Personalizing Risk from Alcohol among HIV+/-: Genetics, Medication Toxicity and PEth

HARP PROJECT 1 SUMMARY Health risks associated with alcohol use in the context of polypharmacy (AP risks) are likely substantial, particularly for people aging with HIV (PAH). Alcohol has known serious adverse interactions with many commonly prescribed medications, including several antiretrovirals (ARVs). These interactive medications are considered “potentially inappropriate medications” among those who drink (A-PIMs) and most PAH drink. They also initiate polypharmacy (5+ medications) a decade earlier than uninfected individuals and both aging and HIV reduce tolerance to the combined effects of alcohol and polypharmacy due to increased physiologic frailty. AP risks are complex, interacting, and highly individual. They depend on the health outcome of interest, the degree of physiologic frailty, the level of exposure to alcohol and polypharmacy, and underlying genetic liability. Among PAH, risks for neuro-cognitive compromise and alcohol associated liver disease (AALD) likely increase with any alcohol use in the context of polypharmacy and A-PIMs may be particularly problematic. Accounting for physiologic frailty (VACS Index), using self-reported alcohol use (AUDIT-C) and employing multiple metrics of polypharmacy (medication count, A-PIMS), we have begun to characterize AP risks associated with serious falls, pneumonia, hospitalization, mortality and delirium. We now propose to extend this work among PAH and uninfected individuals to include genetic liability and AP risk for AALD resulting in decompensated liver cirrhosis (DLC), a critically important outcome given the hepatic metabolism of most medications, including ARVs. Personalized medicine combines large-scale, real-world data, high-powered computing and data analytics to summarize complex information on an individual level. Based on our prior work and in collaboration with our extended expert network and Administrative/Data Analytic (ADA) Core, we will use data analytics to develop personalized, accurate combined measure of AP risk for DLC and other patient outcomes considering the role of physiologic frailty (VACS Index), A-PIMS, and genetic liability for pharmacogenomic interactions (PGx-PIMS) (Aim 1). In Aim 2 we explore the role of genetic liability for unhealthy alcohol use by testing whether a polygenic risk score (PRS) modifies AP risk or response to AUD treatment differentially by HIV status. PRS from Aims 2 will inform further AP modeling (Aim 1) and evaluation of candidate repurposed medications (Project 2, aims 1 and 2). Importantly, personalized AP risk must be effectively communicated to optimize its impact on behavior change. Informed by our expert Risk Communication (Resource) Core (RCC), we will implement personalized AP risk assessments in a series of theory-based Information-Motivation- Behavioral Skills /Motivational Interviewing (IMB-MI) behavior change pilot studies to evaluate our approach (Aim 3). Lessons learned will also be applied in pilots targeting PAH with alcohol use disorder (AUD) adding repurposed medications for alcohol (Project 2, Aim 3).