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

HIV 中酒精的个体化风险 /-：遗传学、药物毒性和 PEth

• 批准号: 10304506
• 负责人: Amy Caroline Justice
• 金额: $ 29.58万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-10 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10304506
• 关键词: Accounting; Aging; Alcohol consumption; Alcohols; Anti-Retroviral Agents; Behavioral; Collaborations; Communication; Complex; Consumption; Data; Data Analytics; Delirium; Drug Prescriptions; Effectiveness; Evaluation; Genetic; HIV; HIV risk; Health; Hospitalization; Individual; Intervention; Liver Cirrhosis; Liver diseases; Measures; Modeling; Motivation; Neurocognitive; Outcome; Patient Self-Report; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacogenomics; Phenotype; Physiological; Pilot Projects; Pneumonia; Polypharmacy; Readiness; Reporting; Resources; Risk; Risk Assessment; Role; Safety; Series; Testing; Toxic effect; Work; alcohol effect; alcohol exposure; alcohol measurement; alcohol misuse; alcohol research; alcohol response; alcohol risk; alcohol use disorder; base; behavior change; drug repurposing; falls; frailty; improved; indexing; interest; liver metabolism; mortality; motivational enhancement therapy; personalized medicine; polygenic risk score; skills; theories

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).

竖琴项目1摘要 在多药（AP风险）中，与酒精使用相关的健康风险可能很大， 特别是对于患有艾滋病毒（PAH）老化的人。酒精已知与许多人的严重不利相互作用 通常处方药物，包括几种抗逆转录病毒（ARV）。这些互动药物是 在喝酒（A-PIM）和大多数PAH饮料的人中，被认为是“潜在的不当药物”。他们 同样比未感染的个体和衰老和衰老和 HIV降低了由于生理脆弱而导致的酒精和多药对综合作用的耐受性。 AP风险很复杂，相互作用且高度个性化。他们取决于感兴趣的健康结果 物理脆弱的程度，酒精和多药的暴露水平以及基本的遗传责任。 在PAH中，神经认知妥协和酒精相关肝病（AALD）的风险可能会增加 在多药和A-PIM的背景下使用任何饮酒，可能尤其有问题。会计 用于物理脆弱的（VACS索引），使用自我报告的酒精使用（审核-C）并使用多个指标 多药（药物计数，A-PIMS），我们已经开始表征与严重相关的AP风险 瀑布，肺炎，住院，死亡率和del妄。我们现在建议将这项工作扩展到PAH和 未感染的个体包括遗传负债和AP的ALD风险，导致肝脏失代偿 肝硬化（DLC），鉴于大多数药物的肝脏代谢，包括 ARV。个性化药物结合了大规模的现实数据，高功率计算和数据 分析以总结单个级别的复杂信息。根据我们的先前工作和合作 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来 为DLC和其他患者预后开发个性化，准确的AP风险合并测量 生理脆弱的作用（VACS指数），A-PIM和药物基因组相互作用的遗传责任 （PGX-PIMS）（AIM 1）。在AIM 2中，我们通过测试探索遗传责任对不健康饮酒的作用 多基因风险评分（PRS）是否改变了AP风险或对HIV差异化治疗的反应 地位。来自AIMS 2的PR将为进一步的AP建模（AIM 1）和评估候选人的重新使用。 药物（项目2，目标1和2）。重要的是，个性化的AP风险必须有效地传达给 优化其对行为改变的影响。由我们的专家风险通信（资源）核心（RCC）告知， 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 - 行为技能 /动机访谈（IMB-MI）行为改变试点研究以评估我们的方法 （目标3）。经验教训还将应用于针对PAH的饮酒障碍（AUD）的飞行员 重新利用酒精的药物（项目2，AIM 3）。