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Published on: September 5, 2017
Shorter Treatment for Nonsevere Tuberculosis in African and Indian Children
Anna Turkova1, Genevieve H Wills1, Eric Wobudeya1
1From the Medical Research Council Clinical Trials Unit, University College London (A.T., G.H.W., L.C., K.L., M.J.T., D.M.G., A.M.C.), and the Department of Infectious Diseases, Imperial College London (J.A.S.), London, the Centre for Health Economics, University of York, York (J.L.-K.), and the Department of Paediatrics, Birmingham Chest Clinic and Heartlands Hospital, University Hospitals Birmingham, Birmingham (S.B.W.) - all in the United Kingdom; Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (E.W., P.M., R.B.M.); University Teaching Hospital, Lusaka, Zambia (C.C., V. Mulenga, M.K.); Desmond Tutu TB Centre, the Department of Paediatrics and Child Health, Stellenbosch University, Stellenbosch (M.P., M.M.Z., A.-M.D., J.A.S., A.C.H.), and the Division of Clinical Pharmacology, University of Cape Town, Cape Town (H.M.) - both in South Africa; B.J. Medical College, Pune (A.K., V. Mave, P.R.), and the National Institute for Research in Tuberculosis, Chennai (S.H., B.J., P.K.B.) - both in India; Radboud University Medical Center, Nijmegen, the Netherlands (R.A.); the Centre for International Child Health, Department of Paediatrics, University of Melbourne, and Murdoch Children's Research Institute, Royal Children's Hospital - both in Melbourne, VIC, Australia (S.M.G.); and the International Union against Tuberculosis and Lung Disease, Paris (S.M.G.).
Insights
Four months of tuberculosis treatment is as effective as six months for children with nonsevere, drug-susceptible disease. This shorter regimen offers a promising alternative for pediatric tuberculosis management.
Area of Science:
- Pediatric infectious diseases
- Global health
- Clinical trial research
Background:
- Two-thirds of pediatric tuberculosis cases are nonsevere.
- Nonsevere tuberculosis may be treatable with shorter regimens than the current 6-month standard.
- Optimizing treatment duration is crucial for improving patient adherence and resource allocation.
Purpose of the Study:
- To determine if a 4-month antituberculosis treatment regimen is noninferior to the standard 6-month regimen in children with nonsevere tuberculosis.
- To evaluate the efficacy and safety of a shortened treatment duration for pediatric tuberculosis.
Main Methods:
- An open-label, noninferiority trial was conducted in Uganda, Zambia, South Africa, and India.
- 1204 children with nonsevere, smear-negative, presumed drug-susceptible tuberculosis were randomized to 4 or 6 months of treatment.
- The primary outcome was unfavorable status (treatment failure, loss to follow-up, or death) by 72 weeks.
Main Results:
- A total of 1204 children were randomized (602 to each group).
- The 4-month regimen was noninferior to the 6-month regimen, with 3% experiencing an unfavorable outcome in both groups (adjusted difference: -0.4 percentage points).
- Adverse events of grade 3 or higher occurred in 8% of participants, with no significant difference between groups.
Conclusions:
- Four months of antituberculosis treatment is noninferior to six months for children with drug-susceptible, nonsevere, smear-negative tuberculosis.
- The findings support the use of a shorter treatment duration, potentially improving pediatric tuberculosis management.
- Further research may explore the applicability of this shorter regimen in diverse pediatric populations and settings.
Background:
Two thirds of children with tuberculosis have nonsevere disease, which may be treatable with a shorter regimen than the current 6-month regimen.
Methods:
We conducted an open-label, treatment-shortening, noninferiority trial involving children with nonsevere, symptomatic, presumably drug-susceptible, smear-negative tuberculosis in Uganda, Zambia, South Africa, and India. Children younger than 16 years of age were randomly assigned to 4 months (16 weeks) or 6 months (24 weeks) of standard first-line antituberculosis treatment with pediatric fixed-dose combinations as recommended by the World Health Organization. The primary efficacy outcome was unfavorable status (composite of treatment failure [extension, change, or restart of treatment or tuberculosis recurrence], loss to follow-up during treatment, or death) by 72 weeks, with the exclusion of participants who did not complete 4 months of treatment (modified intention-to-treat population). A noninferiority margin of 6 percentage points was used. The primary safety outcome was an adverse event of grade 3 or higher during treatment and up to 30 days after treatment.
Results:
From July 2016 through July 2018, a total of 1204 children underwent randomization (602 in each group). The median age of the participants was 3.5 years (range, 2 months to 15 years), 52% were male, 11% had human immunodeficiency virus infection, and 14% had bacteriologically confirmed tuberculosis. Retention by 72 weeks was 95%, and adherence to the assigned treatment was 94%. A total of 16 participants (3%) in the 4-month group had a primary-outcome event, as compared with 18 (3%) in the 6-month group (adjusted difference, -0.4 percentage points; 95% confidence interval, -2.2 to 1.5). The noninferiority of 4 months of treatment was consistent across the intention-to-treat, per-protocol, and key secondary analyses, including when the analysis was restricted to the 958 participants (80%) independently adjudicated to have tuberculosis at baseline. A total of 95 participants (8%) had an adverse event of grade 3 or higher, including 15 adverse drug reactions (11 hepatic events, all but 2 of which occurred within the first 8 weeks, when the treatments were the same in the two groups).
Conclusions:
Four months of antituberculosis treatment was noninferior to 6 months of treatment in children with drug-susceptible, nonsevere, smear-negative tuberculosis. (Funded by the U.K. Medical Research Council and others; SHINE ISRCTN number, ISRCTN63579542.).
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