Safety and Effectiveness of Medications for Alcohol Use Disorder among HIV+/-

竖琴项目2摘要 尽管艾滋病毒医疗保健提供者很少解决这一问题，但酒精使用障碍(AUD)是导致 老年艾滋病毒携带者的发病率和死亡率。只有三种食品和药品 政府批准的治疗AUD的药物，这些药物对几个国家的接受度和摄取率有限 理由。HIV提供者不熟悉AUD药物，也不愿在 先前存在的多元药房和生理脆弱的复杂背景。即使在不太复杂的环境中， 平均而言，这些药物的有效性并不高，部分原因可能是遗传易感性的差异。 此外，尽管多环芳烃对酒精相关性肝病(AALD)造成的肝损伤负有过度责任，但我们缺乏 减轻这种伤害的药物。随着越来越多的人感染艾滋病毒并继续饮酒，在那里 是否越来越需要确定和评估安全有效的AUD和AALD候选药物 在多药和生理脆弱的背景下。对大规模、真实世界数据的分析可能会帮助我们 确定和评估用于再利用的候选药物(即，通常用于其他用途的药物 也可能减少饮酒或肝脏损伤的目的)。建立在我们强大的合作历史和 在更大的艾滋病毒和酒精研究中心专注于多药(HARP)计划的支持下，我们将 应用创新方法，加强对重新定位的候选人的及时发现和初步评估 治疗AUD和AALD的药物。在目标1中，我们应用可解释的人工智能方法和系统 生物数据来自国家退伍军人管理局医疗保健(VA)电子健康记录链接到 基因数据和公共数据，以确定候选的AUD和AALD药物在 基因网络，这可能提供生物层面的机械细节。在目标2中，我们使用来自 特征良好的VA队列家族，包括60,000名PAH和数百万未感染的对照组，以 进行倾向得分匹配分析，以检查四名候选人的安全性和有效性 治疗AUD和AALD的药物(哌唑嗪、吡格列酮、维拉帕米和AALD的二甲双胍) 未受感染的个体。在目标3中，根据这些分析，我们之前在艾滋病毒治疗中的酒精干预 设置，并与风险沟通和管理/数据分析核心合作，我们将 使用临床药剂师提供的个性化风险信息进行三项试点研究，并确定 候选药物，以产生关于这些药物的可行性、可接受性和有效性的时间敏感数据 治疗AUD或AALD的药物。总之，这些研究将共同加快从 发现和评价治疗PAH中AUD和AALD的新药。

HARP PROJECT 2 SUMMARY Although rarely addressed by HIV healthcare providers, alcohol use disorder (AUD) is a major cause of morbidity and mortality among people aging with HIV (PAH). There are only three Food and Drug Administration-approved medications for AUD and these have had limited acceptability and uptake for several reasons. HIV providers are unfamiliar with AUD medications and reticent to add an unfamiliar medication in the complex context of pre-existing polypharmacy and physiologic frailty. Even in less complex contexts, the effectiveness of these medications is modest on average, likely due in part to variations in genetic liability. Further, despite PAH’s excess liability for hepatic injury from alcohol-associated liver disease (AALD), we lack medications to mitigate this injury. As more people are aging with HIV and they continue to drink alcohol, there is growing need to identify and evaluate candidate AUD and AALD medications that will be safe and effective in the context of polypharmacy and physiologic frailty. Analyses of large scale, real-world data may help us identify and evaluate candidate medications for repurposing (i.e., medications commonly used for other purposes that may also decrease drinking or hepatic injury). Building on our strong collaborative history and supported by the larger HIV and Alcohol Research center focused on Polypharmacy (HARP) Program, we will apply innovative approaches to enhance timely discovery and initial evaluation of candidate repurposed medications for AUD and AALD. In Aim 1 we apply Explainable Artificial Intelligence methods and systems biology to data from the national Veterans Administration Healthcare (VA) electronic health record linked to genetic data and public data to identify candidate repurposed AUD and AALD medications in the context of gene networks, which may provide mechanistic details at the biological level. In Aim 2 we use data from the well-characterized VA family of cohorts encompassing >60,000 PAH and millions of uninfected controls, to conduct propensity score matched analyses to examine the safety and effectiveness of four candidate medications (prazosin, pioglitazone, and verapamil for AUD and metformin for AALD) among PAH and uninfected individuals. In Aim 3, informed by these analyses, our prior alcohol interventions in HIV treatment settings, and in collaboration with the Risk Communication and Administrative/Data Analytic Cores, we will conduct three pilot studies employing clinical pharmacist-delivered personalized risk messaging and identified candidate medications to generate time sensitive data on the feasibility, acceptability, and efficacy of these medications to address AUD or AALD. Together, these studies will collectively expedite the pipeline from discovery to evaluation of novel medications to address AUD and AALD among PAH.