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.
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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DOI：
10.1007/s00228-012-1429-9
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发表时间：
2013-05
影响因子：
2.9
通讯作者：
Kawase, Ichiro
中科院分区：
文献类型：
--
作者：
Azuma, Junichi;Ohno, Masako;Kubota, Ryuji;Yokota, Soichiro;Nagai, Takayuki;Tsuyuguchi, Kazunari;Okuda, Yasuhisa;Takashima, Tetsuya;Kamimura, Sayaka;Fujio, Yasushi;Kawase, Ichiro
关键词：
本研究是一项药物遗传学临床试验，旨在阐明N-乙酰转移酶2基因（NAT 2）基因型指导的异烟肼给药是否能改善6个月4种药物标准方案治疗新诊断肺结核的耐受性和疗效。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组（STD治疗：约5 mg/kg异烟肼）或NAT 2基因型指导治疗（PGx治疗：约7.5对于NAT 2 *4纯合子患者，5 mg/kg：快速乙酰化者;对于NAT 2 *4杂合子患者，5 mg/kg：中间乙酰化者;对于无NAT 2 *4的患者，2.5mg/kg：缓慢乙酰化者）。主要结局包括1）治疗前8周内异烟肼相关肝损伤（INH-DILI）的发生率，和2）早期治疗失败，表现为持续阳性培养或第8周胸片无改善。本试验入组了172例日本患者（缓慢乙酰化者，9.3%;快速乙酰化者，53.5%）。在意向治疗（ITT）分析中，STD治疗中78%的缓慢乙酰化者发生INH-DILI，而PGx治疗中没有缓慢乙酰化者发生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治疗的发生率显著低于STD治疗（15.0% vs. 38%）。因此，与传统标准方案相比，NAT 2基因型指导方案导致不利事件、INH-DILI或早期治疗失败的发生率低得多。我们的研究结果清楚地表明，NAT 2基因型指导的异烟肼剂量分层在结核病化疗中具有巨大的潜力。
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. 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. 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. Our results clearly indicate a great potential of the NAT2 genotype-guided dosing stratification of isoniazid in chemotherapy for tuberculosis.
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影响因子：
--
作者：
EVANS, DAP;MANLEY, KA;MCKUSICK, VA
通讯作者：
MCKUSICK, VA
影响因子：
13.5
作者：
Huang, YS;Chern, HD;Lee, SD
通讯作者：
Lee, SD
DOI：
10.1164/rccm.200210-1125oc
发表时间：
2003-05-15
影响因子：
24.7
作者：
Jindani, A;Doré, CJ;Mitchison, DA
通讯作者：
Mitchison, DA
影响因子：
7.2
作者：
DANAN, G;BENICHOU, C
通讯作者：
BENICHOU, C
影响因子：
168.9
作者：
Jindani, A;Nunn, AJ;Enarson, DA
通讯作者：
Enarson, DA