The early closure of a clinical trial assessing the effective ness of oral antiretroviral pre-exposure pro phyl axis (PrEP) in women, FEM-PrEP, 1 is a substantial setback for HIV prevention. Expectations of this trial were high in view of favourable results from the pre-exposure prophylaxis initiative (iPrEX) trial, 2 which studied the same drug and dosing strategy in men who have sex with men, and the Centre for the AIDS Programme of Research in South Africa (CAPRISA 004) trial, 3 which tested tenofovir gel (a topical PrEP formulation) in heterosexual women. As a result, the interim FEM-PrEP trial results, announced on April 18, 2011, which showed no protection against HIV infection, 1 were disappointing. Using publicly available information1 and data from other PrEP studies, we offer a potential explanation for the results of the FEM-PrEP trial.

In high HIV prevalence settings, such as sub-Saharan Africa, young women have disproportionately high HIV incidence rates, up to 8-times higher than for men of the same age. 4 Available HIV prevention strategies provide few options for young women who are at high risk of infection but who are unable to convince their partner to be faithful or use condoms, underscoring the urgent need for a women-initiated HIV prevention technology. To this end, several microbicide trials have been undertaken during the past 17 years. Until 2010, none had shown protection against HIV acquisition. 5 A new approach was needed. Antiretroviral drugs, already shown to be effective in treating HIV infection and prevention of mother-to-child transmission, heralded a new option to prevent sexual transmission. FEM-PrEP was a phase 3, double-blind, randomised, placebo-controlled trial assessing the effectiveness of daily oral tenofovir disoproxil fumarate and emtricitabine for prevention of HIV acquisition in women aged 18–35 years in South Africa, Kenya, and Tanzania. At a scheduled interim analysis, the HIV incidence rate was 5 per 100 person-years in the 1951 women enrolled, and the 56 HIV endpoints were equally distributed between the study groups. 1 Continuation of the study to the planned 72 HIV endpoints in an attempt to show effectiveness was deemed futile, so the decision was made to undertake an orderly closure of the trial. Why did the FEM-PrEP trial not show protection against HIV infection? To conclude that oral tenofovir disoproxil fumarate and emtricitabine does not prevent HIV infection in women would be overly simplistic and premature; several possible explanations exist for the reported primary HIV outcome in the trial. Such results