PARTNERS DEMONSTRATION PROJECT Integrated delivery of PrEP and ART results in sustained near elimination of HIV transmission in African HIV serodiscordant couples: Final results from the Partners Demonstration Project Jared M. Baeten, Renee Heffron, Lara Kidoguchi, Nelly Mugo, Elly Katabira, Elizabeth Bukusi, Stephen Asiimwe, Jennifer Morton, Kenneth Ngure, Nulu Bulya, Josephine Odoyo, Edna Tindimwemba, Jessica E. Haberer, Mark Marzinke, Deborah Donnell, Connie Celum, for on behalf of the Partners Demonstration Project Team AIDS 2016, Durban

Conflicts of Interest I have received research funding for PrEP, ART for HIV prevention, and microbicides from the Bill & Melinda Gates Foundation, the US NIH, and USAID. For some research studies, including that described in the present abstract, PrEP medication has been donated by Gilead Sciences. I have no other conflicts of interest.

Background ART and PrEP substantially reduce HIV risk, by more than 90% when used with high adherence (Cohen et al. NEJM 2011, Baeten et al. NEJM 2012) For HIV serodiscordant couples, both ART and PrEP are recommended prevention tools (WHO 2014/2015) Developing effective strategies to deliver ART and PrEP to couples is a priority. Approaches that integrate ART and PrEP may have maximal benefits, since neither alone eliminates HIV risk: –ART: Delays or declines are common (Mujugira et al. JAIDS 2014) and HIV risk persists for months after ART start (Mujugira et al. JAIDS 2016; Daar & Corado JAMA 2016) –PrEP: When offered, many, but not all, at-risk persons use PrEP (Donnell et al. JAIDS 2014; many others)

Demonstration projects for new innovations in prevention The pathway from a clinical trial results to programmatic roll-out is not fully defined for a new prevention intervention. Demonstration projects have been called for as part of the pathway to scale-up of PrEP –including in Kenya and Uganda, which had hosted one of the pivotal clinical trials of PrEP for HIV prevention, among HIV serodiscordant couples (the Partners PrEP Study) Graphic: AVAC

Partners Demonstration Project The Partners Demonstration Project was an open-label, prospective interventional study of integrated ART and PrEP delivery for HIV prevention among heterosexual HIV serodiscordant couples The project was conducted at 4 clinical sites: –Kisumu & Thika in Kenya and Kabwohe & Kampala in Uganda The overall goal was to evaluate, using implementation science methods, a scalable delivery system for PrEP and ART for HIV prevention in couples –With counseling, adherence promotion, and follow-up designed to reflect approaches suitable for public health clinic settings –Initiated November 2012 & concluded follow-up June 2016

Design Population: –Heterosexual HIV serodiscordant couples, not using ART or PrEP and with characteristics defining higher risk for HIV transmission –None participated in the Partners PrEP Study clinical trial of PrEP Intervention: –ART offered per Kenya/Uganda guidelines, which recommend ART for all infected partners in serodiscordant couples, regardless of CD4 count –PrEP (daily oral FTC/TDF) offered to the uninfected partner until the infected partner has been on ART for 6 months, permitting time to achieve viral suppression (=PrEP as a bridge to ART) Follow-up: –Month 1 and then quarterly thereafter, for 24 months, including HIV testing, risk reduction, brief adherence support, and primary HIV care

PrEP as a bridge to ART For couples initiating ART at enrollment, PrEP was offered through 6 months, then stopped: ART PrEP HIV+ partner HIV- partner

PrEP as a bridge to ART For couples initiating ART at enrollment, PrEP was offered through 6 months, then stopped: PrEP prior to viral suppression in HIV+ partner ART PrEP HIV+ partner HIV- partner

PrEP as a bridge to ART For couples initiating ART at enrollment, PrEP was offered through 6 months, then stopped: Protection through sustained ART use  PrEP prior to viral suppression in HIV+ partner ART PrEP HIV+ partner HIV- partner

PrEP as a bridge to ART For couples initiating ART at enrollment, PrEP was offered through 6 months, then stopped: For couples in which the infected partner delayed or declined ART, PrEP was continued until 6 months after ART initiation: This strategy is supported by mathematical modeling as potentially highly effective and cost-effective (Hallett et al. PLoS Med 2011; Ying et al. JIAS 2015) Protection through sustained ART use  PrEP prior to viral suppression in HIV+ partner ART PrEP HIV+ partner HIV- partner Protection through sustained ART use  PrEP prior to ART initiation and then prior to viral suppression in HIV+ partner ART PrEP ART delayed HIV+ partner HIV- partner

Recruitment of higher-risk couples HIV risk is heterogeneous, even in at-risk populations We previously developed an objective risk scoring tool to identify serodiscordant couples with higher risk (Kahle et al. JAIDS 2013) –Components of the score: younger age, fewer children, lack of circumcision (HIV- men), cohabiting, unprotected sex in the prior month, and high plasma HIV RNA levels in HIV+ partner For the Partners Demonstration Project, we enrolled only couples with high risk scores –To demonstrate whether the highest-risk couples could take up PrEP and ART and achieve high HIV protection

