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

Abstract

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.

Keywords: Clinical Epidemiology; Tuberculosis.

Figure 1

Treatment regimen categorisation. Regimen categorisation flow chart for main analysis. Second question includes RIF in the calculation. Bolded text after final question indicates regimen category (table 1) present in main network (figure 3B). *Levamisole and diphenyl thiourea compound SU 1906 not counted as effective protection. INH, isoniazid; RIF, rifampicin.

Figure 2

Pairwise direct effects forest plots across all isoniazid resistance profiles. Pairwise direct effects forest plots for the four regimen pairs where such comparisons were possible. Regimen RIF ED<3 D<6m the baseline for plots (A–C) and regimen RIF ED<3 D=6m for plot (D). Regimen (A) RIF ED<3 D=6m, (B) RIF ED<3 Pr6 D=6m, (C) RIF ED≥3 D<6m, (D) RIF ED<3 Pr6 D=6m the comparator. In analysis (D) study STS/BMRC had no events in either arm. Vertical solid line—null hypothesis. Vertical dotted line summary estimate. AWG/BMRC, Algerian Working Group/British Medical Research Council Cooperative Study; EABMRC, East African British Medical Research Council Study; ECA/BMRC, East and Central African/British Medical Research Council; ED, effective drugs; HKCS/BMRC, Hong Kong Chest Service/British Medical Research Council; RIF, rifampicin; STS/BMRC, Singapore TB Service/British Medical Research Council.

Figure 3

Data network. Data networks (A) for the main analysis containing all isoniazid resistance patterns, (B) for the main analysis excluding the inconsistent study. Thickness of lines and numbers indicate the number of studies making this comparison. *One study arm classifiable as RIF ED≥3 Pr6 D=6m, RIF ED<3 Pr6 D=6m or RIF ED<3 D=6m compared with RIF ED<3 D=6m; here listed as RIF ED≥3 Pr6 D=6m as per main analysis. ED, effective drugs; RIF, rifampicin.

Figure 4

Forest plots from fixed-effects and random-effects network meta-analyses across all isoniazid resistance profiles. Forest plots of treatment comparisons from the network depicted in figure 3B. (A) Fixed-effects and (B) random-effects derived ORs on a log scale with 95% credible interval. Vertical line—null hypothesis. ED, effective drugs; RIF, rifampicin.

Figure 5

Histograms of relative ranks from fixed-effects and random-effects network meta-analyses across all isoniazid resistance profiles. Relative treatment ranks of treatment comparisons from the network depicted in figure 3B. (A) Fixed effects. (B) Random effects. ED, effective drugs; RIF, rifampicin.