Plasma and Genital HIV Dynamics in Women

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DESCRIPTION (provided by candidate): Candidate: Dr. Neely is an Assistant Professor of Clinical Pediatrics with subspecialty training in infectious diseases and clinical pharmacology. For the last 4 years he has been using population pharmacokinetic (PK) modeling to measure adherence to antiretroviral therapy by women, adolescents, and children, as well as finding that non-nucleoside reverse transcriptase inhibitors (NNRTIs) may be more associated with shedding of HIV RNA from the cervix than are protease inhibitors (PIs). His immediate aims are to prospectively explore this finding using advanced population modeling techniques to compare NNRTI or PI pharmacodynamic (PD) effects on HIV replication in plasma and the female genital tract. His long-term objective is to develop a research center of excellence, using PK-PD modeling to pose and answer therapeutic and scientific questions, particularly in women and children. The University of Southern California is ideally suited for this goal, having a Master's program in Clinical Investigation, the Laboratory of Applied Pharmacokinetics (LAPK), the Biomedical Simulations Resource (BMSR), and over 3500 HIV-infected patients, with the Maternal Child Adolescent (MCA) clinic focused specifically on the needs of HIV- infected women and children. Dr. Neely will be mentored by Dr. Roger Jelliffe (LAPK), as well as a team of advisors including Dr. Andrea Kovacs (MCA) and Dr. David D'Argenio (BMSR). Research: Repeated, paired blood-genital samples will be obtained over a 6-month period from 20 women, stratified by treatment. Blood and directly aspirated vaginal fluid will be analyzed by LC-MS/MS for drug concentrations. HIV RNA will be quantified in blood and cervical swabs by isothermal nucleic acid amplification. Population modeling methods will be used to characterize drug PK in plasma and vaginal fluid and to compare the PD effects on plasma and cervical HIV RNA shedding over time. Relevance: Data from this project will be pertinent to several important, unanswered clinical questions, including: 1) Are some agents more effective in preventing sexual or maternal-to-child transmission of HIV by effectively suppressing viral replication in the genital tract? 2) Is suppression of viral replication in the genital tract necessary to maintain suppression in plasma? 3) Can short-term models of viral dynamics be used to predict long-term responses to therapy? 4) Should women initiate antiretroviral therapy according to different virologic/immunologic criteria than for men?