Remarks

• Non-severe TB is defined as: Peripheral lymph node TB; intrathoracic lymph node TB without airway obstruction; uncomplicated TB pleural effusion or paucibacillary, non-cavitary disease, confined to one lobe of the lungs, and without a miliary pattern.
• Children and adolescents who do not meet the criteria for non-severe TB should receive the standard six-month treatment regimen (2HRZE/4HR), or recommended treatment regimens for severe forms of extrapulmonary TB.
• The use of ethambutol in the first two months of treatment is recommended in settings with a high prevalence of HIV,26 or of isoniazid resistance.27

Subgroup considerations Children with peripheral lymph node TB: Although the number of children with peripheral lymph node TB in the SHINE trial were small (N=19 in the 16-week arm and N=21 in the 24-week arm), there was no difference in the proportion of unfavourable outcomes between the two arms. The SHINE trial also found that 16 weeks of treatment was non-inferior compared to 24 weeks of treatment among children with both peripheral lymph node disease and pulmonary disease (N=182 in the 16-week arm and N=171 in the 24-week arm). These results may provide reassurance to clinicians regarding a seemingly delayed clinical response to TB treatment, frequently seen in children with peripheral lymph node TB (where lymph nodes remain enlarged even after treatment). Children and adolescents living with HIV infection (CALHIV): CALHIV were eligible for enrolment in the SHINE trial; 65 (11%) CALHIV were enrolled in the 16-week arm and 62 (10%) in the 24-week arm. 49% of CALHIV in the 16-week arm and 43% in the 24-week arm were on antiretroviral treatment at the time of enrolment. 20% of CALHIV in both arms had a CD4 count of less than 200 cells per mm3 . 51% of CALHIV in the 16-week arm and 63% in the 24-week arm were classified as severe as per the WHO immunological classification for established HIV infection (59). In this subgroup, the 16-week regimen was non-inferior as compared to the 24-week regimen, although the 95% confidence interval for the risk difference was wide (risk difference -4.3, 95% CI -14.9 to 6.2). In view of the limited evidence, clinicians may consider treating CALHIV with non-severe TB for 4 months, depending on the degree of immunosuppression and ART status, as well as the presence of other opportunistic infections. These children and adolescents will need to be monitored closely, especially at 4 months of treatment, and treatment extended to 6 months if there is insufficient progress. Children with SAM: In the SHINE trial, SAM was defined as weight-for-height Z-score (WHZ) <−3 or MUAC <115 mm (60). Thirty children with SAM (5%) were included in the 16-week arm and 33 (5%) in the 24-week arm. No separate subgroup analysis was therefore conducted for children with SAM. In view of the insufficient evidence on this subgroup, and as SAM is defined as a danger sign, children with SAM and non-severe TB should preferably receive 6 months of TB treatment. Infants <3 months of age and/or weighing <3 kg: Infants <3 months of age and infants weighing <3 kg (including premature birth (<37 weeks) were not eligible for inclusion in the SHINE trial. No new data on the treatment of congenital TB and very young infants (aged 0–3 months) with TB disease was received following a call for data. Therefore, infants aged 0–3 months with suspected or confirmed PTB or tuberculous peripheral lymphadenitis should be promptly treated with the 6-month treatment regimen (2HRZ(E)/4HR), as per the existing recommendation from the 2014 Guidance for national tuberculosis programmes on the management of tuberculosis in children (second edition) (8). Treatment may require dose adjustment to reconcile the effect of age and possible toxicity in young infants. The decision to adjust doses should be taken by a clinician experienced in the management of paediatric TB. Children treated for TB in the past two years: Given the increased risk of treatment failure and of drug resistance, children and adolescents treated in the preceding two years were not eligible for inclusion in the SHINE trial; they should be treated with the 6-month treatment regimen (2HRZ(E)/4HR).

