The Vaginal Microbiome and its Potential to Impact Efficacy of HIV Pre-exposure Prophylaxis for Women

The Science of Prevention (JD Stekler and J Baeten, Section Editors)
Part of the following topical collections:
  1. Topical Collection on The Science of Prevention

Abstract

Purpose of Review

This review describes existing evidence addressing the potential modulation of pre-exposure prophylaxis (PrEP) products, specifically 1% tenofovir (TFV) gel and oral tenofovir-based PrEP, by vaginal dysbiosis and discusses future considerations for delivering novel, long-acting PrEP products to women at high risk for vaginal dysbiosis and HIV.

Recent Findings

We describe results from analyses investigating the modification of PrEP efficacy by vaginal dysbiosis and studies of biological mechanisms that could render PrEP ineffective in the presence of specific microbiota. A secondary analysis from the CAPRISA-004 cohort demonstrated that there is no effect of the 1% TFV gel in the presence of non-Lactobacillus dominant microbiota. Another recent analysis comparing oral tenofovir-based PrEP efficacy among women with and without bacterial vaginosis in the Partners PrEP Study found that oral PrEP efficacy is not modified by bacterial vaginosis. Gardnerella vaginalis, commonly present in women with vaginal dysbiosis, can rapidly metabolize TFV particularly when it is locally applied and thereby prevent TFV integration into cells. Given that vaginal dysbiosis appears to modulate efficacy for 1% TFV gel but not for oral tenofovir-based PrEP, vaginal dysbiosis is potentially less consequential to HIV protection from TFV in the context of systemic drug delivery and high product adherence.

Summary

Vaginal dysbiosis may undermine the efficacy of 1% TFV gel to protect women from HIV but not the efficacy of oral PrEP. Ongoing development of novel ring, injectable, and film-based PrEP products should investigate whether vaginal dysbiosis can reduce efficacy of these products, even in the presence of high adherence.

Keywords

Pre-exposure prophylaxis Efficacy HIV prevention Vaginal dysbiosis Bacterial vaginosis Women 

