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Background:  The signature protease (PI) mutation in PI-naïve individuals failing unboosted atazanavir (ATV) is I50L. Although in vitro data identified N88S as an ATV-resistance mutation, it has not been observed without I50L in clinical studies of ATV in PI-naïve individuals. We describe a case in which N88S emerged independently on ATV/ritonavir (r) therapy and which was associated with high-level ATV resistance.

Methods:  The patient had a viral load of 6547 copies/mL and a CD4 count of 445 cells/mm³ on non-PI HAART. Barring a brief prior exposure to saquinavir (SQV) associated with viral load suppression, he was PI naive. Prior to starting ATV/r, resistance testing revealed no phenotypic or genotypic PI resistance. He commenced ATV, tenofovir (TDF), abacavir (ABC), and lamivudine (3TC). At 3 months the viral load had fallen to 118 copies/mL and ritonovir (RTV) was added to dose-adjusted ATV. The subsequent viral load was < 50 copies/mL but gradually rose to 7535 copies/mL 7 months later. Comparisons were made to the phenotypic profiles of clinical isolates within the ViroLogic database with either N88S or I50L as the only major PI mutation (t-test). Temporal surveillance of N88S and I50L was also performed; mixtures were counted as mutant for this analysis.

Results:  The PR genotype after rebound was K20T, M36I/V, L63P, A71T, and N88S. The susceptibility (fold change) to ATV, APV, IDV, LPV, NFV, and SQV was 56, 0.3, 13, 4.3, 68, 4.2, and, respectively. The replication capacity was 14% (compared with 96% before ATV). Phenotypic profiles of samples in the ViroLogic database with N88S, or I50L for comparison, but no other major PI mutations, are shown in the table. Among samples with at least one primary PI mutation the prevalence of clinical samples with N88S has increased from 1% to 2.5% in 12 months (September 2003 to September 2004), coincident with an increase in prevalence of I50L from 0 to 2%.

p < 0.01 for all drugs between groups

Conclusions:  To our knowledge this is the first case of primary resistance to ATV following ATV/r therapy. High-level ATV resistance and low replication capacity were associated with the N88S mutation in the absence of other primary resistance mutations. In the ViroLogic database isolates with N88S as the only major mutation had cross-resistance to ATV, NFV, and IDV, and APV hypersusceptibility. These findings contrast with isolates bearing the I50L mutation, which is associated with ATV-specific resistance and hypersusceptibility to IDV, LPV, and SQV. These data highlight the potential clinical relevance of the N88S mutation as a mechanism of resistance to ATV-inclusive therapies.

Keywords: atazanavir; protease inhibitor; resistance