Implementation considerations Assessing severity of disease: The feasibility of assessing the severity of TB disease, particularly in settings without access to CXR or capacity for CXR interpretation and WHO-recommended diagnostic tests was identified as a major implementation consideration. Chest radiography was identified by the GDG as a critical tool to evaluate the severity of intrathoracic disease. As indicated under the recommendation remarks, non-severe intrathoracic or PTB disease refers to: intrathoracic lymph node TB without airway obstruction; uncomplicated TB pleural effusion or paucibacillary, non-cavitary disease confined to one lobe of the lungs and without a miliary pattern. Extensive or advanced disease in children under 15 years of age is usually defined by the presence of cavities or bilateral disease on CXR (61). NTPs are encouraged to scale up access to quality CXR and provide training to health care providers in its interpretation. Out-of-pocket expenses for CXR pose a potential barrier to TB diagnosis and access to shorter regimen for eligible children and young adolescents. In the SHINE trial, children who were Xpert MTB/RIF positive, but sputum smear-negative were eligible for inclusion. The 85 children (7%) who were Xpert MTB/RIF positive (45 in the 4-month arm and 40 in the 6-month arm), had very low or low semi-quantitative Xpert MTB/RIF results. Detailed implementation guidance is provided in the Operational handbook on the management of tuberculosis in children and adolescents, taking into consideration differences in the health care system and country context, including the availability of diagnostic tools to make a diagnosis and to assess disease severity. While access to CXR is an important implementation consideration, it should not be a barrier for children and adolescents in lower resourced settings to benefit from the shorter regimen. The implementation guidance in the operational handbook comprises criteria for assessing disease severity, including clinical criteria in the absence of CXR or rapid diagnostics or other bacteriological tests, to determine eligibility for the shorter regimen. Children with Xpert MTB/RIF or Ultra results that are trace, very low or low, who meet radiographical or clinical criteria for non-severe TB, can be treated with the 4-month regimen. Continuum between TB infection and disease: An additional implementation consideration is the concept that a continuum exists between TB infection, non-severe and more severe forms of TB disease in children. Shorter treatment regimens for drug-susceptible TB are now very similar to recently recommended shorter regimens for the treatment of TB infection, in terms of duration and composition, in particular the regimen that consists of 3 months of daily isoniazid and rifampicin (3HR) (14). This implies that incorrectly diagnosing a child who has TB infection as having non-severe TB disease may not have severe consequences. Contact investigation: Another implementation consideration is the scale-up of contact investigation approaches, which can improve early identification of children with non-severe disease who may benefit from the 4-month regimen. Use of ethambutol in the intensive phase of treatment: Children and young adolescents with nonsevere TB who live in settings with low HIV prevalence or a low prevalence of isoniazid resistance and those who are HIV negative can be treated with a three-drug regimen (HRZ) for 2 months, followed by 2 months of HR. Children and young adolescents with non-severe TB who are living in settings where the prevalence of HIV is high30 and/or the prevalence of isoniazid resistance is high31 should be treated with HRZE for 2 months followed by HR for 2 months. In the SHINE trial, ethambutol was used in line with these recommendations as per national guidelines and all CALHIV received ethambutol as part of their treatment. For the 6-month regimen used to treat more severe forms of TB, it is recommended to add ethambutol to the regimen (i.e. 4HRZE/2HR). Child-friendly formulations: NTPs are encouraged to prioritize the use of child-friendly fixed dose combination (FDC) formulations for TB treatment in children up to 25 kg body weight, such as: the 3-FDC HRZ 50/75/150 mg with or without the addition of dispersible ethambutol, and the 2-FDC HR 50/75 mg (available from the Stop TB Partnership Global Drug Facility (GDF)). Capacity building of health care workers at all levels of the health system on diagnostic approaches (including treatment decision algorithms), eligibility for the four-month regimen and monitoring of children on first-line TB treatment will also be critical factors in the successful implementation of the shorter regimen. Treatment of severe PTB in children and young adolescents: Children and young adolescents with forms of PTB that do not meet the eligibility criteria for the four-month regimen should be treated with a standard 6-month regimen that includes a fourth drug (ethambutol) in the intensive phase (such as 2HRZE/4HR). Treatment options for adolescents from 12 years of age: Another implementation consideration is that adolescents aged 12 years and above with TB can benefit from the 4-month regimen that consists of isoniazid, rifapentine, moxifloxacin and pyrazinamide (HPMZ), which is now conditionally recommended by WHO (55). Adolescents aged between 12 and 16 years therefore have three options for treatment: the 4-month HPMZ regimen, the 4-month 2HRZ(E)/2HR regimen, and the standard 6-month 2HRZ(E)/4HR regimen. Adolescents from 16 years of age were not included in the SHINE trial and therefore have two options: the 4-month HPMZ regimen and the standard 6-month 2HRZE/4HR regimen. Choosing an appropriate regimen for this age group will depend on clinical factors (such as the presence of severe disease or if living with HIV, ART status and CD4 count) as well as contextual factors (including the availability of the HPMZ regimen in the country).