References

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

  1. 1.
    Adimora AA, Ramirez C, Auerbach JD, Aral SO, Hodder S, Wingood G, et al. Preventing HIV infection in women. J Acquir Immune Defic Syndr. 2013;63(0 2):S168–73. doi:10.1097/QAI.0b013e318298a166.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Ramjee G, Daniels B. Women and HIV in sub-Saharan Africa. AIDS Res Ther. 2013;10(1):30. doi:10.1186/1742-6405-10-30.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Underhill K, Operario D, Mimiaga MJ, Skeer MR, Mayer KH. Implementation science of pre-exposure prophylaxis: preparing for public use. Curr HIV/AIDS Rep. 2010;7(4):210–9. doi:10.1007/s11904-010-0062-4.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Celum CL, Delany-Moretlwe S, McConnell M, van Rooyen H, Bekker L-G, Kurth A, et al. Rethinking HIV prevention to prepare for oral PrEP implementation for young African women. J Int AIDS Soc. 2015;18(4 Suppl 3):20227. doi:10.7448/IAS.18.4.20227.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Marcus JL, Volk JE, Pinder J, Liu AY, Bacon O, Hare CB, et al. Successful implementation of HIV preexposure prophylaxis: lessons learned from three clinical settings. Curr HIV/AIDS Rep. 2016;13(2):116–24. doi:10.1007/s11904-016-0308-x.CrossRefPubMedGoogle Scholar
  6. 6.
    Cáceres CF, O’Reilly KR, Mayer KH, Baggaley R. PrEP implementation: moving from trials to policy and practice. J Int AIDS Soc. 2015;18(4 Suppl 3):20222. doi:10.7448/IAS.18.4.20222.PubMedPubMedCentralGoogle Scholar
  7. 7.
    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. doi:10.1056/NEJMoa1108524.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    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. doi:10.1056/NEJMoa1110711.CrossRefPubMedGoogle Scholar
  9. 9.
    • 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;375:2121–32. doi:10.1056/NEJMoa1506110. This article presents the primary analysis from the ASPIRE phase 3, randomized, double-blind, placebo-controlled trial of the monthly dapivirine ring. The study demonstrated that the dapivirine ring can prevent HIV acquisition, particularly for women over 21 years of age. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    • 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. doi:10.1056/NEJMoa1602046. This article presents the primary analysis from the phase 3, randomized, double-blind, placebo-controlled trial of the monthly dapivirine ring in South Africa and Uganda. The study demonstrated that the dapivirine ring can prevent HIV acquisition and did not find a difference in efficacy by age group. CrossRefPubMedGoogle Scholar
  11. 11.
    • Schlesinger E, Johengen D, Luecke E, Rothrock G, McGowan I, van der Straten A, et al. A tunable, biodegradable, thin-film polymer device as a long-acting implant delivering tenofovir alafenamide fumarate for HIV pre-exposure prophylaxis. Pharm Res. 2016;33(7):1649–56. doi:10.1007/s11095-016-1904-6. This article describes the use of a thin-film polymer device (TFPD) as a biodegradable implant for PrEP. The device demonstrated linear drug release for up to 60 or 90 days, depending on desired drug quantity. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Akil A, Agashe H, Dezzutti CS, Moncla BJ, Hillier SL, Devlin B, et al. Formulation and characterization of polymeric films containing combinations of antiretrovirals (ARVs) for HIV prevention. Pharm Res. 2015;32(2):458–68. doi:10.1007/s11095-014-1474-4.CrossRefPubMedGoogle Scholar
  13. 13.
    •• Klatt NR, Cheu R, Birse K, Zevin AS, Perner M, Noel-Romas L, et al. Vaginal bacteria modify HIV tenofovir microbicide efficacy in African women. Science. 2017;356:938–45. doi:10.1126/science.aai9383. This article presents findings on associations between vaginal microbiota and tenofovir gel microbicide efficacy in the CAPRISA-004 trial. Gel-based PrEP was not efficacious in women with non- Lactobacillus dominant microbiota, potentially because Gardnerella vaginalis present in these women could metabolize tenofovir. CrossRefPubMedGoogle Scholar
  14. 14.
