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Review

Investigational drugs for HIV: trends, opportunities and key players

ORCID Icon, ORCID Icon & ORCID Icon
Pages 127-139 | Received 24 Nov 2022, Accepted 06 Feb 2023, Published online: 15 Feb 2023

References

  • Mesplede T. Evaluating the combination of emtricitabine/ tenofovir alafenamide fumarate to reduce the risk of sexually acquired HIV-1-infection in at-risk adults. Expert Opin Pharmacother. 2021 Jul;22(10):1245–1251.
  • McPherson TD, Sobieszczyk ME, Markowitz M. Cabotegravir in the treatment and prevention of human immunodeficiency virus-1. Expert Opin Investig Drugs. 2018 Apr;27(4):413–420.
  • O’Halloran JA, Sahrmann J, Parra-Rodriguez L, et al. Integrase strand transfer inhibitors are associated with incident diabetes mellitus in people with HIV. Clin Infect Dis. 2022;84(4):396.
  • Pham HT, Mesplede T. Bictegravir in a fixed-dose tablet with emtricitabine and tenofovir alafenamide for the treatment of HIV infection: pharmacology and clinical implications. Expert Opin Pharmacother. 2019 Mar;20(4):385–397.
  • Ambrosioni J, Rojas Lievano J, Berrocal L, et al. Real-life experience with bictegravir/emtricitabine/tenofovir alafenamide in a large reference clinical centre. J Antimicrob Chemother. 2022 Mar 31;77(4):1133–1139.
  • Dvory-Sobol H, Shaik N, Callebaut C, et al. Lenacapavir: a first-in-class HIV-1 capsid inhibitor. Curr Opin HIV AIDS. 2022 Jan 1;17(1):15–21.
  • Link JO, Rhee MS, Tse WC, et al. Clinical targeting of HIV capsid protein with a long-acting small molecule. Nature. 2020 Aug;584(7822):614–618.
  • Marcelin AG, Charpentier C, Jary A, et al. Frequency of capsid substitutions associated with GS-6207 in vitro resistance in HIV-1 from antiretroviral-naive and -experienced patients. J Antimicrob Chemother. 2020 Jun 1;75(6):1588–1590.
  • Margot N, Ram R, Rhee M, et al. Absence of Lenacapavir (GS-6207) phenotypic resistance in HIV gag cleavage site mutants and in isolates with resistance to existing drug classes. Antimicrob Agents Chemother. 2021 Feb 17;65(3):e02057–20.
  • Campbell EM, Hope TJHIV-1. HIV-1 capsid: the multifaceted key player in HIV-1 infection. Nat Rev Microbiol. 2015 Aug;13(8):471–483.
  • Frankel AD, Young JA. HIV-1: fifteen proteins and an RNA. Annu Rev Biochem. 1998;67:1–25.
  • Wei G, Iqbal N, Courouble VV, et al. Prion-like low complexity regions enable avid virus-host interactions during HIV-1 infection. Nat Commun. 2022 Oct 6;13(1):5879.
  • Jogiraju V, Graham H, West SK, et al. Pharmacokinetics of a simplified subcutaneous lenacapavir regimen versus Phase 2/3 regimen. Montreal (Canada): AIDS; 2022.
  • Zhao G, Perilla JR, Yufenyuy EL, et al. Mature HIV-1 capsid structure by cryo-electron microscopy and all-atom molecular dynamics. Nature. 2013 May 30;497(7451):643–646.
  • Passos DO, Li M, Yang R, et al. Cryo-EM structures and atomic model of the HIV-1 strand transfer complex intasome. Science. 2017 Jan 6;355(6320):89–92.
  • Segal-Maurer S, DeJesus E, Stellbrink HJ, et al. Capsid inhibition with lenacapavir in multidrug-resistant HIV-1 infection. N Engl J Med. 2022 May 12;386(19):1793–1803.