Quantifying HIV protection HIV incidence was calculated for follow-up time through June 2016 (* data are updated beyond the published abstract) The comparison was a counterfactual simulation model, bootstrapping data from the placebo arm of the Partners PrEP Study clinical trial (= no PrEP and CD4 <350 cells/µL), sampling for a subset with a matching distribution of risk scores and duration of follow-up –A placebo group or delayed provision of ART & PrEP was deemed not to be ethical for this study, and using a counterfactual model was consistent with the implementation science approach

Results: Participant Characteristics 1013 couples were enrolled. Characteristics were consistent with elevated HIV risk: Characteristic% or median (IQR) Gender, HIV- partner33% female / 67% male Age Median 30 years (IQR 26-36), 20% <25 years No children with study partner56% Unprotected sex in the prior month65% CD4 count, HIV+ partner Median 436 (IQR ), 41% >500 cells/µL Plasma HIV RNA, HIV+ partner Median 37,095 (IQR ,462), 41% >50,000 copies/mL

Results: Follow-up High retention and high risk –~1700 person-years of follow-up, retention 86% at 24 months –Pregnancy incidence = 18.5%/year High use of PrEP and ART: –PrEP: 97% initiated. Tenofovir detected in 82% of plasma samples. –ART: 91% initiated by 24 months, viral suppression >90% after initiation –Appealing, acceptable, safe approach to prevention. (Mugwanya et al., abstract FRAE0106LB; Wyatt et al., abstract FRAE0103) For 20% of follow-up, couples used PrEP alone (prior to initiating ART), 33% had PrEP & ART overlapping, 39% ART alone, and 7% neither PrEP nor ART. –ART increased & PrEP decreased over longer follow-up, reflecting the use of PrEP as a bridge to ART in the partnership. Median duration of PrEP use = 12 months (IQR 6-18) (Heffron et al., abstract WEPEC250)

HIV incidence EXPECTED Given the risk score distribution of the enrolled population, the counterfactual simulations predicted 83 HIV infections would be expected to date in this population, at an overall incidence of 4.9 per 100 person-years N=83 infections incidence = 4.9 (95% CI )

HIV incidence EXPECTED However, only four incident HIV infections were observed, for an HIV incidence of 0.2 per 100 person-years N=83 infections incidence = 4.9 (95% CI ) OBSERVED N=4 infections incidence = 0.2 (95% CI )

HIV incidence EXPECTED The observed incidence is a 95% reduction compared to expected, a result that was highly statistically significant N=83 infections incidence = 4.9 (95% CI ) OBSERVED N=4 infections incidence = 0.2 (95% CI ) 95% reduction (95% CI 87-98%) P<0.0001

HIV incidence EXPECTED In subgroup analyses, similarly high HIV protection was seen for: Men (97% p< ) Women (93% p< ) Those in which the HIV- partner was <25 years of age (95% p< ) Couples in which the HIV+ partner had a plasma viral load ≥50,000 copies/mL (95% p< ) N=83 infections incidence = 4.9 (95% CI ) OBSERVED N=4 infections incidence = 0.2 (95% CI ) 95% reduction (95% CI 87-98%) P<0.0001

Incident HIV cases The four HIV seroconverters did not use PrEP (or ART): Case 1. 26F, Month 15, no tenofovir detected in plasma, had separated from HIV+ partner and had partner of unknown HIV status. Case 2. 42M, Month 18, declined PrEP, had multiple partners. Case 3. 19F, Month 12, inconsistent PrEP use, no tenofovir detected in plasma, commercial sex work. Case 4. 30F, Month 3, no tenofovir detected in plasma, HIV+ partner not on ART. None had resistance to TDF or FTC.

Summary In this open-label demonstration project of integrated delivery of ART and PrEP for prevention in HIV serodiscordant couples, we observed virtual elimination of incident HIV. These findings are the first demonstration of the effectiveness of PrEP in Africa outside of clinical trials. Our results demonstrate that time-limited PrEP as a bridge to ART is not only feasible but highly effective in preventing HIV transmission in serodiscordant couples in Kenya and Uganda. –Thus, these findings offer a model for integrated delivery of ART and PrEP for couples as a highly potent combination prevention intervention.

The Partners Demonstration Project is made possible by the United States National Institutes of Health, the Bill and Melinda Gates Foundation, and the generous support of the American people through the United States Agency for International Development. The contents are the responsibility of the University of Washington and study partners and do not necessarily reflect the views of any of the study sponsors or the United States Government. Investigators –University of Washington Coordinating Center: Jared Baeten (protocol chair), Connie Celum (protocol co-chair), Renee Heffron (project director), Deborah Donnell (protocol statistician), Ruanne Barnabas, ICRC Operations, Data and Administration teams –Kabwohe, Uganda (KCRC): Stephen Asiimwe, Edna Tindimwebwa, Elioda Tumwesigye –Kampala, Uganda (Makerere University): Elly Katabira, Nulu Bulya –Kisumu, Kenya (KEMRI): Elizabeth Bukusi, Josephine Odoyo –Thika, Kenya (KEMRI): Nelly Mugo, Kenneth Ngure –MGH/Harvard: Jessica Haberer, Norma Ware –Johns Hopkins: Craig Hendrix, Mark Marzinke –DF/Net Research (data management) Funders –US National Institutes of Health (grants R01 MH095507, R01 MH100940, R01 MH , R21 AI104449, K99 HD076679, R00 HD076679) –Bill & Melinda Gates Foundation (grants OPP47674, OPP ) –US Agency for International Development (contract AID-OAA-A ) Research participants Partners Demonstration Project Team