Men who have sex with men (MSM) are at high risk for gonorrhea and chlamydia in Kenya, where nucleic acid amplification testing (NAAT) is not feasible and most infections therefore go undiagnosed. While development of low-cost point-of-care diagnostics is an urgent priority, low-cost and feasible interventions to control sexually transmitted infections (STI) among MSM are needed now, as we await technology advance. In 2011, the WHO recommended periodic presumptive treatment (PPT) of Neisseria gonorrhoeae (NG) and Chlamydia trachomatis (CT) infections for MSM at high risk for HIV acquisition due to condomless anal intercourse with multiple sex partners or a recent STI exposure. More recently, trials in well-resourced settings have demonstrated the efficacy of doxycycline post-exposure prophylaxis (doxyPEP) at reducing NG, CT, and syphilis infections among high-risk MSM. In this R01 application, we propose a rigorous study to evaluate the impact and cost-effectiveness of WHO-recommended PPT versus doxyPEP, compared to standard syndromic treatment, among Kenyan MSM. Our highly productive research team, including collaborators from the University of Washington, Aurum Institute, Nyanza Reproductive Health Society, and Partners for Health and Development in Africa, has expertise in clinical STI care, epidemiology, research with MSM populations, and intervention trials (MPI Graham and Sanders, co-Is Otieno and Kimani), NG and CT diagnosis and testing for antimicrobial resistance (AMR) (co-I Soge), infectious disease modeling (co-I Hamilton), and costing of interventions (co-I Sharma). This study aims to (1) evaluate the effectiveness and impact on AMR in NG of two interventions: WHO-recommended PPT given every 3 months and doxy-PEP taken 24-72 hours after condomless sex, compared to standard syndromic treatment, for reducing STI burden among Kenyan MSM; (2) assess the acceptability, feasibility, and safety of implementing WHO-recommended PPT and doxy-PEP compared to standard care among providers and patients; and (3) model the health and economic impact of scaling up WHO-recommended STI PPT and doxyPEP compared to standard of care on STI control among MSM and their partners in Kenya. We will conduct an open-label randomized clinical trial with 2900 participants to evaluate these two interventions versus the standard of care assigned in a 2:2:1 ratio, with 18 months of follow-up and rigorous culture-based and molecular analysis of AMR in NG at three MSM-friendly research clinics in Kenya. We will use multidisciplinary science to measure the acceptability, feasibility, and safety of these two interventions, using a conceptual model based on Proctor’s Implementation Science Framework. Finally, Aim 1 and 2 results will inform parameters to update a stochastic model of STI transmission and cost- effectiveness analysis to project the impact of scaled-up STI PPT and doxyPEP in Kenya. This work will provide the critical data needed to inform guidelines and impr...