Effect of CYP2B6 Gene Polymorphisms on Efavirenz Plasma Concentrations in Chinese Patients with HIV Infection.

Xianmin Meng,Yinzhong Shen,Ping Dong,Kang Yin,Jiangrong Wang,Weimin Cai,Li Liu,Hongzhou Lu,Qing Ma,Li Shen,Weijing He

doi:10.1371/journal.pone.0130583

Abstract

ObjectivesThe main aim of this study was to investigate the effect of CYP2B6 gene polymorphisms on efavirenz (EFV) plasma concentrations in Han Chinese patients with human immunodeficiency virus (HIV) infection.MethodsIn total, 322 patients were recruited for study. EFV plasma concentrations at steady-state were determined using high-performance liquid chromatography. Genotyping for seven single nucleotide polymorphisms (SNPs), including 171+967C>A, 171+3212C>T, 171+4335T>C, 516G>T, 785A>G, 1295-913G>A, and *1355A>G of CYP2B6, was performed using ligase detection reaction (LDR). SPSS 18.0 and Haploview 4.2 were applied for statistical analyses.ResultsThe average EFV concentration of patients was 2.35±2.09 μg/mL. Overall, 22% patients displayed EFV concentrations out of the therapeutic range of 1–4 μg/mL (13.1% < 1 μg/mL, 9.3% > 4 μg/mL). We observed significant association of 171+967C>A, 171+4335T>C, 516G>T, 785A>G and *1355A>G with high plasma EFV levels (p<.01). The predictive accuracy values of 171+4335CC, 516TT and 785GG for EFV concentrations > 4 μg/mL were 56.7%, 56.7% and 60%, respectively. We observed strong linkage disequilibrium for 171+967C>A, 171+4335T>C, 516G>T and 785A>G, resulting in five haplotypes. The frequencies of the five haplotypes (high to low) were as follows: CCTG (0.328), ACTG (0.280), ACCT (0.189), ATTG (0.186) and ACCG (0.017). The frequency of CCTG (0.524) in patients with EFV plasma concentrations < 1 μg/mL was significantly higher than that in other patient groups, while that of ACCT (0.733) was significantly higher in patients with EFV concentrations > 4 μg/mL, relative to other patient groups. Average EFV concentrations of patients carrying ACTG (1.78 μg/mL), ACCT (7.50 μg/mL), and ATTG (1.92 μg/mL) haplotypes were markedly higher than those of patients carrying the CCTG haplotype. The predictive accuracy of ACCT for EFV > 4 μg/mL was 81%.ConclusionsChinese patients administered standard doses of EFV require therapeutic drug monitoring or personalized medication management. Based on the current findings, we propose that 171+4335T>C, 516G>T, 785A>G and haplotype ACCT may be effectively used as genomic markers for EFV, which should aid in improving the efficacy of EFV-containing treatments and reduce the incidence of adverse reactions.

Highlights

Efavirenz (EFV) is an important first-line drug for human immunodeficiency virus (HIV)-infected patients in China and widely used globally, in developing countries, owing to its excellent efficacy [1]
Based on the current findings, we propose that 171+4335T>C, 516G>T, 785A>G and haplotype ACCT may be effectively used as genomic markers for EFV, which should aid in improving the efficacy of EFV-containing treatments and reduce the incidence of adverse reactions
Researchers have investigated several single nucleotide polymorphisms (SNPs) of CYP2B6, including 516G>T, 785A>G, 983T>C, and 1459C>T, which are all known to be associated with EFV plasma concentrations [2, 15,16,17,18,19,20,21]

Summary

Introduction

Efavirenz (EFV) is an important first-line drug for HIV-infected patients in China and widely used globally, in developing countries, owing to its excellent efficacy [1]. The EFV plasma concentration is closely related to antiviral effects and adverse reactions [2,3,4,5]. Mutations of the CYP2B6 gene affect the expression and enzyme activity of the translated protein, resulting in significant differences in the pharmacokinetics of EFV among individuals and races, in turn, leading to variations in efficacy and toxicity [2, 13, 14]. Single SNP analysis may not provide sufficient accuracy to predict individual differences of EFV plasma concentrations. Considerable research attention has focused on attempting to integrate the effects of several SNPs that reduce the metabolic function of CYP2B6, with a view to increasing prediction accuracy [22, 23]

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