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Reyataz and It's I50L Mutation
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"Impact of residue 50 substitutions on phenotypic susceptibility to protease inhibitors"
ABSTRACT 18
Antiviral Therapy 2004; 9:S22.
DW Seekins1, NT Parkin2, C Chappey2, SL Hodder1, SM Schnittman3 and RJ Colonno31 Bristol-Myers Squibb Virology, Plainsboro, NJ, USA; 2 Virologic, South San Francisco, Calif., USA; and 3 BMS Pharmaceutical Research Institute, Wallingford, Conn., USA
BACKGROUND: Resistance to the HIV-1 protease inhibitor (PI) atazanavir (ATV) is associated with a signature protease (PR) substitution, I50L. PR substitutionsat four primary positions (32, 50, 54 and 84), including I50V, are associated with resistance to amprenavir (APV). The impact of these substitutions on phenotypic susceptibility to other PIs may impact future treatment options.
METHODS: The Virologic database containing 24,125 clinical samples with matching genotypes and phenotypes was analysed to identify those with the following PR substitutions: I50L, I50V, V32I+I47V or I54L/M, alone or in combination with one or two other primary PR substitutions (D30N, G48V, V82A/T/S/F, I84V or L90M). The mean, median, and range of phenotypicsusceptibility (FC, fold change in IC50 compared to NL4-3), as well as the percentage of samples with phenotypic susceptibility above the assay cutoff (clinical cutoff when available), were determined. Assay cutoffs for APV, ATV, indinavir (IDV), nelfinavir (NFV), ritonavir (RTV), and saquinavir (SQV) were 2.0--2.3, 2.1--2.5, 2.5 and 1.7-fold, respectively. Clinical cutoffs for RTV-boosted IDV and RTV-boosted lopinavir (LPV/r) were both 10-fold.
RESULTS: As expected, 100% of samples with I50L only (n=20) were above the assay cutoff for ATV (median FC=9.0), while none demonstrated resistanceto any of the other PIs (100% below cutoff, median FC <1). Of five samples with I50L and one other primary PI mutation, three had D30N, one V32I and oneL90M. 40% of clinical isolates with the I50L plus a primary PI mutation were above the resistance cutoff for APV, 80% for NFV, and 20% for SQV. 100% were above the resistance cutoff for ATZ. None of the isolates were above the cutoff for Kaletra, IDV/r, or RTV.
In contrast, the I50V substitution alone (n=29), which conferred APV and RTV resistance in all cases, was also sometimes associated with resistance to ATV (6% over cutoff), LPV/r (41%), IDV (21% assay, 0% clinical), NFV (41%) and SQV(34%). Samples with other characteristic APV substitutions, V32I+I47V or I54L/M, demonstrated similar or lower levels of resistance compared to I50V alone, with the exception of ATV and NFV, for which resistance levels were similar or slightly higher.
CONCLUSION: These data indicate that the I50L substitution confers ATV-specific reductions in phenotypic susceptibility without cross-resistance to other marketed PIs. In contrast, APV-selected PI substitutions reduce phenotypic susceptibility to other PIs, in some cases, including LPV/r. Early use of ATV may preserve future treatment options.
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