597 Emergence of Atazanavir Resistance and Maintenance of Susceptibility to Other PIs is Associated with an I50L Substitution in HIV Protease R. Colonno*1, R. Rose1, C. Cianci1, G. Aldrovandi2, N. Parkin3, J. Friborg1 1Bristol-Myers Squibb, Wallingford, CT; 2Univ of Alabama at Birmingham; and 3ViroLogic, San Francisco, CA
Background: Atazanavir (ATV) is a once daily HIV protease inhibitor (PI) in late stage development. ATV was previously shown to displays a distinct resistance profile relative to other PIs using a panel of 950 clinical isolates. In this study, we determined the resistance profile of isolates from patients (pts) failing regimens containing ATV and characterize the impact on susceptibility to ATV and other PIs.
Methods: The phenotype and/or genotype of clinical isolates from pts treated with ATV or ATV/SQV (studies AI424-007/041, -008/044, -009/041, -034 and ACTG 1020) were determined. To confirm the role of mutations, individual and combinations of mutations were made in recombinant HIV proteases and viruses and their biochemical and phenotypic profiles evaluated.
Results: Overall, phenotypic resistance to ATV was infrequent. Of the 19 isolates recovered from pts experiencing virologic failure on regimens containing ATV as the sole PI (treatment duration 24-81 wks), all contained the unique protease substitution I50L. Eleven (11; 58%) also contained an A71V substitution, 5 (26%) had G73S and 4 (21%) had K45R. The median fold change (FC) in ATV susceptibility among these isolates was 8.8 (range 3.5 to 36.6). Resistance was specific for ATV, since the susceptibility to all 6 marketed PIs increased and many had FCs of < 0.4. Of particular interest were those isolates that were resistant to multiple PIs upon treatment initiation and exhibited increased susceptibility or resensitization coincident with the emergence of the I50L substitution. In contrast, none of the 8 isolates obtained from study AI424-009 (ATV+SQV dual PI regimen) had the I50L substitution and nearly all isolates displayed a loss of susceptibility to other PIs in addition to ATV. ATV resistance in these pts required the accumulation of several additional amino acid substitutions, including I84V. Recombinant viruses containing I50L in a variety of backgrounds also displayed the phenotype of ATV specific resistance and increased susceptibility to other PIs and were significantly growth impaired. Biochemical and structural studies are in progress to understand the mechanism(s) involved.
Conclusions: I50L is the signature amino acid change observed following ATV treatment and results in ATV specific resistance and increased susceptibility to all other PIs. This observation and its implications for the future use of ATV and PI sequencing strategies will require further studies.
