Advertisement

Drugs

, Volume 79, Issue 6, pp 609–619 | Cite as

Drug Resistance During HIV Pre-Exposure Prophylaxis

  • Kevin M. Gibas
  • Polly van den Berg
  • Victoria E. Powell
  • Douglas S. KrakowerEmail author
Leading Article

Abstract

Clinical studies have demonstrated that use of tenofovir disoproxil fumarate with or without emtricitabine as antiretroviral pre-exposure prophylaxis (PrEP) can decrease the risk of human immunodeficiency virus (HIV) acquisition when medication adherence is high. However, the potential for PrEP to promote antiretroviral resistance remains an important public health consideration. We performed a search of the medical literature to identify studies that address HIV drug resistance during PrEP use. In this review, we summarize findings about emergent drug resistance during clinical trials of PrEP, case reports of seroconversions in patients adherent to PrEP, and animal studies of PrEP effectiveness against drug-resistant viral strains. We also discuss the potential utility of novel PrEP formulations for protection against drug-resistant HIV, the impact of drug resistance on HIV treatment options, and mathematical models that estimate the potential contribution of PrEP to population-level drug resistance. Evidence suggests that selection for HIV drug resistance with PrEP use is infrequent and most likely to occur when PrEP is used during undiagnosed acute HIV infection. Breakthrough infections during PrEP use with high adherence are possible, but appear to be rare. The prevalence of drug-resistant HIV strains needs to be monitored as PrEP is scaled up. However, the benefit of a decreased HIV incidence with wider PrEP use is likely to outweigh the risk of harms from possible increases in the prevalence of HIV drug resistance.

Notes

Compliance with Ethical Standards

Funding

This article was made possible with help from the Harvard University Center for AIDS Research (CFAR), a National Institutes of Health-funded program (P30 AI060354).

Conflict of interest

Douglas S. Krakower has conducted studies funded by research grants to his institution from Gilead Sciences and has been compensated to author or present continuing medical education materials for Medscape, MED-IQ, DKBmed, and UptoDate, Inc. Kevin M. Gibas, Polly van den Berg, and Victoria E. Powell have no conflicts of interest that are directly relevant to the content of this article.

