HIV-1 Hypersensitivity to NNRTI is Associated with Reduced Susceptibility to NRTI

J. Whitcomb1, W. Huang1, S. Deeks2, T. Wrin1, E. Paxinos1, K. Limoli1, R. Hoh2, N. Hellmann1, C. Petropoulos1

1: ViroLogic, Inc, S.S.F., CA, 2: UCSF Gen Hosp, S.F., CA

Background: We have observed increased NNRTI susceptibility (hypersensitivity) among viruses containing NRTI resistance mutations. This study investigates the relationship between NRTI and NNRTI susceptibilities in virus from HIV-1 infected patients and genetically engineered HIV-1 viruses. 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 PhenoSense™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. In addition, the genotypes of viruses with either i) wild-type, ii) NNRTI hypersensitivity, iii) low level reduced NNRTI susceptibility (2.5 — 10 fold) or iv) high level reduced NNRTI susceptibility (>10 fold) were determined. 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 and viruses with high level reduced NNRTI susceptibility had significantly more NRTI resistance mutations than viruses with wild-type susceptibility or low level reductions in NNRTI-susceptibility. The inverse correlation between NRTI- and NNRTI-susceptibility in patient virus 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.

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