Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Genital inflammation undermines the effectiveness of tenofovir gel in preventing HIV acquisition in women

Abstract

Several clinical trials have demonstrated that antiretroviral (ARV) drugs taken as pre-exposure prophylaxis (PrEP) can prevent HIV infection1, with the magnitude of protection ranging from −49 to 86% (refs. 2,3,4,5,6,7,8,9,10,11). Although these divergent outcomes are thought to be due primarily to differences in product adherence12, biological factors likely contribute13. Despite selective recruitment of higher-risk participants for prevention trials, HIV risk is heterogeneous even within higher-risk groups14,15,16. To determine whether this heterogeneity could influence patient outcomes following PrEP, we undertook a post hoc prospective analysis of results from the CAPRISA 004 trial for 1% tenofovir gel (n = 774 patients), one of the first trials to demonstrate protection against HIV infection. Concentrations of nine proinflammatory cytokines were measured in cervicovaginal lavages at >2,000 visits, and a graduated cytokine score was used to define genital inflammation. In women without genital inflammation, tenofovir was 57% protective against HIV (95% confidence interval (CI): 7–80%) but was 3% protective (95% CI: −104–54%) if genital inflammation was present. Among women who highly adhered to the gel, tenofovir protection was 75% (95% CI: 25–92%) in women without inflammation compared to −10% (95% CI: −184–57%) in women with inflammation. Immunological predictors of HIV risk may modify the effectiveness of tools for HIV prevention; reducing genital inflammation in women may augment HIV prevention efforts.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Tenofovir efficacy in groups stratified according to level of inflammation, defined as a specified number of cytokines detected at elevated concentrations in FGT secretions (n = 774 women).

Similar content being viewed by others

References

  1. Karim, S.S.A. HIV pre-exposure prophylaxis in injecting drug users. Lancet 381, 2060–2062 (2013).

    Article  Google Scholar 

  2. Marrazzo, J.M. et al. Tenofovir-based preexposure prophylaxis for HIV infection among African women. N. Engl. J. Med. 372, 509–518 (2015).

    Article  Google Scholar 

  3. Abdool Karim, Q. et al. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science 329, 1168–1174 (2010).

    Article  CAS  Google Scholar 

  4. Grant, R.M. et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N. Engl. J. Med. 363, 2587–2599 (2010).

    Article  CAS  Google Scholar 

  5. Baeten, J.M. et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N. Engl. J. Med. 367, 399–410 (2012).

    Article  CAS  Google Scholar 

  6. Thigpen, M.C. et al. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N. Engl. J. Med. 367, 423–434 (2012).

    Article  CAS  Google Scholar 

  7. Van Damme, L. et al. Preexposure prophylaxis for HIV infection among African women. N. Engl. J. Med. 367, 411–422 (2012).

    Article  CAS  Google Scholar 

  8. Rees, H. et al. FACTS 001 phase III trial of pericoital tenofovir 1% gel for HIV prevention in women. In Conference of Retroviruses and Opportunistic Infections (CROI) (2015).

  9. Baeten, J.M. et al. Use of a vaginal ring containing dapivirine for HIV-1 prevention in women. N. Engl. J. Med. 375, 2121–2132 (2016).

    Article  CAS  Google Scholar 

  10. McCormack, S. 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 387, 53–60 (2016).

    Article  Google Scholar 

  11. Molina, J.-M. et al. On-demand preexposure prophylaxis in men at high risk for HIV-1 Infection. N. Engl. J. Med. 373, 2237–2246 (2015).

    Article  CAS  Google Scholar 

  12. Baeten, J.M. & Grant, R. Use of antiretrovirals for HIV prevention: what do we know and what don't we know? Curr. HIV/AIDS Rep. 10, 142–151 (2013).

    Article  Google Scholar 

  13. Cohen, J. Drug-laced vaginal ring succeeds against HIV—sometimes. Science http://www.sciencemag.org/news/2016/02/drug-laced-vaginal-ring-succeeds-against-hiv-sometimes/ (2016).