  • Ogbuagu O, Segal-Maurer S, Ratanasuwan W, et al. Efficacy and safety of long-acting subcutaneous lenacapavir in heavily treatment-experienced people with multi-drug resistant HIV: week 52 results. Montreal (Canada): AIDS; 2022.
  • VanderVeen L, Margot N, Naik V, et al. Interim resistance analysis of long-acting lenacapavir in treatment-naive people with HIV at 28 weeks (CALIBRATE). ID Week 2021.
  • Kumar P, Gupta S, Segal-Maurer S, et al. Injection-site reaction experience in clinical studies of people using lenacapavir for HIV treatment. Montreal (Canada): AIDS; 2022.
  • Babiker AG, Lundgren J, Sharma S, et al. Long term benefits from early antiretroviral therapy initiation in HIV infection: findings from the extended follow-up of the START trial. ID Week 2022; Washington D.C.
  • Gupta SK, Sims J, Brinson C, et al. Lenacapavir as part of a combination regimen in treatment-naive people living with HIV: week 54 results. CROI 2022.
  • Vidal SJ, Bekerman E, Hansen D, et al. Long-acting capsid inhibitor protects macaques from repeat SHIV challenges. Nature. 2022 Jan;601(7894):612–616.
  • Cespedes M, Das M, Hojilla JC, et al. Proactive strategies to optimize engagement of Black, Hispanic/ Latinx, transgender, and nonbinary individuals in a trial of a novel agent for HIV pre-exposure prophylaxis (PrEP). PLoS One. 2022;17(6):e0267780.
  • Wang T, Kadow JF, Meanwell NA, et al. The genesis and future prospects of small molecule HIV-1 attachment inhibitors. Adv Exp Med Biol. 2022;1366:45–64.
  • Grant PM, Kozal MJ. Fostemsavir: a first-in-class HIV-1 attachment inhibitor. Curr Opin HIV AIDS. 2022 Jan 1;17(1):32–35.
  • Lai YT. Small Molecule HIV-1. Attachment inhibitors: discovery, mode of action and structural basis of inhibition. Viruses. 2021;13:May.
  • Kozal M, Aberg J, Pialoux G, et al. Fostemsavir in adults with multidrug-resistant HIV-1 infection. N Engl J Med. 2020 Mar 26;382(13):1232–1243.
  • Lataillade M, Lalezari JP, Kozal M, et al. Safety and efficacy 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 Nov;7(11):e740–e751.
  • Aberg J, Shepherd B, Wang M, et al. Efficacy and safety of fostemsavir plus optimized background therapy in heavily treatment-experienced adults with HIV-1: week 240 results of the phase 3 BRIGHTE study. AIDS 2022; Montreal (Canada)
  • Gartland M, Cahn P, DeJesus E, et al. Week 96 genotypic and phenotypic results of the fostemsavir phase 3 BRIGHTE study in heavily treatment-experienced adults living with multidrug-resistant HIV-1. Antimicrob Agents Chemother. 2022 Jun 21;66(6):e0175121.
  • Lagishetty C, Moore K, Ackerman P, et al. Effects of temsavir, active moiety of antiretroviral agent fostemsavir, on QT interval: results from a phase I study and an exposure-response analysis. Clin Transl Sci. 2020 Jul;13(4):769–776.
  • Hsu RK, Brunet L, Fusco JS, et al. Durability and effectiveness of fostemsavir in heavily treatment-experienced people with HIV. ID Week 2022; Washington DC.
  • Stellbrink HJ, Le Fevre E, Carr A, et al. Once-daily maraviroc versus tenofovir/emtricitabine each combined with darunavir/ritonavir for initial HIV-1 treatment. AIDS. 2016 May 15;30(8):1229–1238.
  • Kramer VG, Schader SM, Oliveira M, et al. Maraviroc and other HIV-1 entry inhibitors exhibit a class-specific redistribution effect that results in increased extracellular viral load. Antimicrob Agents Chemother. 2012 Aug;56(8):4154–4160.
