Meng Xianmin, Yin Kang, Wang Jiangrong, Dong Ping, Liu Li, Shen Yinzhong, Shen Li, Ma Qing, Lu Hongzhou, Cai Weimin
Department of Clinical Pharmacy and Pharmaceutical Administration, School of Pharmacy, Fudan University, Shanghai, China; Department of Pharmacy, Shanghai Public Health Clinical Center, Shanghai, China.
Department of Infectious Disease, Shanghai Public Health Clinical Center, Shanghai, China.
PLoS One. 2015 Jun 24;10(6):e0130583. doi: 10.1371/journal.pone.0130583. eCollection 2015.
The 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.
In 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.
The 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%.
Chinese 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.
本研究的主要目的是调查细胞色素P450 2B6（CYP2B6）基因多态性对汉族人类免疫缺陷病毒（HIV）感染患者中依非韦伦（EFV）血浆浓度的影响。
总共招募了322例患者进行研究。使用高效液相色谱法测定稳态时的EFV血浆浓度。采用连接酶检测反应（LDR）对CYP2B6的7个单核苷酸多态性（SNP）进行基因分型，包括171 + 967C>A、171 + 3212C>T、171 + 4335T>C、516G>T、785A>G、1295 - 913G>A和*1355A>G。应用SPSS 18.0和Haploview 4.2进行统计分析。
患者的平均EFV浓度为2.35±2.09μg/mL。总体而言，22%的患者显示EFV浓度超出1 - 4μg/mL的治疗范围（13.1% < 1μg/mL，9.3% > 4μg/mL）。我们观察到171 + 967C>A、171 + 4335T>C、516G>T、785A>G和*1355A>G与高血浆EFV水平显著相关（p<0.01）。171 + 4335CC、516TT和785GG对EFV浓度> 4μg/mL的预测准确性值分别为56.7%、56.7%和60%。我们观察到171 + 967C>A、171 + 43,35T>C、516G>T和785A>G之间存在强连锁不平衡，产生了五种单倍型。这五种单倍型的频率（从高到低）如下：CCTG（0.328）、ACTG（0.280）、ACCT（0.189）、ATTG（0.186）和ACCG（0.017）。EFV血浆浓度< 1μg/mL的患者中CCTG的频率（0.524）显著高于其他患者组，而相对于其他患者组，EFV浓度> 4μg/mL的患者中ACCT的频率（0.733）显著更高。携带ACTG（1.78μg/mL）、ACCT（7.50μg/mL）和ATTG（1.92μg/mL）单倍型的患者的平均EFV浓度明显高于携带CCTG单倍型的患者。ACCT对EFV > 4μg/mL的预测准确性为81%。
接受标准剂量EFV的中国患者需要进行治疗药物监测或个性化药物管理。基于目前的研究结果，我们建议171 + 4335T>C、516G>T、785A>G和单倍型ACCT可有效地用作EFV的基因组标记，这应有助于提高含EFV治疗的疗效并降低不良反应的发生率。
