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.
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Karim, S.S.A. HIV pre-exposure prophylaxis in injecting drug users. Lancet 381, 2060–2062 (2013).
Marrazzo, J.M. et al. Tenofovir-based preexposure prophylaxis for HIV infection among African women. N. Engl. J. Med. 372, 509–518 (2015).
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).
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).
Baeten, J.M. et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N. Engl. J. Med. 367, 399–410 (2012).
Thigpen, M.C. et al. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N. Engl. J. Med. 367, 423–434 (2012).
Van Damme, L. et al. Preexposure prophylaxis for HIV infection among African women. N. Engl. J. Med. 367, 411–422 (2012).
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).
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).
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).
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).
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).
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).
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).
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).
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).
McKinnon, L.R. & Karim, Q.A. Factors driving the HIV epidemic in southern Africa. Curr. HIV/AIDS Rep. 13, 158–169 (2016).
Masson, L. et al. Genital inflammation and the risk of HIV acquisition in women. Clin. Infect. Dis. 61, 260–269 (2015).
Patel, P. et al. Estimating per-act HIV transmission risk: a systematic review. AIDS 28, 1509–1519 (2014).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
McKinnon, L.R. & Kaul, R. Quality and quantity: mucosal CD4+ T cells and HIV susceptibility. Curr. Opin. HIV AIDS 7, 195–202 (2012).
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).
Selhorst, P. et al. Cervicovaginal inflammation facilitates acquisition of less infectious HIV variants. Clin. Infect. Dis. 64, 79–82 (2017).
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).
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).
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).
Klatt, N.R. et al. Vaginal bacteria modify HIV tenofovir microbicide efficacy in African women. Science 356, 938–945 (2017).
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).
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).
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).
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.
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).
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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
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