  • Kramer VG, Hassounah S, Colby-Germinario SP, et al. The dual CCR5 and CCR2 inhibitor cenicriviroc does not redistribute HIV into extracellular space: implications for plasma viral load and intracellular DNA decline. J Antimicrob Chemother. 2015 Mar;70(3):750–756.
  • White JA, Simonetti FR, Beg S, et al. Complex decay dynamics of HIV virions, intact and defective proviruses, and 2LTR circles following initiation of antiretroviral therapy. Proc Natl Acad Sci U S A. 2022 Feb 8;119(6):e2120326119.
  • Perelson AS, Neumann AU, Markowitz M, et al. HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science. 1996 Mar 15;271(5255):1582–1586.
  • Hassounah SA, Mesplede T. Where are we with injectables against HIV infection and what are the remaining challenges? Expert Rev Anti Infect Ther. 2018 Feb;16(2):143–152.
  • Chahine EB, Durham SH. Ibalizumab: the first monoclonal antibody for the treatment of HIV-1 infection. Ann Pharmacother. 2021 Feb;55(2):230–239.
  • Moore JP, Sattentau QJ, Klasse PJ, et al. A monoclonal antibody to CD4 domain 2 blocks soluble CD4-induced conformational changes in the envelope glycoproteins of human immunodeficiency virus type 1 (HIV-1) and HIV-1 infection of CD4+ cells. J Virol. 1992 Aug;66(8):4784–4793.
  • Burkly LC, Olson D, Shapiro R, et al. Inhibition of HIV infection by a novel CD4 domain 2-specific monoclonal antibody dissecting the basis for its inhibitory effect on HIV-induced cell fusion. J Immunol. 1992 Sep 1;149(5):1779–1787.
  • 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 Jul 20;13(11):933–943.
  • Emu B, Fessel J, Schrader S, et al. Phase 3 study of ibalizumab for multidrug-resistant HIV-1. N Engl J Med. 2018 Aug 16;379(7):645–654.
  • 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 Apr 1;86(4):482–489.
  • Le Hingrat Q, Collin G, Bachelard A, et al. Ibalizumab shows in-vitro activity against group A and group B HIV-2 clinical isolates. AIDS. 2022 Jul 1;36(8):1055–1060.
  • Burton DR, Pyati J, Koduri R, et al. Efficient neutralization of primary isolates of HIV-1 by a recombinant human monoclonal antibody. Science. 1994 Nov 11;266(5187):1024–1027.
  • Tipoe T, Fidler S, Frater J. An exploration of how broadly neutralizing antibodies might induce HIV remission: the ‘vaccinal’ effect. Curr Opin HIV AIDS. 2022;17(3):162–170.
  • Spencer DA, Goldberg BS, Pandey S, et al. Phagocytosis by an HIV antibody is associated with reduced viremia irrespective of enhanced complement lysis. Nat Commun. 2022 Feb 3;13(1):662.
  • Waters L, de Miguel-Buckley R, Poulin S, et al. Broadly neutralizing antibodies for HIV treatment: broad in theory, narrow in reality. Clin Infect Dis. 2022 Oct 28;ciac835.
  • Gaebler C, Nogueira L, Stoffel E, et al. Prolonged viral suppression with anti-HIV-1 antibody therapy. Nature. 2022 Jun;606(7913):368–374.
  • Sneller MC, Blazkova J, Justement JS, et al. Combination anti-HIV antibodies provide sustained virological suppression. Nature. 2022 Jun;606(7913):375–381.
  • Gunst JD, Pahus MH, Rosas-Umbert M, et al. Early intervention with 3BNC117 and romidepsin at antiretroviral treatment initiation in people with HIV-1: a phase 1b/2a, randomized trial. Nat Med. 2022 Oct 17;28(11):2424–2435.
  • Rosas-Umbert M, Gunst JD, Pahus MH, et al. Administration of broadly neutralizing anti-HIV-1 antibodies at ART initiation maintains long-term CD8(+) T cell immunity. Nat Commun. 2022 Oct 29;13(1):6473.