  14. McKinnon, L.R. et al. Risk factors for HIV acquisition in a prospective Nairobi-based female sex worker cohort. AIDS Behav. 19, 2204–2213 (2015).

    Article  Google Scholar 

  15. Tanser, F., de Oliveira, T., Maheu-Giroux, M. & Bärnighausen, T. Concentrated HIV subepidemics in generalized epidemic settings. Curr. Opin. HIV AIDS 9, 115–125 (2014).

    Article  Google Scholar 

  16. Nagelkerke, N.J.D. et al. The rise and fall of HIV in high-prevalence countries: a challenge for mathematical modeling. PLOS Comput. Biol. 10, e1003459 (2014).

    Article  Google Scholar 

  17. McKinnon, L.R. & Karim, Q.A. Factors driving the HIV epidemic in southern Africa. Curr. HIV/AIDS Rep. 13, 158–169 (2016).

    Article  Google Scholar 

  18. Masson, L. et al. Genital inflammation and the risk of HIV acquisition in women. Clin. Infect. Dis. 61, 260–269 (2015).

    Article  Google Scholar 

  19. Patel, P. et al. Estimating per-act HIV transmission risk: a systematic review. AIDS 28, 1509–1519 (2014).

    Article  Google Scholar 

  20. Cottrell, M.L. 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. 214, 55–64 (2016).

    Article  CAS  Google Scholar 

  21. Seifert, S.M. et al. Intracellular tenofovir and emtricitabine anabolites in genital, rectal, and blood compartments from first dose to steady state. AIDS Res. Hum. Retroviruses 32, 981–991 (2016).

    Article  CAS  Google Scholar 

  22. Rerks-Ngarm, S. et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N. Engl. J. Med. 361, 2209–2220 (2009).

    Article  CAS  Google Scholar 

  23. Buchbinder, S.P. et al. HIV pre-exposure prophylaxis in men who have sex with men and transgender women: a secondary analysis of a phase 3 randomised controlled efficacy trial. Lancet Infect. Dis. 14, 468–475 (2014).

    Article  Google Scholar 

  24. Murnane, P.M. et al. Efficacy of preexposure prophylaxis for HIV-1 prevention among high-risk heterosexuals: subgroup analyses from a randomized trial. AIDS 27, 2155–2160 (2013).

    Article  CAS  Google Scholar 

  25. Shannon, B. et al. Distinct effects of the cervicovaginal microbiota and herpes simplex type 2 infection on female genital tract immunology. J. Infect. Dis. 215, 1366–1375 (2017).

    Article  CAS  Google Scholar 

  26. Kashuba, A.D.M. 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. 69, 264–269 (2015).

    Article  CAS  Google Scholar 

  27. Boily, M.-C. et al. Heterosexual risk of HIV-1 infection per sexual act: systematic review and meta-analysis of observational studies. Lancet Infect. Dis. 9, 118–129 (2009).

    Article  Google Scholar 

  28. Powers, K.A., Poole, C., Pettifor, A.E. & Cohen, M.S. Rethinking the heterosexual infectivity of HIV-1: a systematic review and meta-analysis. Lancet Infect. Dis. 8, 553–563 (2008).

    Article  Google Scholar 

  29. Arnold, K.B. et al. Increased levels of inflammatory cytokines in the female reproductive tract are associated with altered expression of proteases, mucosal barrier proteins, and an influx of HIV-susceptible target cells. Mucosal Immunol. 9, 194–205 (2016).

    Article  CAS  Google Scholar 

  30. McKinnon, L.R. & Kaul, R. Quality and quantity: mucosal CD4+ T cells and HIV susceptibility. Curr. Opin. HIV AIDS 7, 195–202 (2012).

    Article  CAS  Google Scholar 

  31. Liebenberg, L.J.P. et al. Genital–systemic chemokine gradients and the risk of HIV acquisition in women. J. Acquir. Immune Defic. Syndr. 74, 318–325 (2017).

    Article  CAS  Google Scholar 

  32. Selhorst, P. et al. Cervicovaginal inflammation facilitates acquisition of less infectious HIV variants. Clin. Infect. Dis. 64, 79–82 (2017).

