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An International Randomized Trial

Fred Gordin, MD; Richard E. Chaisson, MD; John P. Matts, PhD; Carol Miller, MPH; Maria de Lourdes Garcia, MD, PhD; Richard Hafner, MD; Jose Luis Valdespino, MD, MPH; Jacqueline Coberly, PhD; Mauro Schechter, MD, PhD; Alan J. Klukowicz, MD; M. Anita Barry, MD, MPH; Richard J. O'Brien, MD; for the Terry Beirn Community Programs for Clinical Research on AIDS, the Adult AIDS Clinical Trials Group, the Pan American Health Organization, and the Centers for Disease Control and Prevention Study Group

JAMA. 2000;283:1445-1450.

Context  Because of problems with adherence, toxicity, and increasing resistance associated with 6- to 12-month isoniazid regimens, an alternative short-course tuberculosis preventive regimen is needed.

Objective  To compare a 2-month regimen of daily rifampin and pyrazinamide with a 12-month regimen of daily isoniazid in preventing tuberculosis in persons with human immunodeficiency virus (HIV) infection.

Design  Randomized, open-label controlled trial conducted from September 1991 to May 1996, with follow-up through October 1997.

Setting  Outpatient clinics in the United States, Mexico, Haiti, and Brazil.

Participants  A total of 1583 HIV-positive persons aged 13 years or older with a positive tuberculin skin test result.

Interventions  Patients were randomized to isoniazid, 300 mg/d, with pyridoxine hydrochloride for 12 months (n = 792) or rifampin, 600 mg/d, and pyrazinamide, 20 mg/kg per day, for 2 months (n = 791).

Main Outcome Measures  The primary end point was culture-confirmed tuberculosis; secondary end points were proven or probable tuberculosis, adverse events, and death, compared by treatment group.

Results  Of patients assigned to rifampin and pyrazinamide, 80% completed the regimen compared with 69% assigned to isoniazid (P<.001). After a mean follow-up of 37 months, 19 patients (2.4%) assigned to rifampin and pyrazinamide and 26 (3.3%) assigned to isoniazid developed confirmed tuberculosis at rates of 0.8 and 1.1 per 100 person-years, respectively (risk ratio, 0.72 [95% confidence interval, 0.40-1.31]; P = .28). In multivariate analysis, there were no significant differences in rates for confirmed or probable tuberculosis (P = .83), HIV progression and/or death (P = .09), or overall adverse events (P = .27), although drug discontinuation was slightly higher in the rifampin and pyrazinamide group (P = .01). Neither regimen appeared to lead to the development of drug-resistant tuberculosis.

Conclusions  Our data suggest that for preventing tuberculosis in HIV-infected patients, a daily 2-month regimen of rifampin and pyrazinamide is similar in safety and efficacy to a daily 12-month regimen of isoniazid. This shorter regimen offers practical advantages to both patients and tuberculosis control programs.

Author Affiliations: Veterans Affairs Medical Center and Georgetown University, Washington, DC (Dr Gordin); the Department of Medicine, School of Medicine (Dr Chaisson), and Department of International Health, School of Hygiene and Public Health (Dr Coberly), Johns Hopkins University, Baltimore, Md; the Community Programs for Clinical Research on AIDS Statistical Center and Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis (Dr Matts and Ms Miller); the National Institute of Public Health, Cuernavaca, Mexico (Drs Garcia and Valdespino); the Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, Md (Dr Hafner); Infectious Diseases Service, Hospital Universitário Clementino Fraga Filho, Department of Preventive Medicine, Universidade Federal do Rio de Janeiro, Brazil (Dr Schechter); Pulmonary Division, Saint Michael's Medical Center, Newark, NJ (Dr Klukowicz); Communicable Disease Control, Boston Public Health Commission, Boston, Mass (Dr Barry); and the Division of Tuberculosis Elimination, National Center for HIV, STD and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Ga (Dr O'Brien).

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