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Hepatotoxicity of Pyrazinamide

Cohort and Case-Control Analyses

¹ Tuberculosis and Chest Service, Centre for Health Protection, Department of Health, Hong Kong, China; and ² Tuberculosis and Chest Unit, Grantham Hospital, Hospital Authority, Hong Kong, China

Correspondence and requests for reprints should be addressed to Dr. Kwok Chiu Chang, M.B., M.Sc., Wanchai Chest Clinic, 1st Floor, Wanchai Polyclinic, 99 Kennedy Road, Wanchai, Hong Kong, China. E-mail: kc_chang{at}dh.gov.hk

Rationale: Relatively little is known about the hepatotoxicity of pyrazinamide.

Objectives: We compared continuation-phase regimens incorporating pyrazinamide, isoniazid, and/or rifampin with those containing isoniazid and rifampin to evaluate the hepatotoxicity of pyrazinamide.

Methods: Cohort and nested case-control analyses were conducted on a cohort of 3,007 patients with active tuberculosis (TB) managed at government chest clinics under a TB control program with treatment started from January 1 through June 30, 2001. Cases included all patients with probable hepatotoxicity from 12 or more weeks after starting treatment. Hepatotoxicity was considered probable when serum alanine transaminase exceeded three times the upper limit of normal. Each case was matched by sex and age with three control subjects selected randomly from the rest of the cohort. Treatment regimens of cases within 4 weeks preceding hepatotoxicity were compared with those of matched control subjects in comparable periods relative to the date of commencing treatment.

Measurements and Main Results: Hepatotoxicity occurred in 150 (5.0%) patients at any time including 48 (1.6%) cases. From 12 or more weeks after starting treatment, the estimated risk of hepatotoxicity was 2.6% for regimens incorporating pyrazinamide, isoniazid, and/or rifampin, and 0.8% for standard regimens containing isoniazid and rifampin. Multivariable conditional logistic analysis showed a significant association between hepatotoxicity and, respectively, hepatitis B, previous hepatotoxicity, and treatment regimens. The adjusted odds ratio (95% confidence interval) of hepatotoxicity for regimens incorporating pyrazinamide, isoniazid, and/or rifampin relative to standard regimens was 2.8 (1.4–5.9).

Conclusions: Adding pyrazinamide to isoniazid and rifampin increases the risk of hepatotoxicity appreciably.

Key Words: hepatotoxicity • pyrazinamide • tuberculosis

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Relatively little is known about the hepatotoxicity of pyrazinamide. Previous controlled trials that suggested nonsignificant hepatotoxicity for pyrazinamide were neither designed nor sufficiently powered for evaluating hepatotoxicity. What This Study Adds to the Field Adding pyrazinamide to isoniazid and rifampin increases the risk of hepatotoxicity appreciably.