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Reduced Susceptibility to NRTI Is Associated with NNRTI Hypersensitivity in Virus from HIV-1-Infected Patients J. WHITCOMB*1, S. DEEKS2, W. HUANG1, T. WRIN1, E. PAXINOS1, K. LIMOLI1, R. HOH2, N. HELLMANN1, and C. PETROPOULOS1.
1ViroLogic, S. San Francisco, CA; and 2Univ. of California, San Francisco AIDS Program, San Francisco Gen. Hosp Background: Recent clinical trials evaluating salvage regimens in NRTI-experienced patients (ACTG 364, ACTG 370) have suggested a superior virologic response in the NNRTI-containing treatment arms. We have observed increased NNRTI susceptibility ("hypersensitivity") among viruses containing NRTI resistance mutations. This study investigates the relationship between NRTI and NNRTI susceptibilities.
Methods: Quantitative measurements of drug susceptibility were obtained for 331 NRTI/NNRTI naïve ("naïve") and 447 NRTI experienced/NNRTI naïve ("NRTI-exp") patient viruses using PhenoSenseTM HIV. Regression analyses and non-parametric statistics were used to evaluate correlations between NRTI and NNRTI susceptibility. Hypersensitivity and reduced susceptibility were defined as fold change < 0.4 and > 2.5, respectively, compared to a drug sensitive reference virus.
Results: Hypersensitivity to NNRTIs (DLV, EFV, NVP) was observed in a significantly greater percentage of viruses from NRTI-exp patients (29, 26, 21%) compared to naïve patients (5, 9, 11%). In NRTI-exp patients, regression analyses demonstrated significant inverse correlations (p<0.0001) between reduced NRTI susceptibility (ZDV, 3TC) and increased NNRTI susceptibility. Viruses with NNRTI hypersensitivity (n=53) had significantly more NRTI resistance mutations (mean=4.5) than viruses with minor reductions (2-10 fold) in NNRTI susceptibility (n=41, mean=0.9). Site-directed mutants containing multiple NRTI-mutations also show increased sensitivity to NNRTI. The inverse correlation between NRTI and NNRTI susceptibility was further demonstrated by phenotypic testing of serial plasma samples from an NNRTI naïve patient following interruption of a failing NRTI-containing treatment regimen: fading NRTI resistance over time was associated with loss of NNRTI hypersensitivity.
Conclusions: Reduced susceptibility to NRTIs was significantly correlated with NNRTI hypersensitivity. This observation may provide an explanation for the superior virologic response to NNRTI containing salvage regimens in NRTI-experienced patients. The clinical implications of NNRTI hypersensitivity require additional study.
Key Words: NNRTI, phenotype, resistance
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