Reintroduction of anti-tuberculosis therapy following drug-induced liver injury: a randomised controlled trial

Following the occurrence of anti-TB drug-induced liver injury (DILI), there are currently two reintroduction regimens that are recommended with no consensus as regards which regimen is more beneficial. Both regimens are accepted as standard of care in the NHS and globally. Based on weak evidence, one regimen may be associated with a lower DILI recurrence frequency but entails a longer total duration of treatment (9 months vs 6 months). The Research Aim is to compare the relative safety and effectiveness, including cost, of the two different drug reintroduction regimens in adults with TB following an episode of anti-TB DILI. Objectives 1. To determine if reintroduction of a non-pyrazinamide (Z)-containing regimen results in a lower DILI recurrence rate compared to a Z-containing regimen in adults who have experienced an episode of DILI when being treated for active TB. 2. To determine the cost-effectiveness of reintroducing a non-Z-containing versus Z-containing regimen. 3. To determine a) the frequency and b) quality of life impacts of DILI episodes in adults being treated for latent TB infection. This is a pragmatic multi-centre open randomised superiority trial with economic analysis. The target population comprises adults treated within the NHS for active TB with standard 4-drug anti-TB therapy (ATT) who have experienced an episode of DILI requiring these drugs to be stopped. Participants (n=350) will be randomly assigned by concealed individual allocation (1:1) to reintroduction of either (A) Intervention arm - Sequential full-dose non-Z-containing 3-drug ATT (comprising EHR), as recommended by the American Thoracic Society TB Guideline or (B) Control arm - Sequential full-dose Z-containing 4-drug ATT (comprising EHRZ), as recommended by the NICE TB Guideline. Participant follow up will be to 12 months post-randomisation. The primary outcome is DILI recurrence within 12 months of randomisation. Secondary outcomes include a) severity of DILI, b) physician-rated clinical cure, c) total number of days on ATT, d) adverse event rate, e) ATT adherence rate, f) mortality, g) QoL using the EQ-5D tool, and healthcare resource use. Health economic analysis will take the NHS perspective, considering patient health impacts (measured in QALYs) and healthcare resource costs, following methods recommended by NICE.This is essential for an informed understanding of the trial results; the 3-drug ATT regimen may benefit from a lower DILI recurrence rate but at the cost of a longer duration of treatment, incurring increased NHS costs and potentially having a lower treatment completion rate, with associated health detriment. An observational cohort study of adults treated for latent TB infection (LTBI) who experience a DILI event will be conducted alongside the clinical trial. Reintroduction of treatment will be at the discretion of attending clinicians. Follow up will be to the end of treatment. Primary outcome: DILI recurrence at the end of treatment.