1932

Abstract

Antiretroviral drugs have revolutionized the treatment and prevention of HIV infection; however, adherence is critical for sustained efficacy. Current HIV treatment consists of three-drug regimens, and current HIV pre-exposure prophylaxis (PrEP) consists of a two-drug regimen; both generally require adherence to once-daily dosing. Long-acting formulations are useful in the treatment and prevention of other conditions (e.g., contraceptives, antipsychotics) and help promote adherence. Newer long-acting formulations of approved and investigational antiretroviral drugs in existing and newer mechanistic classes are under study for HIV treatment and prevention, including some phase III trials. Although long-acting antiretroviral drugs hold promise, some clinical challenges exist, including managing side effects, drug-drug interactions, pregnancy, and long-lasting drug concentrations that could lead to the development of drug resistance. This review aims to summarize currently available information on long-acting antiretroviral drugs for HIV treatment and prevention.

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2019-01-27
2024-04-16
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Literature Cited

  1. 1.  Samji H, Cescon A, Hogg RS et al. 2013. Closing the gap: increases in life expectancy among treated HIV-positive individuals in the United States and Canada. PLOS ONE 8:e81355
    [Google Scholar]
  2. 2.  May MT, Gompels M, Delpech V et al. 2014. Impact on life expectancy of HIV-1 positive individuals of CD4+ cell count and viral load response to antiretroviral therapy. AIDS 28:1193–202
    [Google Scholar]
  3. 3.  Lohse N, Obel N 2016. Update of survival for persons with HIV infection in Denmark. Ann. Intern. Med. 165:749–50
    [Google Scholar]
  4. 4. US Dep. Health Hum. Serv. Antiretroviral Ther. Guidel. Panel. 2018. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV AIDSinfo, US Dep. Health Hum. Serv. https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv/0
  5. 5.  Günthard HF, Saag MS, Benson CA et al. 2018. Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2018 recommendations of the International Antiviral Society-USA Panel. JAMA 316:191–210
    [Google Scholar]
  6. 6. EACS (Eur. AIDS Clin. Soc.). 2017. Guidelines, Version 9.1 Eur. AIDS Clin. Soc Brussels, Belg: http://www.eacsociety.org/files/guidelines_9.0-english.pdf
  7. 7. WHO (World Health Organ.). 2016. Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection: Recommendations for a Public Health Approach Geneva: WHO. , 2nd ed.. http://www.who.int/hiv/pub/arv/arv-2016/en/
  8. 8.  Molina JM, Capitant C, Spire B et al. 2015. On-demand preexposure prophylaxis in men at high risk for HIV-1 infection. N. Engl. J. Med. 373:2237–46
    [Google Scholar]
  9. 9.  McCormack S, Dunn DT, Desai M et al. 2016. Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open-label randomised trial. Lancet 387:53–60
    [Google Scholar]
  10. 10.  Amico KR 2012. Adherence to preexposure chemoprophylaxis: the behavioral bridge from efficacy to effectiveness. Curr. Opin. HIV AIDS 7:542–48
    [Google Scholar]
  11. 11.  Swindells S, Flexner C, Fletcher CV et al. 2011. The critical need for alternative antiretroviral formulations, and obstacles to their development. J. Infect. Dis. 204:669–74
    [Google Scholar]
  12. 12.  Williams J, Sayles HR, Meza JL et al. 2013. Long-acting parenteral nanoformulated antiretroviral therapy: interest and attitudes of HIV-infected patients. Nanomedicine 8:1807–13
    [Google Scholar]
  13. 13.  Weld ED, Rana MS, Dallas R et al. 2017. Readiness of youth living with HIV for long-acting antiretrovirals. 9th International AIDS Society Conference on HIV Science July 23–26 Paris (Abstr. TUPEB0460). http://programme.ias2017.org/Abstract/Abstract/245
    [Google Scholar]
