BACKGROUND
The 2022 WHO guidelines on multi-drug/rifampicin resistant tuberculosis (MDR/RR-TB) recommend six months of bedaquiline (Bdq) in the all-oral 9-month shorter regimen and six 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 six months. We examine the frequency and incidence of QT prolongation based on duration of Bdq and/or Dlm use in longer regimens.
METHODS
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 2015-30 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.
RESULTS
Among 2,553 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 six-month periods.
CONCLUSION
We demonstrate that Bdq and/or Dlm use beyond six months is safe in longer MDR/RR-TB regimens with most clinically relevant QT prolongation events occurring in the first six months. ECG monitoring for early identification of QT prolongating events is possible in programmatic conditions.
Quantification of recurrence risk following successful treatment is crucial to evaluating regimens for multidrug- or rifampicin-resistant (MDR/RR) tuberculosis (TB). However, such analyses are complicated when some patients die or become lost during post-treatment-follow-up.
METHODS
We analyzed data on 1,991 patients who successfully completed a longer MDR/RR-TB regimen containing bedaquiline and/or delamanid between 2015 and 2018 in 16 countries. Using five approaches for handling post-treatment deaths, we estimated the six-month post-treatment TB recurrence risk overall, and by HIV status. We used inverse-probability-weighting to account for patients with missing follow-up and investigated the impact of potential bias from excluding these patients without applying inverse-probability weights.
RESULTS
The estimated TB recurrence risk was 7.4 per 1000 (95% confidence interval (CI): 3.5,12.9) when deaths were handled as non-recurrences, and 7.6 per 1000 (95% CI: 3.6,13.1) when deaths were censored and inverse-probability weights were applied to account for the excluded deaths. The estimated risk of composite recurrence outcomes were 25.5 (95% CI: 15.4,38.1), 11.7 (95% CI: 6.5,18.3), and 8.6 (95% CI: 4.2,14.6) per 1000 for recurrence or 1) any death, 2) death with unknown or TB-related cause, 3) TB-related death, respectively. Corresponding relative risks for HIV status varied in direction and magnitude. Exclusion of patients with missing follow-up without inverse-probability-weighting had a small impact on estimates.
CONCLUSIONS
The estimated six-month TB recurrence risk was low, and the association with HIV status was inconclusive due to few recurrence events. Estimation of post-treatment recurrence will be enhanced by explicit assumptions about deaths and appropriate adjustment for missing follow-up data.
Effectiveness of bedaquiline use beyond six months in patients with multidrug-resistant tuberculosis
Current recommendations for the treatment of rifampin- and multidrug-resistant tuberculosis include bedaquiline used for six months or longer. Evidence is needed to inform the optimal duration of bedaquiline.
OBJECTIVES
We emulated a target trial to estimate the effect of three bedaquiline duration treatment strategies (6 months, 7-11 months, ≥ 12 months) on the probability of successful treatment among patients receiving a longer individualized regimen for multidrug-resistant tuberculosis.
METHODS
To estimate the probability of successful treatment, we implemented a three-step approach comprising cloning, censoring, and inverse-probability weighting.
MAIN RESULTS
The 1,468 eligible individuals received a median of four (IQR: 4-5) likely effective drugs. In 87.1% and 77.7%, this included linezolid and clofazimine, respectively. The adjusted probability of successful treatment (95% CI) was 0.85 (0.81, 0.88) for 6 months of BDQ, 0.77 (0.73, 0.81) for 7-11 months, and 0.86 (0.83, 0.88) for > 12 months. Compared with 6 months of bedaquiline, the ratio of treatment success (95% CI) was 0.91 (0.85, 0.96) for 7-11 months and 1.01 (0.96, 1.06) for > 12 months. Analyses that did not account for immortal time bias found a higher probability of successful treatment with > 12 months: ratio 1.09 (1.05, 1.14).
CONCLUSIONS
Bedaquiline use beyond six months did not increase the probability of successful treatment among patients receiving longer regimens that commonly included new and repurposed drugs. When not properly accounted for, immortal person-time can bias estimate of effects of treatment duration. Future analyses should explore the effect of duration of bedaquiline and other drugs in subgroups with advanced disease and/or receiving less potent regimens.