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World Tuberculosis Day: 4-month treatment as good as 6-month treatment for children with nonsevere TB

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Dr Surya Kant, Professor and Head, Dept. of Respiratory Medicine, KGMU, UP, Lucknow. National Vice Chairman IMA-AMS    24 March 2022

Antituberculosis treatment (ATT) for six months did not offer any additional benefit compared to 4 months of ATT in children with nonsevere, smear-negative tuberculosis (TB), according to the results of the SHINE trial reported in the New England Journal of Medicine.

The SHINE phase III trial (Shorter Treatment for Minimal Tuberculosis in Children) designed as a multicenter, open-label, noninferiority clinical trial included children younger than 16 years of age (mean age 3.5 years) with symptomatic but nonsevere, smear-negative TB (on gastric aspirate or other respiratory sample) and were scheduled to begin first-line ATT. Participants were recruited from South Africa, Uganda, Zambia and India, countries with a high burden of TB. Among the exclusion criteria were children with smear-positive TB on respiratory specimen or severe TB on chest x-ray or known drug confirmed drug-resistance or known exposure to an adult with drug-resistant TB or known liver or kidney disease. The objective of the trial was to assess the noninferiority of 4 months of antituberculosis treatment (ATT) vis-à-vis 6 months of ATT including the cost-effectiveness of the shortened treatment regime.

Non-severe TB was defined as peripheral lymph node TB, respiratory TB restricted to one lobe with no cavities, no miliary TB, no pleural effusion without any clinically significant airway obstruction. Just 3% of the children had peripheral lymph node TB, while 66% had respiratory TB; 29% had both. Eleven percent of children also had HIV coninfection.

From 2016 to 2018, a total of 1204 children were randomized to 8-week treatment with standard first-line ATT with WHO recommended pediatric fixed-dose combinations of isoniazid, rifampin and pyrazinamide, with or without ethambutol. They were then assigned to treatment with isoniazid and rifampin in a fixed-dose combination for another 8 weeks in the 4-month group (study group) or 16 weeks in the 6-month group (control group).

Treatment was successful in 97.1% of children in the 4-month treatment group vs 96.9% in the 6-month treatment group. Eighteen children (3.1%) in the six-month treatment group had a primary outcome event by 72 weeks, defined as treatment failure, treatment extension, change of treatment drug, restarting treatment or TB recurrence, loss to follow up or death due to any cause. The corresponding number in the 4-month treatment group was 16 (2.8%). The adjusted difference between the two treatment groups was −0.4% (unadjusted −0. 3%). The noninferiority of 4 months of treatment was consistent across the intention-to-treat, per-protocol plus a secondary analysis in a subset of children who were judged to have TB at baseline by the trial Endpoint Review Committee, which was uninformed about the treatment randomizations.

Fifteen adverse drug reactions (ADRs) were recorded, which included those related to the liver. Except for two, all the ADRs occurred during the first 8 weeks of therapy when the treatments were the same in the two groups. There were 12 deaths in the 4-month group and 19 in the 6-month group. The number of patients hospitalized due to a respiratory bacterial infection in the 4-month treatment group was 26 vs 19 in the 6-month group. The 4-month treatment was also found to be more cost-effective and saved roughly $17 per child.

This trial has demonstrated the noninferiority of the 4-month treatment regime compared to the standard 6 months of treatment. It provides evidence that children with mild TB can be treated with 4 months of standard ATT with favorable outcomes. Most children do not have severe TB and therefore can benefit from a shorter treatment course. India ranks high among countries with the highest out-of-pocket expenditure. Hence, a shortened treatment regime would also be financially advantageous for many families.

In its updated guidelines released on Monday this week, the World Health Organization (WHO) also recommends “a 4-month treatment regimen 2HRZ(E)/2HR) for children and adolescents between 3 months and 16 years of age with non-severe TB (without suspicion or evidence of multidrug- or rifampicin-resistant TB (MDR/RR-TB)” based on the results of this trial.

Reference

  1. Turkova A, et al; SHINE Trial Team. Shorter treatment for nonsevere tuberculosis in African and Indian Children. N Engl J Med. 2022 Mar 10;386(10):911-922. doi: 10.1056/NEJMoa2104535.
  2. WHO consolidated guidelines on tuberculosis. Module 5: management of tuberculosis in children and adolescents. Geneva: World Health Organization; 2022.

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