  14. 14.  Jacobson JM, Flexner CW 2017. Universal antiretroviral regimens: thinking beyond one-pill-once-a-day. Curr. Opin. HIV AIDS 12:343–50
    [Google Scholar]
  15. 15.  Margolis DA, Gonzalez-Garcia J, Stellbrink HJ et al. 2017. Long-acting intramuscular cabotegravir and rilpivirine in adults with HIV-1 infection (LATTE-2): 96-week results of a randomised, open-label, phase 2b, non-inferiority trial. Lancet 390:1499–1510
    [Google Scholar]
  16. 16.  Winner B, Peipert JF, Zhao Q et al. 2012. Effectiveness of long-acting reversible contraception. N. Engl. J. Med. 366:1998–2007
    [Google Scholar]
  17. 17.  Mäkäräinen L, van Beek A, Tuomivaara L et al. 1998. Ovarian function during the use of a single contraceptive implant: Implanon compared with Norplant. Fertil. Steril. 69:714–21
    [Google Scholar]
  18. 18.  Rattan J, Noznesky E, Curry DW et al. 2016. Rapid contraceptive uptake and changing method mix with high use of long-acting reversible contraceptives in crisis-affected populations in Chad and the Democratic Republic of the Congo. Glob. Health Sci. Pract. 4:Suppl. 2S5–20
    [Google Scholar]
  19. 19.  Fok WK, Blumenthal PD 2017. HIV and contraception. Curr. Opin. Obstet. Gynecol. 29:419–26
    [Google Scholar]
  20. 20.  Scarsi KK, Darin KM, Nakalema S et al. 2016. Unintended pregnancies observed with combined use of the levonorgestrel contraceptive implant and efavirenz-based antiretroviral therapy: a three-arm pharmacokinetic evaluation over 48 weeks. Clin. Infect. Dis. 62:675–82
    [Google Scholar]
  21. 21.  Morris MT, Tarpada SP 2017. Long-acting injectable paliperidone palmitate: a review of efficacy and safety. Psychopharmacol. Bull. 47:42–52
    [Google Scholar]
  22. 22.  Plosker GL, Brogden RN 1994. Leuprorelin. A review of its pharmacology and therapeutic use in prostatic cancer, endometriosis and other sex hormone-related disorders. Drugs 48:930–67
    [Google Scholar]
  23. 23.  Kalra A, Rehman H, Khera S et al. 2017. New-generation coronary stents: current data and future directions. Curr. Atheroscler. Rep. 19:14
    [Google Scholar]
  24. 24.  Yoshinaga T, Kobayashi M, Seki T et al. 2015. Antiviral characteristics of GSK1265744, an HIV integrase inhibitor dosed orally or by long-acting injection. Antimicrob. Agents Chemother. 59:397–406
    [Google Scholar]
  25. 25.  Karmon SL, Mohri H, Spreen W, Markowitz M 2015. GSK1265744 demonstrates robust in vitro activity against various clades of HIV-1. J. Acquir. Immune Defic. Syndr. 68:e39–41
    [Google Scholar]
  26. 26.  Stellbrink HJ, Hoffmann C 2018. Cabotegravir: its potential for antiretroviral therapy and preexposure prophylaxis. Curr. Opin. HIV AIDS 13:334–40
    [Google Scholar]
  27. 27.  Spreen W, Min S, Ford SL et al. 2013. Pharmacokinetics, safety, and monotherapy antiviral activity of GSK1265744, an HIV integrase strand transfer inhibitor. HIV Clin. Trials. 14:192–203
    [Google Scholar]
  28. 28.  Spreen W, Ford SL, Chen S et al. 2014. GSK1265744 pharmacokinetics in plasma and tissue after single-dose long-acting injectable administration in healthy subjects. J. Acquir. Immune Defic. Syndr. 67:481–86
    [Google Scholar]
  29. 29.  Markowitz M, Frank I, Grant RM et al. 2017. Safety and tolerability of long-acting cabotegravir injections in HIV-uninfected men (ECLAIR): a multicentre, double-blind, randomised, placebo-controlled, phase 2a trial. Lancet HIV 4:e331–40
    [Google Scholar]
  30. 30.  Landovitz R, Li S, Grinsztejn B et al. 2017. Safety, tolerability and pharmacokinetics of long-acting injectable cabotegravir in low-risk HIV-uninfected women and men: HPTN 077. 9th International AIDS Society Conference on HIV Science July 23–26, Paris (Abstr. TUAC0106LB). http://programme.ias2017.org/Abstract/Print/?abstractid=5481
  31. 31.  Cohen CJ, Andrade-Villanueva J, Clotet B et al. 2011. Rilpivirine versus efavirenz with two background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naive adults infected with HIV-1 (THRIVE): a phase 3, randomised, non-inferiority trial. Lancet 378:229–37
