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N Engl J Med. 2018 Aug 2;379(5):440-453. doi: 10.1056/NEJMoa1714283.

Four Months of Rifampin or Nine Months of Isoniazid for Latent Tuberculosis in Adults.

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From the Respiratory Epidemiology and Clinical Research Unit, Montreal Chest Institute, McGill University Health Centre Research Institute (D.M., A.T., C.V., K.H., M.-J.D., P.Z.L., K.S., A.B.), and the Department of Epidemiology and Biostatistics (D.M., A.B.), McGill University, Montreal, the Faculty of Medicine and Dentistry, University of Alberta, Edmonton (R.L.), the Faculty of Medicine, University of Saskatchewan, Saskatoon (V.H.), and the BC Centre for Disease Control and the University of British Columbia, Vancouver (K.E., V.J.C.) - all in Canada; Centre National Hospitalier Universitaire de Pneumo-Phtisiologie, Cotonou, Benin (M.A., M.G.); the Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia (R.R., L.A., R.C.K.); State University of Rio de Janeiro (A.T.), Programa Academico de Tuberculose-Faculdade de Medicina, Universidade Federal do Rio de Janeiro-Rede TB (A.K.), and National Institute of Infectious Diseases Evandro Chagas (V.R.) - all in Rio de Janeiro; Service de Pneumophtisiologie, Hôpital National Ignace Deen, Université Gamal Abdel Nasser de Conakry, Conakry, Guinea (O.S., B.B., A.C.); Korean Institute of Tuberculosis, Seoul, South Korea (H.K.); Komfo Anokye Teaching Hospital, Kumasi, Ghana (J.O.B., I.B.); University of New South Wales (G.B.M.) and University of Sydney (H.G.), Sydney; Centre for International Health, University of Otago, Dunedin, New Zealand (P.C.H.); and the Department of Medicine, King Saud University, King Abdulaziz Medical City, Riyadh, Saudi Arabia (H.A.-J.).



A 9-month regimen of isoniazid can prevent active tuberculosis in persons with latent tuberculosis infection. However, the regimen has been associated with poor adherence rates and with toxic effects.


In an open-label trial conducted in nine countries, we randomly assigned adults with latent tuberculosis infection to receive treatment with a 4-month regimen of rifampin or a 9-month regimen of isoniazid for the prevention of confirmed active tuberculosis within 28 months after randomization. Noninferiority and potential superiority were assessed. Secondary outcomes included clinically diagnosed active tuberculosis, adverse events of grades 3 to 5, and completion of the treatment regimen. Outcomes were adjudicated by independent review panels.


Among the 3443 patients in the rifampin group, confirmed active tuberculosis developed in 4 and clinically diagnosed active tuberculosis developed in 4 during 7732 person-years of follow-up, as compared with 4 and 5 patients, respectively, among 3416 patients in the isoniazid group during 7652 person-years of follow-up. The rate differences (rifampin minus isoniazid) were less than 0.01 cases per 100 person-years (95% confidence interval [CI], -0.14 to 0.16) for confirmed active tuberculosis and less than 0.01 cases per 100 person-years (95% CI, -0.23 to 0.22) for confirmed or clinically diagnosed tuberculosis. The upper boundaries of the 95% confidence interval for the rate differences of the confirmed cases and for the confirmed or clinically diagnosed cases of tuberculosis were less than the prespecified noninferiority margin of 0.75 percentage points in cumulative incidence; the rifampin regimen was not superior to the isoniazid regimen. The difference in the treatment-completion rates was 15.1 percentage points (95% CI, 12.7 to 17.4). The rate differences for adverse events of grade 3 to 5 occurring within 146 days (120% of the 4-month planned duration of the rifampin regimen) were -1.1 percentage points (95% CI, -1.9 to -0.4) for all events and -1.2 percentage points (95% CI, -1.7 to -0.7) for hepatotoxic events.


The 4-month regimen of rifampin was not inferior to the 9-month regimen of isoniazid for the prevention of active tuberculosis and was associated with a higher rate of treatment completion and better safety. (Funded by the Canadian Institutes of Health Research and the Australian National Health and Medical Research Council; number, NCT00931736 .).

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