Background:  The I50L substitution is the signature resistance mutation for atazanavir (ATV) and results in ATV-specific resistance and increased susceptibility to other protease inhibitors (PI) in treatmentreatment-naïve patients. In this evaluation, ATV resistance pathways in treatment-experienced patients are examined along with a retrospective analysis of substitutions at residue 50.

Methods:  Phenotypic (ViroLogic Inc.) and/or genotypic (ViroLogic Inc. and LabCorp Inc.) evaluations were performed on baseline and on-treatment isolates from nearly 700 treatment-experienced patients treated with either ATV or lopinavir/ritonavir (LPV/r) regimens in clinical studies AI424-009, -043, and -045. Additionally, phenotypic patterns associated with I50L or I50V (1 of several APV signature mutations) were analyzed using the Virologic database.

Results:  ATV resistance was observed in 102 clinical isolates (21%) from ATV treatment-experienced patients. Unlike treatment-naive patients, I50L was detected in only 29% (vs. 100%) of treatment-experienced patients treated with ATV (n = 13) or ATV/r (n = 5). None of 40 ATV/SQV-treated patient isolates contained an I50L. I50L-containing viruses displayed ATV resistance and either unchanged or increased susceptibility to LPV, NFV, RTV, and SQV. Equivalent susceptibility increases were not observed for ATV- and LPV/r-resistant isolates lacking I50L. Five other PI mutations frequently accompanied emergence of I50L: A71V (in 50% of I50L viruses), G73S (31%), K45R (26%), E34X (19%), and L33F (17%). Continued ATV treatment in patients with virus containing I50L showed maintenance of the unique resistance phenotype and no significant accumulation of additional PI substitutions. Viruses in the ViroLogic database containing I50L (n = 18) had a median ATV FC of 9.0, but <1 for other PI; no sample had an FC over the biological cutoff for any PI other than ATV. In contrast, the presence of I50V was associated with a median ATV FC of 1.1, and median FC of 20.2 and 8.4 for APV and LPV, respectively (no other primary PI mutations were allowed; n = 29); 41% of I50V isolates had a FC above the 10-fold cutoff for LPV/r.

Conclusions:  The I50L pathway to ATV resistance is an important and unique pathway in both treatment-naive and treatment-experienced patients, and confers increased phenotypic susceptibility to multiple PI in both treatment-naive and treatment-experienced patients. In contrast, APV-related PI substitutions may reduce phenotypic susceptibility to subsequent PI therapy, including LPV/r. Early use of atazanavir may preserve future treatment options.

Keywords: atazanavir; resistance; protease inhibitor