Pharmacogenomics of HIV Therapy

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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.