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; 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 抗逆转录病毒疗法（ART）导致患者患有艾滋病毒（PLWH），现在生存时间长， 较高的并发症和合并状况的比率很高。这是由于HIV之间的复杂相互作用 感染，宿主遗传学和传统风险因素导致合并症。了解遗传的作用 通过药物遗传学（PGX）评估对药物对特定ART组合的反应进行修改可以 提高药物功效，减轻与艺术相关的副作用并减少合并症。发现内容丰富 ART-PGX变体不仅可以帮助识别有与艺术相关的不良事件的风险和 合并症，但也可以预期新生艺​​术组合的副作用。但是，尽管终身需要 ART，没有对PLWH中遗传变异在临床护理中的作用的全面分析 已经进行了艺术方案，以更好地了解他们的多种不良临床结果 经验。我们将使用CNIC（艾滋病综合临床系统研究网络），这是一个大型 在美国具有深入的纵向临床数据的良好表征的PLWH的前瞻性队列 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 迄今为止，这项最大的PLWH遗传研究，我们将表征多种不良的遗传景观 使用现有全基因组阵列数据和新生成的与艺术方案相关的副作用接下来 从种族/种族多样的表型极端产生测序数据。我们还将使用系统 药理学方法是鉴定与艺术诱导的途径有关的途径 使用相关细胞模型系统的不良事件。我们将检验以下假设，即增加的风险 与艺术相关的不利影响和合并症至少可以部分通过 加剧艺术作用的常见和/或低频遗传变异。目标1：进行全基因组 筛选改变艺术功效的变体，包括CD4和病毒载荷的变化；艺术耐受性， 包括肾脏和肝毒性，以及大约14,000 plwh的艺术裁决合并症 CNICS队列。重大发现将在独立人群中得到验证；目标2：确定生物学 途径和相关的关键驱动基因，各种艺术方案使用A促进不良事件 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 技术，确定与艺术诱导的不同不良临床相关的单个PGX基因曲线 表型通过测序PLWH具有最严重的毒性，功效和耐受性差，并且不利 效果或合并症。拟议的研究有望增强我们对生物学的理解 艺术反应的机制，有助于减少与HIV相关的并发症。识别遗传修饰符 组合艺术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学建立强大的证据基础。