Comparative Effectiveness of Regimens for Drug-Susceptible Tuberculous Meningitis in Children and Adolescents: A Systematic Review and Aggregate-Level Data Meta-Analysis

Abstract

Background: Before August 2021, the only regimen recommended by the World Health Organization (WHO) to treat pediatric drug-susceptible tuberculous meningitis was a 12-month regimen consisting of isoniazid, rifampicin, ethambutol, and pyrazinamide (2HRZE/10HR). The comparative effectiveness of shorter regimens is unknown. Methods: To inform a WHO guideline update, we undertook a systematic review and meta-analysis to evaluate outcomes from regimens of six- to less than 12-months’ duration that included, at a minimum, isoniazid, rifampicin, and pyrazinamide. We included studies that applied rigorous diagnostic criteria and reported outcomes for ≥10 children or adolescents. Using generalized linear mixed models, we estimated the random effects pooled proportions of patients with key outcomes. Results: Of seven included studies, none compared regimens head-to-head. Three studies (724 patients) used a six-month intensive regimen, which includes isoniazid and rifampicin at higher doses, pyrazinamide, and ethionamide instead of ethambutol (6HRZEto). Outcomes for this vs. the 12-month regimen (282 patients, three studies) were respectively: death, 5.5% (95% CI: 2.1-13.4%) vs. 23.9% (95% CI: 17.5-31.7%); treatment success (survival with or without sequelae), 94.6% (95% CI: 73.9-99.1%) vs. 75.4% (95% CI: 68.7-81.1%); and neurological sequelae among survivors, 66.0% (95% CI: 55.3-75.3%) vs. 36.3% (95% CI: 30.1-43.0%). Relapse did not occur among 148 patients followed-up for two years after completing the six-month intensive regimen. Conclusions: Our findings are limited by the small number of studies and substantial potential for confounding. Nonetheless, the 6HRZEto regimen was associated with high treatment success and is now recommended by WHO as an alternative to the 12-month regimen.

A model-based approach for a practical dosing strategy for the short, intensive treatment regimen for paediatric tuberculous meningitis

“…Young children are disproportionately at risk for TBM and its attendant high risk of morbidity and mortality. While the optimal doses for children remain to be established, we now have the tools to deliver a highly effective regimen to children globally ( Sulis et al, 2022 ).…”

“…The authors report a treatment success (survival with or without sequelae) in 95% (95%CI 74%–99%) of the participants in the 6-month regimen versus 75% (95% CI: 69%–81%) in the 12-month regimen. Also in terms of neurological sequelae among survivors the 6-month regimen performed well with 36% (95% CI, 30%–43%) versus 66% (95% CI, 55%–75%) in the 12-month regimen ( Sulis et al, 2022 ). Based on this, in March 2022, WHO recommended, that children and adolescents with bacteriologically confirmed or clinically diagnosed TBM (without suspicion or evidence of multi-drug resistant or rifampicin-resistant tuberculosis) could receive the 6-month intensive regimen (6HRZEto) as an alternative option to the 12-month regimen (2HRZE/10HR).…”

“…A systematic review and meta-analysis was conducted to compare the effectiveness of the short, intensive regimen used in South Africa versus the WHO-recommended 12-month regimen to inform a WHO guideline update ( Sulis et al, 2022 ). The authors report a treatment success (survival with or without sequelae) in 95% (95%CI 74%–99%) of the participants in the 6-month regimen versus 75% (95% CI: 69%–81%) in the 12-month regimen.…”

“…To seek advice on the most suitable dosing strategy for the newly recommended 6-month intensive TBM regimen, WHO convened an expert consultation involving experts in clinical pharmacology, pharmacokinetics, and pharmacodynamics, as well as TB paediatricians and researchers. First, these experts reviewed the data collected in a meta-analysis to explore if 6HRZEto could be used ( Sulis et al, 2022 ). After the advice that this regimen could indeed be recommended by the WHO, a dosing table needed to be created that took the globally available formulations into account.…”

World Tuberculosis Day: Time to Translate New Clinical Findings in Pediatric Tuberculosis in Routine Practice

“…A similar importance practice-shift has been suggested from experts and endorsed by the WHO for the treatment of TB meningitis, historically treated for 12 months, while South Africa experts implemented an intensified 6-month regimen. 5 The shorter intensive regimen (3 studies, involving 724 participants) had a death rate of 8.0% (95% CI: 2%–13%) versus 24.0% (95% CI: 18%–32%) for the 12-month regimen (3 studies and 282 participants). Treatment success for the shorter intensive regimen was 83% (95% CI: 74%–99%) versus 75% for the 12-month regimen (95% CI: 69%–81%), although neurologic sequelae occurred more frequently in survivors treated with the short course.…”