  • Julg B, Stephenson KE, Wagh K, et al. Safety and antiviral activity of triple combination broadly neutralizing monoclonal antibody therapy against HIV-1: a phase 1 clinical trial. Nat Med. 2022 Jun;28(6):1288–1296.
  • Orkin C, Schapiro JM, Perno CF, et al. Expanded multivariable models to assist patient selection for long-acting cabotegravir + Rilpivirine treatment: clinical utility of a combination of patient, drug concentration, and viral factors associated with virologic failure over 152 weeks. HIV Glasgow 2022.
  • Zhao AV, Crutchley RD, Guduru RC, et al. A clinical review of HIV integrase strand transfer inhibitors (INSTIs) for the prevention and treatment of HIV-1 infection. Retrovirology. 2022 Oct 22;19(1):22.
  • Qazzaz H, Parganas C, Cory TJ. An evaluation of long-acting cabotegravir + rilpivirine for the treatment of virologically suppressed adults living with HIV. Expert Opin Pharmacother. 2022 Sep;23(13):1485–1495.
  • Borch J, Scherzer J, Jonsson-Oldenbuttel C, et al. 6-month outcomes of every 2 months long-acting cabotegravir and rilpivirine in a real-world setting - effectiveness, adherence to injections, and patient- reported outcomes of people living with HIV in the German CARLOS cohort. HIV Glasglow 2022.
  • Christopoulos KA, Grochowski J, Mayorga-Munoz F, et al. First demonstration project of long-acting injectable antiretroviral therapy for persons with and without detectable HIV Viremia in an Urban HIV clinic. Clin Infect Dis. 2022 Aug 1;76(3):e645–e651.
  • Spinelli MA, Grinsztejn B, Landovitz RJ. Promises and challenges: cabotegravir for preexposure prophylaxis. Curr Opin HIV AIDS. 2022 Jul 1;17(4):186–191.
  • Landovitz RJ, Donnell D, Clement ME, et al. Cabotegravir for HIV prevention in cisgender men and transgender women. N Engl J Med. 2021 Aug 12;385(7):595–608.
  • Delany-Moretlwe S, Hughes JP, Bock P, et al. Cabotegravir for the prevention of HIV-1 in women: results from HPTN 084, a phase 3, randomised clinical trial. Lancet. 2022 May 7;399(10337):1779–1789.
  • Jamieson L, Johnson LF, Nichols BE, et al. Relative cost-effectiveness of long-acting injectable cabotegravir versus oral pre-exposure prophylaxis in South Africa based on the HPTN 083 and HPTN 084 trials: a modelled economic evaluation and threshold analysis. Lancet HIV. 2022 Nov 7;9(12):e857–67.
  • Joob B, Wiwanikit V. Changing from tenofovir/emtricitabine to cabotegravir for pre exposure prophylaxis for HIV in men who have sex with men: a cost utility analysis from an endemic country. J Assoc Physicians India. 2022 Feb;70(2):11–12.
  • Neilan AM, Landovitz RJ, Le MH, et al. Cost-effectiveness of long-acting injectable HIV preexposure prophylaxis in the United States: a cost-effectiveness analysis. Ann Intern Med. 2022 Apr;175(4):479–489.
  • Phillips AN, Bansi-Matharu L, Cambiano V, et al. The potential role of long-acting injectable cabotegravir-rilpivirine in the treatment of HIV in sub-Saharan Africa: a modelling analysis. Lancet Glob Health. 2021 May;9(5):e620–e627.
  • Parker B, Ward T, Hayward O, et al. Cost-effectiveness of the long-acting regimen cabotegravir plus rilpivirine for the treatment of HIV-1 and its potential impact on adherence and viral transmission: a modelling study. PLoS One. 2021;16(2):e0245955.
  • Marzinke MA, Grinsztejn B, Fogel JM, et al. Characterization of Human Immunodeficiency Virus (HIV) infection in cisgender men and transgender women who have sex with men receiving injectable cabotegravir for HIV prevention: HPTN 083. J Infect Dis. 2021 Nov 16;224(9):1581–1592.
