Abstract:

Objective To explore the effect of bedaquiline-containing regimen on QT interval in patients with multidrug-resistant tuberculosis (MDR-TB), with the purpose to provide evidence for clinical safe use and monitoring of the drug. Methods One hundred and twenty eligible patients were enrolled from Feb.2018 to Oct.2019 according to the inclusion and exclusion criteria in Beijing Chest Hospital, provided with bedaquline-containing treatment regimen. The QTcF values of electrocardiograph (ECG) were monitored and recorded at baseline before treatment and then serial follow-up ECG were done at the end of week 2,4,8,12,16,20,24 after treatment initiation. Thereafter once per 12 week for 1 year after bedaquiline duration was completed. Firstly, t-test, ANOVA test and Mann-Whitney U test were applied to analyze the distribution of baseline QTcF values among groups with age, gender, body mass index and drug resistance type. Secondly, independent sample t-test was used to compare the QTcF values at different time points during the treatment with that at baseline. Finally, multi-variate logistic regression analysis was performed to analyze the risk factors associated with QT interval prolongation. Results The mean value of QTcF of 120 patients at baseline was (404.90±19.27) ms. During exposure of bedaquiline-containing regimen, QTcF prolongation from baseline value ≥60 ms occurred in 23 cases (19.2%) while QTcF ≥500 ms occurred in 10 patients (8.3%). The mean value of QTcF increased gradually with the increase of bedaquiline administration duration and hit the peak at the end of week 20, and the QTcF monitored at each time point before it presented significant difference compared with that at baseline: at the end of week 2,QTcF was (413.51±22.69) ms (t=4.064, P=0.000);at the end of week 4,QTcF was (413.38±17.81) ms (t=4.022, P=0.000);at the end of week 8,QTcF was (414.78±23.71) ms (t=3.796, P=0.000);at the end of week 12,QTcF was (416.23±25.06) ms (t=3.752, P=0.000);at the end of week 16,QTcF was (419.23±29.18) ms (t=4.584, P=0.000);at the end of week 20,QTcF was (425.45±30.84) ms (t=5.865, P=0.000). Within the 6 months after bedaquiline duration was completed, the mean QTcF was (419.10±31.38) ms and (419.60±27.74) ms at the end of week 36 and 48 respectively with statistically significant differences compared with that at baseline (at the end of week 36, t=3.698, P=0.000; at the end of week 48, t=2.790, P=0.007). However, within the 6-12 months after bedaquiline duration was completed, there was no significant difference at the end of week 60 and 72 respectively compared with that at baseline (at the end of week 60, QTcF was (409.70±19.60) ms (t=0.759, P=0.453);at the end of week 72,QTcF was (412.77±15.96) ms (t=2.051, P=0.051)). No serious ventricular arrhythmia was found in all patients during the above observation period. Multivariate analysis showed that the risk of QT interval prolongation was 4.473 times (95%CI: 1.614-12.401) higher in patients with age no less than 45 years compared with that between 18-<45 years. Conclusion The occurrence of QT interval prolongation caused by bedaquiline-containing regimen is relatively high. Moreover, the QTcF values of MDR-TB patients increased with the increase of bedaquiline exposure. However, the QTcF values returned to the baseline level around 6 months after completion of bedaquiline administration. Multivariate analysis indicated that age ≥45 is the risk factor for occurrence of QT interval prolongation. The effect of QT prolongation during treatment did not lead to severe ventricular arrhythmia.

Key words: Tuberculosis, pulmonary, Tuberculosis, multidrug-resistant, Drug therapy, Electrocardiograph, Drug toxicity, Bedaquiline