Abstract/Project Summary: HIV pre-exposure prophylaxis (PrEP) has been shown to be highly effective for HIV prevention in randomized clinical trials but uptake of PrEP in the U.S. has been limited. One of the barriers to PrEP implementation is lack of healthcare provider (HCP) knowledge and willingness to prescribe it. As outcomes of current PrEP formulations in real-world settings and different populations are reported and novel PrEP formulations are introduced, HCPs will continue to require support and guidance to optimize the clinical and public health impact of this valuable HIV prevention strategy. We propose a PrEP optimization intervention targeted at HCPs to increase PrEP uptake and persistence among those at risk for HIV acquisition. This intervention includes: (1) an integrated web-based panel management tool called PrEP-Rx, which provides structured HIV risk assessment, automates reminders for laboratory testing and appointments, and reports patients' history of PrEP use; and (2) a centralized PrEP coordination overseen by a clinical support staff (referred to as the PrEP coordinator) who can identify individuals at high risk for HIV through direct patient contact or by reviewing registries for sexually transmitted infections (STIs) and who can support multiple HCPs. We propose the following aims: Primary Aim: Evaluate the efficacy of the PrEP optimization intervention (PrEP Coordinator + PrEP-Rx) to increase PrEP prescriptions through a stepped-wedge design among 10 primary care clinics. We hypothesize that the mean number of prescriptions issued will be significantly higher when the clinics use the PrEP intervention versus when they do not. Secondary Aims: 1- Explore differences in PrEP initiation, duration of use, and reasons for discontinuation based on patient's age, race/ethnicity, and sex/gender, and by clinic and HCP characteristics among study clinics. 2- Explore sustainability of the intervention during an eight-month follow-up after the stepped-wedge Phase. 3- Investigate facilitators and barriers of PrEP delivery and experiences with the proposed PrEP intervention through qualitative interviews with HCPs, PrEP Coordinators, and clinic directors of study clinics. The combination of the PrEP Coordinator plus PrEP-Rx has the potential to improve all steps of the PrEP continuum and enhance overall care by identifying individuals at high risk of HIV acquisition, standardizing HIV risk assessment, helping in PrEP initiation, systematizing follow-up visits or laboratory assessments, and educating HCPs about emerging PrEP data. These goals can have a significant public health impact and be attained with minimal burden on existing clinic resources. We are using innovative approaches for PrEP delivery which will result in training of HCPs to increase the number of HCPs capable of offering PrEP. Ultimately, the proposed research has the potential to reduce gaps in the PrEP cascade.