Shorter Treatment for Nonsevere Tuberculosis in African and Indian Children. A clinical trial summary

In countries with a high burden of tuberculosis, such as Africa and India, the condition is prevalent in children, and the associated mortality rates in this younger population group are as high as 20%. 

Nonetheless, for several reasons, including difficulties in establishing confirmation of the disease, children have been excluded from clinical trials that examine the efficacy of anti-tubercular drugs.^1(pg7) Consequently, treatment protocols for paediatrics and young adults have been extrapolated from those established for adults - the current international guidelines recommend six months of antituberculosis treatment for population groups.

In contrast to adults, however, most children present with nonsevere, smear-negative tuberculosis, and their infections would likely respond positively to shorter treatment duration. The main obstacle to implementing such a foreshortening has been the lack of data to support such a change.

The Research Question

Turkova et al., in their recent paper published in NEJM, set out to investigate whether, in children with nonsevere, smear-negative, drug-susceptible tuberculosis, it was possible to reduce the length of treatment using the fixed-dose combination antituberculosis treatment formulae.

Specifically, they wanted to determine if four months of treatment would be as effective as six months. The cost-effectiveness of shortening the treatment regimen was also of interest given the socio-economic profile of the countries where most of these cases occur.

Their study, entitled SHINE, was an “…open-label treatment-shortening non-inferiority trial in children with nonsevere, symptomatic, presumed drug-susceptible, smear-negative tuberculosis, in Uganda, Zambia, South Africa and India.” ^1(pg2)

Research Objectives
 

The primary efficacy outcome of this research was the development of an unfavourable status by Week 72, defined as either:

• Treatment failure - either extension, change or restart of treatment

• Tuberculosis recurrence

• Loss to follow-up during treatment, or 

• Death 

The primary safety outcome was the occurrence of an adverse event of grade 3 or higher, either during treatment or within 30 days post-treatment. 

The secondary efficacy outcome was the development of an unfavourable status at 72 weeks in participants who were “…adjudicated by the end-point review committee as having tuberculosis at baseline.” ^1(pg7) 
Additional secondary outcomes included death, adverse drug events, bacterial infection requiring hospitalisation, acceptability, and adherence to the treatment regimen.

Methodology 

The trial included one thousand two hundred four children with nonsevere, symptomatic, drug-susceptible, smear-negative tuberculosis. 

The profile of the sample was as follows:

• Uganda – 376 participants, Zambia – 364, South Africa -315, and India -149 participants.

• The median age was 3.5 years, with a range from 2 months to 15 years

• “52% were male, 11% had HIV infection, and 14% had bacteriologically confirmed tuberculosis” ^1(pg2)

The group was then randomised into two groups of 602 participants. The participants received either four or six months of treatment with the first-line antituberculosis treatment in the paediatric fixed-dose combination recommended by the World Health Organisation.

Findings

At the end of Week 72, participant retention was 95%, with a 94% adherence rate.

The results were “…consistent across all the analyses, including the subgroup of children who were adjudicated to have tuberculosis at baseline.” ^1(pg7)

• 3% of the participants in both the four-and the six-month group experienced an unfavourable status

• In the secondary efficacy group (those patients adjudicated to have tuberculosis at baseline), the results were similar: 2% of children in the 4-month group had a primary outcome event, compared with 3%  in the 6- month group

• Adverse events of grade 3 or higher occurred in 8% of the patients in both groups

Conclusion

Based on these results, the authors concluded that four months of antituberculosis treatment was non-inferior to 6 months of treatment in children with drug-susceptible, nonsevere, smear-negative tuberculosis.  

They suggest, therefore, that a more nuanced approach to the treatment of tuberculosis in these children should be considered, as opposed to the existing standard protocols currently recommended.
 

Access the original research here

Shorter Treatment for Nonsevere Tuberculosis in African and Indian Children. The New England journal of medicine

You may find the below-associated content of interest

Updated WHO Guidelines for on Management of tuberculosis in children and adolescent Retrieved 21st March 2022
 

References:

1. Turkova, A., Wills, G. H., Wobudeya, E., Chabala, C., Palmer, M., Kinikar, A., Hissar, S., Choo, L., Musoke, P., Mulenga, V., Mave, V., Joseph, B., LeBeau, K., Thomason, M. J., Mboizi, R. B., Kapasa, M., van der Zalm, M. M., Raichur, P., Bhavani, P. K., McIlleron, H., … SHINE Trial Team (2022). Shorter Treatment for Nonsevere Tuberculosis in African and Indian Children. The New England journal of medicine, 386(10), 911–922. https://doi.org/10.1056/NEJMoa2104535
 

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