Effects of CYP2B6 G516T polymorphisms on plasma efavirenz and nevirapine levels when co-administered with rifampicin in HIV/TB co-infected Thai adults.
Effects of CYP2B6 G516T polymorphisms on plasma efavirenz and nevirapine levels when co-administered with rifampicin in HIV/TB co-infected Thai adults.
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DOI：
10.1186/1742-6405-7-8
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发表时间：
2010-03-26
影响因子：
2.2
通讯作者：
Khusmith S
中科院分区：
文献类型：
--
作者：
Uttayamakul S;Likanonsakul S;Manosuthi W;Wichukchinda N;Kalambaheti T;Nakayama EE;Shioda T;Khusmith S
细胞色素P450 2B 6（CYP 2B 6）代谢依法韦仑和奈韦拉平，这是泰国主要的抗艾滋病毒核心药物。利福平是结核病（TB）治疗的关键成分，是一种强效的β-内酰胺酶活性诱导剂。CYP 2B 6和CYP 3A 4的多态性与肝脏中肝酶活性的改变和导致治疗疗效的药代动力学相关。本研究旨在研究在HIV/TB合并感染的泰国成人中，当与利福平联合给药时，CYP 2B 6或CYP 3A 4多态性是否对血浆依法韦仑和奈韦拉平浓度产生影响。我们研究了124例同时感染HIV-1/TB的利福平接受者，接受基于抗逆转录病毒治疗（ART）的依法韦仑（600 mg/天）（n = 65）或奈韦拉平（400 mg/天）（n = 59）。CYP 2B 6-G516 T基因GG、GT和TT基因型频率在依非韦伦组分别为38.46%、47.69%和13.85%;在奈韦拉平组分别为44.07%、52.54%和3.39%。ART治疗第6周和第12周以及利福平停药后1个月，TT基因型患者的平均12小时血浆依法韦仑浓度分别为10.97 ± 2.32、13.62 ± 4.21和8.48 ± 1.30 mg/L，显著高于GT组（分别为3.43 ± 0.29、3.35 ± 0.27和3.21 ± 0.22 mg/L）（p < 0.0001）或GG基因型（分别为2.88 ± 0.33、2.45 ± 0.26和2.08 ± 0.16 mg/L）（p < 0.0001）。同样，ART治疗第6周和第12周以及利福平停药后1个月，TT基因型患者给药后平均12小时血浆奈韦拉平浓度（14.09 ± 9.49，7.94 ± 2.76和9.44 ± 0.17）mg/L（分别为5.65 ± 0.54、5.58 ± 0.48和7.03 ± 0.64 mg/L）或GG基因型（分别为5.42 ± 0.48、5.34 ± 0.50和6.43 ± 0.64 mg/L）（分别为p = 0.003、p = 0.409和p = 0.448）。与CYP 2B 6 - 516 TT基因型的影响相比，我们可以观察到利福平对血浆依法韦仑和奈韦拉平水平的影响很小。两种药物方案治疗12周后，与GT或GG基因型患者相比，CYP 2B 6-TT基因型患者达到HIV-1 RNA水平<50拷贝/mL的比例有更高的趋势。这是第一份报告，以证明CYP 2B 6 G516 T多态性对血浆依法韦仑和奈韦拉平浓度的影响时，共同管理与利福平在艾滋病毒/结核病合并感染的泰国成人。CYP 2B 6-TT基因型对依非韦伦和奈韦拉平的血药浓度有影响，而利福平联合给药仅具有较小的影响。
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.
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10.1086/597125
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2009-03-15
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