Acetylator status-guided rapid reintroduction of isoniazid in tuberculosis patients with drug-induced hepatotoxicity

Background People who slowly metabolize isoniazid are at increased risk of drug-induced liver injury (DILI) and interruption of tuberculosis treatment. We hypothesized that immediate identification of slow acetylators among patients with DILI will facilitate rapid and safe reintroduction of isoniazid. Methods Between 2021 and 2023, at our tuberculosis referral centre in The Netherlands, we evaluated an isoniazid acetylator status-guided rapid reintroduction of anti-tuberculous drugs in a cohort of patients with DILI. Patients' acetylator status was determined by phenotyping after a single dose of isoniazid, regardless of liver function abnormalities. Results In total, 49 tuberculosis patients underwent Therapeutic Drug Monitoring (TDM) from 2021 to 2023, with 67% being slow acetylators as assessed by phenotyping. Out of 10 patients with DILI, 8 were slow acetylators, and the total exposure to isoniazid (AUC 0-24h ) inversely correlated with the days until onset of hepatotoxicity in those patients (R = -0.84, p = 0.002). Six out of ten patients with DILI received a single dose of isoniazid for phenotyping, five of whom appeared to be slow acetylators. These slow acetylators were restarted at a lower dose of isoniazid. The phenotyping strategy led to a shorter total treatment duration compared to current guidelines for DILI. However, we also propose an even more optimized strategy, in which fewer than 14 days of therapy are ultimately missed, which could further reduce the total treatment duration by more than a month. Conclusion In tuberculosis patients with DILI, assessment of isoniazid acetylator status can guide rapid reintroduction of isoniazid. Combined with AUC 0-24h measurement through TDM, this approach supports appropriate dosing and may help shorten total treatment duration.