    [Google Scholar]
  32. 32.  Molina JM, Cahn P, Grinsztejn B et al. 2011. Rilpivirine versus efavirenz with tenofovir and emtricitabine in treatment-naive adults infected with HIV-1 (ECHO): a phase 3 randomised double-blind active-controlled trial. Lancet 378:238–46
    [Google Scholar]
  33. 33.  Williams PE, Crauwels HM, Basstanie ED 2015. Formulation and pharmacology of long-acting rilpivirine. Curr. Opin. HIV AIDS 10:233–38
    [Google Scholar]
  34. 34.  Ferretti F, Boffito M 2018. Rilpivirine long-acting for the prevention and treatment of HIV infection. Curr. Opin. HIV AIDS 13:300–7
    [Google Scholar]
  35. 35.  Verloes R, Deleu S, Niemeijer N et al. 2015. Safety, tolerability and pharmacokinetics of rilpivirine following administration of a long-acting formulation in healthy volunteers. HIV Med 16:477–84
    [Google Scholar]
  36. 36.  Jackson AG, Else LJ, Mesquita PM et al. 2014. A compartmental pharmacokinetic evaluation of long-acting rilpivirine in HIV-negative volunteers for pre-exposure prophylaxis. Clin. Pharmacol. Ther. 96:314–23
    [Google Scholar]
  37. 37.  Penrose KJ, Parikh UM, Hamanishi KA et al. 2016. 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. 213:1013–17
    [Google Scholar]
  38. 38.  McGowan I, Dezzutti CS, Siegel A et al. 2016. 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 3:e569–78
    [Google Scholar]
  39. 39.  Bekker L-G, Li S, Tolley E et al. 2017. HPTN 076: TMC278 LA safe, tolerable and acceptable for HIV pre-exposure prophylaxis. Conference on Retroviruses and Opportunistic Infections February 13–16, Seattle, WA (Abstr. 421LB). http://www.croiconference.org/sessions/hptn-076-tmc278-la-safe-tolerable-and-acceptable-hiv-preexposure-prophylaxis
  40. 40.  Margolis DA, Brinson CC, Smith GHR et al. 2015. 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. 15:1145–55
    [Google Scholar]
  41. 41.  Spreen W, Williams P, Margolis D et al. 2014. Pharmacokinetics, safety, and tolerability with repeat doses of GSK1265744 and rilpivirine (TMC278) long-acting nanosuspensions in healthy adults. J. Acquir. Immune Defic. Syndr. 67:487–92
    [Google Scholar]
  42. 42.  Burkly LC, Olson D, Shapiro R et al. 1992. Inhibition of HIV infection by a novel CD4 domain 2–specific monoclonal antibody. J. Immunol. 149:1779–87
    [Google Scholar]
  43. 43.  Kuritzkes DR, Jacobson JM, Powderly WG et al. 2004. Antiretroviral activity of the anti-CD4 monoclonal antibody TNX-355 in patients infected with human immunodeficiency virus type 1. J. Infect. Dis. 189:286–91
    [Google Scholar]
  44. 44.  Jacobson JM, Kuritzkes DR, Godofsky E et al. 2009. Safety, pharmacokinetics and antiretroviral activity of multiple doses of ibalizumab (formerly TNX-355), an anti-CD4 monoclonal antibody, in HIV-1 infected adults. Antimicrob. Agents Chemother. 53:450–57
    [Google Scholar]
  45. 45.  Emu B, Fessel J, Schrader S et al. 2018. Phase 3 study of ibalizumab for multidrug-resistant HIV-1. N. Engl. J. Med. 379:645–54
    [Google Scholar]
  46. 46.  Murga J, Franti M, Pevear DC et al. 2006. Potent antiviral synergy between monoclonal antibody and small-molecule CCR5 inhibitors of human immunodeficiency virus type 1. Antimicrob. Agents Chemother. 50:3289–96
    [Google Scholar]
  47. 47.  Jacobson JM, Saag MS, Thompson MA et al. 2008. Antiviral activity of single-dose PRO 140, a CCR5 monoclonal antibody, in HIV-infected adults. J. Infect. Dis. 198:1345–52
    [Google Scholar]
  48. 48.  Jacobson JM, Lalezari JP, Thompson MA et al. 2010. Phase 2a study of the CCR5 monoclonal antibody PRO 140 administered intravenously to HIV-infected adults. Antimicrob. Agents Chemother. 54:4137–42
    [Google Scholar]
  49. 49.  Jacobson JM, Thompson MT, Lalezari JP et al. 2010. Anti-HIV activity of weekly or bi-weekly treatment with subcutaneous PRO140, a CCR5 monoclonal antibody. J. Infect. Dis. 201:1481–87
