15th International HIV Drug Resistance Workshop 13-17 June 2006, Sitges, Spain

EVALUATION OF RESISTANCE PATTERNS IN TREATMENT-NAÏVE SUBJECTS WITH VIROLOGICAL FAILURE ON ATAZANAVIR- OR ATAZANAVIR/RITONAVIR-CONTAINING REGIMENS

Antivir Ther. 2006, 11:S97 (abstract no. 87)

D McGrath, J Hammond, D Frederick, M Mathew, K Kastango, and C McLaren
Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT, USA

BACKGROUND: The atazanavir (ATV) signature I50L substitution has been found in ATV-resistant isolates from treatment-naïve patients with virological failure on non-boosted ATV regimens, and has been associated with reduced in vitro susceptibility to ATV and increased susceptibility to other protease-inhibitors (PIs). We investigated the resistance profile of isolates from treatment-naïve subjects with virological failure on boosted or non-boosted ATV regimens.

METHODS: Treatment-naïve subjects (study AI424089) were randomized to ritonavir-boosted ATV (ATV300/RTV100) (n=95) or non-boosted ATV (ATV400) (n=105), each with lamivudine and stavudine (investigational extended-release formulation). Baseline and on-study isolates (HIV RNA ≥500 c/ml) from subjects experiencing virological failure (rebound or no response) were tested for geno- and phenotypic resistance.

RESULTS: Virological failure was reported in 3 (3%) ATV300/RTV100 and 10 (10%) ATV400 treated subjects, of whom 2 and 8, respectively, had paired isolates for resistance testing. PI phenotypic resistance (to nelfinavir) was observed in 1 subject (on ATV400) at baseline. In addition one, or more, non-primary PI-resistance-related substitutions (predominantly L10I, L63P, and V77I) were present at baseline in each of the tested viral-failure subjects. Neither the ATV signature I50L substitution nor other PI-specific substitutions were found in the isolates from the 2 ATV300/RTV100-failure subjects, which were susceptible to all 7 tested PIs. A newly emergent I50L substitution (with M36M/V, A71V and N88N/S) was detected in one of 8 failure subjects on ATV400; this isolate was phenotypically-resistant to ATV (foldchange =26) but had a 2-12 fold increased susceptibility to 5 other PIs. Two viral failure subjects on ATV400 developed a mixed I50I/L population (with emergent E34E/Q, and G73G/S plus T74T/A substitutions, respectively); neither isolate had phenotypic resistance to the 7 PIs tested. An M184V substitution and phenotypic resistance to 3TC developed in 1 of 2 and 7 of 8 failure subjects on ATV300/RTV100 and ATV400, respectively.

CONCLUSIONS: Phenotypic PI resistance or primary PI substitutions, including I50L, were not seen in the small number of subjects with virological failure on initial ATV300/RTV100 therapy. The ATV-signature I50L – or I50I/L – substitution was detected only in ATV400-subjects. The NRTI M184V substitution was found in the majority of on-study isolates from virological failures.

2006-06-13
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