San Francisco Community Health Center (SFCHC) - a well-established, multi-service, community-focused federally qualified health center (FQHC) with robust peer outreach and substance use treatment programs - requests funding through the SAMHSA FY 2023 Minority AIDS Initiative: High Risk Populations grant program (TI-23-008) to implement Project REACT (Responsive Equitable Action for Community Treatment). Project REACT is an innovative, peer-focused, community-driven initiative which will take a syndemic approach to addressing the interwoven crises of substance use, HIV infection, and STI and viral hepatitis infection among homeless and unstably housed persons of color living in San Francisco’s hard-hit Tenderloin neighborhood, with a primary focus on Black/African American and Latinx substance users and on transgender substance users of color. Fully one-third of the Tenderloin’s nearly 35,000 residents live below the federal poverty level, while more than 60% of SF’s entire homeless population resides in this neighborhood. SFCHC will conduct extensive street and community-based outreach and engagement activities using established peer and street medicine teams, while engaging additional clients and providing innovative on-site services through our two new, state-of-the-art homeless and transgender drop-in centers. Clients enrolling in the program will complete a minimum 4-month course of treatment that incorporates ongoing case management; participation in weekly treatment groups for at least 16 weeks; peer-based social support services; individual mental health therapy; and socialization and recreational events. All clients will also receive HIV, sexually transmitted infection (STI), and viral hepatitis testing, while being linked to comprehensive medical and treatment services within our co-located FQHC medical, behavioral, and dental clinics, including on-site post-exposure prophylaxis (PEP) and pre-exposure prophylaxis (PrEP) treatment. The overarching goal of the program will be to increase engagement in culturally competent, trauma-informed medical and behavioral health treatment for underserved persons of color with SUDs and/or co-occurring mental health conditions who are at high risk of or living with HIV infection. Over the course of the 5-year grant period, Project REACT will conduct preliminary HIV risk and SUD screening for a minimum of 450 homeless, unstably housed, and/or transgender persons of color; enroll at least 340 of these persons in a 16-week SUD treatment program; ensure that all clients receive preliminary HIV and viral hepatitis testing, while linking all positive clients to treatment through SFCHC’s on-site FQHC primary medical clinic; and provide education on and linkage to PEP and PrEP treatment and support services for clients who test negative for HIV. Key outcome objectives to be achieved by the end of the project period include: a) ensuring that at least 60% of project clients complete the full 16-week intervention; b) documenting self-reported reductions in the frequency and severity of substance use 6 months following admission for at least 50% of clients who complete the full 16-week treatment intervention; c) documenting significantly enhanced mental health status and improved outlook 6 months following program admission for at least 60% of clients who complete the full intervention; d) identifying and linking to care within 14 days at least 25 newly diagnosed persons with HIV; e) identifying and referring to on-site treatment at least 40 newly diagnosed persons with hepatitis B or C; and f) linking at least 75 persons at high risk for HIV to PEP and/or PrEP treatment through the SFCHC medical clinic. SFCHC will implement a comprehensive, multi-faceted data collection and reporting system for Project REACT that includes timely fulfillment of all federal reporting requirements under the GPRA Modernization Act of 2010, along with development of a local evaluation plan.