References

  1. 1.
    UNAIDS. Global HIV & AIDS statistics: 2018 fact sheet. http://www.unaids.org/en/resources/fact-sheet. Accessed 15 Nov 2018.
  2. 2.
    Centers for Disease Control and Prevention. HIV in the United States: at a glance. 2018. https://www.cdc.gov/hiv/statistics/overview/ataglance.html. Accessed 15 Nov 2018.
  3. 3.
    Grant RM, Lama JR, Anderson PL, McMahan V, Liu AY, Vargas L, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010;363(27):2587–99.CrossRefGoogle Scholar
  4. 4.
    Thigpen MC, Kebaabetswe PM, Paxton LA, Smith DK, Rose CE, Segolodi TM, et al. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N Engl J Med. 2012;367(5):423–34.CrossRefGoogle Scholar
  5. 5.
    Choopanya K, Martin M, Suntharasamai P, Sangkum U, Mock PA, Leethochawalit M, et al. Antiretroviral prophylaxis for HIV infection in injecting drug users in Bangkok, Thailand (the Bangkok Tenofovir Study): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2013;381(9883):2083–90.CrossRefGoogle Scholar
  6. 6.
    Baeten JM, Donnell D, Ndase P, Mugo NR, Campbell JD, Wangisi J, et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med. 2012;367(5):399–410.CrossRefGoogle Scholar
  7. 7.
    Dimitrov DT, Boily M-C, Hallett TB, Albert J, Boucher C, Mellors JW, et al. How much do we know about drug resistance due to PrEP use? Analysis of experts’ opinion and its influence on the projected public health impact. PLoS One. 2016;11(7):e0158620.CrossRefGoogle Scholar
  8. 8.
    Liegler T, Abdel-Mohsen M, Bentley LG, Atchison R, Schmidt T, Javier J, et al. HIV-1 drug resistance in the iPrEx preexposure prophylaxis trial. J Infect Dis. 2014;210(8):1217–27.CrossRefGoogle Scholar
  9. 9.
    Lehman DA, Baeten JM, McCoy CO, Weis JF, Peterson D, Mbara G, et al. Risk of drug resistance among persons acquiring HIV within a randomized clinical trial of single-or dual-agent preexposure prophylaxis. J Infect Dis. 2015;211(8):1211–8.Google Scholar
  10. 10.
    Baeten JM, Donnell D, Mugo NR, Ndase P, Thomas KK, Campbell JD, et al. Single-agent tenofovir versus combination emtricitabine plus tenofovir for pre-exposure prophylaxis for HIV-1 acquisition: an update of data from a randomised, double-blind, phase 3 trial. Lancet Infect Dis. 2014;14(11):1055–64.CrossRefGoogle Scholar
  11. 11.
    Van Damme L, Corneli A, Ahmed K, Agot K, Lombaard J, Kapiga S, et al. Preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2012;367(5):411–22.CrossRefGoogle Scholar
  12. 12.
    Chirwa LI, Johnson JA, Niska RW, Segolodi TM, Henderson FL, Rose CE, et al. CD4 + cell count, viral load, and drug resistance patterns among heterosexual breakthrough HIV infections in a study of oral preexposure prophylaxis. AIDS. 2014;28(2):223–6.CrossRefGoogle Scholar
  13. 13.
    Marrazzo JM, Ramjee G, Richardson BA, Gomez K, Mgodi N, Nair G, et al. Tenofovir-based preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2015;372(6):509–18.CrossRefGoogle Scholar
  14. 14.
    Molina J-M, Capitant C, Spire B, Pialoux G, Cotte L, Charreau I, et al. On-demand preexposure prophylaxis in men at high risk for HIV-1 infection. N Engl J Med. 2015;373(23):2237–46.CrossRefGoogle Scholar
  15. 15.
    Delaugerre C, Rodriguez C, Capitant C, Nere M-L, Mercier-Darty M, Carette D, et al. Drug resistance among patients who acquired HIV infection in a preexposure prophylaxis trial. AIDS. 2018;32(16):2353–61.Google Scholar
  16. 16.
    Sivay MV, Li M, Piwowar-Manning E, Zhang Y, Hudelson SE, Marzinke MA, et al. Characterization of HIV seroconverters in a TDF/FTC PrEP study: HPTN 067/ADAPT. J Acquir Immune Defic Syndr. 2017;75(3):271–9.CrossRefGoogle Scholar
  17. 17.
    Baeten JM, Heffron R, Kidoguchi L, Mugo NR, Katabira E, Bukusi EA, et al. Integrated delivery of antiretroviral treatment and pre-exposure prophylaxis to HIV-1-serodiscordant couples: a prospective implementation study in Kenya and Uganda. PLoS Med. 2016;13(8):e1002099.CrossRefGoogle Scholar
  18. 18.
    Grant RM, Anderson PL, McMahan V, Liu A, Amico KR, Mehrotra M, et al. Uptake of pre-exposure prophylaxis, sexual practices, and HIV incidence in men and transgender women who have sex with men: a cohort study. Lancet Infect Dis. 2014;14(9):820–9.CrossRefGoogle Scholar
