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

INTRODUCTION: Adverse drug reactions (ADRs) remain a major challenge in tuberculosis treatment and frequently compromise therapeutic adherence and outcomes. Hepatotoxicity represents the most clinically significant toxicity. Genetic variability in N‑acetyltransferase 2 (NAT2), the key enzyme involved in isoniazid metabolism, has been associated with toxicity risk, although findings across studies and populations remain heterogeneous. METHODS: acetylation phenotype and ADRs during tuberculosis treatment. Literature searches were performed across major databases up to September 2025. Geographical variability was assessed by region‑based stratification, while potential methodological and clinical sources of heterogeneity using meta‑regression analyses. RESULTS: Sixty-seven studies, including nearly 14 000 individuals from diverse regions, were analyzed. Slow acetylators showed a significant increased risk of anti‑tuberculosis drug‑induced hepatotoxicity (ATDH) 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. Association with other ADRs was more modest (OR 1.65, 95% CI 1.01-2.67). Meta-regression identified age and study size as heterogeneity contributors. Sensitivity analyses confirmed the robustness of the findings. CONCLUSION: slow acetylation phenotype is a robust determinant of ATDH risk and supports phenotype‑guided precision therapeutic strategies. PROTOCOL REGISTRATION: PROSPERO registration number CRD420261297224.