CYP2B6 Polymorphism and Nonnucleoside Reverse Transcriptase Inhibitor Plasma Concentrations in Chinese HIV-Infected Patients

Abstract

The purpose of this study was to investigate the frequency of CYP2B6 polymorphisms and their influence on plasma concentrations of efavirenz and nevirapine in HIV-infected Chinese patients. After written informed consent, 159 patients were enrolled at Shanghai Public Health Clinical Center. Genotyping for 516 G>T, 785 A>G, 983 T>C, and 1459 T>C polymorphisms in CYP2B6, together with CYP3A4 -392 A>G, CYP3A5 6986 A>G, and ABCB1 (2677 G>T/A, 3435 C>T), were performed. Plasma efavirenz and nevirapine concentrations of 120 patients at steady state were assessed by high-performance liquid chromatography-mass spectrometry. The minor allele frequency for CYP2B6 516 G>T, 785 A>G, 983 T>C, and 1459 T>C was 0.16, 0.24, 0, and 0, respectively; and 0.07, 0.32, 0.15, and 0.35 for CYP3A4 -392 A>G, CYP3A5 6986 A>G, ABCB1 2677 G>T/A, and ABCB1 3435 C>T, respectively. Univariate analysis indicated associations between 516 G>T (P < 0.01) with efavirenz but not nevirapine plasma concentrations. None of other genetic variants was associated with plasma efavirenz or nevirapine concentrations. Although CYP2B6 516 G>T was associated with high plasma efavirenz concentrations, such an association was not evident with nevirapine in this Chinese patient population. CYP3A4 -392 A>G, CYP3A5 6986 A>G, and ABCB1 (2677 G>T/A, 3435 C>T) had no significant impact on plasma efavirenz or nevirapine concentrations.

Impact of Pharmacogenetic Markers ofCYP2B6, Clinical Factors, and Drug-Drug Interaction on Efavirenz Concentrations in HIV/Tuberculosis-Coinfected Patients

“…CYP2B6 499CϾG and 1375AϾG were the absent SNPs in this study, and CYP2B6 1459CϾT was rarely detected, which is consistent with previous reports from studies of Chinese patients (18,19) and Japanese patients (16). No CYP2B6 genetic polymorphism was found in one-third of all patients whose haplotype was determined to be *1/*1, and this haplotype was one of the risk factors associated with a low plasma efavirenz concentration by multivariate analysis.…”

“…First, other genetic variations associated with the plasma efavirenz concentration, for instance, CYP2B6 983TϾC, were not investigated in this study. An association with high efavirenz concentrations in Africans has been previously indicated for CYP2B6 983TϾC (26); nonetheless, it was absent in Asians (18,27). Second, other pathways of efavirenz metabolism via CYP2A6 in patients with impaired CYP2BC function have been previously reported (28).…”

Population Pharmacokinetic/Pharmacogenetic Model for Optimization of Efavirenz Therapy in Caucasian HIV-Infected Patients

“…Previous studies examined the influence of genetic covariates on the kinetic behavior of EFV (7,9,11,20,21,33,34,38,42,50,51,57,59), primarily SNPs in genes coding for the main metabolizing enzymes. The CYP2B6 gene is highly polymorphic, with numerous SNPs and associated haplotypes.…”

“…Intra-and interday CV precisions were consistently Ͻ5.7% for all internal quality controls (0.5, 2.0, and 10.0 g/ml). The quantification limit was 0.25 g/ml, and the absence of interference from the 21 11 SNPs in MRP4, 1 SNP in UGT2B7, 1 SNP in ABCA1, and 3 SNPs in BCRP) were chosen using the above criteria and included in the analysis. SNPs investigated and their frequencies in the patients included in this study are shown in Table 2.…”

The Dual Role of Pharmacogenetics in HIV Treatment: Mutations and Polymorphisms Regulating Antiretroviral Drug Resistance and Disposition

“…Many studies have reported an association between genetic polymorphisms of CYP2B6 and the pharmacokinetics of efavirenz (Haas et al, 2005;Carr et al, 2010;Chen et al, 2010). Tsuchiya et al (2004) reported an increase in efavirenz plasma concentrations among CYP2B6*6/*6 individuals.…”