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Open Access NAT2 variants and toxicity related to anti-tuberculosis agents: a systematic review and meta-analysis

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BACKGROUND: Tuberculosis (TB) patients receiving anti-tuberculosis treatment may experience serious adverse drug reactions (ADRs) such as hepatotoxicity. Variants of the N-acetyltransferase 2 (NAT2) gene may increase the risk of experiencing such toxicity events.

OBJECTIVE: To provide a comprehensive evaluation of the evidence base for associations between NAT2 variants and anti-tuberculosis drug-related toxicity.

METHOD: This was a systematic review and meta-analysis. We searched for studies in Medline, PubMed, EMBASE, BIOSIS and Web of Science. We included data from 41 articles (39 distinct cohorts of patients). We pooled effect estimates for each genotype on each outcome using meta-analyses stratified by country.

RESULTS: We assessed the quality of the included studies, which was variable, with many areas of concern. Slow/intermediate NAT2 acetylators were statistically significantly more likely to experience hepatotoxicity than rapid acetylators (OR 1.59, 95%CI 1.26–2.01). Heterogeneity was not detected in the overall pooled analysis (I 2 = 0%). NAT2 acetylator status was significantly associated with the likelihood of experiencing anti-tuberculosis drug-related hepatotoxicity.

CONCLUSION: We encountered several challenges in performing robust syntheses of data from pharmacogenetic studies, and we outline recommendations for the future reporting of pharmacogenetic studies to enable high-quality systematic reviews and meta-analyses to be performed.
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Keywords: adverse events; evidence synthesis; pharmacogenetics; tuberculosis

Document Type: Research Article

Affiliations: 1: Department of Biostatistics, University of Liverpool, Liverpool 2: Cochrane Editorial Unit, London 3: School of Medicine, University of St Andrews, St Andrews 4: Department of Clinical Infection, Microbiology and Immunology, University of Liverpool, Liverpool, UK

Publication date: March 1, 2019

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  • The International Journal of Tuberculosis and Lung Disease publishes articles on all aspects of lung health, including public health-related issues such as training programmes, cost-benefit analysis, legislation, epidemiology, intervention studies and health systems research. The IJTLD is dedicated to the continuing education of physicians and health personnel and the dissemination of information on lung health world-wide.

    To share scientific research of immediate concern as rapidly as possible, The Union is fast-tracking the publication of certain articles from the IJTLD and publishing them on The Union website, prior to their publication in the Journal. Read fast-track articles.

    Certain IJTLD articles are also selected for translation into French, Spanish, Chinese or Russian. These are available on the Union website.

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