ACTG A5211 HIV-1 ENTRY INHIBITOR, SCH 417690, TO TREAT HIV INFECTED SUBJECTS

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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. The development of new treatment options is critical for heavily treatment-experienced, HIV-infected patients. Drugs with new mechanisms of action, such as the HIV entry inhibitors, demonstrate activity even in patients with resistance to currently available reverse transcriptase and protease inhibitors. SCH 417690 (formerly known as Schering D) is an inhibitor of HIV-1 infection that acts by specifically blocking the CCR5 coreceptor. Data from phase I studies in HIV-infected treatment-naive subjects demonstrate that SCH 417690 given as monotherapy is safe and generally well-tolerated at doses of 10, 25, and 50 mg BID and demonstrates antiretroviral activity. At these doses, a nadir in HIV-1 RNA was observed after 10-14 days of dosing. SCH 417690 will be coadministered with a ritonavir-boosted protease inhibitor-based ART regimen in A5211. The proposed doses ranging from 5 to 15 mg QD were chosen based partly on the increases in Cmax and AUC of SCH 417690 observed in pharmacokinetic studies when SCH 417690 10 mg BID was administered with ritonavir (100 mg QD, 100 mg BID, 200 mg BID, or 400 mg BID), and on extrapolation from these data to predict the anticipated Cmax and AUC for the QD doses. Ritonavir has a similar effect at the doses tested and was shown to increase SCH 417690 Cmax approximately 2-3 fold and AUC approximately 4-6 fold. The current phase II study will validate the phase I findings and demonstrate longer-term safety and efficacy data for SCH 417690 with ritonavir pharmacokinetic enhancement in treatment-experienced subjects.