Current HIV/AIDS Reports

, Volume 14, Issue 2, pp 63–71 | Cite as

Long-Acting Antiretrovirals: Where Are We now?

  • Amesika N Nyaku
  • Sean G Kelly
  • Babafemi O Taiwo
HIV Pathogenesis and Treatment (AL Landay and N Utay, Section Editors)
Part of the following topical collections:
  1. Topical Collection on HIV Pathogenesis and Treatment

Abstract

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.

Recent Findings

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.

Summary

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.

Keywords

Long-acting antiretrovirals HIV treatment HIV prevention Pre-exposure prophylaxis 

Notes

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.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Walensky RP, Paltiel AD, Losina E, Mercincavage LM, Schackman BR, Sax PE, et al. The survival benefits of AIDS treatment in the United States. J Infect Dis. 2006;194(1):11–9. doi: 10.1086/505147.CrossRefPubMedGoogle Scholar
  2. 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
  3. 3.
    Samji H, Cescon A, Hogg RS, Modur SP, Althoff KN, Buchacz K, et al. Closing the gap: increases in life expectancy among treated HIV-positive individuals in the United States and Canada. PLoS One. 2013;8(12):e81355. doi: 10.1371/journal.pone.0081355.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Wada N, Jacobson LP, Cohen M, French A, Phair J, Munoz A. Cause-specific mortality among HIV-infected individuals, by CD4(+) cell count at HAART initiation, compared with HIV-uninfected individuals. AIDS. 2014;28(2):257–65. doi: 10.1097/QAD.0000000000000078.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Ortego C, Huedo-Medina TB, Llorca J, Sevilla L, Santos P, Rodriguez E, et al. Adherence to highly active antiretroviral therapy (HAART): a meta-analysis. AIDS Behav. 2011;15(7):1381–96. doi: 10.1007/s10461-011-9942-x.CrossRefPubMedGoogle Scholar
  6. 6.
    WHO. Guideline on when to start antiretroviral therapy and on pre-exposure prophylaxis for HIV. 2015. p. 78.Google Scholar
  7. 7.
    Amico KR, Stirratt MJ. Adherence to preexposure prophylaxis: current, emerging, and anticipated bases of evidence. Clin Infect Dis. 2014;59(Suppl 1):S55–60. doi: 10.1093/cid/ciu266.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Gonzalez JS, Batchelder AW, Psaros C, Safren SA. Depression and HIV/AIDS treatment nonadherence: a review and meta-analysis. J Acquir Immune Defic Syndr. 2011;58(2):181–7. doi: 10.1097/QAI.0b013e31822d490a.CrossRefPubMedGoogle Scholar
  9. 9.
    Viswanathan S, Detels R, Mehta SH, Macatangay BJ, Kirk GD, Jacobson LP. Level of adherence and HIV RNA suppression in the current era of highly active antiretroviral therapy (HAART). AIDS Behav. 2015a;19(4):601–11. doi: 10.1007/s10461-014-0927-4.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Leaver CA, Bargh G, Dunn JR, Hwang SW. The effects of housing status on health-related outcomes in people living with HIV: a systematic review of the literature. AIDS Behav. 2007;11(6 Suppl):85–100. doi: 10.1007/s10461-007-9246-3.CrossRefPubMedGoogle Scholar
  11. 11.
    Waddell EN, Messeri PA. Social support, disclosure, and use of antiretroviral therapy. AIDS Behav. 2006;10(3):263–72. doi: 10.1007/s10461-005-9042-x.CrossRefPubMedGoogle Scholar
  12. 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. 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
  14. 14.
    Muller RH, Gohla S, Keck CM. State of the art of nanocrystals—special features, production, nanotoxicology aspects and intracellular delivery. Eur J Pharm Biopharm. 2011;78(1):1–9. doi: 10.1016/j.ejpb.2011.01.007.CrossRefPubMedGoogle Scholar
  15. 15.
    Ford SL, Gould E, Chen S, Margolis D, Spreen W, Crauwels H, et al. Lack of pharmacokinetic interaction between rilpivirine and integrase inhibitors dolutegravir and GSK1265744. Antimicrob Agents Chemother. 2013;57(11):5472–7. doi: 10.1128/AAC.01235-13.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Mundhra DB, Pan R. Pharmaceutical Compositions. Google Patents; 2013.Google Scholar
  17. 17.
    Spreen W, Min S, Ford SL, Chen S, Lou Y, Bomar M, et al. Pharmacokinetics, safety, and monotherapy antiviral activity of GSK1265744, an HIV integrase strand transfer inhibitor. HIV Clin Trials. 2013;14(5):192–203. doi: 10.1310/hct1405-192.CrossRefPubMedGoogle Scholar
  18. 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. 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. 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. 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
  22. 22.
    Williams PE, Crauwels HM, Basstanie ED. Formulation and pharmacology of long-acting rilpivirine. Curr Opin HIV AIDS. 2015;10(4):233–8. doi: 10.1097/coh.0000000000000164.CrossRefPubMedGoogle Scholar
  23. 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
  24. 24.
