Pharmacogenomics of HIV Therapy

HIV治疗的药物基因组学

基本信息

批准号：
7559048
负责人：
David W Haas
金额：
$ 83.61万
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 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7559048
关键词：
AIDS clinical trial group Abbreviations Acquired Immunodeficiency Syndrome Adult Advisory Committees Affect Anti-Retroviral Agents Antiviral Agents Appendix Area Arts Caring Charge Class 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 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 Research Research Personnel Resources Single Nucleotide Polymorphism Site System Testing Therapeutic Toxic effect Translating Treatment Protocols 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 predictive modeling prospective repository response

项目摘要

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.

描述（由申请人提供）：获得有效的抗逆转录病毒药物明显降低了获得的免疫缺陷综合征（AIDS）的发病率和死亡率。但是，响应于人类免疫缺陷病毒1型（HIV-1）治疗的疗效和毒性的人体间个体差异很大。对药物的可变反应至少部分受到影响药物代谢和药物处置的频繁人类遗传变异的影响。由于次优反应可能对个人和人群产生毁灭性后果，因此定义人类遗传学对HIV治疗反应的预测价值具有深远的影响。与HIV疗法相关的基因组发现的速度相对较慢且分散。有效地将艾滋病毒药物基因组学从长凳转移到床边再到社区，将通过跨越抗逆转录病毒药物和药物类别的方法极大地促进，以便全世界受HIV影响的人可能会从人类的基因组革命中受益。拟议的研究将确定人类药物基因组学对临床HIV护理的实用性。总体假设是，人类遗传变异与HIV治疗反应之间的关联知识将改善HIV治疗结果。该提案将重点放在与药物吸收，分布，代谢和消除（ADME）相关的基因上，并由选定的非ADME多态性补充。这将通过分析来自前瞻性临床试验的5,000多名参与者的数据和DNA来实现。基于人类遗传变异的知识，将开发针对抗逆转录病毒疗法的反应的预测模型。这些分析的结果还可能为一项前瞻性随机临床试验的设计提供信息，以测试当人基因测试告知处方时，HIV治疗反应是否会改善。这项工作最终可能导致更好的个性化治疗（个性化医学），并改善了居住在全球资源有限国家的人的抗逆转录病毒治疗指南。为了最大程度地提高影响力和增值，该项目将是与其他研究人员合作的平台。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。在美国，大约有100万个人，全世界有4000万人生活在艾滋病毒/艾滋病中。了解人类遗传差异如何预测治疗对HIV药物的治疗反应可能有助于为公共卫生政策的决策提供有关在美国和全球最安全，最有效使用抗逆转录病毒方案的决定。