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Wednesday 19 September 2018
Treatment of latent tuberculosis in adults

The article we suggest this week has been published recently on The New England Journal of Medicine: "Four Months of Rifampin or Nine Months of Isoniazid for Latent Tuberculosis in Adults".


Tuberculosis is a major global health problem, with an estimated 10.4 million new cases worldwide in 2015. It has been estimated that one quarter of the global population has latent tuberculosis infection. The World Health Organization (WHO) recommends the treatment of latent tuberculosis infection with isoniazid for 6 or 9 months, with the longer duration showing evidence of greater protective efficacy. However, the benefit of treatment with isoniazid is substantially reduced because of poor rates of regimen completion and because of hepatotoxic effects. Observational studies have shown superior rates of regimen completion and lower rates of hepatotoxic effects with a 4-month regimen of daily rifampin than with the 9-month regimen of isoniazid. The authors themselves have previously reported the results of two randomized trials, in which a 4-month regimen of rifampin was associated with a significantly lower incidence of grade 3 or 4 drug-related adverse events, lower costs, and a higher rate of treatment completion, than a 9-month isoniazid regimen.

The authors reported the results of a phase 3, open-label, parallel-group, 1:1 randomized, controlled trial, comparing a 4-month regimen of rifampin (10 mg/Kg/day, maximum dose 600 mg) with a 9-month regimen of isoniazid (5 mg/Kg/day, maximum dose 300 mg), for the treatment of latent tuberculosis infection in adults (≥18 years of age), in Australia, Benin, Brazil, Canada, Ghana, Guinea, Indonesia, Saudi Arabia, and South Korea.

Before randomization, adults underwent medical evaluation, including radiography of the chest, to rule out active tuberculosis. Testing for the human immunodeficiency virus (HIV) was offered. The exclusion criteria were: exposure to a patient with active tuberculosis, whose isolates were resistant to either trial drug, current or planned pregnancy, the use of medications with potentially serious interactions with either trial drug, history of allergy to either trial drug, or current active tuberculosis.

The authors assessed 16,907 potential participants, from October 2009 through December 2014, of whom, 6063 underwent randomization. Of these, 5744 participants (95.5%) completed 28 months of follow-up after treatment.

The rate of treatment completion was significantly higher with the 4-month rifampin regimen than with the 9-month isoniazid regimen (difference, 15.1 percentage points).

There were 8 cases of confirmed active tuberculosis and 9 cases of clinically diagnosed active tuberculosis during active follow-up; the rifampin regimen was not superior to the isoniazid regimen.

The authors highlighted the strengths of their trial: the minimization of selection bias, through randomization and through the absence of differences in the demographic and clinical characteristics between the two trial groups; the large sample size; the widely varying levels of resources of the involved settings; the trial drugs administration by the patients, which might less affect treatment completion and the detection of adverse events. The authors themselves stressed, also, some limitations, such as the open-label design, the absence of a directed observed therapy regimen, the small involvement of HIV infected people, the low observed event rate of active tuberculosis in each group in the modified intention-to-treat analysis.

The authors concluded that the 4-month regimen of rifampin was not inferior to a 9-month regimen of isoniazid in preventing active tuberculosis; however, the rifampin regimen was also not superior to the isoniazid regimen. The rate of treatment completion was higher in the rifampin group than in the isoniazid group. In the rifampin group, there was a significantly lower incidence of adverse events of grades 3 to 5, particularly hepatotoxic adverse events, than in the isoniazid group.


AUTHORS: D. Menzies, M. Adjobimey, R. Ruslami, A. Trajman, O. Sow, H. Kim, J. Obeng Baah, G.B. Marks, R. Long, V. Hoeppner, K. Elwood, H. Al‑Jahdali, M. Gninafon, L. Apriani, R.C. Koesoemadinata, A. Kritski, V. Rolla, B. Bah, A. Camara, I. Boakye, V.J. Cook, H. Goldberg, C. Valiquette, K. Hornby, M.-J. Dion, P.-Z. Li, P.C. Hill, K. Schwartzman, and A. Benedetti.