Pharmacogenomics of HIV Therapy

HIV治疗的药物基因组学

• 批准号: 8845957
• 负责人: David W Haas
• 金额: $ 42.97万
• 依托单位: VANDERBILT UNIVERSITY
• 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/8845957
• 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.

描述（由申请人提供）：获得安全有效的抗逆转录病毒治疗 (ART) 是全球抗击艾滋病毒/艾滋病的基石，该疾病影响着美国约 100 万人和全球约 3400 万人。存在明显的个体差异 针对 ART 的药物毒性、病毒学功效和免疫恢复方面的反应。事实上，每种抗逆转录病毒药物都会受到药物吸收、分布、代谢和消除 (ADME) 的影响，并且已知 ADME 基因的遗传多态性具有功能效应，脱靶基因也是如此。 ADME 和脱靶基因的大效应通常揭示与小样本量的关联。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，这种关联通常是依赖于环境的。这是加快药物基因组学发现的步伐和范围的绝佳机会。一项令人兴奋的新的高影响策略是全表组关联研究（PheWAS），该研究询问遗传多态性是否与整个表组中的一个或多个临床特征（即表型）相关。 PheWAS 在表型方面基本没有偏见，非常适合询问大量上下文相关关联。大型、前瞻性、随机临床试验数据为基因型-表型关联提供了独特的窗口。该提案将首次将 PheWAS 应用于前瞻性临床试验的数据，并将强调上下文相关的关联。这将涉及超过 5,500 名在艾滋病临床试验组的前瞻性、随机试验中启动 ART 的个体。我们将应用全表型策略来发现遗传多态性（特别是已知的 ADME 基因）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。我们将在艾滋病毒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测试的临床效用，从而为抗逆转录病毒处方提供信息。我们的愿景是确定足够强大的协会，以转化为临床护理，并影响全世界的艾滋病毒/艾滋病。