HARP OVERALL PROJECT SUMMARY The goal of the HIV and Alcohol Research center focused on Polypharmacy (HARP) is to design and implement effective personalized interventions for people aging with HIV (PAH) experiencing medical harm from unhealthy alcohol use (at risk and Alcohol Use Disorder [AUD]) and polypharmacy (5+ medications). Using large scale, national Veterans Healthcare Administration Electronic Health Record data (EHR data), we have shown strong independent, dose-response, associations between polypharmacy (medication count and A-PIMS), alcohol use, and adverse health outcomes. In HARP Project 1, we further explore alcohol and polypharmacy (AP) risks using a direct alcohol biomarker (Phosphatidylethanol [PEth]), considering genetic liability, and exploring associations with decompensated liver cirrhosis as a manifestation of alcohol-associated liver disease (AALD). Polypharmacy and genetic liability also complicate selection of treatment for AUD. In HARP Project 2, we use genetic liability and real-world data to identify and evaluate candidate medications in the context of polypharmacy. Further, AP risks, especially genetic liability, are complex and challenging to summarize. Both summarizing effects of multiple risk factors and using genetic data to identify medications for repurposing requires large-scale, real-world data, high performance computing and sophisticated analytics. With support from our Administrative/Data Analytic (ADA) Core, the Department of Energy (DOE), an extended VA family of EHR cohorts (VACo Family), and an expanded network of experts, we are uniquely poised to harness “big” data to personalize AP risks for PAH and evaluate medications for AUD. Finally, effective communication of AP risk messages needs to be integrated into a comprehensive, theory-based behavior change intervention. We have assembled a Risk Communication Core (RCC) of experts to facilitate risk communication and motivational interviewing (MI) in our pilot intervention studies. The core includes Dr. Jeffrey Fisher, co-developer of the Information-Motivation-Behavioral Skills (IMB) model of health behavior change. In collaboration with Dr. Fisher, this core will guide our application of the IMB-MI model to communicate personalized risk and other elements required for health behavior change in a linked series of pharmacist- delivered pilot interventions. Project 1 pilots will compare patient’s responses to AP risk messages (employing different measures of exposure and outcomes) delivered in the larger context of an IMB-MI intervention for PAH who are at risk drinkers; Project 2 pilots will incorporate lessons learned in Project 1 and adapt the IMB- MI intervention to target PAH with AUD, adding a candidate repurposed medication for AUD.