HIV Pre-exposure prophylaxis (PrEP) with co-formulated emtricitabine tenofovir (FTC/TDF) in HIV negative persons is a powerful strategy for preventing HIV infection. While FTC/TDF has an excellent overall safety profile, it does produce subtle decreases in bone mineral density (BMD). Men who have sex with men (MSM) bear a major burden of HIV infection worldwide and have been shown to have low bone mineral density even in the absence of FTC/TDF treatment. Hence, understanding the nature of BMD effects of FTC/TDF is important optimizing the risk benefit ratio of PrEP. The investigators have conducted a NIH-funded project that included a randomized placebo controlled trial of FTC/TDF v. placebo for PrEP in a global sample of HIV- MSM at risk of acquiring HIV infection and an open label extension to that trial. As a part of that study, we conducted a substudy of bone and body composition effects in approximately 20% of the study participants who underwent dual x-ray absorptiometry (DEXA) scans. We recently concluded an open-label extension to the original trial. The trial found that PrEP was effective in preventing HIV infection with intent-to-treat effects of a 42% reduction in HIV infection. Comparing the randomization arm in the DEXA substudy found a mean decrease in BMD of 0.6% in the hip and 0.9% in the spine on FTC/TDF compared to placebo. The study had low overall adherence (55% at week 8) and so biological effects of FTC/TDF on bone may be underestimated. Preliminary indications are this decrement is stronger among US-enrolled participants and those with higher bone mineral density but it unclear if this is a differential response to FTC/TDF or merely a surrogate for higher adherence. There is an indication that the decrement in BMD, begins to rebound after FTC/TDF is stopped; however, we have only examined this in the first 6 months after stopping drug. An additional follow-up one year of off-drug follow-up is now available as a part of the open-label extension. We propose to combine data for our randomized study and open label extension to examine changes in BMD after discontinuation of FTC/TDF, explore subgroups most vulnerable to BMD loss from FTC/TDF and attempting to estimate the mean BMD changes expected under perfect adherence. The project concluded in late 2014. Funding this proposal will allow us to pursue important outstanding questions from an available data source.