Extensive Population Pharmacokinetic-Pharmacogenetic Study of Nevirapine in HIV-Infected Cambodian Patients
Julie Bertrand (1), Monidarin Chou (2), Danielle M Richardson (3), Céline Verstuyft (4), Paul D Leger (3), France Mentré (1), Anne-Marie Taburet (4), David W Haas (3), and ANRS 12154 study group
(1) INSERM, Paris, France; (2) Phnom Penh University, Phnom Penh, Cambodia; (3) Vanderbilt University, Nashville, TN, United States; (4) Bicêtre University hospital, Kremlin Bicêtre, France
Objectives: Focused genotyping of CYP2B6 516G/T in HIV-infected Cambodians in the ANRS12154 study showed its association with steady-state NVP clearance (Cl/F) using nonlinear mixed effect models (NLMEM) to analyse the concentrations data [1]. The present study more thoroughly investigated CYP2B6 and other genes to better understand the genetics of NVP Cl/F.
Methods: Analyses included patients from the Phnom Penh Esther cohort who consented for genetic testing. All received standard dose NVP plus two nucleoside analogs and NVP trough plasma concentrations were measured 18 and 36 months after the treatment onset along with complete pharmacokinetic profiles (5 samples) in 10 patients.
A one compartment model with first-order absorption and elimination was used accounting for between and within subject variability on Cl/F. Empirical Bayes estimates of NVP Cl/F were derived from the model and the average over the occasions was used as phenotype in the analyses.
Linear regressions on minor allele dosage were performed on all single nucleotide polymorphisms (SNP) genotyped and their haplotypes with a FDR correction to account for tests multiplicity. Analyses were performed in PLINK [2], and haplotype blocks defined with the D' confidence intervals method in Haploview [3].
Results: Genotypes were obtained in 129 patients. The population Cl/F estimate was 2.67 L/h with between and within subject variability of 28 and 17%, respectively. The derived average individual NVP Cl/F estimates over the occasions were ranging from 1.06 to 7.81 L/h with a mean at 2.72 L/h.
Of the 196 SNPs assayed in CYP2B6, CYP3A4, CYP3A5, NR1I2 (PXR) and ABCB1, 126 were polymorphic in this population. Minor allele frequencies of CYP2B6 516G/T and CYP3A5 6986A/G (loss-of-function variant) were 0.34 and 0.37, respectively.
In univariate analyses, 17 SNPs in CYP2B6 and 1 in CYP3A4 as well as 6 haplotypes in CYP2B6 were associated with Cl/F. In multivariate analyses conditioned on 516G/T, no other SNP was independently associated to Cl/F. CYP2B6 516TT homozygosity predicted a 36% reduction in Cl/F.
Conclusions: NLMEM enabled the quantification of between and within subject variability of NVP Cl/F in this HIV-infected Cambodian population and investigate the influence of several genetic polymorphisms. The strong association between CYP2B6 516G/T and decreased steady-state NVP Cl/F may represent the effect of an extended CYP2B6 haplotype block that encompasses promoter regions and multiple exons.
References:
[1] M. Chou, J. Bertrand, O. Segeral, C. Verstuyft, L. Borand, E. Comets, C. Le Tiec, L. Becquemont, V. Ouk, F. Mentre, and A.-M. Taburet, "Population pharmacokinetic-pharmacogenetic study of nevirapine in HIV-infected Cambodian patients.," Antimicrobial Agents and Chemotherapy, vol. 54, 2010, pp. 4432-4439.
[2] S. Purcell, B. Neale, K. Toddbrown, L. Thomas, M. Ferreira, D. Bender, J. Maller, P. Sklar, P. Debakker, and M. Daly, "PLINK: A Tool Set for Whole-Genome Association and Population-Based Linkage Analyses," The American Journal of Human Genetics, vol. 81, 2007, pp. 559-575.
[3] J.C. Barrett, B. Fry, J. Maller, and M.J. Daly, "Haploview: analysis and visualization of LD and haplotype maps.," Bioinformatics, vol. 21, 2005, pp. 263-265.
