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

Junichi Azuma, Masako Ohno, Ryuji Kubota, Soichiro Yokota, Takayuki Nagai, Kazunari Tsuyuguchi, Yasuhisa Okuda, Tetsuya Takashima, Sayaka Kamimura, Yasushi Fujio, Ichiro Kawase, Pharmacogenetics-based tuberculosis therapy research group, Junichi Azuma, Soichiro Yokota, Masako Ohno, Ichiro Kawase, Soichiro Yokota, Masami Ito, Masahide Mori, Takeya Fujikawa, Mari Miki, Toshihiko Yamaguchi, Yukihiro Yano, Masaharu Motone, Seigo Kitada, Kenji Fushitani, Yoshinobu Namba, Manabu Niinaka, Nobuyuki Naka, Hiromi Kimura, Hisako Hashimoto, Shin-ichi Kagami, Takayuki Nagai, Tetsuya Takashima, Yoshitaka Tamura, Hanako Kuhara, Kazunari Tsuyuguchi, Mitsunori Sakatani, Katsuhiro Suzuki, Seijiro Minamoto, Seiji Hayashi, Yasuhisa Okuda, Koji Inoue, Masataka Miyake, Tsuyoshi Ogura, Shigeru Kageyama, Ryoji Maekura, Hideki Nishikawa, Hideki Hara, Yasushi Fujio, Shinpei Nonen, Makiko Maeda, Miyuki Furutsuka, Tomoko Tanabe, Satoshi Nakayama, Airi Tokuda, Mika Takahashi, Akiko Yamamoto, Yuka Nakamura, Masako Ohno, Ryuji Kubota, Satomi Kamo, Sayaka Kamimura, Hiroshi Tamada, Junichi Azuma, Masako Ohno, Ryuji Kubota, Soichiro Yokota, Takayuki Nagai, Kazunari Tsuyuguchi, Yasuhisa Okuda, Tetsuya Takashima, Sayaka Kamimura, Yasushi Fujio, Ichiro Kawase, Pharmacogenetics-based tuberculosis therapy research group, Junichi Azuma, Soichiro Yokota, Masako Ohno, Ichiro Kawase, Soichiro Yokota, Masami Ito, Masahide Mori, Takeya Fujikawa, Mari Miki, Toshihiko Yamaguchi, Yukihiro Yano, Masaharu Motone, Seigo Kitada, Kenji Fushitani, Yoshinobu Namba, Manabu Niinaka, Nobuyuki Naka, Hiromi Kimura, Hisako Hashimoto, Shin-ichi Kagami, Takayuki Nagai, Tetsuya Takashima, Yoshitaka Tamura, Hanako Kuhara, Kazunari Tsuyuguchi, Mitsunori Sakatani, Katsuhiro Suzuki, Seijiro Minamoto, Seiji Hayashi, Yasuhisa Okuda, Koji Inoue, Masataka Miyake, Tsuyoshi Ogura, Shigeru Kageyama, Ryoji Maekura, Hideki Nishikawa, Hideki Hara, Yasushi Fujio, Shinpei Nonen, Makiko Maeda, Miyuki Furutsuka, Tomoko Tanabe, Satoshi Nakayama, Airi Tokuda, Mika Takahashi, Akiko Yamamoto, Yuka Nakamura, Masako Ohno, Ryuji Kubota, Satomi Kamo, Sayaka Kamimura, Hiroshi Tamada

Abstract

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 the 8th 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.

Trial registration: ClinicalTrials.gov NCT00298870.

Figures

Fig. 1
Fig. 1
Trial profile. Abbreviations: RA-type, rapid acetylator genotype homozygous for NAT2*4; IA-type, intermediate acetylator genotypes heterozygous for NAT2*4; SA-type, slow acetylator genotypes without NAT2*4; PGx, NAT2 genotype-guided treatment in which INH dosage was pharmacogenetically stratified based on individual NAT2 genotype; STD, conventional standard treatment with standardized dosage for all; Low-dose, half the conventional standard dose; High-dose, 1.5 times the standard dose; St-dose, conventional standard dose; INH-DILI, Drug-induced liver injury associated with isoniazid
Fig. 2
Fig. 2
Overall incidence of combined unfavorable events in the patients who received PGx-therapy and in those who received empirical therapy
Fig. 3
Fig. 3
Cumulative incidence curves of isoniazid related drug-induced liver injury (INH-DILI) over time among the 172 patients. RA-type, rapid acetylator genotype; IA-type, intermediate acetylator genotypes; SA-type, slow acetylator genotypes; PGx, PGx-guided treatment; STD, conventional standard-treatment
Fig. 4
Fig. 4
Incidence of isoniazid induced liver injury (INH-DILI) and persistent positive culture among the patients with drug sensitive tuberculosis on sputum culture at screening. Closed columns, INH-DILI; open columns, persistent positive culture; RA-type, rapid acetylator genotype; IA-type, intermediate acetylator genotypes; SA-type, slow acetylator genotypes; PGx, PGx-guided treatment; STD, conventional standard-treatment
Fig. 5
Fig. 5
Incidence of combined unfavorable events among the patients with drug sensitive tuberculosis on sputum culture at screening. RA + IA-type, combined with rapid or slow acetylator genotypes; IA-type, intermediate acetylator genotypes; PGx, PGx-guided treatment; STD, conventional standard-treatment

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