Long-Acting Antiretrovirals: Where Are We now?
- 793 Downloads
Purpose of Review
Current HIV treatment options require daily use of combination antiretroviral drugs. Many persons living with HIV experience treatment fatigue and suboptimal adherence as a result. Long-acting antiretroviral drugs are being developed to expand options for HIV treatment. Here, we review the agents in development, and evaluate data from recent clinical trials. In addition, we anticipate challenges to successful widespread use of long-acting antiretrovirals.
Parenteral nanosuspensions of cabotegravir and rilpivirine, and dapivirine vaginal ring are the farthest in clinical development. Long-acting modalities in earlier development stages employ drug-loaded implants, microparticles, or targeted mutagenesis, among other innovations.
Long-acting antiretroviral drugs promise new options for HIV prevention and treatment, and ways to address poor adherence and treatment fatigue. Further studies will identify the long-acting agents or combinations that are suitable for routine use. Creative solutions will be needed for anticipated implementation challenges.
KeywordsLong-acting antiretrovirals HIV treatment HIV prevention Pre-exposure prophylaxis
Compliance with Ethical Standards
Conflict of Interest
Amesika N. Nyaku and Sean G. Kelly report no conflict.
Babafemi O.Taiwo has served as a consultant to ViiV, GlaxoSmithKline (GSK), and Gilead Sciences, and has received research support to Northwestern University from ViiV Healthcare.
Human and Animal Rights and Informed Consent
This manuscript does not contain studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 2.Wada N, Jacobson LP, Cohen M, French A, Phair J, Munoz A. Cause-specific life expectancies after 35 years of age for human immunodeficiency syndrome-infected and human immunodeficiency syndrome-negative individuals followed simultaneously in long-term cohort studies, 1984-2008. Am J Epidemiol. 2013;177(2):116–25. doi: 10.1093/aje/kws321.CrossRefPubMedPubMedCentralGoogle Scholar
- 6.WHO. Guideline on when to start antiretroviral therapy and on pre-exposure prophylaxis for HIV. 2015. p. 78.Google Scholar
- 12.Nachega JB, Parienti JJ, Uthman OA, Gross R, Dowdy DW, Sax PE, 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):1297–307. doi: 10.1093/cid/ciu046.CrossRefPubMedPubMedCentralGoogle Scholar
- 13.Viswanathan S, Justice AC, Alexander GC, Brown TT, Gandhi NR, McNicholl IR, et al. Adherence and HIV RNA suppression in the current era of highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2015b;69(4):493–8. doi: 10.1097/QAI.0000000000000643.CrossRefPubMedPubMedCentralGoogle Scholar
- 16.Mundhra DB, Pan R. Pharmaceutical Compositions. Google Patents; 2013.Google Scholar
- 18.Ford SL, Chiu J, Lovern M, et al Population PK approach to predict cabotegravir (CAB, GSK1265744) long-acting injectable doses for phase 2b. 54th Interscience Conference on Antimicrobial Agents and Chemotherapy; Washington, DC 2014.Google Scholar
- 19.Culp A, Bowers G, Gould E, et al. Metabolism, excretion, and mass balance of the HIV integrase inhibitor, cabotegravir (GSK1265744) in humans. 54th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2014 September 5–9; Washington, DC. 2014.Google Scholar
- 20.Azijn H, Tirry I, Vingerhoets J, de Bethune MP, Kraus G, Boven K, et al. TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1. Antimicrob Agents Chemother. 2010;54(2):718–27. doi: 10.1128/AAC.00986-09.CrossRefPubMedGoogle Scholar
- 21.Wilkin A, Pozniak AL, Morales-Ramirez J, Lupo SH, Santoscoy M, Grinsztejn B, et al. Long-term efficacy, safety, and tolerability of rilpivirine (RPV, TMC278) in HIV type 1-infected antiretroviral-naive patients: week 192 results from a phase IIb randomized trial. AIDS Res Hum Retrovir. 2012;28(5):437–46. doi: 10.1089/AID.2011.0050.PubMedGoogle Scholar
