PROJECT SUMMARY / ABSTRACT In HIV-endemic settings, many HIV-uninfected women choose to conceive with an HIV-infected or unknown- serostatus partner. For a woman who cannot depend on a partner to test, initiate and adhere to ART, sex without condoms puts her at high risk of acquiring HIV and increases perinatal transmission risks. Daily, oral TDF/FTC PrEP dramatically reduces a woman’s risk of HIV-acquisition and is the only female-controlled option for reducing her risk of periconception HIV-acquisition. Understanding whether daily, oral PrEP is feasible for uninfected women seeking pregnancy is critical to reducing HIV incidence among women and their children. We are conducting a single-arm study to offer daily, oral PrEP for periconception use to 330 HIV-uninfected women in KwaZulu-Natal, South Africa who report personal or partner plans for pregnancy with an infected or unknown serostatus partner (R01MH108412). Women who become pregnant on PrEP have the option to continue PrEP during pregnancy. PrEP is offered as part of a safer conception package inclusive of couples- based HIV counseling and testing. In Aim 1, we evaluate the proportion of women initiating PrEP and determine factors associated with uptake. In Aim 2, we evaluate objectively-measured PrEP adherence during periconception and pregnancy follow-up. Level, patterns, and correlates of adherence are evaluated using plasma drug concentrations and electronic pill caps. From formative studies in South Africa, we hypothesize that adherence to a proven intervention (TDF/FTC PrEP) for a defined risk period (periconception, pregnancy) with a clear end point (live birth) will be high (protective tenofovir concentrations at 80% of visits, adherence to >80% of prescribed pills). In Aim 3, longitudinal quantitative data and in-depth interviews will inform our conceptual framework for periconception PrEP uptake and adherence. To date, we enrolled 330 women and 64% initiated PrEP. During the first 3 months, mean weekly adherence was 71% (95% CI: 66-77%). This project will determine whether oral PrEP is a feasible HIV-prevention strategy for HIV-exposed women who conceive. Given the repercussions of acquiring HIV during conception and pregnancy, this is an important step towards providing a key prevention strategy to women and their children. We now propose to supplement this proposal by adding STI testing and treatment in order to further minimize HIV acquisition risks for this HIV-exposed population, describe curable STI prevalence and incidence among women planning for or with pregnancy to inform STI and PrEP policy, explore how STI diagnosis influences HIV risk perceptions, PrEP uptake, and adherence. The supplemental aims align with the Parent Study Aims and address OAR priorities to reduce HIV incidence.