Pharmacogenomics of HIV Therapy

HIV治疗的药物基因组学

基本信息

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
项目类别：
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

项目摘要

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.

抽象的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（艾滋病）发病率和死亡率。但是，有很多个体响应人类免疫缺陷病毒1型（HIV-1）治疗的变异性关于功效和毒性。对药物的可变反应受到影响，在至少部分是通过影响药物代谢和药物的频繁人类遗传变异性格。因为次优响应可能会对个人和人群，定义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。基因组发现的速度与HIV治疗相关的疗法相对缓慢且分散。有效移动 HIV药物基因组学从长凳到床边再到社区将大大促进一种跨越逆转录病毒药物和药物类别的方法，以便受到影响的人全世界的艾滋病毒可能会从人类的基因组革命中受益。提出的研究将确定人类药物基因组学对临床HIV护理的实用性。这总体假设是对人遗传之间关联的知识变异和HIV治疗反应将改善HIV治疗结果。这提案将重点关注与药物吸收，分布，代谢和消除（ADME），并由选定的非ADME多态性补充。这将是通过分析来自5,000多名参与者的数据和DNA的分析前瞻性临床试验。对抗逆转录病毒疗法反应的预测模型将根据人类遗传变异的知识开发。这些分析的结果还可以告知一项前瞻性随机临床试验的设计，以测试HIV是否当人基因测试告知处方时，治疗反应将有所改善。这工作最终可能会导致更好的个性化疗法（个性化医学），并且改进了生活在资源有限的人的抗逆转录病毒治疗指南全球国家。为了最大化影响和增值，该项目将是一个平台与其他调查员合作。项目叙述艾滋病大流行是最大的公共卫生传染病挑战之一在历史上。美国大约有100万个人和4000万人全世界与艾滋病毒/艾滋病生活在一起。了解人类遗传差异如何预测对艾滋病毒药物的治疗反应许多有助于告知公共卫生政策决策关于在美国最安全，最有效的抗逆转录病毒方案的使用以及全世界。