Rifampin and pyrazinamide vs isoniazid for prevention of tuberculosis in HIV-infected persons - An international randomized trial

Context Because of problems with adherence, toxicity, and increasing resist ance associated with 6- to 12-month isoniazid regimens, an alternative shor t-course tuberculosis preventive regimen is needed. Objective To compare a 2-month regimen of daily rifampin and pyrazinamide w ith a 12-month regimen of daily isoniazid in preventing tuberculosis in per sons with human immunodeficiency virus (HIV) infection. Design Randomized, open-label controlled trial conducted from September 199 1 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 wi th a positive tuberculin skin test result. Interventions Patients were randomized to isoniazid, 300 mg/d, with pyridox ine hydrochloride for 12 months (n = 792) or rifampin, 600 mg/d, and pyrazi namide, 20 mg/kg per day, for 2 months (n = 791). Main Outcome Measures The primary end point was culture-confirmed tuberculo sis; secondary end points were proven or probable tuberculosis, adverse eve nts, and death, compared by treatment group. Results Of patients assigned to rifampin and pyrazinamide, 80% completed th e regimen compared with 69% assigned to isoniazid (P<.001). After a mean fo llow-up of 37 months, 19 patients (2.4%) assigned to rifampin and pyrazinam ide 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, th ere were no significant differences in rates for confirmed or probable tube rculosis (P =.83), HIV progression and/or death (P =.09), or overall advers e events (P =.27), although drug discontinuation was slightly higher in the rifampin and pyrazinamide group (P =.01). Neither regimen appeared to, lea d to the development of drug-resistant tuberculosis. Conclusions Our data suggest that for preventing tuberculosis in HIV-infect ed patients, a daily 2-month regimen of rifampin and pyrazinamide is simila r in safety and efficacy to a daily 12-month regimen of isoniazid. This sho rter regimen offers practical advantages to both patients and tuberculosis control programs.