Pharmacogenomics of HIV Therapy

HIV治疗的药物基因组学

基本信息

批准号：
9100608
负责人：
David W Haas
金额：
$ 8.3万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-08 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9100608
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

项目摘要

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疗法（ART）是全球与艾滋病毒/艾滋病的斗争的基石，该斗争影响了美国约100万人，在全球范围内影响了3400万人。个体间的变异性明显响应有关药物毒性，病毒功效和免疫恢复的ART。实际上，每种抗逆转录病毒都受到药物吸收，分布，代谢和消除（ADME）的影响（ADME），并且已知ADME基因中的遗传多态性与脱靶基因一样具有功能效应。具有ADME和脱靶基因的较大效应大小通常揭示出与样本量较小的关联。量化人类遗传变异对艾滋病毒治疗反应的影响的挑战是，关联通常取决于上下文。有很好的机会加速了药物基因组发现的步伐和范围。一个令人兴奋的新的高影响力策略是全现象的关联研究（PHEWAS），该研究询问整个现象中遗传多态性是否与一个或多个临床性状（即表型）相关。 Phewas在表型方面基本上是公正的，非常适合审问大量与上下文有关的关联。大型，前瞻性的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，并将强调与背景相关的关联。这将涉及> 5,500个人，他们在AIDS临床试验小组的前瞻性，随机试验中发起了ART。我们将采用全面的策略来发现遗传多态性（尤其是已知ADME基因）和HIV治疗反应表型之间的新型关联，这是来自前瞻性，随机临床试验的数据。在HIV治疗试验数据集内外，我们将完善和复制关联。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实用性，以告知抗逆转录病毒处方。我们的愿景是确定足够强大的联想，可以转化为临床护理，并影响全球的艾滋病毒/艾滋病。