Shorter treatment for non-severe tuberculosis in African and Indian children

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Title: Shorter treatment for non-severe tuberculosis in African and Indian children
Authors: Turkova, A
Wills, GH
Wobudeya, E
Chabala, C
Palmer, M
Kinikar, A
Hissar, S
Choo, L
Musoke, P
Mulenga, V
Mave, V
Joseph, B
LeBeau, K
Thomason, MJ
Mboizi, RB
Kapasa, M
Van der Zalm, MM
Raichur, P
Bhavani, PK
McIlleron, H
Demers, A-M
Aarnoutse, R
Love-Koh, J
Seddon, JA
Welch, SB
Graham, SM
Hesseling, AC
Gibb, DM
Crook, AM
Item Type: Journal Article
Abstract: 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. opens in new tab.)
Issue Date: 10-Mar-2022
Date of Acceptance: 15-Dec-2021
DOI: 10.1056/NEJMoa2104535
ISSN: 0028-4793
Publisher: Massachusetts Medical Society
Start Page: 911
End Page: 922
Journal / Book Title: New England Journal of Medicine
Volume: 386
Copyright Statement: © 2022 Massachusetts Medical Society. All rights reserved.
Keywords: 11 Medical and Health Sciences
General & Internal Medicine
Publication Status: Published
Embargo Date: 2022-09-09
Appears in Collections:Department of Infectious Diseases