Pharmacogenomics of HIV Therapy

HIV治疗的药物基因组学

• 批准号: 9252792
• 负责人: David W Haas
• 金额: $ 150.42万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-08 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9252792
• 关键词: AIDS clinical trial group; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Affect; Anti-Retroviral Agents; Architecture; Atazanavir; Biological; Biological Assay; CD4 Lymphocyte Count; CYP2B6 gene; Clinical; Clinical Trials; Collaborations; Communicable Diseases; Computerized Medical Record; Cost Effectiveness Analysis; Data; Data Set; Databases; Drug toxicity; Epidemiology; Failure; Frequencies; Gene Targeting; Genes; Genetic; Genetic Polymorphism; Genetic screening method; Genotype; Goals; HIV; HIV therapy; Health; Health Policy; Human Genetics; Human Genome; Hypersensitivity; Immune; Individual; Knowledge; Laboratories; Life; Metabolism; Modeling; Nevirapine; Outcome; Pennsylvania; Pharmaceutical Preparations; Pharmacogenetics; Pharmacogenomics; Phenotype; Plasma; Public Health; Publishing; Randomized Clinical Trials; Reaction; Recording of previous events; Recovery; Regimen; Research; Research Personnel; Rifampin; Sample Size; Specimen; Testing; Time; Translating; Translations; UGT1A1 gene; Universities; Variant; Vision; absorption; antiretroviral therapy; clinical care; clinical phenotype; clinical practice; clinically relevant; cohort; cost effective; efavirenz; genetic association; genetic variant; genome wide association study; genome-wide; human leukocyte antigen testing; isoniazid; models and simulation; novel; pandemic disease; phenome; prospective; randomized trial; response; tool; trait; treatment response; treatment trial

DESCRIPTION (provided by applicant): Access to safe and effective antiretroviral therapy (ART) is a cornerstone in the global struggle against HIV/AIDS, which affects approximately 1 million individuals in the US and 34 million worldwide. There is marked interindividual variability in response to ART regarding drug toxicity, virologic efficacy, and immune recovery. Virtually every antiretroviral is affected by drug absorption, distribution, metabolism, and elimination (ADME), and genetic polymorphisms in ADME genes are known to have functional effects, as do off-target genes. Large effect sizes with ADME and off-target genes often reveal associations with small sample sizes. A challenge in quantifying the impact of human genetic variants on HIV treatment response is that associations are often context dependent. There is great opportunity to accelerate the pace and scope of pharmacogenomic discovery. An exciting new high impact strategy is the phenome-wide association study (PheWAS), which asks whether genetic polymorphisms are associated with one or more clinical traits (i.e. phenotypes) across the entire phenome . PheWAS is largely unbiased regarding phenotypes, and is ideal for interrogating large numbers of context-dependent associations. Large, prospective, randomized clinical trials data offer a unique window to genotype-phenotype associations. This proposal will, for the first time, apply PheWAS to data from prospective clinical trials, and will emphasize context- dependent associations. This will be involve >5,500 individuals who initiated ART in prospective, randomized trials of the AIDS Clinical Trials Group. We will apply a phenome-wide strategy to discover novel associations between genetic polymorphisms, particularly in known ADME genes, and HIV treatment response phenotypes in data from prospective, randomized clinical trials. We will refine and replicate associations, both within and beyond HIV treatment trials datasets. We will also apply simulation modeling and cost-effectiveness analysis to assess the clinical utility of upfront genetic tests to inform antiretroviral prescribing. Our vision is t identify associations that are sufficiently robust to translate into clinical care, and to impact HIV/AIDS worldwide.

获得安全有效的抗逆转录病毒疗法（ART）是全球抗击艾滋病毒/艾滋病的基石，美国约有100万人感染艾滋病毒/艾滋病，全球约有3400万人感染艾滋病毒/艾滋病。个体间差异显著 在药物毒性、病毒学功效和免疫恢复方面对ART的响应。几乎每一种抗逆转录病毒药物都受到药物吸收、分布、代谢和消除（ADME）的影响，已知ADME基因的遗传多态性与脱靶基因一样具有功能效应。ADME和脱靶基因的大效应量通常与小样本量相关。量化人类遗传变异对艾滋病毒治疗反应的影响的一个挑战是，相关性往往取决于背景。有很大的机会来加快药物基因组学发现的速度和范围。一个令人兴奋的新的高影响力策略是全表型关联研究（PheWAS），该研究询问遗传多态性是否与整个表型组中的一个或多个临床特征（即表型）相关。PheWAS在很大程度上对表型没有偏见，并且是询问大量上下文相关性的理想选择。大型、前瞻性、随机临床试验数据为基因型-表型关联提供了一个独特的窗口。该提案将首次将PheWAS应用于前瞻性临床试验的数据，并将强调背景依赖性关联。这将涉及在艾滋病临床试验组的前瞻性随机试验中开始抗逆转录病毒治疗的5,500多人。我们将应用一个全表型的策略来发现遗传多态性，特别是在已知的ADME基因中，与前瞻性随机临床试验数据中的HIV治疗反应表型之间的新关联。我们将在HIV治疗试验数据集内外完善和复制关联。我们还将应用模拟建模和成本效益分析来评估前期基因检测的临床效用，以告知抗逆转录病毒药物处方。我们的愿景是确定足够强大的协会，以转化为临床护理，并在全世界范围内影响艾滋病毒/艾滋病。