The clinical relevance of non-nucleoside reverse transcriptase inhibitor hypersusceptibility: A prospective cohort analysis

Objective: To evaluate the clinical significance of hypersusceptibility to non-nucleoside reverse transcriptase inhibitors (NNRTI). Design: Analysis of a prospective clinical trial cohort. Patients: NNRTI-naive patients failing a stable antiretroviral regimen. Measurements: HIV phenotype, HIV RNA, and CD4 cell counts were prospectively collected after patients changed to a new regimen. Hypersusceptibility to NNRTI was defined as a fold-change (FC) in IC₅₀ (inhibitory concentration of 50%) of < 0.4. Results: The 177 patients had a mean HIV RNA of 4.1 log₁₀ copies/ml, CD4 cell count of 322 × 10⁶ cells/l and 41 months of prior antiretroviral treatment. Hypersusceptibility to one or more NNRTI was present in 29%. Both longer duration and reduced susceptibility to nucleoside reverse transcriptase inhibitors were associated with efavirenz hypersusceptibility (P < 0.05). NNRTI-containing regimens were initiated in 106 patients at baseline. The mean change in log₁₀ HIV RNA after 6 months was greater for patients with hypersusceptibility (-1.2 log₁₀ copies/ml; n = 21) than in patients without (-0.8 log₁₀ copies/ml; n = 77) (P = 0.016). Differences persisted to month 12 (P = 0.023). Multiple linear regression models confirmed that hypersusceptibility to NNRTI was a significant independent predictor of the magnitude of early (months 1-4) HIV RNA reduction, after accounting for the baseline HIV RNA and the number of drugs to which the patient's virus was susceptible (P < 0.02). CD4 cell increases (months 4-10) were 28- 60 × 10⁶ cells/l greater in patients with hypersusceptible virus (P ≤ 0.1). Conclusion: NNRTI hypersusceptibility occurred in more than 20% of nucleoside-experienced patients and was associated with greater reduction of HIV RNA and increase in CD4 cells.