Pharmacogenomics and Systems Pharmacology Approaches to Toxicity, Tolerability, and Comorbidities Associated with Modern Antiretroviral Therapies

摘要 抗逆转录病毒疗法（ART）导致艾滋病毒感染者（PLWH）现在衰老，生存期延长， 但并发症和合并症的发生率很高。这是由于艾滋病毒和艾滋病之间复杂的相互作用， 感染、宿主遗传学和导致合并症的传统风险因素。了解基因的作用 通过药物遗传学（PGx）评价， 改善药物功效、减轻ART相关副作用和减少合并症。发现信息 ART-PGx变异不仅有助于识别ART相关不良事件风险的PLWH， 合并症，但也预期新生ART组合的副作用。然而，尽管终身需要 ART，没有综合分析PLWH间遗传变异的作用，在临床护理上应联合应用 进行ART方案是为了更好地了解各种不良临床结果， 体验.我们将使用CNICS（艾滋病研究中心综合临床系统网络），一个大型的 美国PLWH治疗中的一个特征良好的前瞻性队列，具有深入的纵向临床数据 包括药物治疗、健康行为、实验室测试结果以及经验证和裁定的诊断。在 这项迄今为止在PLWH中进行的最大规模的遗传研究，我们将描述各种不利因素的遗传景观。 使用现有的全基因组阵列数据和新生成的下一个数据， 从人种/种族多样的极端表型中产生测序数据。我们还将使用 药理学方法，以确定参与发病机制的特定ART诱导途径 使用相关细胞模型系统的不良事件。我们将检验这样一个假设， 与ART相关的不良反应和合并症至少部分可以解释为 常见和/或低频率的遗传变异，加剧ART效应。目标1：进行全基因组 筛选改变ART功效的变体，包括CD 4和病毒载量的变化; ART耐受性， 包括肾脏和肝脏毒性，以及ART相关的裁定合并症，来自 CNICS队列。将在独立队列中验证重要发现;目标2：确定生物学 各种ART方案促进不良事件的途径和相关关键驱动基因， 系统药理学方法，并验证临床队列中的发现，目的3：使用新的 技术，确定与ART诱导的各种不良临床 通过测序PLWH表型，具有最严重的毒性、较差的疗效和耐受性以及不良反应。 影响或合并症。拟议中的研究有望增强我们对生物学的理解。 抗逆转录病毒治疗反应机制，帮助减少艾滋病毒相关并发症。基因修饰物的鉴定 联合抗逆转录病毒疗法是朝着风险分层、预防策略和量身定制的目标迈出的重要一步。 PLWH的治疗选择，最终帮助制定个性化医疗的强有力的证据基础。

ABSTRACT Antiretroviral therapy (ART) has resulted in people living with HIV (PLWH) now aging with prolonged survival, yet high rates of complications and comorbid conditions. This is due to a complex interplay between HIV infection, host genetics, and traditional risk factors leading to comorbidities. Understanding the role of genetic modification of drug responses to specific ART combinations through pharmacogenetic (PGx) evaluation could improve drug efficacy, mitigate ART-related side effects and reduce comorbidities. Discovering informative ART-PGx variants could not only help identify PLWH at risk for ART-associated adverse events and comorbidities, but also anticipate side effects of nascent ART combinations. However, despite lifelong need for ART, no comprehensive analysis of the role of genetic variation among PLWH in clinical care on combination ART regimens have been conducted to better understand the wide variety of adverse clinical outcomes they experience. We will use CNICS (Centers for AIDS Research Network of Integrated Clinical Systems), a large well-characterized prospective cohort of PLWH in care in the U.S with in-depth longitudinal clinical data including medications, health behaviors, laboratory test results, and validated and adjudicated diagnoses. In this largest genetic study in PLWH to date, we will characterize the genetic landscape of a variety of adverse side effects associated with ART regimens using existing genome-wide array data and newly generated next generation sequencing data from ethnically/racially diverse phenotypic extremes. We will also use the systems pharmacology approach to identify specific ART-induced pathways that are involved in the pathogenesis of adverse events using relevant cell model systems. We will test the hypothesis that the increased risk of adverse effects and comorbidities associated with ART can be explained, at least in part, by a burden of common and/or low frequency genetic variants that exacerbate ART effects. Aim 1: Conduct a genome-wide screening of variants that modify ART efficacy, including change in CD4 and viral load; ART tolerability, including renal and hepatic toxicity, and ART-associated adjudicated comorbidities in ~14,000 PLWH from the CNICS cohort. The significant findings will be validated in independent cohorts; Aim 2: Identify biological pathways and related key driver genes through which various ART regimens promote adverse events using a systems pharmacology approach and validate the findings in clinical cohorts, and Aim 3: Using novel technologies, determine individual PGx gene profiles associated with ART-induced diverse adverse clinical phenotypes by sequencing PLWH with the most severe toxicities, poor efficacy and tolerability, and adverse effects or comorbidities. The proposed studies promise to enhance our understanding of the biological mechanisms of ART response, helping reduce HIV-related complications. Identification of genetic modifiers of combination ART regimens is an important step towards risk stratification, prevention strategies and tailored treatment options for PLWH, ultimately helping develop a strong evidence base for personalized medicine.