Hepatotoxicity of Different Doses of Rifapentine in Patients Receiving 4-month Regimen for Drug-sensitive Tuberculosis: Findings From a Multicenter Randomized Controlled Study

Abstract Introduction: Potential hepatotoxicity, particularly significant hyperbilirubinemia, is a major challenge to promoting the rifapentine-based 4-month regimen (2HPMZ/2PMZ) for drug-sensitive tuberculosis. A more detailed description of hepatotoxicity profiles during the application of the 2HPMZ/2PMZ regimen is necessary to investigate a liver-friendly dosage range of rifapentine. Methods: The ORIENT study, a multicenter, open-label, phase II/III randomized controlled trial in China, was launched to evaluate the efficacy and safety of 2HPMZ/2PMZ regimen and search for the optimal dose of rifapentine. Participants were recruited and randomly assigned into the control arm using standardized six-month regimen (2HRZE/4HR) and three investigational arms of 2HPMZ/2PMZ with rifapentine at different dose levels (10 mg/kg, 15 mg/kg, and 20 mg/kg). Liver function tests were conducted at baseline and at weeks 1, 2, 3, 4, 6, 8, 12, 17, 21, and 26 after the initiation of treatment. We analyzed the liver function monitoring data among patients who received at least one dose of medication. All liver function parameters were converted to upper limit of normal (ULN) for analysis. Pearson's Chi-square (χ2) test, Fisher's exact test, or the Kruskal-Wallis test for comparisons was properly applied in statistics analysis, with Bonferroni correction used for pairwise comparison. Results: As of October 31, 2024, a total of 392 participants were included in the analysis. Elevations in ALT and ALP, as well as the median peak values of ALT and ALP, showed no statistic differences across the groups. The median peak total bilirubin (TBIL) levels increased sequentially in the rifapentine 10mg/kg, 15mg/kg and 20mg/kg groups, and were significantly higher than the control group (P<0.001). The frequency of TBIL elevation in the rifapentine 20mg/kg group was significantly higher than 10mg/kg arm (80.0% vs 53.6%, P<0.001) and control arm (80.0% vs 19.2%, P<0.001), while with no difference to 15mg/kg arm (80.0% vs 72.3%, P=1.000). Among patients with elevated TBIL, the median time to TBIL elevation was within two weeks in three rifapentine groups, significantly shorter than the control group (P=0.002). Hyperbilirubinemia was principally driven by direct bilirubin (DBIL) elevation, especially in three investigational arms. There was no statistical difference in drug-induced liver injury between groups, primarily manifesting as hepatocellular pattern (77.3%, 17/22). No patients experienced liver failure. Conclusions: The usage of daily, high-dose rifapentine in the 2HPMZ/2PMZ regimen led to significant, dose-dependent isolated hyperbilirubinemia, primarily characterized by DBIL elevation in the early stage of treatment.