    Atashili J, Poole C, Ndumbe PM, Adimora AA, Smith JS. Bacterial vaginosis and HIV acquisition: a meta-analysis of published studies. AIDS. 2008;22(12):1493–501. doi:10.1097/QAD.0b013e3283021a37.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Passmore J-AS, Jaspan HB, Masson L. Genital inflammation, immune activation and risk of sexual HIV acquisition. Curr Opin HIV AIDS. 2016;11(2):156–62. doi:10.1097/COH.0000000000000232.CrossRefPubMedGoogle Scholar
  16. 16.
    • Masese L, Baeten JM, Richardson BA, Bukusi E, John-Stewart G, Graham SM, et al. Changes in the contribution of genital tract infections to HIV acquisition among Kenyan high-risk women from 1993 to 2012. AIDS. 2015;29(9):1077–85. doi:10.1097/QAD.0000000000000646. This article presents findings on associations between genital tract infections and HIV incidence among women in Kenya during a 20-year follow-up period. The estimated PAR% for bacterial vaginosis and intermediate microbiota was high during the follow-up period. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    McClelland RA. Vaginal microbiome and susceptibility to HIV [Abstract #54]. Oral Presentation at: Conference on Retroviruses and Opportunistic Infections (CROI) 2017; March 4-7, 2017;Seattle, WA, USA.Google Scholar
  18. 18.
    • Gosmann C, Anahtar MN, Handley SA, Farcasanu M, Abu-Ali G, Bowman BA, et al. Lactobacillus-deficient cervicovaginal bacterial communities are associated with increased HIV acquisition in young South African women. Immunity. 2017;46(1):29–37. doi:10.1016/j.immuni.2016.12.013. This article presents findings from a prospective cohort study examining associations between genital inflammation and HIV acquisition among South African women. Having diverse vaginal microbiota (not Lactobacillus -dominant) was associated with elevated HIV risk and increased activated CD4+ T cells. CrossRefPubMedGoogle Scholar
  19. 19.
    •• Passmore JS, Williams B. Role of vaginal microbiota in genital inflammation and enhancing HIV acquisition in women [Abstract #TUSS0605]. Oral Presentation at AIDS 2016; July 18-22, 2016; Durban, South Africa. In a case-control study with women from the CAPRISA-004 trial, HIV-infected cases were found to have an upregulation in inflammatory cytokines prior to HIV acquisition. Specifically, bacterial vaginosis with an abundance of Prevotella bivia was associated with inflammatory cytokine response and increased HIV risk. Google Scholar
  20. 20.
    Burgener A, McGowan I, Klatt NR. HIV and mucosal barrier interactions: consequences for transmission and pathogenesis. Curr Opin Immunol. 2015;36:22–30. doi:10.1016/j.coi.2015.06.004.CrossRefPubMedGoogle Scholar
  21. 21.
    • Anahtar MN, Byrne EH, Doherty KE, Bowman BA, Yamamoto HS, Soumillon M, et al. Cervicovaginal bacteria are a major modulator of host inflammatory responses in the female genital tract. Immunity. 2015;1(5):965–76. doi:10.1016/j.immuni.2015.04.019. In a prospective cohort study with 146 HIV-negative South African women, high diversity of vaginal microbiota was correlated with genital pro-inflammatory cytokine response. In addition, there were significantly more CCR5+ CD4+ T cells found in the endocervical canal of women with higher cytokine responses (which tended to also be those with the most diverse vaginal flora). CrossRefGoogle Scholar
  22. 22.
    • Dimitrov DT, Mâsse BR, Donnell D. PrEP adherence patterns strongly affect individual HIV risk and observed efficacy in randomized clinical trials. J Acquir Immune Defic Syndr. 2016;72(4):444–51. doi:10.1097/QAI.0000000000000993. This simulation study presents findings on expected PrEP efficacy associated with different levels of oral pill adherence. Pill-taking patterns were found to have a large effect on estimated PrEP efficacy, after comparing model findings with results from PrEP randomized controlled trials. CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    • 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. doi:10.1056/NEJMoa1402269. This article presents the primary analysis from the VOICE randomized, placebo-controlled trial of oral tenofovir disoproxil fumarate, oral tenofovir-emtricitabine, or 1% tenofovir gel as HIV PrEP. The study did not find oral or gel-based regimens to be efficacious in preventing HIV; however, adherence to the daily regimens was low. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    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. doi:10.1056/NEJMoa1202614.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Hanscom B, Janes HE, Guarino PD, Huang Y, Brown ER, Chen YQ, et al. Preventing HIV-1 infection in women using oral pre-exposure prophylaxis: a meta-analysis of current evidence. J Acquir Immune Defic Syndr. 2016;73(5):606–8. doi:10.1097/QAI.0000000000001160.CrossRefPubMedGoogle Scholar
