Pharmacogenomics of HIV Therapy

描述(由申请人提供)：获得有效的抗逆转录病毒药物可显著降低获得性免疫缺陷综合征(艾滋病)的发病率和死亡率。然而，对人类免疫缺陷病毒1型(HIV-1)治疗的反应在有效性和毒性方面存在相当大的个体差异。对药物的不同反应至少部分受到影响药物新陈代谢和药物处置的频繁的人类遗传变异的影响。由于次优反应可能会对个人和人群造成毁灭性的后果，因此定义人类遗传学对艾滋病毒治疗反应的预测价值具有深远的意义。与艾滋病毒治疗相关的基因组发现的步伐相对缓慢且支离破碎。一种跨越抗逆转录病毒药物和药物类别的方法将极大地促进将艾滋病毒药物基因组学从工作台到床边再到社区的高效转移，从而使世界各地受艾滋病毒影响的人可以从人类基因组革命中受益。拟议的研究将确定人类药物基因组测试在临床艾滋病毒护理中的效用。最重要的假设是，了解人类基因变异和艾滋病毒治疗反应之间的关联将改善艾滋病毒治疗结果。这项建议将重点放在与药物吸收、分配、代谢和消除(ADME)相关的基因上，并辅以选定的非ADME多态。这将通过分析来自5000多名来自预期临床试验的参与者的数据和DNA来实现。将根据人类基因变异的知识开发对抗逆转录病毒治疗反应的预测模型。这些分析的结果也可能为设计一项前瞻性随机临床试验提供依据，以测试当人类基因测试为处方提供信息时，艾滋病毒治疗反应是否会改善。这项工作可能最终导致更好的个体化治疗(个人化药物)，并改进世界各地资源有限国家的抗逆转录病毒治疗指南。为了最大限度地发挥影响和增加价值，该项目将成为与其他调查人员合作的平台。公共卫生相关性艾滋病大流行是历史上最大的公共卫生传染病挑战之一。美国大约有100万人，全世界有4000万艾滋病毒/艾滋病患者。了解人类基因差异如何预测对艾滋病毒药物的治疗反应，可能有助于为公共卫生政策决策提供信息，了解在美国和世界范围内最安全和最有效的抗逆转录病毒疗法的使用。

DESCRIPTION (provided by applicant): Access to potent antiretroviral drugs markedly reduces acquired immunodeficiency syndrome (AIDS) morbidity and mortality. However, there is considerable interindividual variability in response to human immunodeficiency virus type 1 (HIV-1) therapy regarding both efficacy and toxicity. Variable responses to medications are influenced, at least in part, by frequent human genetic variants that affect drug metabolism and drug disposition. Because suboptimal response can have devastating consequences for individuals and populations, defining the predictive value of human genetics for HIV treatment response has far-reaching implications. The pace of genomic discovery relevant to HIV therapeutics has been relatively slow and fragmented. Efficiently moving HIV pharmacogenomics from bench to bedside to community will be greatly facilitated by an approach that spans antiretroviral drugs and drug classes so that persons affected by HIV worldwide may benefit from the human genomic revolution. The proposed studies will determine the utility of human pharmacogenomic testing for clinical HIV care. The overarching hypothesis is that knowledge of associations between human genetic variants and HIV treatment responses will improve HIV treatment outcomes. This proposal will focus on genes relevant to drug absorption, distribution, metabolism, and elimination (ADME), complemented by selected non-ADME polymorphisms. This will be accomplished through analyses of data and DNA from over 5,000 participants from prospective clinical trials. Predictive models for responses to antiretroviral therapies will be developed based on knowledge of human genetic variants. Results of these analyses may also inform the design of a prospective randomized clinical trial to test whether HIV treatment responses will improve when human genetic testing informs prescribing. This work may ultimately result in better individualized therapy (personalized medicine), and improved antiretroviral treatment guidelines for persons living in resource-limited countries worldwide. To maximize impact and value added, this project will be a platform for collaboration with other investigators. PUBLIC HEALTH RELEVANCE The AIDS pandemic is one of the greatest public health infectious diseases challenges in history. There are approximately 1 million individuals in the US and 40 million worldwide living with HIV/AIDS. Understanding how human genetic differences predict treatment response to HIV medications may help inform public health policy decisions about the safest and most effective use of antiretroviral regimens in the US and worldwide.