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首页> 外文期刊>European journal of clinical pharmacology >NAT2 genotype guided regimen reduces isoniazid-induced liver injury and early treatment failure in the 6-month four-drug standard treatment of tuberculosis: A randomized controlled trial for pharmacogenetics-based therapy
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NAT2 genotype guided regimen reduces isoniazid-induced liver injury and early treatment failure in the 6-month four-drug standard treatment of tuberculosis: A randomized controlled trial for pharmacogenetics-based therapy

机译：NAT2基因型指导方案可在6个月的四药标准结核病治疗中减少异烟肼引起的肝损伤和早期治疗失败：药物遗传学基础治疗的随机对照试验

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Objective: This study is a pharmacogenetic clinical trial designed to clarify whether the N-acetyltransferase 2 gene (NAT2) genotype-guided dosing of isoniazid improves the tolerability and efficacy of the 6-month four-drug standard regimen for newly diagnosed pulmonary tuberculosis. Methods: In a multicenter, parallel, randomized, and controlled trial with a PROBE design, patients were assigned to either conventional standard treatment (STD-treatment: approx. 5 mg/kg of isoniazid for all) or NAT2 genotype-guided treatment (PGx-treatment: approx. 7.5 mg/kg for patients homozygous for NAT2*4: rapid acetylators; 5 mg/kg, patients heterozygous for NAT2*4: intermediate acetylators; 2.5 mg/kg, patients without NAT2*4: slow acetylators). The primary outcome included incidences of 1) isoniazid-related liver injury (INH-DILI) during the first 8 weeks of therapy, and 2) early treatment failure as indicated by a persistent positive culture or no improvement in chest radiographs at the8th week. Results: One hundred and seventy-two Japanese patients (slow acetylators, 9.3 %; rapid acetylators, 53.5 %) were enrolled in this trial. In the intention-to-treat (ITT) analysis, INH-DILI occurred in 78 % of the slow acetylators in the STD-treatment, while none of the slow acetylators in the PGx-treatment experienced either INH-DILI or early treatment failure. Among the rapid acetylators, early treatment failure was observed with a significantly lower incidence rate in the PGx-treatment than in the STD-treatment (15.0 % vs. 38 %). Thus, the NAT2 genotype-guided regimen resulted in much lower incidences of unfavorable events, INH-DILI or early treatment failure, than the conventional standard regimen. Conclusion: Our results clearly indicate a great potential of the NAT2 genotype-guided dosing stratification of isoniazid in chemotherapy for tuberculosis.
机译：目的：这项研究是一项药物遗传学临床试验，旨在阐明N-乙酰基转移酶2基因（NAT2）基因型引导的异烟肼剂量是否可以提高6个月四药标准疗法对新诊断的肺结核的耐受性和疗效。方法：在一项采用PROBE设计的多中心，平行，随机和对照试验中，患者被分配到常规标准治疗（STD治疗：所有异烟肼均为5 mg / kg异烟肼）或NAT2基因型指导治疗（PGx -治疗：对于NAT2 * 4纯合的患者，约7.5 mg / kg：快速乙酰化剂;对于NAT2 * 4纯合的患者，约5 mg / kg：中间乙酰化剂; 2.5 mg / kg，没有NAT2 * 4的患者：慢速乙酰化剂。主要结局包括1）治疗前8周的异烟肼相关肝损伤（INH-DILI）和2）早期治疗失败，如持续的阳性培养或第8周胸部X光片未见改善。结果：172名日本患者（慢速乙酰化药物，占9.3％;快速乙酰化药物，占53.5％）参加了该试验。在意向性治疗（ITT）分析中，STD处理中78％的慢速乙酰化剂中发生了INH-DILI，而PGx处理中的慢速乙酰化剂均未发生INH-DILI或早期治疗失败。在快速乙酰化剂中，观察到早期治疗失败，PGx治疗的发生率明显低于STD治疗（15.0％比38％）。因此，与常规标准方案相比，以NAT2基因型为指导的方案导致不良事件，INH-DILI或早期治疗失败的发生率低得多。结论：我们的结果清楚地表明，异烟肼的NAT2基因型指导的剂量分层在结核病化疗中具有巨大潜力。

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