4th International Workshop on HIV Drug Resistance & Treatment Strategies Sitges, Spain, 12–16 June 2000

BMS-232632 SENSITIVITY OF A PANEL OF HIV-1 CLINICAL ISOLATES RESISTANT TO ONE OR MORE APPROVED PROTEASE INHIBITORS

Antivir Ther. 2000 Jun 12-16; 5 (Suppl. 3):7 (Abstract 8

RJ Colonno¹, K Hertogs², BA Larder², K Limoli³, G Heilek-Snyder³ and N Parkin^3
1Bristol-Myers Squibb Research Laboratories, Wallingford, Conn., USA; ²Virco, Cambridge, UK; and ³ViroLogic Inc., South San Francisco, Calif., USA

OBJECTIVE: BMS-232632 is an azapeptide HIV protease inhibitor currently in Phase III clinical trials. As a result of its excellent potency and favourable pharmacokinetic profile, BMS-232632 has the potential to be the first stand alone protease inhibitor with once-daily dosing. A panel of HIV-1 isolates showing resistance to the current approved protease inhibitors was tested for sensitivity to BMS-232632 to obtain a greater understanding of its resistance profile.

METHODS: A panel of >60 clinical isolates was selected from the ViroLogic and Virco collections of HIV-1 clinical isolates. The selected isolates exhibited a wide array of resistance profiles (from specific to multi-resistant) and genotypic patterns. Each isolate was assayed for sensitivity to BMS-232632, amprenavir, indinavir, nelfinavir, ritonavir and saquinavir using ViroLogic’s PhenoSense (n=33) or Virco’s Antivirogram (n>25). Genotypic profiles were also evaluated and compared for each of the isolates.

RESULTS: The resistance profile exhibited by BMS232632 against this panel of isolates did not parallel that of any of the other individual protease inhibitors tested. In general, sensitivity to BMS-232632 was retained among isolates resistant to one or two of the currently approved protease inhibitors. There was no obvious mutational pattern that coincided with resistance to BMS-232632, other than a requirement of several mutations to be present. There was a clear trend toward loss of sensitivity to BMS-232632 against isolates exhibiting very high resistance levels to multiple (>3) protease inhibitors. These isolates also tended to have the greatest number of amino acid substitutions.

CONCLUSIONS: BMS-232632 appears to have a favourable resistance profile, which did not parallel any of the individual protease inhibitors currently in use. Loss of sensitivity to BMS-232632 was correlated with high-level cross-resistance to three or more inhibitors. Reciprocal studies examining cross-resistance of BMS-232632 resistant isolates will need to await analysis of treatment failures from ongoing trials.

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2000-06-12
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