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

竖琴项目1摘要 与在多家药房中饮酒相关的健康风险(AP风险)可能很大， 尤其是对艾滋病毒(PAH)老年患者。酒精已经知道与许多人有严重的不良反应 常用的处方药，包括几种抗逆转录病毒药物(ARV)。这些互动药物是 在饮酒者(A-PIM)和大多数PAH饮用者中被认为是“潜在的不适当药物”。他们 也比未感染的人早十年开始多药联用(5种药物)，并且老龄化和 艾滋病毒降低了对酒精和多种药物的联合作用的耐受性，这是因为增加了生理上的脆弱性。 AP风险是复杂的、相互作用的、高度个人化的。它们取决于感兴趣的健康结果， 生理脆弱程度、接触酒精和服用多种药物的程度，以及潜在的遗传风险。 在PAH中，神经认知损害和酒精相关性肝病(AALD)的风险可能会增加 在多药房和A-PIM的情况下使用任何酒精可能特别成问题。会计核算 对于生理脆弱(Vacs指数)，使用自我报告的饮酒量(AUDIT-C)并采用多种指标 对于多药联用(药物计数，A-PIMS)，我们已经开始表征与严重的AP相关的风险 跌倒、肺炎、住院、死亡和精神错乱。我们现在建议将这项工作扩展到PAH和 未感染的个人包括导致肝脏失代偿的急性酒精性肝病的遗传责任和AP风险 肝硬变(DLC)，考虑到大多数药物的肝脏代谢，这是一个至关重要的结果，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 在个人层面上总结复杂信息的分析。基于我们之前的工作，并在合作中 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来 考虑到DLC和其他患者的预后，制定个性化、准确的AP风险组合测量 生理脆弱(Vacs指数)、A-PIMS和遗传易感性在药物基因组相互作用中的作用 (PGx-PIMS)(目标1)。在目标2中，我们通过测试来探索不健康饮酒的遗传易感性的作用。 多基因风险评分(PR)是否改变了AP风险或HIV对AUD治疗的不同反应 状态。来自AIMS 2的PR将为进一步的AP建模(AIMS 1)和评估重新调整用途的候选人提供信息 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中实施个性化的AP风险评估-- 评估我们的方法的行为技能/动机访谈(IMB-MI)行为改变先导研究 (目标3)。吸取的经验教训也将应用于针对患有酒精使用障碍(AUD)的PAH的飞行员，增加 改变酒精用途的药物(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).