The clinical relevance of non-nucleoside reverse transcriptase inhibitor hypersusceptibility

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Abstract
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.