The Frequency and Incidence of QT Prolongation With Extended Use of Bedaquiline or Delamanid in a Large, Multi-Country Multidrug-Resistant/Rifampicin-Resistant Tuberculosis Cohort.

Abstract

The 2022 World Health Organization (WHO) guidelines on multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) recommend 6 months of bedaquiline (Bdq) in the all-oral 9-month shorter regimen and 6 months or longer for Bdq and delamanid (Dlm) in the 18-20-month longer regimen. However, lack of evidence on extended treatment using Bdq or Dlm has limited their use to 6 months. We examine the frequency and incidence of QT prolongation based on duration of Bdq and/or Dlm use in longer regimens. We analyzed a prospective cohort of MDR/RR-TB patients from 16 countries who initiated treatment with Bdq and/or Dlm containing regimens from 1 April 2015 to 30 September 2018. Data were systematically collected using a shared protocol. The outcome of interest was the first clinically relevant prolonged QT interval (grade 3 or above) or a serious adverse event (SAE) involving prolonged QT of any grade. Among 2553 patients, 59% received >6 months of Bdq and/or Dlm. Of these, 579 (20.9%) patients experienced a prolonged QT event, the majority (95.5%) being grade 1 or 2. Sixty-four (2.5%) patients experienced the outcome of interest with only 12 (0.5%) having ≥1 QT prolonging drugs permanently suspended. The incidence rate of the first prolonged QT event was highest in the first six months of treatment and lower in subsequent 6-month periods. We demonstrate that Bdq and/or Dlm use beyond 6 months is safe in longer MDR/RR-TB regimens with most clinically relevant QT prolongation events occurring in the first 6 months. Electrocardiogram (ECG) monitoring for early identification of QT prolongating events is possible in programmatic conditions.