Book traversal links for 5.1.1. Justification and evidence
The majority of children with TB have less severe forms of the disease than adults. Treatment regimens that are shorter than those for adults may be effective in treating children with TB, however solid evidence to substantiate this has been lacking to date. Shorter treatment regimens can result in lower costs to families and health services, potentially less toxicity, lower risks of drug-drug interactions in children living with HIV, and fewer problems with adherence. Shorter, safe and effective treatment regimens for children with both drug-susceptible and DR-TB benefit children with TB and their families, and are a key intervention to achieve the End TB Strategy targets, as well as targets related to children set during the UNGA High-Level Meeting on the fight against tuberculosis in 2018. New evidence from a recently completed trial on the shortened treatment of drug-susceptible TB in children and adolescents has paved the way for new recommendations on shorter regimens for this group.
The SHINE trial (Shorter Treatment for Minimal Tuberculosis in Children) was the first and only large phase three trial to evaluate the duration of TB treatment in children with non-severe drug-susceptible TB. Therefore, evidence from the trial rather than a systematic review, was used to answer this PICO question (57). The SHINE trial was a multi-centre, open-label, parallel-group, non-inferiority, randomized, controlled, two-arm trial comparing 4-month (16 weeks) versus the standard 6-month (24 weeks) treatment durations in children under 16 years of age with symptomatic non-severe TB. Children and young adolescents aged below 16 years were treated with rifampicin, isoniazid, pyrazinamide with or without ethambutol using WHO recommended doses, appropriate for paediatric dosing (58).
PICO question: In children and adolescents with non-severe TB, should a 4-month intervention regimen versus the standard 6-month regimen conforming to WHO guidelines be used?
Evidence: In the SHINE trial, the primary efficacy outcome was a composite of treatment failure (including an extension of treatment beyond the replacement of missed doses, TB treatment drug changes or restarts due to suspected treatment failure), on-treatment loss-to-follow-up, TB recurrence or death by 72 weeks (from randomization), excluding children not reaching 16 weeks follow-up (modified-intention-to-treat). The non-inferiority margin for the primary efficacy outcome was 6%. The primary safety outcome was grade 3-5 adverse events recorded while on TB treatment.
The SHINE trial definition of non-severe TB was: peripheral lymph node TB or respiratory TB (including uncomplicated intrathoracic lymph node disease) confined to one lobe without cavities, no significant airway obstruction, uncomplicated pleural effusion, and no miliary TB.
The SHINE trial inclusion criteria were: children and young adolescents aged 28 clinician's decision to treat with a standard first-line regimen; not treated for TB in the previous two years; known HIV status (positive or negative). Trial exclusion criteria were: respiratory sample acid fast bacilli smear-positive (a smear-positive peripheral lymph node sample was allowed); premature birth (
A total of 1204 children were enrolled in the trial between July 2016 and July 2018. The median age of enrolled children was 3.5 years (range: 2 months - 15 years), 52% were male, 11% had HIV-infection, and 14% had bacteriologically confirmed TB. Retention in the trial by 72 weeks and adherence29 to allocated TB treatment were 95% and 94%, respectively. Sixteen (2.8%) versus 18 (3.1%) children reached the primary efficacy outcome (treatment failure) in the 16- versus 24-week arms respectively, with an unadjusted difference of -0.3% (95% CI: -2.3, 1.6). Treatment success was reported in 97.1% of participants receiving the 16-week regimen versus 96.9% in those receiving the 24-week regimen (relative risk (RR): 1.00, 95% CI: 0.98-1.02). Non-inferiority of the 16-week regimen was consistent across all intention-to-treat, per-protocol and key secondary analyses. This included restricting the analysis to the 958 (80%) children that were independently adjudicated to have TB at baseline by the trial Endpoint Review Committee. A total of 7.8% of children experienced a grade 3-5 adverse event in the 16-week arm, versus 8.0% in the 24-week arm (RR: 0.98, 95% CI: 0.67-1.44). There were 115 on-treatment grade >3 adverse events in 95 (8%) children, 47 (8%) in the 16-week and 48 (8%) in the 24-week arm, most common being pneumonia or other chest infections (29 (25%)) or liver-related events (11 (10%)) across both arms. There were 17 grade 3 or 4 adverse reactions (considered possibly, probably or definitely) related to trial drugs, including 11 hepatic events; all adverse reactions except three occurred in the first eight weeks of treatment.
GDG considerations: The GDG judged that while the desirable effects related to this PICO question are related to treatment outcomes, shortening the duration of treatment is also important and desirable (as reducing the length of treatment could make treatment easier for children and caregivers as well as reduce cost for families and the health system). The GDG discussed that since the SHINE trial was a non-inferiority trial, no difference in unfavourable outcomes between the two arms is what the trial aimed to detect. Therefore, both desirable and undesirable effects were judged by most GDG members as trivial. Since non-inferiority of the 4-month regimen was demonstrated in the trial, the balance of effects was judged to not favour either the shorter or the longer duration of treatment.
However, the GDG noted that treatment duration is a critical issue which was further considered in the context of issues such as cost, acceptability and feasibility.
The GDG also discussed that presumably, a shorter duration of treatment would reduce costs to both the health care system and to children with TB and their families. The GDG ultimately agreed on 'moderate savings' despite the varying views on the level of these savings. The GDG judged that equity was probably increased with a shorter duration of treatment. Despite no direct evidence on acceptability, the GDG judged that the shorter regimen was acceptable to stakeholders.
In addition, the GDG felt that, in the absence of exposure to DR-TB, access to CXR would help distinguish between non-severe and severe disease. However, the panel recognized that access to CXR is often limited or quality of CXR and capacity for interpretation is insufficient at lower levels of the health care system, which may have equity implications. Therefore, feasibility was judged to vary by setting. The GDG noted that it is critically important to clearly define "non-severe" disease and that NTPs be encouraged to scale up access to quality CXR and train health care providers in its interpretation. Overall, the GDG judged that if the severity of TB disease in children can be adequately determined under programmatic conditions, then implementation of a 4-month regimen is highly feasible.
²⁶ Defined as countries, subnational administrative units, or selected facilities, where the HIV prevalence among adult pregnant women is ≥1% or among TB patients is ≥5% in the 2014 Guidance for national tuberculosis programmes on the management of tuberculosis in children (second edition) (8).
²⁷ WHO does not intend to establish thresholds for low, moderate or high levels of prevalence of isoniazid resistance; NTPs will establish definitions for their own countries.
²⁸ In the SHINE trial, children with Xpert MTB/RIF results had very low or low semi-quantitative results, or a negative result. Xpert Ultra was not used in the SHINE trial.
²⁹ In the SHINE trial, adherence was defined as the proportion of children who received an adequate amount of treatment (as defined in the statistical analysis plan for both the intervention and control regimens; generally, a cut off of 80% of the allocated doses was used, within a certain time frame of starting each phase of treatment (i.e. intensive phase versus continuation phase).