Impact of NAT2 acetylation phenotype on toxicity in tuberculosis therapy: a systematic review and meta-analysis

NAT2 encodes N-acetyltransferase 2, the key enzyme in isoniazid metabolism; the slow acetylator phenotype is associated with an increased risk of hepatotoxicity during tuberculosis treatment.

Adverse drug reactions remain a major obstacle to adherence during tuberculosis treatment, with hepatotoxicity the most clinically consequential. Genetic variability in NAT2, the key enzyme in isoniazid metabolism, is associated with this risk, but published results remain heterogeneous across studies and populations. This systematic review and random-effects meta-analysis (PROSPERO CRD420261297224, searches up to September 2025) included 67 studies and nearly 14,000 individuals from diverse regions, with region-based stratification and meta-regression of heterogeneity sources. Slow acetylators had a significantly increased risk of anti-tuberculosis drug-induced hepatotoxicity compared with rapid or intermediate acetylators (OR 3.14, 95 % CI 2.64-3.74), with a consistent direction of effect across populations despite moderate heterogeneity; the association with other adverse reactions was more modest (OR 1.65, 95 % CI 1.01-2.67). Meta-regression identified age and study size as heterogeneity contributors, and sensitivity analyses confirmed the robustness of the findings.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

An OR of 3.14 across 67 studies, with a consistent direction of effect between regions, places the slow acetylator phenotype among the hepatic risk factors one documents before starting treatment, alongside underlying liver disease. The limitation is definitional rather than statistical: these 67 studies did not classify acetylators by the same rules, which explains part of the residual heterogeneity — and this is exactly what the CPIC allele function assignment published the same week corrects, an argument for redoing this kind of synthesis on a unified nomenclature. In practice the missing step is unchanged: moving from relative risk to a validated isoniazid dosing strategy.

Analysis by Dr Thibaut Benquey