“No conflicts of interest to declare” Conflict of Interest “No conflicts of interest to declare”

Lessons Learned from Tenofovir Vaginal Gel Studies Topical agents for PrEP: As Good as Systemic PrEP? IAS symposium, 24 July 2017 Salim S. Abdool Karim Director: CAPRISA CAPRISA Professor of Global Health, Columbia University Pro Vice-Chancellor (Research): University of KwaZulu-Natal Adjunct Professor of Medicine, Cornell University CAPRISA is the UNAIDS Collaborating Centre for HIV Research and Policy CAPRISA hosts a DST-NRF Centre of Excellence in HIV Prevention

Overview Current clinical trial evidence for tenofovir gel 4 lessons from tenofovir gel trials: Adherence is a challenge Vaginal microbiome impacts topical PrEP efficacy Genital inflammation undermines gel protection Potential multi-purpose technology (HIV & HSV-2) The world needs many options… Conclusion

Current clinical trial evidence for tenofovir gel Effect size (95% CI) Study CAPRISA 004 – coital Tenofovir gel (South Africa) 39% (6; 60) MTN003/VOICE – daily Tenofovir gel (South Africa, Uganda, Zimbabwe) 15% (-21; 40) FACTS 001– coital TFV gel (South Africa) 0% (-40, 30) -40 -20 20 40 60 80 100 Effectiveness (%)

Lesson 1: Adherence is essential Association between drug detection and HIV incidence in tenofovir gel studies Source: a - Marrazzo et al. NEJM 2015; b - Kashuba et al. JAIDS 2015; c - Rees et al. CROI 2015

High adherence is essential # HIV N HIV incidence Effect p-value TFV Placebo High adherers (>80% gel adherence) 36 336 4.2 9.3 54% 0.03 Intermediate adherers (50-80% adherence) 20 181 6.3 10.0 38% 0.29 Low adherers (<50% gel adherence) 41 367 6.2 8.6 28% 0.30 CAPRISA 004 was developed… …”after extensive consultation with international scientific experts and review of monkey challenge data.” “Just as importantly, it followed detailed consultation with the communities involved.” Source: Abdool Karim S, Abdool Karim Q, Nature, 446; 2007 Source of data in table: Abdool Karim Q, Abdool Karim SS, Frohlich J, et al. Science 2010

Women with Lactobacillus dominance Women with <50% Lactobacilli Lesson 2: Women with Lactobacillus dominance Women with <50% Lactobacilli Effectiveness: 61% (95%CI: 11; 84%), p=0.013 Effectiveness: 18% (95%CI: -77; 63%), p=0.644

Vaginal microbiome impacts tenofovir & tenofovir-DP concentrations Abiotic L. Iners L. Crispatus G. vaginalis TFV alone TFV + cells TFV + cells + G. vaginalis TFV + cells + L. Iners TFV + cells + L. Crispatus

Lesson 3: Genital inflammation reduces tenofovir gel efficacy in women Adherence < 50% Adherence > 50% Probability of HIV infection Placebo gel Tenofovir gel Inflammation Inflammation No inflammation No inflammation *Genital inflammation defined as >5/9 cytokines elevated Source: McKinnon et al. submitted manuscript

Low cytokines High cytokines

Lesson 4: Topical tenofovir prevents HSV-2 Aaaa Aaa aaa Probability of HSV-2 infection 0.5 0.4 0.3 0.2 0.1 0.0 p=0.003 Tenofovir gel Placebo gel Months of follow-up 6 18 30 Effectiveness: 51% (95%CI: 23-70%), p=0.003

HIV prevalence in pregnant SA rural women (2001-2013) Age Group (Years) HIV Prevalence (N=4818) ≤16 11.5% 17-18 21.3% 19-20 30.4% 21-22 39.4% 23-24 49.5% >25 51.9% The need for prevention tools for young women in Africa remains urgent Source: Abdool Karim Q, 2014

A range of options is needed… Truvada ARV rings eg. Dapivirine Broadly neutralising antibodies Injectable ARVs: Cabotegravir & Rilpivirine CAP256-VRC26.25 IgG Potential future prevention technologies Topical ARV gels New oral ARVs eg. F/TAF Altering the vaginal microbiome - Treat BV & Lactin-V ARV implants eg. TAF Multi-purpose technologies

Conclusion Tenofovir gel prevents HIV and HSV-2 in women Trial outcomes varied - zero to modest efficacy Adherence is a challenge Future PrEP trials need to factor in the effects of genital inflammation and the vaginal microbiome Women want a range of HIV prevention options While tenofovir gel could contribute to HIV prevention, the higher priority is a long-acting formulation that reduces the burden of adherence on women, especially young women…

Acknowledgements RESEARCH SUPPORT WAS PROVIDED BY: Key investigators involved in these studies: Quarraisha Abdool Karim, CAPRISA & Columbia University Adam Burgenor, Public Health Agency of Canada Nichole Klatt, University of Washington-Seattle Jo-Ann Passmore, CAPRISA & University of Cape Town Carolyn Williamson, CAPRISA & University of Cape Town Lyle McKinnon, CAPRISA & University of Manitoba Research teams involving >180 scientists & students RESEARCH SUPPORT WAS PROVIDED BY: