Department of Microbiology and Immunology, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
AIDS Res Ther. 2010 Mar 26;7:8. doi: 10.1186/1742-6405-7-8.
Cytochrome P450 2B6 (CYP2B6) metabolizes efavirenz and nevirapine, the major core antiretroviral drugs for HIV in Thailand. Rifampicin, a critical component of tuberculosis (TB) therapy is a potent inducer of CYP enzyme activity. Polymorphisms of CYP2B6 and CYP3A4 are associated with altered activity of hepatic enzyme in the liver and pharmacokinetics resulting in treatment efficacy. This study aimed to investigate whether CYP2B6 or CYP3A4 polymorphisms had effects on plasma efavirenz and nevirapine concentrations when co-administered with rifampicin in HIV/TB co-infected Thai adults.
We studied 124 rifampicin recipients with concurrent HIV-1/TB coinfection, receiving efavirenz (600 mg/day) (n = 65) or nevirapine (400 mg/day) (n = 59) based antiretroviral therapy (ART). The frequencies of GG, GT and TT genotypes of CYP2B6-G516T were 38.46%, 47.69% and 13.85% in efavirenz group and 44.07%, 52.54% and 3.39% in nevirapine group, respectively. The mean 12-hour post-dose plasma efavirenz concentration in patients with TT genotype at weeks 6 and 12 of ART and 1 month after rifampicin discontinuation (10.97 +/- 2.32, 13.62 +/- 4.21 and 8.48 +/- 1.30 mg/L, respectively) were significantly higher than those with GT (3.43 +/- 0.29, 3.35 +/- 0.27 and 3.21 +/- 0.22 mg/L, respectively) (p < 0.0001) or GG genotypes (2.88 +/- 0.33, 2.45 +/- 0.26 and 2.08 +/- 0.16 mg/L, respectively) (p < 0.0001). Likewise, the mean 12-hour post-dose plasma nevirapine concentration in patients carrying TT genotype at weeks 6 and 12 of ART and 1 month after rifampicin discontinuation (14.09 +/- 9.49, 7.94 +/- 2.76 and 9.44 +/- 0.17 mg/L, respectively) tended to be higher than those carrying GT (5.65 +/- 0.54, 5.58 +/- 0.48 and 7.03 +/- 0.64 mg/L, respectively) or GG genotypes (5.42 +/- 0.48, 5.34 +/- 0.50 and 6.43 +/- 0.64 mg/L, respectively) (p = 0.003, p = 0.409 and p = 0.448, respectively). Compared with the effects of CYP2B6-516TT genotype, we could observe only small effects of rifampicin on plasma efavirenz and nevirapine levels. After 12 weeks of both drug regimens, there was a trend towards higher percentage of patients with CYP2B6-TT genotype who achieved HIV-1 RNA levels <50 copies/mL compared to those with GT or GG genotypes. This is the first report to demonstrate the effects of CYP2B6 G516T polymorphisms on plasma efavirenz and nevirapine concentrations when co-administered with rifampicin in HIV/TB co-infected Thai adults.
CYP2B6-TT genotype had impact on plasma efavirenz and nevirapine concentrations, while rifampicin co-administration had only small effects.
细胞色素 P450 2B6（CYP2B6）代谢依非韦伦和奈韦拉平，这是泰国 HIV 主要的核心抗逆转录病毒药物。利福平是结核病（TB）治疗的关键组成部分，是一种强有力的 CYP 酶活性诱导剂。CYP2B6 和 CYP3A4 的多态性与肝酶的活性改变和药代动力学相关，从而影响治疗效果。本研究旨在探讨 CYP2B6 或 CYP3A4 多态性在 HIV/TB 合并感染的泰国成年人同时接受利福平治疗时，对依非韦伦和奈韦拉平的血浆浓度有何影响。
我们研究了 124 名同时感染 HIV-1/TB 的利福平接受者，他们接受依非韦伦（600mg/天）（n=65）或奈韦拉平（400mg/天）（n=59）的抗逆转录病毒治疗（ART）。在依非韦伦组中，CYP2B6-G516T 的 GG、GT 和 TT 基因型的频率分别为 38.46%、47.69%和 13.85%，在奈韦拉平组中分别为 44.07%、52.54%和 3.39%。在 ART 治疗的第 6 周和第 12 周以及利福平停药后 1 个月时，TT 基因型患者的 12 小时后血浆依非韦伦浓度（分别为 10.97±2.32、13.62±4.21 和 8.48±1.30mg/L）明显高于 GT（分别为 3.43±0.29、3.35±0.27 和 3.21±0.22mg/L）（p<0.0001）或 GG 基因型（分别为 2.88±0.33、2.45±0.26 和 2.08±0.16mg/L）（p<0.0001）。同样，在 ART 治疗的第 6 周和第 12 周以及利福平停药后 1 个月时，携带 TT 基因型的患者的 12 小时后血浆奈韦拉平浓度（分别为 14.09±9.49、7.94±2.76 和 9.44±0.17mg/L）趋于高于携带 GT（分别为 5.65±0.54、5.58±0.48 和 7.03±0.64mg/L）或 GG 基因型（分别为 5.42±0.48、5.34±0.50 和 6.43±0.64mg/L）（p=0.003，p=0.409 和 p=0.448，分别）。与 CYP2B6-516TT 基因型的影响相比，我们仅观察到利福平对依非韦伦和奈韦拉平水平的小影响。在两种药物治疗 12 周后，与 GT 或 GG 基因型相比，CYP2B6-TT 基因型患者中 HIV-1 RNA 水平<50 拷贝/ml 的比例有升高的趋势。这是第一项报告表明 CYP2B6 G516T 多态性对 HIV/TB 合并感染的泰国成年人同时接受利福平治疗时依非韦伦和奈韦拉平的血浆浓度有影响。
CYP2B6-TT 基因型对依非韦伦和奈韦拉平的血浆浓度有影响，而利福平的联合治疗只有较小的影响。