    [Google Scholar]
  50. 50.  Wu H, Yao C, Zhang T et al. 2016. Efficacy and safety of long acting HIV fusion inhibitor albuvirtide in antiretroviral-experienced adults with HIV-1: interim 48 week results from the randomized, controlled, phase 3, non-inferiority TALENT study. HIV Drug Therapy Glasgow, UK: Oct 23–26 (Abstr. O336). http://www.natap.org/2016/GLASGOW/GLASGOW_38.htm
  51. 51.  Markowitz M, Sarafianos SG 2018. 4′-Ethynyl-2-fluoro-2′-deoxyadenosine, MK-8591: a novel HIV-1 reverse transcriptase translocation inhibitor. Curr. Opin. HIV AIDS 13:294–99
    [Google Scholar]
  52. 52.  Bernatchez JA, Paul R, Tchesnokov EP et al. 2015. Derivatives of mesoxalic acid block translocation of HIV-1 reverse transcriptase. J. Biol. Chem. 290:1474–84
    [Google Scholar]
  53. 53.  Stoddart CA, Galkina SA, Joshi P et al. 2015. Oral administration of the nucleoside EFdA (4′-ethynyl-2-fluoro-2′-deoxyadenosine) provides rapid suppression of HIV viremia in humanized mice and favorable pharmacokinetic properties in mice and the rhesus macaque. Antimicrob. Agents Chemother. 59:4190–98
    [Google Scholar]
  54. 54.  Oliveira M, Brenner BG, Xu H et al. 2017. M184I/V substitutions and E138K/M184I/V double substitutions in HIV reverse transcriptase do not significantly affect the antiviral activity of EFdA. J. Antimicrob. Chemother. 72:3008–11
    [Google Scholar]
  55. 55.  Flexner C 2018. Antiretroviral implants for treatment and prevention of HIV infection. Curr. Opin. HIV AIDS 13:374–80
    [Google Scholar]
  56. 56.  Barrett SE, Teller RS, Forster SP et al. 2018. Extended-duration MK-8591-eluting implant as a candidate for HIV treatment and prevention. Antimicrob. Agents Chemother 62:10 In press
    [Google Scholar]
  57. 57.  Cohen YZ, Caskey M 2018. Broadly neutralizing antibodies for treatment and prevention of HIV-1 infection. Curr. Opin. HIV AIDS 13:366–73
    [Google Scholar]
  58. 58.  Koup R 2018. New-generation high-potency and designer antibodies: role in HIV treatment. Annu. Rev. Med. 69:409–19
    [Google Scholar]
  59. 59.  Gautam R, Nishimura Y, Gaughan N et al. 2018. A single injection of crystallizable fragment domain–modified antibodies elicits durable protection from SHIV infection. Nat. Med. 24:610–16
    [Google Scholar]
  60. 60.  Chen J, Flexner C, Liberman RG et al. 2012. Biphasic elimination of tenofovir diphosphate and nonlinear pharmacokinetics of zidovudine triphosphate in a microdosing study. J. Acquir. Immune Defic. Syndr. 61:593–99
    [Google Scholar]
  61. 61.  Ruane PJ, DeJesus E, Berger D et al. 2013. Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of tenofovir alafenamide as 10-day monotherapy in HIV-1-positive adults. J. Acquir. Immune Defic. Syndr. 63:449–55
    [Google Scholar]
  62. 62.  Sax PE, Wohl D, Yin MT et al. 2015. Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-blind, phase 3, non-inferiority trials. Lancet 385:2606–15
    [Google Scholar]
  63. 63.  Gunawardana M, Remedios-Chan M, Miller CS et al. 2015. Pharmacokinetics of long-acting tenofovir alafenamide (GS-7340) subdermal implant for HIV prophylaxis. Antimicrob. Agents Chemother. 59:3913–19
    [Google Scholar]
  64. 64.  Mackman RL, Ray AS, Hui HC et al. 2010. Discovery of GS-9131: design, synthesis and optimization of amidate prodrugs of the novel nucleoside phosphonate HIV reverse transcriptase (RT) inhibitor GS-9148. Bioorg. Med. Chem. 18:3606–17
    [Google Scholar]
  65. 65.  Murphy R, Kravchenko AV, Orlova-Morozova E et al. 2017. Elsulfavirine as compared to efavirenz in combination with TDF/FTC: 48-week study. Conference on Retroviruses and Opportunistic Infections Feb 13–16 Seattle, WA. (Abstr. 452LB)
  66. 66.  Al-Salama ZT 2017. Elsulfavirine: first global approval. Drugs 77:1811–16
    [Google Scholar]
