This is a proposal for a translational epidemiology study that aims to 1) determine the patterns of antiretroviral drug resistance that occur during viral rebound among Women's Interagency HIV Study (WIHS) participants who receive HAART based on treatment history, level of exposure to antiretroviral drugs over time, and adherence; 2) identify factors that predict CD4 cell count trajectory after viral rebound in HAART recipients including measures of treatment exposure, viral genotype, and immunologic indicators of activation and CD4 cell repletion; 3) develop assays that measure the long-term average exposure to antiretroviral drugs using standard methods of drug concentration determination using hair specimens, and comparing the hair measurements to intensive pharmacokinetics modeling data being produced by WlHS. The proposed research is important because viral rebound during HAART is common in general and in the WIHS cohort. Viral rebound is well tolerated; in terms of CD4 count preservation, in many persons, while others experience CD4 loss and attendant clinical consequences. Treatment discontinuation and regimen changes are not beneficial in many circumstances of viral rebound, particularly if CD4 cell counts could be predicted to remain stable. Thus predictive measures of CD4 outcome during viral rebound would be very useful for clinical care as well as in research. The WlHS cohort includes a group of participants (women and minorities) who are greatly underrepresented in HIV clinical trials and who have more risk factors for pharmacologic interactions with antiretroviral drugs than trials participants. In addition, while characteristics of HIV, such as pretreatment genotype, exposure to antiretrovirals (influenced by both patient adherence and pharmacologic parameters) and host immunologic response, impact on the outcome of HAART, few studies have tested hypotheses related to the interaction of all 3 sets of factors in a representative population. Measurement of long-term exposure to antiretroviral drugs using hair specimens would represent a significant advance in therapeutic drug monitoring methods by permitting assessment of exposure over weeks to months in a non-invasive and cost effective manner. These methods have been successfully applied to a variety of drugs that are used chronic diseases, including indinavir. The research program proposed in this application, a continuation of a previous study, the WlHS Viral Rebound and Resistance Study, would provide important insights into the interactions of pharmacology, virology and immunology among persons receiving HAART. ? ?
