Appropriate chemopreventive strategy for anti-tubercular therapy related liver injury is unsettled: Results from a systematic review and network meta-analysis

ABSTRACT

Background

Role of chemoprophylaxis for prevention of antitubercular therapy-related drug-induced liver injury (ATT-DILI) is uncertain.

Methods

Electronic databases were searched for randomized trials reporting on chemoprophylaxis agents for prevention of ATT-DILI. We included studies evaluating the role of a drug in comparison to controls/placebo. The primary outcome was the occurrence of ATT-DILI. We performed a Bayesian random-effects network meta-analysis to calculate odds ratios (ORs) and 95% credible intervals (CrI) for those arms where at least two studies were available. Additional comparative studies for these arms were also identified.

Results

Fourteen studies were identified and seven included in the meta-analysis. The agents used for prevention of ATT-DILI were silymarin/silibinin (4 trials), N-acetylcysteine (NAC) (3 studies), herbal preparations (5 studies) and one study each for cholecalciferol and carnitine. Compared with controls/placebo, the odds of occurrence of hepatotoxicity with NAC was 7 * 10⁻¹⁷ (95% CrI: 2.8 * 10⁻⁵³, 0.0053) and Silymarin was 0.68 (95% CrI: 0.084, 4.6). NAC had the highest probability of rank 1 (0.99) which was followed by Silymarin (0.004).

Conclusion

N-acetyl cysteine, but not Silymarin/Silibinin, appears to be beneficial in prevention of ATT-DILI. However, the results were limited by the possible risk of bias in included studies, variable definitions of ATT-DILI and limited number and category of patients.

KEYWORDS:

• Drug-induced liver injury
• gastrointestinal tuberculosis
• hepatic tuberculosis
• hepatotoxicity
• Tuberculosis

Article highlights

• Antitubercular therapy (ATT) is associated with significant adverse effects and drug-induced liver injury (DILI) is an important adverse effect.

• Certain factors like age, nutritional status and comorbidities (like chronic hepatitis or cirrhosis) may increase the risk of ATT DILI

• Chemoprevention of ATT-DILI is an area of interest to clinicians but the most appropriate strategy is unclear

• Various agents like N-acetylcysteine, silymarin and related compounds, carnitine, cholecalciferol and herbal products have been used for chemoprevention of ATT-DILI

• Most of the published studies have significant limitations related to trial design, small number of patients, definition of ATT DILI and lack of masking.

• N-acetyl cysteine seems to be effective for chemoprevention of ATT DILI in a subgroup of patients whereas silymarin and related compounds do not seem to be efficacious.

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

A. Singh and S. Verma contributed equally to study selection, manuscript writing, review and approval to manuscript and data extraction. P. Kumar-M with data analysis. H. Soni, S. Sharma and S. Sharma with literature search and study selection. A. Patil with Risk of Bias, Manuscript writing and important intellectual content. V. Sharma with Conception, Data check, Important intellectual content, literature review and final approval.

Supplementary material

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Additional information

Funding

This paper was not funded