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

HARP项目2总结 虽然很少由艾滋病毒的医疗保健提供者解决，酒精使用障碍（AUD）是一个主要的原因， 艾滋病毒（PAH）感染者的发病率和死亡率。只有三个食品和药物 政府批准的AUD药物，这些药物的可接受性和吸收有限， 原因HIV提供者不熟悉AUD药物，并且不愿在治疗中添加不熟悉的药物。 预先存在的多种药物和生理脆弱的复杂背景。即使在不太复杂的环境中， 这些药物的有效性平均来说是适度的，可能部分是由于遗传易感性的变化。 此外，尽管PAH对酒精相关性肝病（AALD）造成的肝损伤有过度的易感性，但我们缺乏 药物来减轻这种伤害。随着越来越多的人携带艾滋病毒老化，他们继续饮酒， 越来越需要识别和评估安全有效的候选AUD和AALD药物 在多种药物和生理脆弱的背景下。对大规模真实世界数据的分析可能有助于我们 识别和评估用于再利用的候选药物（即，其他常用药物 也可以减少饮酒或肝损伤的目的）。基于我们强大的合作历史， 在更大的艾滋病毒和酒精研究中心的支持下，专注于多药疗法（HARP）计划，我们将 采用创新方法，加强对重新调整用途的候选人的及时发现和初步评价 治疗AUD和AALD。在目标1中，我们应用可解释的人工智能方法和系统 生物学与来自国家退伍军人管理局医疗保健（VA）电子健康记录的数据相关联， 基因数据和公共数据，以确定候选的重新用途的AUD和AALD药物， 基因网络，它可以提供生物水平上的机制细节。在目标2中，我们使用来自 包括> 60，000例PAH和数百万例未感染对照的特征明确的VA队列家族， 进行倾向评分匹配分析，以检查四种候选药物的安全性和有效性 PAH中的药物（哌唑嗪、吡格列酮和维拉帕米治疗AUD，二甲双胍治疗AALD）， 未受感染的人。在目标3中，根据这些分析，我们先前在艾滋病毒治疗中的酒精干预措施 设置，并与风险沟通和管理/数据分析核心合作，我们将 进行三项试点研究，采用临床药师提供的个性化风险信息，并确定 候选药物，以生成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。这些研究将共同加快从 旨在评价治疗PAH中AUD和AALD的新型药物的发现。

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.