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

HARP项目1摘要 在多种药物治疗的背景下，与酒精使用相关的健康风险（AP风险）可能很大， 特别是对于艾滋病毒（PAH）的老年人。酒精与许多人有严重的不良相互作用。 常用处方药，包括几种抗逆转录病毒药物（ARV）。这些相互作用的药物是 在饮酒者（A-PIM）和大多数PAH饮酒者中被认为是“潜在不适当的药物”。他们 也开始多种药物（5+药物）比未感染的人早十年， 由于增加的生理脆弱性，HIV降低了对酒精和多种药物联合作用的耐受性。 AP风险是复杂的，相互作用的，并且高度个体化。它们取决于感兴趣的健康结果， 生理脆弱程度、酒精和多种药物的暴露水平以及潜在的遗传倾向。 在PAH中，神经认知功能损害和酒精相关性肝病（AALD）的风险可能增加 在多种药物和A-PIM的情况下使用任何酒精可能特别成问题。会计 生理虚弱（VACS指数），使用自我报告的酒精使用（AUDIT-C），并采用多种指标 多药治疗（药物计数，A-PIMS），我们已经开始描述与严重 福尔斯、肺炎、住院、死亡和谵妄。我们现在建议将这项工作扩展到PAH和 未感染个体包括导致肝脏失代偿的AALD的遗传易感性和AP风险 肝硬化（DLC），考虑到大多数药物（包括 抗逆转录病毒药物个性化医疗结合了大规模、真实世界的数据、高性能计算和数据 分析，以总结个人层面的复杂信息。基于我们之前的工作和合作 借助我们扩展的专家网络和管理/数据分析（ADA）核心，我们将使用数据分析， 制定针对DLC的AP风险和其他患者结局的个性化、准确的综合指标， 生理脆弱性（VACS指数）、A-PIMS和遗传易感性在药物基因组学相互作用中的作用 （PGx-PIMS）（目标1）。在目标2中，我们通过测试来探讨遗传易感性对不健康饮酒的作用。 多基因风险评分（PRS）是否通过HIV差异改变AP风险或对AUD治疗的反应 status.目标2中的PRS将为进一步的AP建模（目标1）和重新调整用途的候选人评估提供信息 药物（项目2，目标1和2）。重要的是，必须将个性化AP风险有效地传达给 优化其对行为改变的影响。由我们的专家风险沟通（资源）核心（RCC）提供信息， 我们将在一系列基于理论的信息-动机- 行为技能/动机面试（IMB-MI）行为改变试点研究，以评估我们的方法 (Aim 3）。吸取的经验教训也将应用于针对PAH伴酒精使用障碍（AUD）的试点， 用于酒精的药物（项目2，目标3）。

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).