  • Eshleman SH, Fogel JM, Halvas EK, et al. HIV RNA screening reduces integrase strand transfer inhibitor resistance risk in persons receiving long-acting cabotegravir for HIV prevention. J Infect Dis. 2022 Oct 14;226(12):2170–2180.
  • Oliveira M, Ibanescu RI, Anstett K, et al. Selective resistance profiles emerging in patient-derived clinical isolates with cabotegravir, bictegravir, dolutegravir, and elvitegravir. Retrovirology. 2018 Aug 17;15(1):56.
  • Rhee SY, Parkin N, Harrigan PR, et al. Genotypic correlates of resistance to the HIV-1 strand transfer integrase inhibitor cabotegravir. Antiviral Res. 2022 Sep 30;208:105427.
  • Cutrell AG, Schapiro JM, Perno CF, et al. Exploring predictors of HIV-1 virologic failure to long-acting cabotegravir and rilpivirine: a multivariable analysis. AIDS. 2021 Jul 15;35(9):1333–1342.
  • Thoueille P, Alves Saldanha S, Schaller F, et al. Real-life therapeutic concentration monitoring of long-acting cabotegravir and rilpivirine: preliminary results of an ongoing prospective observational study in Switzerland. Pharmaceutics. 2022 Jul 29;14(8):1588.
  • Han K, Shaik JS, Crauwels H, et al. Pharmacokinetics and tolerability of cabotegravir and rilpivirine long-acting intramuscular injections to the vastus lateralis (lateral thigh) muscles of healthy adult participants. Montreal (Canada): AIDS; 2022.
  • Spreen W, Ford SL, Chen S, et al. GSK1265744 pharmacokinetics in plasma and tissue after single-dose long-acting injectable administration in healthy subjects. J Acquir Immune Defic Syndr. 2014 Dec 15;67(5):481–486.
  • Smith J, Bansi-Matharu L, Cambiano V, et al. Predicted effects of the introduction of long-acting injectable cabotegravir pre-exposure prophylaxis in sub-Saharan Africa: a modelling study. Lancet HIV. 2023 Jan 12;S2352-3018(22):00365–4.
  • Fletcher CV, Staskus K, Wietgrefe SW, et al. Persistent HIV-1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues. Proc Natl Acad Sci U S A. 2014 Feb 11;111(6):2307–2312.
  • Fletcher CV, Kroon E, Schacker T, et al. Persistent HIV transcription and variable antiretroviral drug penetration in lymph nodes during plasma viral suppression. AIDS. 2022 Jun 1;36(7):985–990.
  • Ferrara M, Bumpus NN, Ma Q, et al. Antiretroviral drug concentrations in brain tissue of adult decedents. AIDS. 2020 Nov 1;34(13):1907–1914.
  • Asahchop EL, Meziane O, Mamik MK, et al. Reduced antiretroviral drug efficacy and concentration in HIV-infected microglia contributes to viral persistence in brain. Retrovirology. 2017 Oct 16;14(1):47.
  • Pasternak AO, Vroom J, Kootstra NA, et al. Non-nucleoside reverse transcriptase inhibitor-based combination antiretroviral therapy is associated with lower cell-associated HIV RNA and DNA levels compared to protease inhibitor-based therapy. Elife. 2021 Aug 13;10:e68174.
  • Ferrara M, Cusato J, Salvador E, et al. Inflammation and intracellular exposure of dolutegravir, darunavir, tenofovir and emtricitabine in people living with HIV. Br J Clin Pharmacol. 2022 Sep 17.
  • Deodhar S, Sillman B, Bade AN, et al. Transformation of dolutegravir into an ultra-long-acting parenteral prodrug formulation. Nat Commun. 2022 Jun 9;13(1):3226.
  • Kovarova M, Benhabbour SR, Massud I, et al. Ultra-long-acting removable drug delivery system for HIV treatment and prevention. Nat Commun. 2018 Oct 8;9(1):4156.
