Phenotypic hypersusceptibility to non-nucleoside reverse transcriptase inhibitors in treatment-experienced HIV-infected patients: impact on virological response to efavirenz-based therapy

Background: Enhanced susceptibility to non-nucleoside reverse transcriptase inhibitors (NNRTI) was recently described in association with increased re sistance to nucleoside analogs (nucleoside reverse transcriptase inhibitors ; NRTI). Objectives: To determine the prevalence of NNRTI hypersusceptibility, the g enotypic correlates, and its impact on virologic response to efavirenz-base d salvage therapy. Methods: Genotype and phenotype testing was performed retrospectively on ba seline isolates from 30 patients who received salvage therapy containing ef avirenz. NNRTI hypersusceptibility was defined as a 50% inhibitory concentr ation (IC50) Of < 0.5 that of the wild-type control. Results: Eight isolates had major NNRTI mutations. Among the 22 isolates wi th no major NNRTI mutations, 11 (50%) were hypersusceptible to efavirenz, 1 0 (45%) to delavirdine, and eight (36%) to nevirapine. Among eight isolates with NNRTI mutations, NNRTI resistance was present, but at lower than expe cted levels. The number of NRTI mutations was correlated inversely with the fold decrease in susceptibility to efavirenz (Spearman's rho, -0.57; P = 0 .0053, delavirdine (rho, -0.43; P = 0.04), and nevirapine (rho, -0.69; P < 0.001). Excluding subjects with NNRTI mutations, subjects with efavirenz hy persusceptibility at baseline had significantly better virologic suppressio n over 24 weeks than those without efavirenz hypersusceptibility (P < 0.001 ). Conclusion: NNRTI hypersusceptibility is common in heavily treated but NNRT I naive patients and is related directly to NRTI resistance mutations. Amon g patients receiving efavirenz-containing regimens, NNRTI hypersusceptibili ty was associated with an improved virologic outcome after 24 weeks of ther apy. A reversal of phenotypic resistance was seen in patients with NNRTI mu tations in the presence of multiple NRTI mutations, but no obvious virologi c benefit of this phenomenon was seen in this study. (C) 2001 Lippincott Wi lliams & Wilkins.