  26. 26.
    Celum C, Baeten JM. Tenofovir-based pre-exposure prophylaxis for HIV prevention: evolving evidence. Curr Opin Infect Dis. 2012;25(1):51–7. doi:10.1097/QCO.0b013e32834ef5ef.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Abdool Karim Q, Abdool Karim SS, Frohlich JA, Grobler AC, Baxter C, Mansoor LE, et al. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science. 2010;329(5996):1168–74. doi:10.1126/science.1193748.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    • Rees H, Delany-Moretlwe S, Lombard C, Baron D, Panchia R, Myer L, et al. FACTS 001 phase III trial of pericoital tenofovir 1% gel for HIV prevention in women [Abstract #26LB]. Oral Presentation at: Conference on Retroviruses and Opportunistic Infections (CROI) 2015; February 23-26, 2015. Seattle, WA, USA. In the FACTS 001, phase III, multi-center, double-blind, randomized, placebo-controlled trial, 1% tenofovir gel was not found to be efficacious for HIV prevention among South African women. While the gel effectiveness was highest in women who reported product use, overall adherence was low in this cohort. Google Scholar
  29. 29.
    Friend DR, Kiser PF. Assessment of topical microbicides to prevent HIV-1 transmission: concepts, testing, lessons learned. Antivir Res. 2013;99(3):391–400. doi:10.1016/j.antiviral.2013.06.021.CrossRefPubMedGoogle Scholar
  30. 30.
    Montgomery ET, Mensch B, Musara P, Hartmann M, Woeber K, Etima J, et al. Misreporting of product adherence in the MTN-003/VOICE trial for HIV prevention in Africa: participants’ explanations for dishonesty. AIDS Behav. 2017;21(2):481–91. doi:10.1007/s10461-016-1609-1.CrossRefPubMedGoogle Scholar
  31. 31.
    •• Heffron RA, McClelland RS, Balkus J, Celum CL, Cohen C, Mugo N, et al. Daily oral PrEP is effective among women with abnormal vaginal microbiota [Abstract #85]. Oral Presentation at: Conference on Retroviruses and Opportunistic Infections (CROI) 2017; March 4-7, 2017; Seattle, WA, USA. This work examines the associations between vaginal microbiota and oral PrEP efficacy in the Partners PrEP Study. Oral PrEP efficacy was not significantly different among women with bacterial vaginosis and intermediate microbiota, compared with women who had normal microbiota. Google Scholar
  32. 32.
    Hendrix CW, Chen BA, Guddera V, Hoesley C, Justman J, Nakabiito C, et al. MTN-001: randomized pharmacokinetic cross-over study comparing tenofovir vaginal gel and oral tablets in vaginal tissue and other compartments. PLoS One. 2013;8(1):e55013. doi:10.1371/journal.pone.0055013.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    •• Hillier SL, Meyn L, Bunge K, Austin M, Moncla BJ, Dezzutti C, et al. Impact of vaginal microbiota on genital tissue and plasma concentrations of tenofovir [Abstract #86LB]. Oral Presentation at: Conference on Retroviruses and Opportunistic Infections (CROI) 2017; March 4-7, 2017; Seattle, WA, USA. In the FAME-04 study of tenofovir gel and film, women with higher concentrations of Gardnerella vaginalis were found to have lower tenofovir drug levels in cervicovaginal fluid and plasma after 7 days. This study highlights the potential for Gardnerella vaginalis to rapidly metabolize PrEP. Google Scholar
  34. 34.
    •• Zevin AS, Xie IY, Birse K, Arnold K, Romas L, Westmacott G, et al. Microbiome composition and function drives wound-healing impairment in the female genital tract. PLoS Pathog. 2016;12(9):e1005889. doi:10.1371/journal.ppat.1005889. This article presents findings on epithelial barrier integrity and immune activation among women with Gardnerella vaginalis dominant vaginal microbiota, compared with women with Lactobacillus dominant microbiota. Women with Gardnerella vaginalis dominant microbiota had increased abundance of membrane transport proteins which could influence drug metabolism. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Cottrell ML, Srinivas N, Kashuba ADM. Pharmacokinetics of antiretrovirals in mucosal tissue. Expert Opin Drug Metab Toxicol. 