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.
Safety and Side Effects of Rifampin versus Isoniazid in Children
This week's recommended reading is the article "Safety and Side Effects of Rifampin versus Isoniazid in Children", published in August 2018 on The New England Journal of Medicine.
Tuberculosis is a major global health problem, with an estimated 10.4 million new cases worldwide in 2016; of these cases, 1.0 million occurred in children. It is estimated that 25% of persons worldwide have latent infection with Mycobacterium tuberculosis (M. tuberculosis), and that 10% of those who are infected will develop active tuberculosis.
The World Health Organization (WHO) is now recommending treatment for children under the age of 5 years, who are household contacts of a person with tuberculosis, in all settings. The currently recommended standard treatment for latent tuberculosis infection is isoniazid for 6 or 9 months, which, however, has been limited by poor adherence rates. In adults, shorter regimes with rifampin alone or isoniazid plus rifapentine have been found to be noninferior to 6-9 months of isoniazid. In a recent pediatric trial, investigators found better rates of safety and adherence with 3 months of isoniazid plus rifapentine than with 9 months of isoniazid.
The authors reported the results of a noninferiority, open-label, randomized trial, which compared 4 months of rifampin (10-20 mg/Kg/day) with 9 months of isoniazid (10-15 mg/Kg/day) for the treatment of latent tuberculosis infection in children (0 to 17 years of age), in Australia, Benin, Brazil, Canada, Ghana, Guinea, and Indonesia; the trial was part of a larger one, that involved both adults and children.
From October 2011 through January 2014, 829 subjects were enrolled. Of them, 128 were under 5 years of age, and 79 were under 2 years of age. No children infected with the human immunodeficiency virus (HIV) were enrolled. The drugs were administered by the participants or their caretakers. At each visit, providers performed pill counts to determine the doses administered.
The rate of overall treatment completion was significantly higher among children in the rifampin group than among those in the isoniazid group. No events of grades 1 through 5 were attributed to either trial drug. Among the children, who returned for at least one visit, there was no significant between-group difference in the percentage which reported minor symptoms.
Among the children in the rifampin group, no cases of active tuberculosis were diagnosed, during a total of 562 person-years of follow-up, as compared with 2 cases in 542 person-years of follow-up in the isoniazid group (rate difference: −0.37 cases per 100 person-years). One case occurred in a child, who had completed 9 months of isoniazid, which corresponded to a rate of 0.24 per 100 person-years, and 1 occurred in a child, who had not completed such therapy.
The authors reported no significant safety concerns with either regimen, but the rifampin group had better treatment-completion rates, and no adverse event, resulting in the permanent discontinuation of a trial drug, occurred in either group.
Although the occurrence of adverse events in the isoniazid group was much lower than predicted, the authors concluded that 4 months of rifampin was not inferior to 9 months of isoniazid with respect to safety. In addition, the two regimens were associated with similarly low rates of minor symptoms, probably due to actual low drug exposure in this population, following new WHO age-based dose recommendations, with the highest doses in the drug ranges administered to very young children.
Although the only cases of active tuberculosis were diagnosed in the isoniazid group, the authors did not conclude that 4 months of rifampin was either superior or noninferior to 9 months of isoniazid for the prevention of active tuberculosis, but they suggested its possible effectiveness.
The authors highlighted the several strengths of their trial, such as the randomized design, the large sample size, and the different socio-economic status of participants. They also reported the main limitation of the trial, which was its open-label design, even though, to reduce the risk of bias in ascertaining and reporting outcomes, all adverse events and active cases of tuberculosis were adjudicated by independent panels in a blinded manner.
They concluded that, in children with latent tuberculosis, a regimen of 4 months of rifampin had better rates of completion than 9 months of isoniazid, with similar safety profiles in the two trial groups.
AUTHORS: T. Diallo, M. Adjobimey, R. Ruslami, A. Trajman, O. Sow, J. Obeng Baah, G.B. Marks, R. Long, K. Elwood, D. Zielinski, M. Gninafon, D.A. Wulandari, L. Apriani, C. Valiquette, F. Fregonese, K. Hornby, P.-Z. Li, P.C. Hill, K. Schwartzman, A. Benedetti, and D. Menzies.