INTEGRATING PHARMACOKINETICS AND ANTIRETROVIRAL RESISTANCE TESTING

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This application describes a method of integrating pharmacolunetic (PK) and viral phenotypic drug susceptibility (IC50) information to assist clinicians in choosing optimal regimens for salvage therapy of their treatment-experienced HIV-infected patients. PK models with built-in variability were created for each regimen and used to simulate 100 concentration-time curves for each regimen. The IC50 for a PI or NNRTI is corrected for plasma protein binding and compared with the range of simulated trough levels (Cmin). The hypothesis is that integration of PK and phenotypic information maximizes the benefit of antiretroviral therapy in the management of treatment experienced subjects. The specific aims of this application are: 1) to prospectively validate the Probability Estimations method by correlating the estimated probability of achieving PI trough concentrations above the PB IC95 for each participant at baseline, and 2) to assess short-term virologic response in a prospective, 16-week "proof-of-concept" pilot study by enrolling 60 subjects with moderate-level drug resistance into two randomized arms. One arm will have their subsequent salvage regimen chosen using a phenotypic test for clinician guidance, the other arm will use the Probability Estimations approach that inherently includes phenotyping plus drug pharmacokinetics for clinician guidance. The long-term objectives of this work are: (1) to allow expansion of these observations into a larger, well-controlled clinical trial; and (2) to expand these findings into less treatment-experienced patients.