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Research Suggests Viral Failure to Atazanavir Results in Increased Susceptibility to Other Protease Inhibitors
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"Emergence of unique I50L substitution in response to Atazanavir treatment in naive and PI experienced patients"
HIV Medicine April 2003, Volune 6, Issue 3. 1st European HIV Drug Resistance Workshop, March 6-8 2003, Luxemborg. Abstract 4: P 1.4. Rich Colonno, Bristol-Myers Squibb
Background: Atazanavir (ATV) is a once daily HIV protease inhibitor (PI) with a distinct resistance profile relative to other PIs. In this study, we extend our initial observations regarding the emergence of I50L as the signature change for ATV resistance aming patients receiving ATV containing regimens.
Methods: The phenotype and/or genotype of >50 clinical isolates from patients in studies AI424-007/041, -008/044, -009, -034, -043, and -045 who were designated as virological failures on ATV containing regimens were determined. All of these isolates displayed reduced susceptibility to ATV. Relationships between viral baseline phenotypes/genotypes and the emergence of the I50L change were studied and evaluated.
Results: Overall, ATV phenotypic resistance was observed infrequently among virologic failures. All 19 (100%) isolates recovered from treatment naive patients receiving ATV as the sole PI and designated as virological failures contained the unique substitution I50L. The I50L substitution was also observed among 6 isolates obtained from PI experienced subjects treated with ATV. ATV-specific resistance was noted in all of these isolates along with increased susceptibilities to 6 other approved PIs. In contrast, none of the 14 isolates obtained from study AI424-009 and -045 subjects (PI-experienced) treated with the dual PI regimen of ATV + SQV (Saquinavir) had the I50L substitution and nearly all displayed a loss of susceptibility to other PIs in addition to ATV and SQV. In addition, there were also 16 isolates from PI-experienced subjects treated with ATV as the only PI, who failed to induce the I50L change. These 16 isolates displayed reduced susceptibility to ATV (fold change >2) at baseline and the presence of two or more of the 14 key ATV resistance substitutions described previously. Recombinant viruses containing I50L alone in a variety of background displayed the phenotype of ATV-specific resistance and increased susceptibility to other PIs, and were significantly growth impaired.
Conclusions: I50L is the signature amino acid change for ATV-specific resistance and results in increased susceptibility to other PIs. The I50L change was only induced in those isolates that were susceptible at baseline and had a minimal number of PI resistance mutations.
Editorial note from Jules Levin: these findings need confirmation in clinical studies in patients who experience viral failure and have the I50L change and switch to a new PI regimen to see what the actual response is. Patients who experience the I50L may have to remain on Atazanavir to maintain the I50L mutation. This is similar to having to stay on 3Tc to maintain the M184V mutation after experiencing viral failure to 3TC.
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