Assessing hepatotoxicity in novel and standard short regimens for rifampicin-resistant tuberculosis: Insights from the TB-TRUST and TB-TRUST-plus trials

Objectives Efforts to shorten rifampicin-resistant tuberculosis (RR-TB) treatment have led to concerns about hepatotoxicity in shorter regimens. We evaluated hepatotoxicity in two novel regimens against the standard shorter regimen recommended by the World Health Organization (WHO). Methods Participants from the TB-TRUST and TB-TRUST plus trials were assigned to the WHO shorter regimen, a levofloxacin (Lfx)-based regimen, or a bedaquiline (Bdq)-based regimen. Liver function was tested bi-weekly in the first month, then monthly until treatment ended. Eligibility required receiving at least one drug dose and undergoing at least two liver function tests. Results Of 429 patients, hepatotoxicity was most prevalent in the WHO shorter group (26.7% of 169), compared to 4.7% in the Lfx group (172 patients), and 5.7% in the Bdq group (88 patients). The median peak alanine aminotransferase levels were 1.67 × upper limit of normal (ULN) for WHO, 0.82 × ULN for Lfx, and 0.88 × ULN for Bdq groups. The incidence of drug-induced liver injury was significantly higher in the WHO group (18.3%) than in the Lfx (3.5%) and Bdq (4.6%) groups. The time to significant alanine aminotransferase elevation was about 2.8 months, with no differences between groups. Conclusions Two novel regimens demonstrated lower hepatotoxicity compared to the WHO's shorter regimen. Entire course management monitoring is recommended in RR-TB treatment.