• Efficacy of BMS-232632 against a Panel of HIV-1 Clinical Isolates Resistant to Currently used Protease Inhibitors
  Slide Session 2114
  Authored by R. J. Colonno, K. Hertogs, B. A. Larder, K. Limoli, G. Heilek-Snyder, N. Parkin

This oral abstract presented information regarding the drug resistance profile for BMS-232632. This drug is a new azapeptide protease inhibitor, which is a selective and competitive protease gene inhibitor. A brief review was presented that described prior in vitro work. This compound is 86% protein bound, has an EC50 of 0.82nM that is decreased by three- to four-fold with the addition of serum. A mutation at codon 88 (N88S) in the protease gene was found to be significant in conferring drug resistance to BMS-232632 in vitro. It was further discovered that there was only partial cross-resistance to currently available PIs.

62 clinical isolates that had documented protease inhibitor resistance were analyzed. Both genotypic and phenotypic data were presented. The analysis was performed looking at isolates resistant to anywhere from one to all five of the currently available PIs. In general, 34 or 38 (89%) of isolates resistant to one to three PIs were sensitive to BMS-232632. In isolates that were resistant to four or more PIs, BMS-232632 demonstrated resistance as well. An analysis of mutational patterns of these isolates revealed a range of 4 to 22 protease gene mutations per isolate. There was no correlation between number of mutations and presence of phenotypic resistance. There was no obvious signature mutation or combination of mutations that conferred BMS-232632 resistance. In addition, multiple mutations (>4) were required to show phenotypic resistance.

Although there is no specific signature mutation that documents clinically significant resistance, it appears that BMS-232632 has activity and therefore potential clinically utility in patients who have failed a prior PI-containing regimen. In those patients in whom a significant number of known PI-associated mutations that confer broad-class resistance are present, it is doubtful that this compound will demonstrate significant activity either. Further elucidation of the resistance profile for BMS-232632 awaits the results of clinical trials.