Bamrasnaradura Infectious Diseases Institute, Ministry of Public Health, Nonthaburi, Thailand.
Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
Int J Antimicrob Agents. 2014 Mar;43(3):292-6. doi: 10.1016/j.ijantimicag.2013.10.022. Epub 2013 Nov 25.
Data on the pharmacogenetic markers of CYP2B6 and biological factors associated with hepatotoxicity in HIV-infected patients receiving an efavirenz-based antiretroviral therapy (ART) regimen are very limited. A total of 134 HIV-infected Thai adults were prospectively enrolled to receive a once-daily regimen of efavirenz 600 mg/tenofovir/lamivudine. Seven single nucleotide polymorphisms (SNPs) within CYP2B6 were genotyped using real-time PCR. At 12 weeks after ART, plasma efavirenz concentrations at 12h after dosing were measured. The mean ± standard deviation patient age was 37 ± 8 years, and 77.6% were male. The median (IQR) CD4 count was 43 cells/mm(3) (17-105 cells/mm(3)). Eighteen patients (13.4%) had positive anti-HCV and 5 patients (3.7%) had positive HBsAg. The frequencies of heterozygous/homozygous mutants of each SNP were 64C>T (11%), 499C>G (0%), 516G>T (55%), 785A>G (63%), 1375A>G (0%), 1459C>T (3%) and 21563C>T (62%). The three most frequent haplotypes identified included *1/*6 (40.3%), *1/*1 (34.3%) and *6/*6 (8.2%). The median (IQR) plasma efavirenz concentration was 2.3mg/L (1.4-3.7 mg/L). At 24 weeks, median (IQR) serum ALP was 98 mg/dL (73-133 mg/dL) and direct bilirubin was 0.11 mg/dL (0.10-0.19 mg/dL). The proportion of grade 1 and grade 2 elevated serum ALP was 12.7% and 1.5%, respectively. By multivariate analysis, factors associated with high ALP, total bilirubin and direct bilirubin included CYP2B6 haplotype *6/*6, high serum ALP at Week 0 and positive anti-HCV (all P<0.05). In summary, HIV-infected patients with the pharmacogenetic marker 'CYP2B6 haplotype *6/*6' may have increased susceptibility to hepatotoxicity with efavirenz-based ART.
关于接受依非韦伦为基础的抗逆转录病毒治疗（ART）方案的 HIV 感染者中 CYP2B6 的遗传标记物和与肝毒性相关的生物学因素的数据非常有限。共前瞻性纳入 134 例泰国 HIV 感染成人，接受每日一次的依非韦伦 600mg/替诺福韦/拉米夫定方案治疗。使用实时 PCR 对 CYP2B6 内的 7 个单核苷酸多态性（SNP）进行基因分型。在 ART 后 12 周时，测定给药后 12 小时的血浆依非韦伦浓度。患者年龄的平均值±标准差为 37±8 岁，77.6%为男性。中位数（IQR）CD4 计数为 43 个细胞/mm3（17-105 个细胞/mm3）。18 例（13.4%）患者抗 HCV 阳性，5 例（3.7%）HBsAg 阳性。每个 SNP 的杂合子/纯合子突变的频率为 64C>T（11%）、499C>G（0%）、516G>T（55%）、785A>G（63%）、1375A>G（0%）、1459C>T（3%）和 21563C>T（62%）。鉴定出的三种最常见的单倍型包括*1/*6（40.3%）、*1/1（34.3%）和6/6（8.2%）。中位（IQR）血浆依非韦伦浓度为 2.3mg/L（1.4-3.7mg/L）。在 24 周时，中位（IQR）血清碱性磷酸酶为 98mg/dL（73-133mg/dL），直接胆红素为 0.11mg/dL（0.10-0.19mg/dL）。血清碱性磷酸酶升高 1 级和 2 级的比例分别为 12.7%和 1.5%。多变量分析显示，与高 ALP、总胆红素和直接胆红素相关的因素包括 CYP2B6 单倍型6/6、第 0 周时高血清 ALP 和抗 HCV 阳性（均 P<0.05）。总之，携带遗传标记物“CYP2B6 单倍型6/*6”的 HIV 感染者可能在用依非韦伦为基础的 ART 时更易发生肝毒性。