  19. 19.
    Hosek S, Rudy B, Landovitz R, Kapogiannis B, Siberry G, Rutledge B, et al. An HIV pre-exposure prophylaxis (PrEP) demonstration project and safety study for young MSM. J Acquir Immune Defic Syndr. 2017;74(1):21.CrossRefGoogle Scholar
  20. 20.
    McCormack S, Dunn DT, Desai M, Dolling DI, Gafos M, Gilson R, et al. 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. 2016;387(10013):53–60.CrossRefGoogle Scholar
  21. 21.
    Grohskopf LA, Chillag KL, Gvetadze R, Liu AY, Thompson M, Mayer KH, et al. Randomized trial of clinical safety of daily oral tenofovir disoproxil fumarate among HIV-uninfected men who have sex with men in the United States. J Acquir Immune Defic Syndr. 2013;64(1):79–86.CrossRefGoogle Scholar
  22. 22.
    Peterson L, Taylor D, Roddy R, Belai G, Phillips P, Nanda K, et al. Tenofovir disoproxil fumarate for prevention of HIV infection in women: a phase 2, double-blind, randomized, placebo-controlled trial. PLoS Clin Trials. 2007;2(5):e27.CrossRefGoogle Scholar
  23. 23.
    Mutua G, Sanders E, Mugo P, Anzala O, Haberer JE, Bangsberg D, et al. Safety and adherence to intermittent pre-exposure prophylaxis (PrEP) for HIV-1 in African men who have sex with men and female sex workers. PLoS One. 2012;7(4):e33103.CrossRefGoogle Scholar
  24. 24.
    Kibengo FM, Ruzagira E, Katende D, Bwanika AN, Bahemuka U, Haberer JE, et al. Safety, adherence and acceptability of intermittent tenofovir/emtricitabine as HIV pre-exposure prophylaxis (PrEP) among HIV-uninfected Ugandan volunteers living in HIV-serodiscordant relationships: a randomized, clinical trial. PLoS One. 2013;8(9):e74314.CrossRefGoogle Scholar
  25. 25.
    Heffron R, Ngure K, Odoyo J, Bulya N, Tindimwebwa E, Hong T, et al. Pre-exposure prophylaxis for HIV-negative persons with partners living with HIV: uptake, use, and effectiveness in an open-label demonstration project in East Africa. Gates Open Res. 2017;1:3.CrossRefGoogle Scholar
  26. 26.
    Grant RM, Liegler T, Defechereux P, Kashuba AD, Taylor D, Abdel-Mohsen M, et al. Drug resistance and plasma viral RNA level after ineffective use of oral pre-exposure prophylaxis in women. AIDS. 2015;29(3):331–7.CrossRefGoogle Scholar
  27. 27.
    Clutter DS, Jordan MR, Bertagnolio S, Shafer RW. HIV-1 drug resistance and resistance testing. Infect Genet Evol. 2016;46:292–307.CrossRefGoogle Scholar
  28. 28.
    Fonner VA, Dalglish SL, Kennedy CE, Baggaley R, O’reilly KR, Koechlin FM, Koechlin FM, et al. Effectiveness and safety of oral HIV preexposure prophylaxis for all populations. AIDS. 2016;30(12):1973–83.CrossRefGoogle Scholar
  29. 29.
    Corneli AL, Deese J, Wang M, Taylor D, Ahmed K, Agot K, et al. FEM-PrEP: adherence patterns and factors associated with adherence to a daily oral study product for pre-exposure prophylaxis. J Acquir Immune Defic Syndr. 2014;66(3):324–31.CrossRefGoogle Scholar
  30. 30.
    Cong M-E, Youngpairoj AS, Zheng Q, Aung W, Mitchell J, Sweeney E, et al. Protection against rectal transmission of an emtricitabine-resistant simian/human immunodeficiency virus SHIV162p3M184V mutant by intermittent prophylaxis with Truvada. J Virol. 2011;85(15):7933–6.CrossRefGoogle Scholar
  31. 31.
    Cong M-E, Mitchell J, Sweeney E, Bachman S, Hanson DL, Heneine W, et al. Prophylactic efficacy of oral emtricitabine and tenofovir disoproxil fumarate combination therapy against a tenofovir-resistant simian/human immunodeficiency virus containing the K65R mutation in macaques. J Infect Dis. 2013;208(3):463–7.CrossRefGoogle Scholar
  32. 32.
    Knox DC, Anderson PL, Harrigan PR, Tan DH. Multidrug-resistant HIV-1 infection despite preexposure prophylaxis. N Engl J Med. 2017;376(5):501–2.CrossRefGoogle Scholar
  33. 33.
    Colby DJ, Kroon E, Sacdalan C, Gandhi M, Grant RM, Phanuphak P, et al. Acquisition of multidrug-resistant human immunodeficiency virus type 1 infection in a patient taking preexposure prophylaxis. Clin Infect Dis. 2018;67(6):962–4.CrossRefGoogle Scholar
