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

现代抗逆转录病毒疗法相关毒性、耐受性和合并症的药物基因组学和系统药理学方法

• 批准号: 10668985
• 负责人: Heidi M. Crane
• 金额: $ 82.35万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-10 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10668985
• 关键词: Acquired Immunodeficiency Syndrome; Adverse effects; Adverse event; Aging; Alleles; Anti-Retroviral Agents; Atazanavir; Atherosclerosis; Biological; Biological Models; Bone necrosis; Caring; Cell Line; Cell model; Cells; Chronic; Clinical; Clinical Data; Combined Modality Therapy; Complex; Data; Diagnosis; Drug Kinetics; End stage renal failure; Ethnic Origin; Evaluation; Frequencies; Genes; Genetic; Genetic Screening; Genetic Transcription; Genetic Variation; Genetic study; Glomerular Filtration Rate; HIV; HIV Infections; HLA-B Antigens; Health behavior; Hepatic; Hepatotoxicity; Hypersensitivity; Individual; Inflammation; Ischemia; Ischemic Stroke; Kidney; Kidney Diseases; Laboratories; Link; Liver diseases; Lopinavir; Metabolism; Modernization; Myocardial Infarction; Nevirapine; Outcome; Pathogenesis; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Pharmacogenetics; Pharmacogenomics; Pharmacology; Phenotype; Prevention strategy; Prospective cohort; Reaction; Regimen; Research; Research Personnel; Risk; Risk Factors; Role; Site; Stroke; System; Test Result; Testing; Toxic effect; Treatment Efficacy; Treatment-related toxicity; Validation; Variant; Viral Load result; Virus Diseases; abacavir; absorption; adjudication; antiretroviral therapy; biobank; clinical care; clinical phenotype; cohort; comorbidity; design; differential expression; drug efficacy; drug modification; efavirenz; end stage liver disease; ethnic diversity; evidence base; experience; experimental study; gene network; gene regulatory network; genetic variant; genome wide screen; genome-wide; genomic data; improved; individualized medicine; mortality; new technology; next generation sequencing; non-alcoholic fatty liver disease; novel; personalized medicine; prevent; racial diversity; response; risk stratification; screening; side effect; standard of care; treatment response

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.

抽象的 抗逆转录病毒治疗（ART）已导致艾滋病毒感染者（PLWH）现在衰老并延长了生存期， 但并发症和合并症的发生率很高。这是由于艾滋病毒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。了解遗传的作用 通过遗传药理学 (PGx) 评估来改变药物对特定 ART 组合的反应可以 提高药物疗效，减轻 ART 相关副作用并减少合并症。发现信息丰富 ART-PGx 变异不仅可以帮助识别有 ART 相关不良事件风险的 PLWH， 合并症，还可以预测新兴 ART 组合的副作用。然而，尽管终生需要 ART，未全面分析 PLWH 遗传变异在临床护理中的作用 进行 ART 治疗方案是为了更好地了解其所产生的各种不良临床结果 经验。我们将使用 CNICS（综合临床系统艾滋病研究中心网络），这是一个大型的 美国护理中的 PLWH 前瞻性队列，具有深入的纵向临床数据 包括药物、健康行为、实验室测试结果以及经过验证和裁定的诊断。在 在这项迄今为止最大规模的 PLWH 基因研究中，我们将描述各种不良基因的遗传图谱 使用现有的全基因组阵列数据和新生成的下一个数据来评估与 ART 方案相关的副作用 来自民族/种族多样化表型极端的世代测序数据。我们还将使用该系统 药理学方法来识别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。我们将检验以下假设： 与 ART 相关的不良反应和合并症至少可以部分解释为 常见和/或低频遗传变异会加剧 ART 的影响。目标 1：进行全基因组研究 筛选改变 ART 功效的变异体，包括 CD4 和病毒载量的变化；艺术耐受性， 包括肾毒性和肝毒性，以及约 14,000 名 PLWH 中判定的与 ART 相关的合并症 CNICS 队列。重要发现将在独立队列中得到验证；目标 2：识别生物 各种 ART 治疗方案通过以下途径促进不良事件的发生： 系统药理学方法并验证临床队列中的发现，目标 3：使用新颖的 技术，确定与 ART 诱导的多种不良临床相关的个体 PGx 基因谱 通过对具有最严重毒性、疗效和耐受性差以及不良反应的感染者进行测序来确定表型 影响或合并症。拟议的研究有望增强我们对生物学的理解 ART 反应机制，有助于减少 HIV 相关并发症。遗传修饰剂的鉴定 联合 ART 治疗方案是迈向风险分层、预防策略和量身定制的重要一步 PLWH 的治疗选择，最终有助于为个性化医疗建立强有力的证据基础。