biological and antiviral properties. AIDS Res Hum Retroviruses. 1997;13(11):933-943. doi:10.1089/aid.1997.13.933

25. 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. doi:10.1056/NEJMoa1711460

26. Trogarzo. Prescribing information. Theratechnologies Inc; 2022. Accessed November 9, 2022. https://www.trogarzo.com/assets/pdfs/THER-TRO-P437-E%20Prescribing%20Information%20(2022).pdf

27. 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. doi:10.1056/NEJMoa1902493

28. Rukobia. ViiV Healthcare; 2022. Accessed November 9, 2022. https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Rukobia/pdf/RUKOBIA-PI-PIL.PDF

29. Link JO, Rhee MS, Tse WC, et al. Clinical targeting of HIV capsid protein with a long-acting small molecule. Nature. 2020;584(7822):614-618. doi:10.1038/s41586-020-2443-1

30. Segal-Maurer S, DeJesus E, Stellbrink H-J, et al; CAPELLA Study Investi-gators. Capsid inhibition with lenacapavir in multidrug-resistant HIV-1 infec-tion. N Engl J Med. 2022;386(19):1793-1803. doi:10.1056/NEJMoa2115542

31. Gilead announces first global regulatory approval of Sunlenca (lenacapa-vir), the only twice-yearly HIV treatment option. News release. Gilead. August 22, 2022. Accessed November 9, 2022. https://www.gilead.com/news-and-press/press-room/press-releases/2022/8/gilead-announces-first-global-reg-ulatory-approval-of-sunlenca-lenacapavir-the-only-twiceyearly-hiv-treat-ment-option#:~:text=In%20July%2C%20the%20U.S.%20Food,date%20 of%20December%2027%2C%202022

32. DeJesus E, Harward S, Jewell RC, et al. A phase IIa study evaluating safety, pharmacokinetics, and antiviral activity of GSK2838232, a novel, second-generation maturation inhibitor, in participants with human immunodeficiency virus type 1 infection. Clin Infect Dis. 2020;71(5):1255-1262. doi:10.1093/cid/ciz938

33. Su B, Yao C, Zhao Q-X, et al; TALENT Study Team. Efficacy and safety of the long-acting fusion inhibitor albuvirtide in antiretroviral-experienced adults with human immunodeficiency virus-1: interim analysis of the randomized, controlled, phase 3, non-inferiority TALENT study. Chin Med J (Engl). 2020;133(24):2919-2927. doi:10.1097/CM9.0000000000001273

34. Al-Salama ZT. Elsulfavirine: first global approval. Drugs. 2017;77(16):1811-1816. doi:10.1007/s40265-017-0820-3

35. Study of single ascending doses of elsulfavirine to evaluate the safety, tolerability, and pharmacokinetics of elsulfavirine and its active metabolite VM-1500A in healthy subjects. Clinicaltrials.gov. Updated April 13, 2022. Accessed November 8, 2022. https://clinicaltrials.gov/ct2/show/NCT05165550

36. Brogan AJ, Talbird SE, Davis AE, La EM, Kumar PN. The cost-effectiveness and budget impact of ibalizumabuiyk for adults with multidrug-resistant HIV-1 infection in the United States. Pharmacoeconomics. 2021;39(4):421-432. doi:10.1007/s40273-020-00992-6

37. 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. doi:10.1097/QAI.0000000000002241

38. Singh K, Sarafianos SG, Sönnerborg A. Long-acting anti-HIV drugs targeting HIV-1 reverse transcriptase and integrase. Pharmaceuticals (Basel). 2019;12(2):62. doi:10.3390/ph12020062

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