  34. 34.
    Thaden JT, Gandhi M, Okochi H, Hurt CB, McKellar MS. Seroconversion on preexposure prophylaxis: a case report with segmental hair analysis for timed adherence determination. AIDS. 2018;32(9):F1–4.CrossRefGoogle Scholar
  35. 35.
    Markowitz M, Grossman H, Anderson PL, Grant R, Gandhi M, Horng H, et al. Newly acquired infection with multidrug-resistant HIV-1 in a patient adherent to preexposure prophylaxis. J Acquire Immune Defic Syndr. 2017;76(4):e104–6.CrossRefGoogle Scholar
  36. 36.
    Cohen SE, Sachdev D, Lee SA, Scheer S, Bacon O, Chen M-J, et al. Acquisition of tenofovir-susceptible, emtricitabine-resistant HIV despite high adherence to daily pre-exposure prophylaxis: a case report. Lancet HIV. 2019;6(1):e43–50.CrossRefGoogle Scholar
  37. 37.
    Hoornenborg E, Prins M, Achterbergh RC, Woittiez LR, Cornelissen M, Jurriaans S, et al. Acquisition of wild-type HIV-1 infection in a patient on pre-exposure prophylaxis with high intracellular concentrations of tenofovir diphosphate: a case report. Lancet HIV. 2017;4(11):e522–8.CrossRefGoogle Scholar
  38. 38.
    Parikh U. Sensitive next-generation sequencing of HIV-1 from seroconverters in the MTN-020/ASPIRE Dapivirine Vaginal Ring Study. HIV Research for Prevention (HIVR4P) Conference; 21–25 Oct 2018; Madrid.Google Scholar
  39. 39.
    Nel A, van Niekerk N, Kapiga S, Bekker L-G, Gama C, Gill K, et al. Safety and efficacy of a dapivirine vaginal ring for HIV prevention in women. N Engl J Med. 2016;375(22):2133–43.CrossRefGoogle Scholar
  40. 40.
    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;375(22):2121–32.CrossRefGoogle Scholar
  41. 41.
    Weis JF, Baeten JM, McCoy CO, Warth C, Donnell D, Thomas KK, et al. Preexposure prophylaxis-selected drug resistance decays rapidly after drug cessation. AIDS. 2016;30(1):31–5.CrossRefGoogle Scholar
  42. 42.
    Supervie V, García-Lerma JG, Heneine W, Blower S. HIV, transmitted drug resistance, and the paradox of preexposure prophylaxis. Proc Natl Acad Sci USA. 2010;107(27):12381–6.CrossRefGoogle Scholar
  43. 43.
    Baggaley RF, Powers KA, Boily M-C. What do mathematical models tell us about the emergence and spread of drug-resistant HIV? Curr Opin HIV AIDS. 2011;6(2):131–40.CrossRefGoogle Scholar
  44. 44.
    Supervie V, Barrett M, Kahn JS, Musuka G, Moeti TL, Busang L, et al. Modeling dynamic interactions between pre-exposure prophylaxis interventions and treatment programs: predicting HIV transmission & resistance. Sci Rep. 2011;1:185.CrossRefGoogle Scholar
  45. 45.
    Abbas UL, Hood G, Wetzel AW, Mellors JW. Factors influencing the emergence and spread of HIV drug resistance arising from rollout of antiretroviral pre-exposure prophylaxis (PrEP). PLoS One. 2011;6(4):e18165.CrossRefGoogle Scholar
  46. 46.
    Abbas UL, Glaubius R, Mubayi A, Hood G, Mellors JW. Antiretroviral therapy and pre-exposure prophylaxis: combined impact on HIV transmission and drug resistance in South Africa. J Infect Dis. 2013;208(2):224–34.CrossRefGoogle Scholar
  47. 47.
    Parikh UM, Mellors JW. Should we fear resistance from tenofovir/emtricitabine PrEP? Curr Opin HIV AIDS. 2016;11(1):49–55.CrossRefGoogle Scholar
  48. 48.
    ClinicalTrials.gov. HPTN 083: a phase 2b/3 double blind safety and efficacy study of injectable cabotegravir compared to daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), for pre-exposure prophylaxis in HIV-uninfected cisgender men and transgender women who have sex with men. https://clinicaltrials.gov/ct2/show/NCT02720094. Accessed 01 Mar 2019.
  49. 49.
    Grulich AE, Guy R, Amin J, Jin F, Selvey C, Holden J, et al. Population-level effectiveness of rapid, targeted, high-coverage roll-out of HIV pre-exposure prophylaxis in men who have sex with men: the EPIC-NSW prospective cohort study. Lancet HIV. 2018;5(11):e629–37.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Division of Infectious DiseasesBeth Israel Deaconess Medical CenterBostonUSA
  2. 2.The Fenway Institute, Fenway HealthBostonUSA
  3. 3.Department of Population MedicineHarvard Medical SchoolBostonUSA

Personalised recommendations