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

BACKGROUND: Two-thirds of children with tuberculosis have non-severe disease. METHOD: SHINE was an open-label treatment-shortening non-inferiority trial in children with non-severe, symptomatic, presumed drug-susceptible, smear-negative tuberculosis, in Uganda, Zambia, South Africa and India. Children aged <16 years were randomised to 16- versus 24-week standard first-line anti-tuberculosis treatment using WHO-recommended paediatric fixed-dose-combinations and a non-inferiority margin of 6% was used. The primary efficacy outcome was a composite of treatment failure, anti-tuberculosis treatment changes/restarts, on-treatment loss-to-follow-up, TB recurrence or death by 72 weeks, excluding children not reaching 16 weeks follow-up (modified-intent-to-treat). Primary safety outcome was on-treatment grade ≥3 adverse events. RESULTS: 1204 children (602 in each group) were enrolled between July 2016 and July 2018; median age 3.5 years (range 2 months-15 years), 52% male, 11% HIV-infected, 14% bacteriologically-confirmed tuberculosis. Retention by 72 weeks and adherence to allocated anti-tuberculosis treatment were 95% and 94%, respectively. Sixteen (3%) versus 18 (3%) children reached the primary efficacy outcome in 16- versus 24-week arms respectively: unadjusted difference -0.4%, 95% CI (-2.2, 1.5). Non-inferiority of 16-weeks was consistent across intention-to-treat, per-protocol and key secondary analyses including when restricting analysis to the 958 (80%) children independently adjudicated to have tuberculosis at baseline. 95 (8%) children experienced grade ≥3 adverse events, including 17 adverse reactions (11 hepatic, all except three occurred within first 8 weeks, when treatment arms were the same). CONCLUSIONS: 4-months anti-tuberculosis treatment was non-inferior to 6 months for children treated for drug-susceptible non-severe smear-negative tuberculosis. (Supported by University College London; Trial Registration: ISRCTN 63579542)