Remarks

• The shorter intensive regimen is suitable for children and adolescents who have no evidence of drug resistance and in children and adolescents who have a low likelihood of drug-resistant TB, e.g. those without risk factors for any form of drug-resistant TB.
• The recommendation from the Guidance for national tuberculosis programmes on the management of tuberculosis in children (second edition, 2014) remains an option for the treatment of children and adolescents with suspected or confirmed TB meningitis (TBM): Children and adolescents with suspected or confirmed tuberculous meningitis should be treated with a fourdrug regimen (HRZE) for 2 months, followed by a two-drug regimen (HR) for 10 months, the total duration of treatment being 12 months (Strong recommendation, low certainty of evidence).
• Due to a lack of data, the shorter intensive treatment regimen recommendation should not be used in children and adolescents living with HIV who are diagnosed with TB meningitis.

Subgroup considerations Children living with HIV infection: Most studies in the review were restricted to HIV-negative children. HIV-positive children represented a small proportion of children with TBM overall, and all received the intervention regimen. In the three studies using the intervention regimen included in the evidence review, 11 children were identified as having HIV infection (of a total of 724 children). Therefore, it was not possible to undertake analyses stratified by HIV infection. An additional small study of 13 children from South Africa used an extended duration of the intervention regimen (i.e. 9 months of HRZEto). Therefore, the recommendation on the 6-month regimen does not apply to HIV-infected children who are diagnosed with TBM. Adolescents: The population in the PICO question included both children (aged 0–9 years) and adolescents (aged 10–19 years). Based on the available information in the studies the median age of patients in the three studies using the intervention regimen were: 35 months (range: 2 months–14 years), 28 months (range: 2 months–15 years) and 30 months (5–82 months). In the studies using the comparator regimen, the age structure reported in two of the three studies was: <18 years and 3.3 years (range: 1–16 years). This recommendation therefore applies to both adolescents and children. Other subgroup analyses: Several subgroup analyses were pre-planned by the systematic reviewers (including subgroup analyses by: age group, for patients with DR-TB (including isoniazid-resistant TB), for patients who were microbiologically confirmed versus those clinically diagnosed, by Medical Research Council stage at diagnosis, and for patients with complications including tuberculoma and hydrocephalus). However, these analyses could not be conducted due to insufficient data.

Implementation considerations One key implementation consideration is the administration of the intervention regimen with the correct dosages of the included medicines, using currently available child-friendly formulations, including FDC formulations when possible. The regimen includes isoniazid, rifampicin, pyrazinamide and ethionamide, and is dosed as follows:

• Isoniazid: 20 mg per kg, maximum 400 mg daily
• Rifampicin: 20 mg per kg, maximum 600 mg daily
• Pyrazinamide: 40 mg per kg, maximum 2000 mg daily
• Ethionamide: 20 mg per kg, maximum 750 mg daily Historically, the regimen was dosed using a child-friendly FDC (dispersible tablet) of isoniazid and rifampicin (60 mg/60 mg) with pyrazinamide and ethionamide added as single medicines. This 60/60 mg FDC has limited availability globally, while a 50/75 mg isoniazid/rifampicin dispersible tablet is widely available through the Stop TB Partnership Global Drug Facility in over 100 countries (at the time of the GDG meeting). Using this formulation, rifampicin is dosed at slightly higher mg per kg doses as the drug ratio between isoniazid and rifampicin is 1:1.5 in the formulation. Higher doses of rifampicin are being used in several other trials including the SURE trial, TBM Kids and OptiRif Kids. Results from the SURE trial and TBM Kids are expected in the coming years while the results from the OptiRif Kids trial (74) were published after the GDG meeting. The dosing of the shorter intensive regimen was the subject of an expert consultation convened by the WHO after the GDG meeting and information on dosing for this regimen is included in the Operational Handbook. A dispersible paediatric formulation of ethionamide (125 mg) has been available from the Stop TB Partnership GDF since March 2018. Although orders for ethionamide are received from high MDR-TB burden countries consistently (this formulation was supplied by GDF to 41 countries between 2019 and 2021 at the time of the GDG meeting), the GDG members discussed that the paediatric formulation of ethionamide may not be available in all countries or health care levels where it is needed. Ethionamide is a component of the shorter all-oral bedaquiline-containing regimens to treat MDR/RR-TB; however, at the time that the GDG meeting was held (May-June 2021) the shorter regimen was only recommended for children aged 6 years and above. The GDG members also noted that this regimen should ideally be used in children with TBM that is bacteriologically confirmed as drug susceptible. However, it can also be used for children who are clinically diagnosed, but there should be no suspicion of DR-TB, such as in children or adolescents who have a history of contact with a patient with confirmed DR-TB (including isoniazid resistance, rifampicin resistance or multi-drug resistance). In countries or areas with a high background prevalence of DR-TB and where ethionamide is in use to treat DR-TB, programmes and clinicians need to consider the risks and benefits of using this regimen. The current recommendation for the diagnosis of TBM is that in adults or children with signs and symptoms of TBM, Xpert MTB/RIF or Xpert Ultra should be used in cerebrospinal fluid as the initial diagnostic test rather than smear microscopy/culture (strong recommendation, moderate certainty of evidence for test accuracy for Xpert MTB/RIF; low certainty of evidence for test accuracy for Xpert Ultra (16).