BACKGROUND A safe, effective vaccine is essential to end HIV. A canarypox/protein HIV vaccine regimen showed modest efficacy at reducing infection in Thailand. An analogous regimen using HIV-1 subtype C virus demonstrated potent humoral and cellular responses in a Phase 1/2a trial and triggered a Phase 2b/3 double-blinded trial to assess the safety and efficacy of this regimen in South Africa. METHODS We enrolled and randomized 5,404 healthy, HIV-uninfected 18-35-year olds at 14 sites to vaccine (2,704 participants) or placebo (2,700 participants) between 26 October 2016 and 21 June 2019. The vaccine regimen consisted of two ALVAC-HIV (vCP2438) (expressing HIV-1 subtype C env, clade B gp41 , gag and pro) immunizations at months 0 and 1, with booster immunizations of ALVAC-HIV plus bivalent subtype C gp120 protein/MF59 adjuvant at months 3, 6, 12 and 18. Efficacy was evaluated by HIV testing every 3 months. RESULTS In January 2020, pre-specified non-efficacy criteria were met at an interim analysis; further vaccinations were subsequently halted. The vaccines were safe and well-tolerated in the study population (median age 24, 70% female-sex-at-birth). Over the primary 24-month follow-up, there were 133 infections among placebo recipients and 138 among vaccinees (hazard ratio = 1.02; 95%CI, 0.81-1.30; P=0.84). Pre-specified subgroup analyses demonstrated no difference in efficacy by sex or when restricting to follow-up post-4 th vaccination, and no difference amongst female-sex-at-birth by age, BMI, prevalent STIs, behavioral risk score or region. CONCLUSIONS The ALVAC/gp120 regimen did not prevent HIV infection in South Africans despite prior evidence of immunogenicity. ClinicalTrials.gov (NCT02968849)

Background Pre-exposure prophylaxis (PrEP) is highly effective and an important prevention tool for African adolescent girls and young women (AGYW), but adherence and persistence are challenging. PrEP adherence support strategies for African AGYW were studied in an implementation study. Methods and findings HIV Prevention Trials Network (HPTN) 082 was conducted in Cape Town, Johannesburg (South Africa) and Harare (Zimbabwe) from October 2016 to October 2018 to evaluate PrEP uptake, persistence, and the effect of drug level feedback on adherence. Sexually active HIV–negative women ages 16–25 were offered PrEP and followed for 12 months; women who accepted were randomized to standard adherence support (counseling, 2-way SMS, and adherence clubs) or enhanced adherence support with adherence feedback from intracellular tenofovir-diphosphate (TFV-DP) levels in dried blood spots (DBS). PrEP uptake, persistence through 12 months (no PrEP hold or missed visits), and adherence were assessed. The primary outcome was high adherence (TFV-DP ≥700 fmol/punch) at 6 months, compared by study arm. Of 451 women enrolled, median age was 21 years, and 39% had curable sexually transmitted infections (STIs). Most (95%) started PrEP, of whom 55% had uninterrupted PrEP refills through 12 months. Of those with DBS, 84% had detectable TFV-DP levels at month 3, 57% at month 6, and 31% at month 12. At 6 months, 36/179 (21%) of AGYW in the enhanced arm had high adherence and 40/184 (22%) in the standard adherence support arm (adjusted odds ratio [OR] of 0.92; 95% confidence interval [CI] 0.55, 1.34; p = 0.76). Four women acquired HIV (incidence 1.0/100 person-years), with low or undetectable TFV-DP levels at or prior to seroconversion, and none of whom had tenofovir or emtricitabine resistance mutations. The study had limited power to detect a modest effect of incentives on adherence, and there was limited awareness of PrEP at the time the study was conducted. Conclusions In this study, PrEP initiation was high, over half of study participants persisted with PrEP through month 12, and the majority of young African women had detectable TFV-DP levels through month 6 with one-fifth having high adherence. Drug level feedback in the first 3 months of PrEP use did not increase the proportion with high adherence at month 6. HIV incidence was 1% in this cohort with 39% prevalence of curable STIs and moderate PrEP adherence. Strategies to support PrEP use and less adherence-dependent formulations are needed for this population. Trial registration ClinicalTrials.gov NCT02732730.

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Purpose of Review A gap exists between PrEP interest and PrEP uptake in key populations (KP) for HIV prevention that may be ascribed to PrEP delivery services not being acceptable. This review summarizes novel platforms for HIV prevention outside of the traditional health facilities environment. Recent Findings Mobile health clinics provide highly acceptable integrated, KP-focused services at convenient locations with the potential of high PrEP uptake. Telemedicine and health apps decongest health systems and allow for personal agency and informed decision-making on personal health. Pharmacy-led PrEP delivery provides de-medicalized, confidential PrEP services at extended hours in community locations, from trusted medical professionals. Peer-supported delivery encourages continued PrEP use. Summary Community-based, differentiated and de-medicalized PrEP delivery can address uptake and continued use barriers in key populations. Future research should assess scalability, cost-effectiveness and sustainability of these PrEP delivery platforms, as well as focus on ways to simplify PrEP provision.