2015;11(6):893–905. doi:10.1517/17425255.2015.1027682.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    • Kashuba ADM, Gengiah TN, Werner L, Yang K-H, White NR, Karim QA, et al. Genital tenofovir concentrations correlate with protection against HIV infection in the CAPRISA 004 trial: importance of adherence for microbicide effectiveness. J Acquir Immune Defic Syndr. 2015;69(3):264–9. doi:10.1097/QAI.0000000000000607. This article presents findings from a case-control study with the CAPRISA-004 trial cohort. Significantly fewer HIV-infected cases were found to have cervicovaginal fluid tenofovir concentrations >100 ng/mL compared with uninfected controls. Plasma concentrations were <1 ng/mL in all women receiving the 1% tenofovir gel. CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Mayer KH, Maslankowski LA, Gai F, El-Sadr WM, Justman J, Kwiecien A, et al. Safety and tolerability of tenofovir vaginal gel in abstinent and sexually active HIV-infected and uninfected women. AIDS. 2006;20(4):543–51. doi:10.1097/01.aids.0000210608.70762.c3.CrossRefPubMedGoogle Scholar
  38. 38.
    Patterson KB, Prince HA, Kraft E, Jenkins AJ, Shaheen NJ, Rooney JF, et al. Penetration of tenofovir and emtricitabine in mucosal tissues: implications for prevention of HIV-1 transmission. Sci Transl Med. 2011;3(112):112re4. doi:10.1126/scitranslmed.3003174.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    • Cottrell ML, Yang KH, HMA P, Sykes C, White N, Malone S, et al. A translational pharmacology approach to predicting outcomes of preexposure prophylaxis against HIV in men and women using tenofovir disoproxil fumarate with or without emtricitabine. J Infect Dis. 2016;214(1):55–64. doi:10.1093/infdis/jiw077. This study found that tenofovir diphosphate concentrations were approximately ten-fold higher in colorectal tissue than in the lower female genital tract. Results indicate that a minimum adherence level of approximately 6–7 oral PrEP doses per week are required to protected female genital tissue from HIV. CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    • Chen BA, Panther L, Marzinke MA, Hendrix CW, Hoesley CJ, van der Straten A, et al. Phase 1 safety, pharmacokinetics, and pharmacodynamics of dapivirine and maraviroc vaginal rings: a double-blind randomized trial. J Acquir Immune Defic Syndr. 2015;70(3):242–9. doi:10.1097/QAI.0000000000000702. This article presents findings from a multisite, double-blind, randomized, placebo-controlled trial of dapivirine and maraviroc containing vaginal rings for HIV prevention. Dapivirine concentrations in cervicovaginal fluid and tissue dropped rapidly after ring removal. CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Wang L, Koppolu S, Chappell C, Moncla BJ, Hillier SL, Mahal LK. Studying the effects of reproductive hormones and bacterial vaginosis on the glycome of lavage samples from the cervicovaginal cavity. PLoS One. 2015;10(5):e0127021. doi:10.1371/journal.pone.0127021.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Ravel J, Gajer P, Fu L, Mauck CK, Koenig SSK, Sakamoto J, et al. Twice-daily application of HIV microbicides alter the vaginal microbiota. MBio. 2012;3(6):e00370–12. doi:10.1128/mBio.00370-12.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Spence P, Bhatia Garg A, Woodsong C, Devin B, Rosenberg Z. Recent work on vaginal rings containing antiviral agents for HIV prevention. Curr Opin HIV AIDS. 2015;10(4):264–70. doi:10.1097/COH.0000000000000157.CrossRefPubMedGoogle Scholar
  44. 44.
    Boffito M, Jackson A, Owen A, Becker S. New approaches to antiretroviral drug delivery: challenges and opportunities associated with the use of long-acting injectable agents. Drugs. 2014;74(1):7–13. doi:10.1007/s40265-013-0163-7.CrossRefPubMedGoogle Scholar
  45. 45.
    Geary CW, Bukusi EA. Women and ARV-based HIV prevention—challenges and opportunities. J Int AIDS Soc. 2014;17(3 Suppl 2):19356. doi:10.7448/IAS.17.3.19356.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.Department of Global HealthUniversity of WashingtonSeattleUSA
  2. 2.Department of EpidemiologyUniversity of WashingtonSeattleUSA
  3. 3.International Clinical Research CenterUniversity of WashingtonSeattleUSA

Personalised recommendations