Genetic correlates of efavirenz hypersusceptibility

Background: Non-nucleoside reverse transcriptase inhibitor (NNRTI) hypersusceptibility is seen in approximately 30% of HIV isolates with nucleoside reverse transcriptase inhibitor (NRTI) resistance. NNRTI hypersusceptibility has been associated with improved outcomes to NNRTI-based therapy. Objective: To determine the genetic correlates of efavirenz hypersusceptibility. Methods: Paired baseline genotypes and phenotypes were obtained from 444 NRTI-experienced, NNRTI-naive patients. Fisher's exact tests, recursive partitioning (classification and regression trees; CART), and stepwise binary regression were used to identify specific reverse transcriptase (RT) mutations associated with efavirenz hypersusceptibility. Results: In univariate analyses, 26 RT codons were associated with efavirenz hypersusceptibility (P < 0.05), the top five were 215 > 41 > 210 > 118 > 208 (all P < 0.000001). From stepwise model selection, the 215, 208 and 118 mutations remained independently predictive of efavirenz hypersusceptibility. A final binary regression model to predict efavirenz hypersusceptibility included one covariate for the 215 mutation (relative risk 2.6, P < 0.0001) and a second covariate representing either the 208 or 118 mutation (relative risk 1.8, P < 0.0001). Similarly, in a CART analysis, a mutation at codon 215 was the first split selected, followed by mutations at 208 and 118. An efavirenz hypersusceptibility genotypic score using the three mutations 208, 118 and 215 was as accurate at predicting efavirenz hypersusceptibility as a more complex scoring system using 26 mutations. Conclusion: Mutations at 215, 208 and 118 were independently associated with NNRTI hypersusceptibility. After confirmatory studies using other large datasets, incorporating a hypersusceptibility score into genotype interpretation algorithms will improve the prediction of NNRTI hypersusceptibility.