Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
PLoS One. 2011;6(12):e27810. doi: 10.1371/journal.pone.0027810. Epub 2011 Dec 6.
Implication of pharmacogenetic variations and efavirenz pharmacokinetics in concomitant efavirenz based antiviral therapy and anti-tubercular drug induced liver injury (DILI) has not been yet studied. We performed a prospective case-control association study to identify the incidence, pharmacogenetic, pharmacokinetic and biochemical predictors for anti-tubercular and antiretroviral drugs induced liver injury (DILI) in HIV and tuberculosis (TB) co-infected patients.
Newly diagnosed treatment naïve TB-HIV co-infected patients (n = 353) were enrolled to receive efavirenz based ART and rifampicin based anti-TB therapy, and assessed clinically and biochemically for DILI up to 56 weeks. Quantification of plasma efavirenz and 8-hydroxyefaviernz levels and genotyping for NAT2, CYP2B6, CYP3A5, ABCB1, UGT2B7 and SLCO1B1 genes were done. The incidence of DILI and identification of predictors was evaluated using survival analysis and the Cox Proportional Hazards Model. The incidence of DILI was 30.0%, or 14.5 per 1000 person-week, and that of severe was 18.4%, or 7.49 per 1000 person-week. A statistically significant association of DILI with being of the female sex (p = 0.001), higher plasma efavirenz level (p = 0.009), efavirenz/8-hydroxyefavirenz ratio (p = 0.036), baseline AST (p = 0.022), ALT (p = 0.014), lower hemoglobin (p = 0.008), and serum albumin (p = 0.007), NAT2 slow-acetylator genotype (p = 0.039) and ABCB1 3435TT genotype (p = 0.001).
We report high incidence of anti-tubercular and antiretroviral DILI in Ethiopian patients. Between patient variability in systemic efavirenz exposure and pharmacogenetic variations in NAT2, CYP2B6 and ABCB1 genes determines susceptibility to DILI in TB-HIV co-infected patients. Close monitoring of plasma efavirenz level and liver enzymes during early therapy and/or genotyping practice in HIV clinics is recommended for early identification of patients at risk of DILI.
尚未研究药物遗传学变异和依非韦伦药代动力学对同时基于依非韦伦的抗病毒治疗和抗结核药物引起的肝损伤（DILI）的影响。我们进行了一项前瞻性病例对照关联研究，以确定新诊断的、未经治疗的结核分枝杆菌-人类免疫缺陷病毒（TB-HIV）合并感染患者中抗结核和抗逆转录病毒药物引起的肝损伤（DILI）的发生率、药物遗传学、药代动力学和生化预测因素。
新诊断的、未经治疗的、TB-HIV 合并感染的患者（n = 353）接受了基于依非韦伦的 ART 和利福平为基础的抗结核治疗，并在 56 周内进行了临床和生化评估，以确定 DILI。定量检测了血浆中的依非韦伦和 8-羟基依非韦伦水平，并对 NAT2、CYP2B6、CYP3A5、ABCB1、UGT2B7 和 SLCO1B1 基因进行了基因分型。采用生存分析和 Cox 比例风险模型评估 DILI 的发生率和预测因素的识别。DILI 的发生率为 30.0%，即每 1000 人周 14.5 例；严重 DILI 的发生率为 18.4%，即每 1000 人周 7.49 例。DILI 与女性（p = 0.001）、较高的血浆依非韦伦水平（p = 0.009）、依非韦伦/8-羟基依非韦伦比值（p = 0.036）、基线 AST（p = 0.022）、ALT（p = 0.014）、较低的血红蛋白（p = 0.008）和血清白蛋白（p = 0.007）、NAT2 慢乙酰化酶基因型（p = 0.039）和 ABCB1 3435TT 基因型（p = 0.001）显著相关。
我们报告了在埃塞俄比亚患者中抗结核和抗逆转录病毒药物 DILI 的高发生率。在 TB-HIV 合并感染患者中，系统依非韦伦暴露的个体间变异性和 NAT2、CYP2B6 和 ABCB1 基因的药物遗传学变异决定了对 DILI 的易感性。建议在 HIV 诊所中，在早期治疗期间密切监测血浆依非韦伦水平和肝酶，并进行基因分型，以便早期识别有发生 DILI 风险的患者。