  • Sillman B, Bade AN, Dash PK, et al. Creation of a long-acting nanoformulated dolutegravir. Nat Commun. 2018 Feb 6;9(1):443.
  • Maturavongsadit P, Paravyan G, Kovarova M, et al. A new engineering process of biodegradable polymeric solid implants for ultra-long-acting drug delivery. Int J Pharm X. 2021;3:100068.
  • Maturavongsadit P, Shrivastava R, Sykes C, et al. Biodegradable polymeric solid implants for ultra-long-acting delivery of single or multiple antiretroviral drugs. Int J Pharm. 2021 Aug;10(605):120844.
  • Cobb DA, Smith N, Deodhar S, et al. Transformation of tenofovir into stable ProTide nanocrystals with long-acting pharmacokinetic profiles. Nat Commun. 2021 Sep 16;12(1):5458.
  • Landman R, de Truchis P, Assoumou L, et al. A 4-days-on and 3-days-off maintenance treatment strategy for adults with HIV-1 (ANRS 170 QUATUOR): a randomised, open-label, multicentre, parallel, non-inferiority trial. Lancet HIV. 2022 Feb;9(2):e79–e90.
  • Smit PJ, Brady M, Carter M, et al. HIV-related stigma within communities of gay men: a literature review. AIDS Care. 2012;24(4):405–412.
  • Moffatt K, Tekko IA, Vora L, et al. Development and evaluation of dissolving microarray patches for co-administered and repeated intradermal delivery of long-acting rilpivirine and cabotegravir nanosuspensions for paediatric HIV antiretroviral therapy. Pharm Res. 2022 Oct 12;1–24.
  • Wainberg MA, Mesplède T, Raffi F. What if HIV were unable to develop resistance against a new therapeutic agent? BMC Med. 2013;Nov;11:249.
  • Wainberg MA, Mesplede T. Implications for the future of the HIV epidemic if drug resistance against dolutegravir cannot occur in first-line therapy. J Int AIDS Soc. 2015;18:20824.
  • Wainberg MA, Han YS, Mesplède T. Might dolutegravir be part of a functional cure for HIV? Can J Microbiol. 2016 May;62(5):375–382.
  • Mesplède T, Wainberg MA. Resistance against Integrase Strand transfer inhibitors and relevance to HIV persistence. Viruses. 2015. 7. Jul(7):3703–3718.
  • Mesplède T, Wainberg MA. Is resistance to dolutegravir possible when this drug is used in first-line therapy? Viruses. 2014 Aug;6(9):3377–3385.
  • Leone P, Ferro A, Rolle CP, et al. VH3810109 (N6LS) reduces viremia across a range of doses in ART-naive adults living with HIV: proof of concept achieved in the Phase IIa BANNER (207959, NCT04871113) study. HIV Glasgow; 2022.
  • Hassounah SA, Mesplede T, Wainberg MA, et al. Humanized mice for studies of HIV-1 integrase inhibitors: a review. Pathog Immun. 2016;1(1):41–67.
  • Van Rompay KK. The use of nonhuman primate models of HIV infection for the evaluation of antiviral strategies [Review]. AIDS Res Hum Retroviruses. 2012 Jan;28(1):16–35.
  • Van Rompay KKA, Hassounah S, Keele BF, et al. Dolutegravir monotherapy of simian immunodeficiency virus-infected macaques selects for several patterns of resistance mutations with variable virological outcomes. J Virol. 2019 Jan 15;93(2):e01189–18.
  • Vargo R, Robey S, Zang X, et al. Modeling and simulation to optimize islatravir Once Daily (QD) doses in HIV treatment naive and virologically suppressed populations. HIV Glasgow; 2022.
  • Leggat DJ, Cohen KW, Willis JR, et al. Vaccination induces HIV broadly neutralizing antibody precursors in humans. Science. 2022 Dec 2;378(6623):eadd6502.

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