www.thelancet.com/infection Vol 18 November 2018 1241 Articles Introduction Although the annual incidence of new HIV infections has declined or stabilised in many populations, women younger than 25 years in Africa account for a ffth of new HIV infections globally. 1 Young women in the region are up to eight times more likely to be infected with HIV than their same-age male counterparts. 2 In the absence of widely available pre-exposure prophylaxis, HIV prevention options for women have been restricted to partner reduction and condom use, strategies that are seldom under a woman’s direct control. Microbicides, including topical, coitally dependent gels, are a potentially important female-controlled method for HIV prevention. First-generation vaginal microbicides consisted of either surfactants that disrupted cell mem- branes, polyanions that prevent attachment to target cells in the vagina, or acid bufers that maintained vaginal pH in the presence of ejaculate. These products were not specifc to HIV and showed no preventive efect in six Tenofovir 1% vaginal gel for prevention of HIV-1 infection in women in South Africa (FACTS-001): a phase 3, randomised, double-blind, placebo-controlled trial Sinead Delany-Moretlwe, Carl Lombard, Deborah Baron, Linda-Gail Bekker, Busi Nkala, Khatija Ahmed, Modulakgotla Sebe, William Brumskine, Maposhane Nchabeleng, Thesla Palanee-Philips, Julius Ntshangase, Sidney Sibiya, Emilee Smith, Ravindre Panchia, Landon Myer, Jill L Schwartz, Mark Marzinke, Lynn Morris, Elizabeth R Brown, Gustavo F Doncel, Glenda Gray, Helen Rees Summary Background Young women in southern Africa have substantial risk of HIV acquisition. Female-controlled biomedical interventions are needed to mitigate this risk. We aimed to assess the safety and efcacy of a pericoitally applied tenofovir 1% gel. Methods We did a phase 3, double-blind, randomised, placebo-controlled trial at nine community-based clinical trial sites in South Africa to evaluate the safety and efcacy of tenofovir 1% gel. Sexually active women who were HIV negative and aged 18–30 years were enrolled. Participants were randomly assigned (1:1) using sequential participant numbers to either tenofovir 1% gel or a placebo gel (one dose within 12 h before sex and one dose within 12 h after sex [BAT-24 regimen]), using dynamic permuted block sizes of 8 and 16 within each site. Women received monthly HIV-1 testing, risk reduction support, physical examinations, and product dispensing for up to 27 months. The primary efcacy outcome was incident HIV infection and the primary safety outcome was occurrence of grade 2–4 adverse events, both analysed in the modifed intention-to-treat population. To assess the efcacy of tenofovir gel, the cumulative probability of HIV infection was calculated for each treatment using the Kaplan-Meier method. This trial is registered with ClinicalTrials.gov, number NCT01386294. Findings From Oct 11, 2011, to Aug 29, 2014, 3844 women were screened, 2059 enrolled, and 2029 included in the primary analysis (1032 in the tenofovir group and 1027 in the placebo group); 39 (4%) in the tenofovir group and 36 (4%) in the placebo group were lost to follow-up. 123 HIV-1 infections occurred over 3036 woman-years of observation; 61 in the tenofovir group (HIV incidence 4·0 per 100 woman-years, 95% CI 3·1–5·2) and 62 in the placebo group (4·0 per 100 woman-years, 3·1–5·2; incidence rate ratio [IRR] 0·98, 95% CI 0·7–1·4). A higher incidence of grade 2 adverse events was observed in the tenofovir group than in the placebo group (IRR 1·09, 95% CI 1·0–1·2; p=0·02). The most common grade 2 or higher product-related adverse events were hypophosphataemia (n=22 for tenofovir vs n=22 for placebo), genital symptoms (n=6 for tenofovir vs n=2 for placebo), or elevated transaminases (n=2 for tenofovir vs n=2 for placebo). No product-related serious adverse events were reported, and no diferences in product-related adverse events (p=0·78), grade 3 events (p=0·64), or grade 4 events (p=0·74) were observed between treatment groups. Interpretation Overall, pericoital tenofovir gel did not prevent HIV-1 acquisition in this population of young women at risk of HIV infection in South Africa. Alternate safe and efective products that are less user dependent than this product or do not require high adherence are needed. Funding The US Agency for International Development (USAID), the Bill & Melinda Gates Foundation, and the South African Department of Science and Technology and Department of Health. Copyright © 2018 Elsevier Ltd. All rights reserved. Lancet Infect Dis 2018; 18: 1241–50 See Comment page 1166 Wits RHI (S Delany-Moretlwe PhD, D Baron MPH, T Palanee-Philips PhD, Prof H Rees MRCGP), Perinatal HIV Research Unit (B Nkala PhD, R Panchia MBBCh, Prof G Gray DSc), and MATCH (J Ntshangase MBBCh), University of the Witwatersrand, Johannesburg, South Africa; Biostatistics Unit (Prof C Lombard PhD), South African Medical Research Council (Prof G Gray), Cape Town, South Africa; Desmond Tutu HIV Centre (Prof L-G Bekker PhD) and Division of Epidemiology and Biostatistics, School of Public Health and Family Medicine, (Prof C Lombard, E Smith MPH, Prof L Myer PhD), University of Cape Town, Cape Town, South Africa; Setshaba Research Centre, Soshanguve, South Africa (K Ahmed PhD); Aurum Institute, Johannesburg, South Africa (M Sebe MBBCh, W Brumskine MBBCh); Mecru Clinical Research Unit, Sefako Makgatho Health Sciences University, Ga-Rankuwa, South Africa (M Nchabeleng MBChB); Qhakaza Mbokodo Research Centre, Ladysmith, South Africa (S Sibiya MBBCh); CONRAD, Eastern Virginia Medical School, Arlington, VA, USA (J Schwartz MD, Prof G F Doncel MD); Johns Hopkins University School of Medicine, Baltimore, MD, USA (M Marzinke PhD); National Institute for Communicable Diseases, National Health Laboratory Service, Johannesburg, South Africa (Prof L Morris PhD); and Statistical Center for HIV/AIDS Research and