Pharmacogenomics of HIV Therapy

描述(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/艾滋病斗争的基石，美国约有100万人受到影响，全球约有3400万人受到影响。个体间有明显的变异性。 对抗逆转录病毒药物毒性、病毒学疗效和免疫恢复的反应。事实上，每一种抗逆转录病毒药物都受到药物吸收、分配、代谢和消除(ADME)的影响，ADME基因的遗传多态与靶外基因一样具有功能效应。ADME和非靶标基因的大效应大小通常与小样本大小有关。量化人类基因变异对艾滋病毒治疗反应的影响的一个挑战是，关联往往是与背景相关的。有很大的机会加快药物基因组学发现的步伐和范围。一个令人兴奋的新的高影响策略是全表型关联研究(Phewas)，它询问基因多态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在表型方面很大程度上是公正的，是询问大量上下文相关关联的理想选择。大型、前瞻性、随机化的临床试验数据为研究基因-表型相关性提供了一个独特的窗口。这项建议将首次将Phewas应用于来自预期临床试验的数据，并将强调上下文相关的关联。这将涉及艾滋病临床试验组的5,500名发起抗逆转录病毒治疗的前瞻性随机试验。我们将应用一种全表型策略，在前瞻性随机临床试验的数据中发现遗传多态，特别是已知ADME基因的多态与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和之外提炼和复制关联。我们还将应用模拟建模和成本效益分析来评估预先基因测试为抗逆转录病毒处方提供信息的临床用途。我们的愿景是找出足够强大的关联，将其转化为临床护理，并影响全球艾滋病毒/艾滋病。

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.