Optimizing Low Threshold TelePrEP Care in Syringe Service Programs for People who Inject Drugs in Appalachia - ABSTRACT Kentucky (KY) is a high priority Ending the HIV Epidemic (EHE) jurisdiction due to heavy rural HIV burden and exceptionally high rates of new HIV diagnoses driven by injection drug use (IDU). Despite ongoing need for robust HIV prevention and the strong evidence for Pre-Exposure Prophylaxis (PrEP), uptake remains severely limited among people who inject drugs (PWID). PWID are notably impacted by structural challenges that impede entry and retention in PrEP care, including poverty and unstable housing, violence, social isolation, and stigma; in rural and remote areas, including Appalachia, limited healthcare access and a dearth of PrEP providers further constrain access to PrEP along geographic boundaries. An interim assessment of EHE progress notes that PrEP coverage remains well below threshold to reach established EHE targets, and sets out broad policy recommendations to enhance PrEP access by engaging people where they are. For PWID in particular, there is broad scientific consensus that PrEP efforts be intensified and intentional in supporting low threshold PrEP access. The proposed R34 will leverage KY’s robust harm reduction infrastructure to develop, integrate and test a low threshold peer-facilitated TelePrEP intervention for Appalachian PWID in syringe service programs (SSPs) that operate within “PrEP deserts,” filling a critical need to implement innovative approaches that mitigate geographic disparities in PrEP access. The PI’s ongoing research and existing partnerships with local health department SSPs in Appalachian KY have demonstrated that PWID have low PrEP awareness and social determinant barriers to PrEP uptake, yet interest in PrEP is high, at 73%. Building on this existing work, we will conduct a pilot randomized trial to examine efficacy on PrEP initiation (measured by dispensed PrEP prescription) and retention in PrEP care 3- and 6- months post- baseline (measured by self-report and biomarker confirmation) as well as implementation outcomes guided by the Implementation Outcomes Framework. The Specific Aims are to: 1) Collaborate with the Clark County HD (CCHD) and Kentucky River District HD (KRDHD) harm reduction communities to develop the optimal content, delivery structure, and implementation strategies for the peer-facilitated TelePrEP intervention in SSPs and rapidly manualize the novel low threshold protocol; 2) Conduct a pilot randomized trial to evaluate the preliminary efficacy of: a) peer-facilitated, integrated TelePrEP; compared with b) peer-delivered PrEP education and referral, on PrEP initiation and persistence among Appalachian PWID; and, 3) Examine feasibility, acceptability, appropriateness, and fidelity implementation outcomes of the two intervention comparators among PWID participants and partner harm reduction staff using a mixed methods approach. The proposed study will establish preliminary evidence and proof-of-concept for an integrated low-threshold TelePrEP intervention for Appalachian PWID, which is designed to increase PrEP initiation and persistence.