Multiple genetic variants predict steady-state nevirapine clearance in HIV-infected Cambodians

Objective In a previous analysis involving protocol ANRS 12154, interindividual variability in steady-state nevirapine clearance among HIV-infected Cambodians was partially explained by CYP2B6 516G -> T (CYP2B6*6). Here, we examine whether additional genetic variants predict nevirapine clearance in this cohort. Methods Analyses included Phnom Penh ESTHER (Ensemble pour une Solidarite Therapeutique Hospitaliere en Reseau) cohort participants who had consented for genetic testing. All participants were receiving nevirapine plus two nucleoside analogs. The mean individual nevirapine clearance estimates were derived from a population model developed on nevirapine concentrations at 18 and 36 months of therapy. Polymorphisms were assayed in ABCB1, CYP2A6, CYP2B6, CYP2C19, CYP3A4, CYP3A5, and NR1I2. Results Of 198 assayed loci, 130 were polymorphic. Among 129 individuals with evaluable genetic data, nevirapine clearance ranged from 1.06 to 5.00 l/h in 128 individuals and was 7.81 l/h in one individual. In bivariate linear regression, CYP2B6 516G -> T (CYP2B6*6) was associated with lower nevirapine clearances (P=3.5 x 10(-6)). In a multivariate linear regression model conditioned on CYP2B6 516G -> T, independent associations were identified with CYP2B6 rs7251950, CYP2B6 rs2279343, and CYP3A4 rs2687116. The CYP3A4 association disappeared after censoring the outlier clearance value. A model that included CYP2B6 516G -> T (P = 1.0 x 10(-9)), rs7251950 (P = 4.8 x 10(-5)), and rs2279343 (P=7.1 x 10(-5)) explained 11% of interindividual variability in nevirapine clearance. Conclusion Among HIV-infected Cambodians, several CYP2B6 polymorphisms were associated independently with steady-state nevirapine clearance. The prediction of nevirapine clearance was improved by considering several polymorphisms in combination. Pharmacogenetics and Genomics 22:868-876 (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.