From Pages to Practice
Ms. Pothedi is a 34-year-old woman, originally from Botswana, who visits you in clinic. She was recently diagnosed with pulmonary tuberculosis. Tuberculosis screening of her family indicates that all members, including her 4-year-old son, have evidence of latent tuberculosis infection, based on tuberculin skin testing, with no signs of active tuberculosis. When the parents return for follow up in the tuberculosis clinic, they are hesitant to pursue a 9-month regime of isoniazid for their son. Would a shorter regime be safe and effective to manage his latent tuberculosis?
Estimates suggest that 25% of people worldwide have latent infection with Mycobacterium tuberculosis, and 10% of these cases will develop active tuberculosis. In 2016, 1.0 million of the 10.4 million new tuberculosis cases were in children. As part of the End TB Strategy, the World Health Organization recommends treatment of latent tuberculosis in children younger than 5 years to reduce lifetime risk and prevent future transmission. The current treatment recommendation for latent tuberculosis is 6–9 months of isoniazid, with longer duration demonstrating greater efficacy. However, shorter regimes in adults (e.g., 4 months of rifampin) have been shown to be noninferior to 9 months of isoniazid, with less hepatotoxicity.
In a multicenter, open-label, randomized trial, Menzies and colleagues compared the safety, side-effect profile, and treatment adherence associated with either rifampin for 4 months or isoniazid for 9 months in 844 children (age <18 years; 128 children aged <5 years) with latent M. tuberculosis infection. The children were recruited from Australia, Benin, Brazil, Canada, Ghana, Guinea, and Indonesia. The primary outcome was adverse events of grade 1 to 5 that led to drug discontinuation. Secondary outcomes were treatment adherence, side-effect profile, and efficacy (microbiologically confirmed active tuberculosis during 16 months of follow-up).
Of the 829 children who were included in the modified intention-to-treat analysis, 85.3% of children in the rifampin group versus 76.4% in the isoniazid group completed per-protocol therapy. No significant between-group differences were noted in rates of adverse events, with fewer than 5% of children in the combined groups with grade 1 or 2 adverse events considered possibly related to a trial drug. Active tuberculosis was diagnosed in two children in the isoniazid group (1 with resistance to isoniazid), compared to none in the rifampin group. The rates of adverse events were lower than in trials of the same regimes in adults and similar to trials in children treated with rifapentine plus isoniazid.
This large pragmatic randomized trial, with 98% follow-up, drugs administered without direct supervision (by caregivers or patients), and conducted in low-, middle- and high- income countries provides generalizable results and addresses important questions on the safety, side-effect profile, and treatment adherence to the rifampin regimen in children. However, more data are needed in younger children (<5 years) and in children with HIV (who were not included in this study).
NEJM Deputy Editor Dr. Lindsay Baden notes, “Preventing active tuberculosis is a global priority. Improving our ability to provide safe, effective latent TB infection therapy to children is an important tool to improve global TB control.”
Among children younger than 18 years, treatment with rifampin for 4 months was associated with similar safety and efficacy and better treatment adherence than 9 months of treatment with isoniazid. Therefore, this regimen could be considered for Ms. Pothedi’s son.