  67. 67.  Rogovoy B, Koryakova A, Karapetian R et al. 2017. Preclinical development of elsulfavirine/VM1500A long acting injectable formulations. 16th European AIDS Conference European AIDS Clinical Society, Oct 25–27 Milan. (Abstr. PE7/3)
  68. 68.  Murphy RL, Sanne I, Cahn P et al. 2003. Dose-ranging, randomized, clinical trial of atazanavir with lamivudine and stavudine in antiretroviral-naive subjects: 48-week results. AIDS 17:2603–14
    [Google Scholar]
  69. 69.  Squires K, Lazzarin A, Gatell JM et al. 2004. Comparison of once-daily atazanavir with efavirenz, each in combination with fixed-dose zidovudine and lamivudine, as initial therapy for patients infected with HIV. J. Acquir. Immune Defic. Syndr. 36:1011–19
    [Google Scholar]
  70. 70.  Gautam N, Roy U, Balkundi S et al. 2013. Preclinical pharmacokinetics and tissue distribution of long-acting nanoformulated antiretroviral therapy. Antimicrob. Agents Chemother. 57:3110–20
    [Google Scholar]
  71. 71.  Lennox JL, DeJesus E, Lazzarin A et al. 2009. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet 374:796–806
    [Google Scholar]
  72. 72.  Kovarova M, Swanson MD, Sanchez RI et al. 2016. A long-acting formulation of the integrase inhibitor raltegravir protects humanized BLT mice from repeated high-dose vaginal HIV challenges. J. Antimicrob. Chemother. 71:1586–96
    [Google Scholar]
  73. 73.  Wensel D, Sun Y, Li Z et al. 2017. Discovery and characterization of a novel CD4-binding Adnectin with potent anti-HIV activity. Antimicrob. Agents Chemother. 61:e00508–17
    [Google Scholar]
  74. 74.  Krystal M, Wensel D, Sun Y et al. 2016. HIV-1 Combinectin BMS-986197: a long-acting inhibitor with multiple modes of action. Conference on Retroviruses and Opportunistic Infections Feb 22–25 Boston, MA: Abstr. 97
  75. 75.  Tse WC, Link JO, Mulato A et al. 2017. Discovery of novel potent HIV capsid inhibitors with long-acting potential. Conference on Retroviruses and Opportunistic Infections Feb 13–16 Seattle, WA: Abstr. 38
  76. 76.  Perrier M, Bertine M, Le Hingrat Q et al. 2017. Prevalence of gag mutations associated with in vitro resistance to capsid inhibitor GS-CA1 in HIV-1 antiretroviral-naive patients. J. Antimicrob. Chemother. 72:2954–55
    [Google Scholar]
  77. 77.  Kalra A, Rehman H, Khera S et al. 2017. New-generation coronary stents: current data and future directions. Curr. Atheroscler. Rep. 19:14
    [Google Scholar]
  78. 78.  Moffatt K, Wang Y, Raj Singh TR, Donnelly RF 2017. Microneedles for enhanced transdermal and intraocular drug delivery. Curr. Opin. Pharmacol. 36:14–21
    [Google Scholar]
  79. 79.  Kirtane AR, Abouzid O, Minahan D et al. 2018. Development of an oral once-weekly drug delivery system for HIV antiretroviral therapy. Nat. Commun. 9:2
    [Google Scholar]
  80. 80.  Swindells S, Siccardi M, Barrett SE et al. 2018. Long-acting formulations for the treatment of latent tuberculous infection: opportunities and challenges. Int. J. Tuberc. Lung Dis. 22:125–32
    [Google Scholar]
  81. 81.  Swindells S, Ramchandani R, Gupta A et al. 2018. One month of rifapentine/isoniazid to prevent TB in people with HIV: BRIEF-TB/A5279. Conference on Retroviruses and Opportunistic Infections Mar 4–7 Boston, MA: Abstr. 37LB
  82. 82.  Bakshi RP, Tatham LM, Savage AC et al. 2018. Long-acting injectable atovaquone nanomedicines for malaria prophylaxis. Nat. Commun. 9:315
    [Google Scholar]
  83. 83.  McCracken JL, Veeranki SP, Ameredes BT, Calhoun WJ 2017. Diagnosis and management of asthma in adults: a review. JAMA 318:279–90
    [Google Scholar]
  84. 84.  Genovese S, Mannucci E, Ceriello A 2017. A review of the long-term efficacy, tolerability, and safety of exenatide once weekly for type 2 diabetes. Adv. Ther. 34:1791–814
    [Google Scholar]
  85. 85.  Pucci G, Cicero AF, Borghi C, Schillaci G 2017. Emerging biologic therapies for hypercholesterolaemia. Expert Opin. Biol. Ther. 17:1077–87
    [Google Scholar]
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