- 23.Jackson AG, Else LJ, Mesquita PM, Egan D, Back DJ, Karolia Z, et al. A compartmental pharmacokinetic evaluation of long-acting rilpivirine in HIV-negative volunteers for pre-exposure prophylaxis. Clin Pharmacol Ther. 2014;96(3):314–23. doi: 10.1038/clpt.2014.118. This study characterized exposure of different tissue compartments to rilpivirine following administration of the long-acting formulation. CrossRefPubMedGoogle Scholar
- 25.McGowan I, Siegel A, Engstrom J, et al. Persistence of rilpivirine following single dose of long-acting injection. 21st International AIDS Conference (AIDS 2016); Durban, South Africa 2016a.Google Scholar
- 35.Grobler JA, Lai M-T, Barrett SE, Gindy M, Fillgrove K, Ankrom W, et al. Long-acting oral and parenteral dosing of MK-8591 for HIV treatment or prophylaxis In: Conference on Retroviruses and Opportunistic Infections (CROI 2016). Boston, Massachusetts; 2016.Google Scholar
- 36.Friedman E, Schuermann D, Rudd DJ, Fox-Bosetti S, Zhang S, Robberechts M, et al. A single monotherapy dose of MK-8591, a novel NRTI, suppresses HIV for 10 days. In: Conference on Retroviruses and Opportunstic Infections (CROI 2016). Boston, Massachusetts; 2016.Google Scholar
- 37.Krystal M, Wensel D, Sun Y, Davis J, Li Z, McDonagh T, et al. HIV-1 Combinectin BMS-986197: a long-acting inhibitor with multiple modes of action. In: Conference on Retroviruses and Opportunstic Infections (CROI 2016). Boston, Massachusetts; 2016.Google Scholar
- 38.•• Margolis DA, Brinson CC, Smith GH, de Vente J, Hagins DP, Eron JJ, et al. Cabotegravir plus rilpivirine, once a day, after induction with cabotegravir plus nucleoside reverse transcriptase inhibitors in antiretroviral-naive adults with HIV-1 infection (LATTE): a randomised, phase 2b, dose-ranging trial. Lancet Infect Dis. 2015; doi: 10.1016/S1473-3099(15)00152-8. Proof of concept that oral cabotegravir plus rilpivirine is suitable to maintain HIV suppression came from this clinical trial. This paved the way for evaluation of the long-acting formulations of these drugs. PubMedGoogle Scholar
- 39.Margolis DA, González-García J, Stellbrink HJ, J.J E, Yazdanpanah Y, Griffith S et al., editors. Cabotegravir+Rilpivirine as long-acting maintenance therapy: LATTE-2 Week 32 Results. Conference on Retroviruses and Opportunistic Infections; 2016 February 22–25; Boston, MA. 2016a.Google Scholar
- 40.•• Margolis DA, Podzamczer D, Stellbrink H-J, Lutz T, Angel JB, Richmond G et al. Cabotegravir + rilpivirine as long-acting maintenance therapy: LATTE-2 week 48 results. 21st International AIDS Conference (AIDS 2016); Durban, South Africa 2016b. This reported 48 week data on long-acting cabotegravir plus rilpivirine, demonstrating similar efficacy with oral therapy. Google Scholar
- 41.Spreen W, Ford SL, Chen S, Wilfret D, Margolis D, Gould E, et al. GSK1265744 pharmacokinetics in plasma and tissue after single-dose long-acting injectable administration in healthy subjects. J Acquir Immune Defic Syndr. 2014;67(5):481–6. doi: 10.1097/QAI.0000000000000301.CrossRefPubMedGoogle Scholar
- 42.• Radzio J, Spreen W, Yueh YL, Mitchell J, Jenkins L, Garcia-Lerma JG, et al. The long-acting integrase inhibitor GSK744 protects macaques from repeated intravaginal SHIV challenge. Sci Transl Med. 2015;7(270):270ra5. doi: 10.1126/scitranslmed.3010297. This study provided evidence in non-human primates that supported studies of long-acting cabotegravir for PrEP in humans exposed intravaginally to HIV. CrossRefPubMedGoogle Scholar