    Article  CAS  Google Scholar 

  33. García-Lerma, J.G. et al. Natural substrate concentrations can modulate the prophylactic efficacy of nucleotide HIV reverse transcriptase inhibitors. J. Virol. 85, 6610–6617 (2011).

    Article  Google Scholar 

  34. Masson, L. et al. Defining genital tract cytokine signatures of sexually transmitted infections and bacterial vaginosis in women at high risk of HIV infection: a cross-sectional study. Sex. Transm. Infect. 90, 580–587 (2014).

    Article  Google Scholar 

  35. Anahtar, M.N. et al. Cervicovaginal bacteria are a major modulator of host inflammatory responses in the female genital tract. Immunity 42, 965–976 (2015).

    Article  CAS  Google Scholar 

  36. Klatt, N.R. et al. Vaginal bacteria modify HIV tenofovir microbicide efficacy in African women. Science 356, 938–945 (2017).

    Article  CAS  Google Scholar 

  37. Heffron, R. et al. Efficacy of oral pre-exposure prophylaxis (PrEP) for HIV among women with abnormal vaginal microbiota: a post-hoc analysis of the randomised, placebo-controlled Partners PrEP Study. Lancet HIV 4, e449–e456 10.1016/S2352–3018(17)30110–8 (2017).

    Article  Google Scholar 

  38. van de Wijgert, J. & McCormack, S. Vaginal dysbiosis and pre-exposure prophylaxis efficacy. Lancet HIV 4, e427–e429 10.1016/S2352–3018(17)30130–3 (2017).

    Article  Google Scholar 

  39. Karim, Q.A. et al. Recruitment of high risk women for HIV prevention trials: baseline HIV prevalence and sexual behavior in the CAPRISA 004 tenofovir gel trial. Trials 12, 67 (2011).

    Article  Google Scholar 

Download references

Acknowledgements

We would like to thank W. Heneine and D. Kwon for important discussions regarding these data. The study was funded by the National Institutes of Health (5R01AI111936 to J.S.P.) and the DST-NRF Centre of Excellence in HIV Prevention at CAPRISA. The original CAPRISA 004 1% tenofovir gel trial was funded principally by the United States Agency for International Development (USAID) through FHI360 and CONRAD with additional support provided by the South African Department of Science and Technology (DST). We would like to thank all study participants and CAPRISA staff for making the CAPRISA 004 trial possible. L.R.M. is supported by a Canadian Institutes of Health Research (CIHR) New Investigator Award. L.J.L., D.A., and L.M. are funded by South African National Research Foundation (NRF) Research Career Advancement Fellowship awards.

Author information

Authors and Affiliations

Authors

Contributions

L.R.M., L.J.L., J.G.G.L., A.D.K., L.M., L.E.M., Q.A.K., S.S.A.K., and J.-A.S.P. designed the study. L.R.M., L.J.L., D.A., S.N., and A.S. performed the experiments. L.R.M., L.J.L., N.Y.-Z., and N.N. analyzed the data. L.R.M., L.J.L., N.Y.-Z., D.A., S.N., A.S., N.N., J.G.G.L., A.D.K., L.M., L.E.M., Q.A.K., S.S.A.K., and J.-A.S.P. wrote the manuscript.

Corresponding authors

Correspondence to Lyle R McKinnon or Jo-Ann S Passmore.

Ethics declarations

Competing interests

J.G.G.L. is named in a USA government patent titled “Inhibition of HIV Infection through Chemoprophylaxis” (US Patent no. 9,044,509 B2). The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention (CDC).

Supplementary information

Supplementary Table & Figure

Supplementary Table 1 & Supplementary Figure 1 (PDF 1821 kb)

Life Sciences Reporting Summary (PDF 130 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

McKinnon, L., Liebenberg, L., Yende-Zuma, N. et al. Genital inflammation undermines the effectiveness of tenofovir gel in preventing HIV acquisition in women. Nat Med 24, 491–496 (2018). https://doi.org/10.1038/nm.4506

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.4506

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing