What are the most efficacious treatment regimens for isoniazid-resistant tuberculosis? A systematic review and network meta-analysis.

INTRODUCTION: Consensus on the best treatment regimens for patients with isoniazid-resistant TB is limited; global treatment guidelines differ. We undertook a systematic review and meta-analysis using mixed-treatment comparisons methodology to provide an up-to-date summary of randomised controlled trials (RCTs) and relative regimen efficacy. METHODS: Ovid MEDLINE, the Web of Science and EMBASE were mined using search terms for TB, drug therapy and RCTs. Extracted data were inputted into fixed-effects and random-effects models. ORs for all possible network comparisons and hierarchical rankings for different regimens were obtained. RESULTS: 12 604 records were retrieved and 118 remained postextraction, representing 59 studies-27 standalone and 32 with multiple papers. In comparison to a baseline category that included the WHO-recommended regimen for countries with high levels of isoniazid resistance (rifampicin-containing regimens using fewer than three effective drugs at 4 months, in which rifampicin was protected by another effective drug at 6 months, and rifampicin was taken for 6 months), extending the duration of rifampicin and increasing the number of effective drugs at 4 months lowered the odds of unfavourable outcomes (treatment failure or the lack of microbiological cure; relapse post-treatment; death due to TB) in a fixed-effects model (OR 0.31 (95% credible interval 0.12-0.81)). In a random-effects model all estimates crossed the null. CONCLUSIONS: Our systematic review and network meta-analysis highlight a regimen category that may be more efficacious than the WHO population level recommendation, and identify knowledge gaps where data are sparse. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42014015025.