- 43.Andrews CD, St. Bernard L, Poon A, Spreen W, Gettie A, Russell-Lodrigue K et al. Cabotegravir long-acting injection protects Macaques against intravenous challenge. Conference on Retroviruses and Opportunistic Infections (CROI 2016); Boston, Massachusetts 2016.Google Scholar
- 44.• Andrews CD, Spreen WR, Mohri H, Moss L, Ford S, Gettie A, et al. Long-acting integrase inhibitor protects macaques from intrarectal simian/human immunodeficiency virus. Science. 2014;343(6175):1151–4. doi: 10.1126/science.1248707. This provided evidence in non-human primates that support studies of long-acting cabotegravir for PrEP in humans exposed rectally to HIV. CrossRefPubMedPubMedCentralGoogle Scholar
- 45.Markowitz M, Frank I, Grant R, Mayer KH, Margolis DA, Hudson KJ et al. ÉCLAIR: phase 2A safety and PK study of cabotegravir LA in HIV-uninfected men. Conference on Retroviruses and Opportunistic Infections; Boston, Massachusetts; 2016.Google Scholar
- 46.•• Penrose KJ, Parikh UM, Hamanishi KA, Else L, Back D, Boffito M, et al. Selection of rilpivirine-resistant HIV-1 in a seroconverter from the SSAT 040 trial who received the 300-mg dose of long-acting rilpivirine (TMC278LA). J Infect Dis. 2016;213(6):1013–7. doi: 10.1093/infdis/jiv528. First documented case of NNRTI resistance emergence in a recipient of long-acting rilpivirine for PrEP highlights a potential weakness of long-acting PrEP strategy. CrossRefPubMedGoogle Scholar
- 47.•• McGowan I, Dezzutti CS, Siegel A, Engstrom J, Nikiforov A, Duffill K, et al. Long-acting rilpivirine as potential pre-exposure prophylaxis for HIV-1 prevention (the MWRI-01 study): an open-label, phase 1, compartmental, pharmacokinetic and pharmacodynamic assessment. Lancet HIV. 2016b; doi: 10.1016/S2352-3018(16)30113-8. This study showed lower concentration of rilpivirine and no viral inhibition in female genital tissue in contrast to the findings in rectal tissue. PubMedGoogle Scholar
- 48.•• Baeten JM, Palanee-Phillips T, Brown ER, Schwartz K, Soto-Torres LE, Govender V, et al. Use of a vaginal ring containing dapivirine for HIV-1 prevention in women. N Engl J Med. 2016; doi: 10.1056/NEJMoa1506110. This was the first publication of a large randomized clinical trial that evaluated dapivirine vaginal ring for PrEP. PubMedGoogle Scholar
- 49.Brown E, Palanee-Phillips T, Marzinke M, Hendrix C, Dezutti C, Soto-Torres L et al. Residual dapivirine ring levels indicate higher adherence to vaginal ring is associated with HIV-1 protection. 21st International AIDS Conference (AIDS 2016); Durban, South Africa 2016.Google Scholar
- 50.Nel A, Kapiga S, Bekker L-G, Devlin B, Borremans M, Rosenberg Z et al. Safety and efficacy of dapivirine vaginal ring for HIV-1 prevention in African women. Conference on Retroviruses and Opportunistic Infections (CROI 2016); Boston, Massachusetts 2016a.Google Scholar
- 53.Meyers K, Rodriguez K, Moeller RW, Gratch I, Markowitz M, Halkitis PN. High interest in a long-acting injectable formulation of pre-exposure prophylaxis for HIV in young men who have sex with men in NYC: a P18 cohort substudy. PLoS One. 2014;9(12):e114700. doi: 10.1371/journal.pone.0114700.CrossRefPubMedPubMedCentralGoogle Scholar
- 54.Murray MI, Markowitz M, Frank I, Grant R, Mayer KH, Margolis DA et al. Tolerability and acceptability of cabotegravir LA injection: results from ECLAIR study. Conference on Retroviruses and Opportunistic Infections (CROI 2016); Boston, Massachusetts 2016.Google Scholar
- 55.Nel A, Bekker LG, Bukusi E, Hellstrm E, Kotze P, Louw C, et al. Safety, acceptability and adherence of dapivirine vaginal ring in a microbicide clinical trial conducted in multiple countries in sub-Saharan Africa. PLoS One. 2016b;11(3):e0147743. doi: 10.1371/journal.pone.0147743.CrossRefPubMedPubMedCentralGoogle Scholar