Shorter treatment more successful in tackling latent TB

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Treatment of latent tuberculosis is set to transform after a pair of studies from the Research-Institute of the McGill University Health Centre (RI-MUHC) revealed that a shorter treatment was safer and more effective in children and adults compared to the current standard.

Led by Dr Dick Menzies, the study followed 850 children and 6,800 adults with latent TB, a dormant version of the disease that does not cause symptoms but may lead to serious illness if treatment is not provided. This study in children is one of the largest for a paediatric clinical trial related to TB.

Menzies’ team compared results among latent TB patients who underwent the current standard treatment of nine months of isoniazid (INH) or a four-month treatment with rifampin. Over 85% of children completed rifampin without developing active TB compared to 76% of children who completed isoniazid, with two developing active TB. Results were similar in adults; acceptance and completion of rifampin therapy was much better with significantly fewer serious side effects, particularly drug induced hepatitis (INH can cause serious liver toxicity which can prove fatal or require a liver transplant).

In addition to being a much shorter treatment, the rates of development of active TB were slightly lower with rifampin, indicating that it is at least as effective as the nine-month treatment of INH in preventing TB.

“This four-month therapy is a fundamental game-changer in TB prevention,” says Menzies, who is a respirologist with the MUHC and a professor of medicine, epidemiology and biostatistics at McGill University. “The four-month treatment was as effective in preventing TB, safer and more acceptable. We believe this four-month rifampin treatment should replace the nine months on INH for most people who need therapy for latent TB.”

With patients who originated from nine different countries (Australia, Benin, Brazil, Canada, Ghana, Guinea, Indonesia, Saudi Arabia and South Korea) in a study supported by the Canadian Institutes of Health Research, Menzies expects the findings to have a major impact on shaping future global guidelines related to treating latent TB.

“These discoveries will fuel a new look at global practices,” says Menzies, who has acted as an advisor to the Public Health Agency of Canada, Citizenship and Immigration Canada, the Centres for Disease Control (CDC), and the World Health Organisation (WHO) on TB. “We expect this discovery to have a substantial impact on TB, which remains the number one infectious disease killer globally, causing more deaths than Aids, malaria, diarrhoeal diseases, or other tropical illnesses.”

Treatment of latent TB infection is a key part of the End TB strategy & TB-elimination plans in high-income countries from the WHO. One-quarter of the global population is infected with latent TB and 10 per cent of these will develop active TB.

Abstract
Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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.

Authors
Dick Menzies, Menonli Adjobimey, Rovina Ruslami, Anete Trajman, Oumou Sow, Heejin Kim, Joseph Obeng Baah, Guy B Marks, Richard Long, Vernon Hoeppner, Kevin Elwood, Hamdan Al-Jahdali, Martin Gninafon, Lika Apriani, Raspati C Koesoemadinata, Afranio Kritski, Valeria Rolla, Boubacar Bah, Alioune Camara, Isaac Boakye, Victoria J Cook, Hazel Goldberg, Chantal Valiquette, Karen Hornby, Marie-Josée Dion, Pei-Zhi Li, Philip C Hill, Kevin Schwartzman, Andrea Benedetti

McGill University Health Centre material
New England Journal of Medicine abstract


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