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. 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 subjects salvage regimen that is initiated at Step 1 study entry. An NIQ takes into account the subjects 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 subjects plasma PI trough level be higher than the drug level required to inhibit the subject s virus. An NIQ of > 1 means that the subjects IQ is more than the IQ of subjects who had a good response to the same PI. An NIQ = 1 means that the subjects 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. Screening: Treatment-experienced subjects who have virologically failed at least one PI-containing antiretroviral combination regimen will have a screening resistance test performed using a virtual phenotype while they remain on their failing regimen. A5146 is divided into three steps as follows: Step 1: Step 1 is to determine which subjects have NIQs = 1 or > 1. At entry to Step 1, subjects will initiate a new salvage regimen based on the virtual phenotype performed at screening. Two weeks after entry, all subjects will have a timed plasma sample obtained for PI trough levels on the new salvage regimen. This trough level will be used with the fold-change in IC50 from the screening virtual phenotype to calculate an NIQ. All subjects will receive NIQ results before week 4 in order to determine their eligibility for randomization or arm assignment at Step 2 entry. Step 2: At Step 2 entry, a total of 180 subjects with NIQs = 1 will be randomized to standard of care (SOC) (Arm A) or to TDM+SOC (Arm B). In addition, 50 subjects with NIQs > 1 will be followed in an Observational Arm (Arm C). NOTE: Arm C closed on 07/28/04 after reaching target accrual. Subjects with a week 2 NIQ > 1 will be permanently discontinued from the study. Subjects with NIQs = 1 will receive PI dose escalations according to pre-specified dose adjustment algorithms. The PI dosing algorithms were derived by the A5146 study team pharmacologists and are updated periodically to include additional triple-PI combination regimens, newly FDA-approved PI agents, and revised dosing recommendations based on new available safety information. These dose adjustment algorithms will be used by the study team to determine whether a PI dose should be escalated for an NIQ = 1 in a subject who is eligible to receive TDM. The PI dose adjustment recommendation will be transmitted in an electronic report to the site. Subjects in Step 2 without virologic failure at week 24 or later will continue to be followed in Step 2 on their original assigned treatment arms through week 48. Subjects with virologic failure at week 24 or later may choose to enter Step 3. Step 3: Step 3 is to provide the option of TDM to subjects who failed their initial regimen on Step 2, independent of their original treatment arm randomization or assignment. Subjects in any of the Step 2 arms who have a confirmed plasma HIV-1 RNA concentration of = 1000 copies/mL at or after week 24 will be eligible to enter Step 3 and receive a second virtual phenotype drug resistance test. The results of the resistance test will be used to design a Step 3 salvage regimen. Repeat PI drug level(s) will be obtained on this Step 3 salvage regimen, and NIQ values for any PIs in the Step 3 salvage regimen will be provided for all subjects. All subjects with NIQs = 1 will be given the option to receive dose-adjusted PI therapy, using the same dose adjustment algorithms that were used for subjects in the Step 2, TDM+SOC arm. PI dose adjustments in Step 3 cannot occur any later than week 44 of study participation. After registering to Step 3, subjects will be followed for a maximum of 24 weeks on Step 3 but not more than 48 weeks after study entry (week 0, Step 1). See diagram at the end of this schema. 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. At week 4, subjects with NIQ = 1 will be randomized to Arms A or B, and subjects with NIQ >1 will be assigned to Arm C. Arm A: SOC Arm B: TDM+SOC Arm C: Observational Subjects in Arm C (Observational) will be treated in exactly the same manner as subjects randomized to Arm A (SOC) after Step 2 entry through week 24, the only difference being their week 2 NIQ result (Arm A: NIQ = 1; Arm C: NIQ >1). NOTE: Arm C closed on 07/28/04 after reaching target accrual. Antiretroviral regimens will be selected and prescribed by the subject's clinician based on the results of virtual phenotypic resistance testing. A5146 will not provide any antiretroviral drugs.
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