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 6- 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 7 included studies, none compared regimens head-to-head. Three studies (724 patients) used a 6-month intensive regimen, which includes isoniazid and rifampicin at higher doses, pyrazinamide, and ethionamide instead of ethambutol (6HRZEto). Outcomes for this versus the 12-month regimen (282 patients, 3 studies) were, respectively, as follows: death, 5.5% (95% confidence interval [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 2 years after completing the 6-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.

Keywords: World Health Organization guidelines; neurological sequelae; treatment outcomes; tuberculosis.

Figure 1.

Summary results of risk of bias assessment of 7 reporting on the effectiveness of regimens to treat drug-susceptible tuberculous meningitis in children and adolescents. *, Neurological sequelae were ascertained through both clinical exam and reports from patients/caregivers. **, Although stratum-specific data were not available, this was considered of limited concern given the very small number of human immunodeficiency virus (HIV)-positive patients included in the cohort. CSF, cerebrospinal fluid; LTFU, loss to follow-up; TBM, tuberculous meningitis.

Figure 2.

Forest plot of pooled proportions of death, loss to follow-up, treatment success, neurological sequelae, and survival without sequelae across 3 studies of 6-month intensive regimen (6HRZEto) and 3 studies of 12-month standard regimen (2HRZE/10HR). One study of the 12-month regimen (Gupta et al [17]) was excluded from analysis of loss to follow-up because it only included patients with complete follow-up period. In van Well et al [15], 53 of 66 patients who were counted as lost to follow-up were likely alive and had completed treatment, but their outcome was not recorded, and their neurological status could not be assessed. CI, confidence interval; LTFU, loss to follow-up.