Risk of hepatitis with various reintroduction regimens of anti-tubercular therapy: a systematic review and network meta-analysis

ABSTRACT

Objective: To compare risk of hepatotoxicity between various regimens for reintroduction of antitubercular therapy (ATT) in patients with previous episode of ATT hepatitis.

Methods: We searched various databases (PubMed, Embase, CENTRAL, Scopus, WoS and LILACS) for studies comparing ATT reintroduction regimens using terms ‘drug-induced liver injury’ and ‘antitubercular drugs’ AND ‘reintroduction’. The reintroduction regimens i.e concomitant (all drugs introduced together), sequential (reintroduction of one drug in full dose followed by another) or incremental (one drug in a low dose and then higher dose followed by next drug) were compared using Bayesian approach for network meta-analysis with random-effect model. Cochrane revised tool was used to assess risk of bias in included studies (RoB 2.0).

Results: Four randomized studies with 577 patients were eligible for analysis. Compared with concomitant regimen (baseline comparator), incremental regimen appeared to have lower risk of ATT hepatitis (odds ratio [OR] 0.24; 95% CrI 0.017, 1.2) as also the sequential regimen (OR 0.33; 95% CrI 0.033, 1.7). Rifampicin first and isoniazid first reintroduction regimens were similar via-a-vis recurrence of hepatotoxicity.

Conclusion: The sequential and incremental regimen may be better than concomitant regimen in reducing risk of ATT hepatitis although the odds did not achieve statistical significance.

KEYWORDS:

• tuberculosis
• Chemical and drug-Induced Liver Injury
• rifampin
• pyrazinamide
• isoniazid
• Drug-induced liver injury
• Gastrointestinal Tuberculosis

Article highlights

• Drug-induced liver injury is an important problem with the current multidrug antitubercular therapy (ATT). Three of the agents (rifampin, isoniazid and pyrazinamide) are potentially hepatotoxic

• There are three different approaches to the reintroduction of ATT in patients with previous ATT hepatitis: concomitant (all drugs introduced together), sequential (one drug in full dose followed by another and so forth) and incremental (one drug at a time in increasing dose followed by another drug and so forth)

• In this network meta-analysis comparing these three reintroduction approaches, the incremental approach seemed to have the lowest risk of hepatotoxicity while concomitant approach had the highest risk.

• Risk of ATT hepatitis did not differ whether rifampin or isoniazid was reintroduced first.

• Staggered reintroduction (sequential or incremental) may have a lower risk of hepatotoxicity and have added benefit of identification of the culprit agent.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

H Soni: Literature search, Screening of the literature, Risk of Bias, Data extraction, Manuscript writing. P Kumar-M: Data extraction, Data analysis, Manuscript writing. S Mishra: Literature search, Risk of Bias, Manuscript writing. BL Bellam: Literature search, Screening and data extraction. H Singh: Manuscript review and important intellectual content. HS Mandavdhare: Manuscript review and important intellectual content. B Medhi: Manuscript review and important intellectual content. U Dutta: Manuscript review and important intellectual content. V Sharma: Conception, Data verification, Risk of bias, Manuscript writing and Manuscript review. All authors read and approved the final version

Supplementary material

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Additional information

Funding

This paper was not funded.