Background: Rural Kentucky is an epicenter of hepatitis C(HCV), especially among young adults who inject drugs. While the Risk Environment Framework (REF) has been used widely to study and address socio-ecological determinants of infectious disease among people who inject drugs (PWID), it has been almost exclusively applied to urban environments. Applying REF to rural environments can enhance our understanding of the drivers of HCV epidemics in these hard-hit areas, and inform the creation and implementation of harm reduction interventions in this local context. Methods: Participants were recruited between March and August 2017 via community-based outreach methods (e.g., cookouts, flyers) and peer referral. Individuals who met eligibility criteria (aged 18-35, recently used prescription opioids and/or heroin to get high, lived in one of the 5 target counties) participated indepth, semi-structured interviews. The interview guide was informed by the REF, and covered HCV-related risk behaviors and environmental features that shaped vulnerability to engaging in these behaviors. Interviews were transcribed and analyzed using constructivist grounded-theory methods. Results: Participants (N =19) described multiple intersecting risk environment features that shaped vulnerability to HCV transmission. Economic decline generated intergenerational poverty, dwindling employment prospects, and diminished social enrichment opportunities that collectively contributed to substance misuse and risky injection practices. Geographic isolation, lack of collective knowledge about HCV transmission risks, scarce harm reduction services, familial poverty, and fear of law enforcement interacted to increase the odds of people injecting in "trap houses" (akin to shooting galleries) or secluded areas, spaces in which they rushed to inject and shared injection equipment. Pervasive stigma was a structural barrier to adopting, expanding, and using harm reduction services. Conclusion: This exploratory study identified features of rural risk environments that may contribute to significant HCV burdens in Appalachian Kentucky. Findings signal the importance of expanding proven harm reduction strategies and anti-stigma interventions tailored to rural contexts.
