Pharmacogenomics of HIV Therapy

HIV治疗的药物基因组学

• 批准号: 8305154
• 负责人: David W Haas
• 金额: $ 76.81万
• 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8305154
• 关键词: AIDS clinical trial group; Abbreviations; Acquired Immunodeficiency Syndrome; Adult; Advisory Committees; Affect; Anti-Retroviral Agents; Antiviral Agents; Area; Caring; Charge; Clinical; Clinical Trials; Cohort Analysis; Collaborations; Communicable Diseases; Communities; Complement; Comprehension; Computing Methodologies; Country; DNA; DNA Library; Data; Data Analyses; Disease; Drug toxicity; Fostering; Funding; Gene Frequency; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genetic screening method; Genomics; Genotype; Goals; Guidelines; HIV; HIV therapy; HIV-1; Health Policy; Health Services Accessibility; Human; Human Genetics; Individual; Infection; Interdisciplinary Study; Knowledge; Leadership; Life; Medicine; Metabolism; Modeling; Morbidity - disease rate; Multi-Drug Resistance; Names; National Institute of Allergy and Infectious Disease; Nature; Outcome; Participant; Persons; Pharmaceutical Preparations; Pharmacogenomics; Policies; Population; Positioning Attribute; Predictive Value; Principal Investigator; Public Health; Randomized; Randomized Clinical Trials; Recording of previous events; Regimen; Research; Research Personnel; Resources; Single Nucleotide Polymorphism; Site; System; Testing; Therapeutic; Toxic effect; Translating; Treatment outcome; United States; Variant; Viral; Virus; Work; absorption; antiretroviral therapy; base; bench to bedside; cost effectiveness; design; drug metabolism; genetic association; genetic variant; improved; member; mortality; novel strategies; pandemic disease; population based; predictive modeling; prospective; repository; response; treatment response

ABSTRACT 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. PROJECT NARRATIVE 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 many help inform public health policy decisions about the safest and most effective use of antiretroviral regimens in the US and worldwide.

摘要 获得有效的抗逆转录病毒药物显著减少获得性免疫缺陷 综合症(艾滋病)发病率和死亡率。然而，有相当大的个体间 人类免疫缺陷病毒1型(HIV-1)治疗反应的变异性 关于疗效和毒性。对药物的可变反应会受到影响，在 至少在一定程度上，是由于频繁的人类基因变异影响药物代谢和药物 性情。因为次优响应可能会对 个人和人群，确定人类遗传学对艾滋病毒的预测价值 治疗反应具有深远的影响。基因组发现的步伐 与艾滋病毒治疗相关的工作相对缓慢且支离破碎。高效移动 艾滋病毒药物基因组学从工作台到床边再到社区将得到极大的便利 一种跨越抗逆转录病毒药物和药物类别的方法，使受 全世界的艾滋病毒可能会从人类基因组革命中受益。建议进行的研究 将决定人类药物基因组测试在临床艾滋病毒护理中的效用。这个 最重要的假设是人类基因之间的联系的知识 变种和艾滋病毒治疗反应将改善艾滋病毒治疗结果。这 提案将集中在与药物吸收、分布、新陈代谢和 消除(ADME)，辅以选定的非ADME多态。这将是 通过分析来自5000多名来自 前瞻性临床试验。抗逆转录病毒治疗应答的预测模型将 基于对人类基因变异的了解而开发。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信息，以测试艾滋病毒是否 当人类基因检测为处方提供信息时，治疗反应将会改善。这 工作可能最终导致更好的个性化治疗(个性化药物)，以及 为生活在资源有限的人改进的抗逆转录病毒治疗指南 世界各国。为了最大限度地发挥影响和增值，这个项目将成为一个平台 与其他调查人员合作。项目叙事 艾滋病大流行是公共卫生传染病的最大挑战之一 在历史上。在美国，大约有100万人和4000万人 全世界艾滋病毒/艾滋病携带者。了解人类基因差异如何预测 对艾滋病毒药物的治疗反应有助于为公共卫生政策决策提供参考 关于美国和美国最安全和最有效的抗逆转录病毒疗法的使用 全世界。