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)导致艾滋病毒携带者(PLWH)现在老龄化，生存时间延长， 然而，并发症和并存情况的比率很高。这是由于艾滋病毒之间复杂的相互作用造成的。 感染、宿主遗传和导致共病的传统危险因素。了解基因的作用 通过药物遗传学(PGx)评估改变药物对特定ART组合的反应可能 提高药物疗效，减轻与抗逆转录病毒药物相关的副作用，减少并发症。发现信息量大 ART-PGx变异体不仅可以帮助确定PLWH存在ART相关不良事件的风险，而且 合并症，但也预计到新生的艺术组合的副作用。然而，尽管一生都需要 ART，没有全面分析PLWH之间的基因变异在联合临床护理中的作用 ART方案已经被用来更好地了解它们的各种不良临床结果 经验。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 具有深入纵向临床数据的美国护理中PLWH的特征良好的预期队列 包括药物、健康行为、实验室测试结果以及确认和判定的诊断。在……里面 这项迄今为止在PLWH进行的最大规模的遗传研究，我们将描述各种不利的遗传格局 使用现有的全基因组阵列数据和新生成的NEXT与ART方案相关的副作用 来自种族/种族多样性表型极端的世代测序数据。我们还将使用这些系统 用药理学方法识别ART诱导的特定通路，这些通路参与了ART的发病机制 使用相关细胞模型系统的不良事件。我们将检验这一假设，即增加的风险 与抗逆转录病毒治疗相关的不良反应和并发症可以解释，至少部分原因是 加剧ART效应的常见和/或低频遗传变异。目标1：进行全基因组范围的 筛选改变抗逆转录病毒疗法疗效的变体，包括CD4和病毒载量的变化；抗逆转录病毒疗法的耐受性， 包括肾和肝脏毒性，以及与ART相关的合并症，来自 CNICs队列。重要的发现将在独立的队列中得到验证；目标2：确定生物学 途径和相关的关键驱动基因，通过不同的ART方案通过使用 系统药理学方法并在临床队列中验证发现，以及目标3：使用新的 技术，确定与ART诱导的各种不良临床反应相关的个体PGx基因图谱 通过对PLWH进行测序，得出毒性最严重、疗效和耐受性最差、不良反应最严重的表型 影响或并存。拟议的研究有望增强我们对生物的了解 抗逆转录病毒疗法的反应机制，有助于减少艾滋病毒相关并发症。白粉病遗传修饰物的鉴定 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方向迈出的重要一步。 PLWH的治疗选择，最终有助于为个性化药物开发强有力的证据基础。

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.