Childhood Tuberculosis — Time for Shorter and Differentiated Treatment

Well before the Covid-19 pandemic disrupted tuberculosis care,¹ long treatment duration has been a weak link in the continuum of care. But the past decade has been a turning point in the pioneering of shorter treatment and differentiated care, as opposed to the traditional, one-size-fits-all approach. Shortening of treatment is being achieved by exploiting longer-acting drugs, adding new drugs, or, for persons with nonsevere disease, targeting shorter regimens.²

For latent Mycobacterium tuberculosis infection, several shorter alternatives to the traditional 6 to 9 months of isoniazid therapy now exist, including a 3-month regimen of weekly rifapentine plus isoniazid or a 4-month regimen of daily rifampin.³ For drug-resistant tuberculosis, 6 months of oral-only regimens such as bedaquiline, pretomanid, and linezolid⁴ or these drugs plus moxifloxacin⁵ could replace the 24-month standard regimen. For drug-sensitive tuberculosis in adults, a 4-month rifapentine-based regimen containing moxifloxacin was noninferior to the standard 6-month regimen in a recent trial.⁶

Where does this leave children, a vulnerable group that is often excluded from randomized trials of new treatments? According to the World Health Organization, 1.1 million children worldwide became ill with tuberculosis in 2020, predominantly in low- and middle-income countries.⁷ Increasingly, childhood tuberculosis is also identified in the context of acute lower respiratory tract infection or pneumonia.⁸ However, difficulties in confirming a diagnosis of tuberculosis (particularly a lack of microbiologic confirmation), a long duration of treatment, lack of easy access to fixed-dose palatable pediatric formulations, pill burden, and medication side effects are big challenges in treating children. It is therefore timely and commendable that Turkova et al. present in this issue of the Journal⁹ the results of the SHINE trial — a trial that included only children and showed that 4 months of treatment provided similar efficacy to a standard 6-month regimen for nonsevere tuberculosis.

This multicenter, open-label trial involved 1204 children with symptomatic, nonsevere (as assessed radiologically), smear-negative tuberculosis. The median age of the participants was 3.5 years, and 11% of them had human immunodeficiency virus (HIV) infection. In children with microbiologic confirmation of tuberculosis (14% of the trial population), only those with drug-susceptible cases were included. Participants were randomly assigned in a 1:1 ratio to receive either 4 months (16 weeks) or 6 months (24 weeks) of antituberculosis therapy. All the participants received 8 weeks of standard treatment with isoniazid, rifampin, and pyrazinamide as a fixed-dose formulation, with or without ethambutol; this treatment was followed by either 8 weeks or 16 weeks of isoniazid and rifampin in a fixed-dose combination. The primary outcome was unfavorable status (defined as treatment failure [extension, change, or restart of treatment or tuberculosis recurrence], loss to follow-up during treatment, or death) by 72 weeks.

In the primary analysis, the 4-month regimen was found to be noninferior to the standard 6-month regimen. Findings in all the subgroup analyses, including those stratified according to age, HIV infection status, sex, geographic region, body weight, use of ethambutol, or positivity on microbiologic testing, were similar to those in the primary analysis. Results of the safety analyses were similar in the two treatment groups, with adverse events occurring in approximately 8% of the participants in each group, with most events occurring during the first 8 weeks of treatment (during which the treatments were identical in the two groups). Adherence was high in each group, with 94% adherence to at least 80% of the doses throughout the assigned treatment duration. Retention in this trial was impressive, with 95% of the expected participants attending the 72-week visit. Besides the benefits of adherence and reduction in pill burden over time, a cost-effectiveness analysis indicated lower health care costs with the shorter regimen.

The next steps for implementation of the regimen used in the SHINE trial would include revision of global guidelines, adoption by countries, and scaling up of better diagnostic tools as well as pediatric fixed-dose formulations. Although the findings of this trial are applicable only to nonsevere tuberculosis, most cases of tuberculosis in children initially manifest as nonsevere disease, with low bacillary burden on smears and molecular tests.¹⁰ Thus, the trial findings will be applicable to most children with tuberculosis and can be adopted by national programs with the use of fixed-drug formulations that are already available.

However, a key barrier to implementation would be the identification of children with nonsevere tuberculosis. The use of microscopy to rule out smear-positive cases is probably unnecessary, given the low sensitivity in children and the replacement of microscopy with molecular tests such as Xpert MTB/RIF Ultra.¹⁰ Low, very low, or trace positive values on Xpert testing are most common in children with microbiologically confirmed tuberculosis¹⁰ and could be used as a proxy for smear-negative tuberculosis and to simultaneously rule out rifampin resistance. It is therefore imperative that countries invest more in microbiologic diagnosis with molecular testing for childhood tuberculosis, building on the laboratory capacity developed for Covid-19.¹

Reliance on radiography of the chest to identify nonsevere disease may be a challenge in areas where radiology facilities are limited; interobserver variability in interpretation is also an issue. However, these concerns may be addressed with newer, ultra-portable digital radiography systems and artificial intelligence–based software for reading radiographs, with the latter requiring validation in children.¹¹ Given the wide usefulness of radiographs beyond tuberculosis care, greater efforts are needed to make digital radiography more affordable and accessible, as an essential diagnostic tool in primary health care.

Source: NEJM