Understanding factors that influence pre-exposure prophylaxis efficacy for HIV-1 prevention

Thesis (Ph.D.)--University of Washington, 2014Pre-exposure prophylaxis (PrEP) is a promising new HIV-1 prevention strategy, with demonstrated efficacy from four randomized clinical trials. However, two trials of PrEP, both among heterosexual African women, did not find efficacy for protection against HIV-1. While adherence to PrEP has been proposed as the primary driver of the range of results across trials, other factors warrant investigation. This dissertation work contributes to our understanding of behavioral and biological factors that influence the effectiveness of PrEP and aims to inform PrEP implementation strategies. This dissertation was conducted within the Partners PrEP Study, a placebo-controlled, randomized trial of daily oral PrEP among 4747 heterosexual HIV-1 serodiscordant couples (one partner is infected with HIV-1 and the other partner is uninfected) in Kenya and Uganda which demonstrated high efficacy for two daily oral PrEP regimens, tenofovir alone and co-formulated tenofovir-emtricitabine. In a series of secondary analyses of data from the Partners PrEP Study, we evaluated the effect of PrEP among high-risk subgroups to determine whether efficacy was sustained in the context of high HIV exposure, we estimated the causal effect of PrEP when adherence was estimated to be high by applying multiple methods to correct for non-adherence in randomized trials, and we assessed whether PrEP adversely impacted hormonal contraceptive effectiveness for pregnancy prevention, as young women are a priority population for HIV prevention. The work presented here supports the hypothesis that the key driver of divergent PrEP trial results was adherence, and indicates that oral PrEP is highly effective for women and men, reducing HIV-1 risk by over 80% when estimated to have been used with high adherence. These analyses contribute to a more nuanced understanding of how PrEP works and inform guidelines for initiating PrEP among persons at risk of HIV-1 acquisition