    Verloes R, Deleu S, Niemeijer N, Crauwels H, Meyvisch P, Williams P. Safety, tolerability and pharmacokinetics of rilpivirine following administration of a long-acting formulation in healthy volunteers. HIV Med. 2015;16(8):477–84. doi: 10.1111/hiv.12247.CrossRefPubMedGoogle Scholar
  25. 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
  26. 26.
    Malcolm RK, Fetherston SM, McCoy CF, Boyd P, Major I. Vaginal rings for delivery of HIV microbicides. Int J Womens Health. 2012;4:595–605. doi: 10.2147/IJWH.S36282.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Nel A, Haazen W, Nuttall J, Romano J, Rosenberg Z, van Niekerk N. A safety and pharmacokinetic trial assessing delivery of dapivirine from a vaginal ring in healthy women. AIDS. 2014;28(10):1479–87. doi: 10.1097/QAD.0000000000000280.CrossRefPubMedGoogle Scholar
  28. 28.
    Gunawardana M, Remedios-Chan M, Miller CS, Fanter R, Yang F, Marzinke MA, et al. Pharmacokinetics of long-acting tenofovir alafenamide (GS-7340) subdermal implant for HIV prophylaxis. Antimicrob Agents Chemother. 2015;59(7):3913–9. doi: 10.1128/AAC.00656-15.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Cortez Jr JM, Quintero R, Moss JA, Beliveau M, Smith TJ, Baum MM. Pharmacokinetics of injectable, long-acting nevirapine for HIV prophylaxis in breastfeeding infants. Antimicrob Agents Chemother. 2015;59(1):59–66. doi: 10.1128/AAC.03906-14.CrossRefPubMedGoogle Scholar
  30. 30.
    Zhou T, Georgiev I, Wu X, Yang ZY, Dai K, Finzi A, et al. Structural basis for broad and potent neutralization of HIV-1 by antibody VRC01. Science. 2010;329(5993):811–7. doi: 10.1126/science.1192819.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Ko SY, Pegu A, Rudicell RS, Yang ZY, Joyce MG, Chen X, et al. Enhanced neonatal Fc receptor function improves protection against primate SHIV infection. Nature. 2014;514(7524):642–5. doi: 10.1038/nature13612.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Gautam N, Roy U, Balkundi S, Puligujja P, Guo D, Smith N, et al. Preclinical pharmacokinetics and tissue distribution of long-acting nanoformulated antiretroviral therapy. Antimicrob Agents Chemother. 2013;57(7):3110–20.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Puligujja P, Balkundi SS, Kendrick LM, Baldridge HM, Hilaire JR, Bade AN, et al. Pharmacodynamics of long-acting folic acid-receptor targeted ritonavir-boosted atazanavir nanoformulations. Biomaterials. 2015;41:141–50.CrossRefPubMedGoogle Scholar
  34. 34.
    Kovarova M, Swanson MD, Sanchez RI, Baker CE, Steve J, Spagnuolo RA, et al. A long-acting formulation of the integrase inhibitor raltegravir protects humanized BLT mice from repeated high-dose vaginal HIV challenges. J Antimicrob Chemother. 2016;71(6):1586–96.CrossRefPubMedGoogle Scholar
  35. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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
  51. 51.
    Williams J, Sayles HR, Meza JL, Sayre P, Sandkovsky U, Gendelman HE, et al. Long-acting parenteral nanoformulated antiretroviral therapy: interest and attitudes of HIV-infected patients. Nanomedicine (London, England). 2013;8(11):1807–13. doi: 10.2217/nnm.12.214.CrossRefGoogle Scholar
  52. 52.
    Altice FL, Kamarulzaman A, Soriano VV, Schechter M, Friedland GH. Treatment of medical, psychiatric, and substance-use comorbidities in people infected with HIV who use drugs. Lancet (London, England). 2010;376(9738):367–87. doi: 10.1016/s0140-6736(10)60829-x.CrossRefGoogle Scholar
  53. 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. 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. 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
  56. 56.
    Ross EL, Weinstein MC, Schackman BR, Sax PE, Paltiel AD, Walensky RP, et al. The clinical role and cost-effectiveness of long-acting antiretroviral therapy. Clin Infect Dis. 2015;60(7):1102–10. doi: 10.1093/cid/ciu1159.PubMedPubMedCentralGoogle Scholar
  57. 57.
    Walensky RP, Jacobsen MM, Bekker LG, Parker RA, Wood R, Resch SC, et al. Potential clinical and economic value of long-acting preexposure prophylaxis for south African women at high-risk for HIV infection. J Infect Dis. 2016;213(10):1523–31. doi: 10.1093/infdis/jiv523.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Amesika N Nyaku
    • 1
  • Sean G Kelly
    • 2
  • Babafemi O Taiwo
    • 3
    • 4
  1. 1.Division of Infectious Diseases, Department of MedicineRutgers-New Jersey Medical SchoolNewarkUSA
  2. 2.Division of Infectious Diseases, Department of MedicineVanderbilt UniversityNashvilleUSA
  3. 3.Division of Infectious Diseases, Department of Medicine, Northwestern University Feinberg School of Medicine & Center for Global HealthNorthwestern University Feinberg School of MedicineChicagoUSA
  4. 4.Division of Infectious Diseases, Department of Medicine, Feinberg School of MedicineNorthwestern UniversityChicagoUSA

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