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.

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.

• Authors: 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
• Journal: European journal of clinical pharmacology (Eur J Clin Pharmacol) Vol. 69 Issue 5 Pg. 1091-101 (May 2013) ISSN: 1432-1041 [Electronic] Germany
• PMID: 23150149 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antitubercular Agents
• Arylamine N-Acetyltransferase
• NAT2 protein, human
• Isoniazid

Topics

• Adult
• Animals
• Antitubercular Agents (adverse effects, therapeutic use)
• Arylamine N-Acetyltransferase (genetics)
• Asian People (genetics)
• Chemical and Drug Induced Liver Injury (genetics, prevention & control)
• Genetic Predisposition to Disease (genetics)
• Genotype
• Humans
• Isoniazid (adverse effects, therapeutic use)
• Male
• Middle Aged
• Precision Medicine (methods)
• Treatment Failure
• Tuberculosis (drug therapy, genetics)