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. Design: A5146 is an open-label, randomized, multicenter trial. The goal of A5146 is to determine whether dose modification of protease inhibitors (PIs) improves virologic response in PI experienced subjects. PI-resistant HIV needs higher PI levels to be suppressed than PI-sensitive HIV in vitro. A5146 will use therapeutic drug monitoring (TDM) to optimize PI drug concentrations. Optimal drug levels will be calculated by determining the normalized inhibitory quotient (NIQ) for each PI in the subject?s salvage regimen that is initiated at Step 1 study entry. An NIQ takes into account the subject?s trough plasma PI drug level in relation to the degree of resistance of the subjects? virus to that drug (see calculation below). The goal is to have the subject?s plasma PI trough level be higher than the drug level required to inhibit the subject?s virus. An NIQ of 1 means that the subject?s IQ is more than the IQ of subjects who had a good response to the same PI. An NIQ ?1 means that the subject?s IQ is lower than the IQ of subjects who had a good response to the same PI. Either a low drug level or a high level of viral resistance can cause an NIQ to be low (?1). The target NIQ in this study is 1.0 for all PIs. Duration: subjects randomized at Step 2 entry to Arm A or B, or assigned to Arm C, will be followed for 48 weeks after Step 1 entry. Sample Size: The sample size goal is to have 230 subjects enter Step 2 (90 subjects each in the TDM+SOC arms, and 50 in the Observational Arm). In order to achieve this goal, approximately 360 subjects will be required to enter the study. Enrollment of subjects onatazanavir-based regimens is limited to 36, representing 10% of the estimated number of subjects entering Step 1of the study. Population: Men and women18 year of age. HIV-1 infected subjects who have viirologically failed at least one PI-containing combination antiretroviral regimen (i.e., there is no upper limit on the number of failed regimen.
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