Bedaquiline Correlation to QT Interval Prolongation in DR-TB Patients

Introduction: Drug-Resistant Tuberculosis (DR-TB) requires adequate treatment. Bedaquiline is a priority medicine in the treatment regimen of DR-TB. One of the adverse events is QT interval prolongation, which can increase the risk of torsade de pointes (TdP) and lead to death. DR-TB patient screening before starting the treatment and monitoring QT interval during the treatment should be performed. This study aimed to determine Bedaquiline correlation to QT interval prolongation in DR-TB patients. Methods: This was a retrospective study using an observational design by viewing medical records of DR-TB patients who underwent treatment from January 2019 to March 2022. Results : This study involved 46 DR-TB patients with a regimen of Bedaquiline. The comparison of Baseline QT intervals before and after one month of therapy showed QT interval prolongation (457.1 ± 18.2 ms and 443.8 ± 10.2 ms; p < 0.001). The comparison of QT intervals before the therapy and six months after the therapy showed prolongation QT intervals (443.8 ± 10.2 ms and 458.4 ± 23.7 ms; p < 0.001). QT intervals after one month of therapy compared to six months after the therapy showed insignificant slight prolongation (457.1 ± 18.2 ms and 458.4 ± 23.7 ms; p = 0.587).. Conclusion: QT interval prolongation occurred in DR-TB patients who received treatment using Bedaquiline regimen. It was seen significantly between baseline QT interval compared to after receiving the therapy for one month and baseline QT interval compared to after receiving the therapy for six months.


INTRODUCTION
Bedaquiline is a drug which has been approved to use as a treatment for Drug Resistance-Tuberculosis (DR-TB). In 2012, Food and Drug Administration (FDA) released information about the good potency of Bedaquiline and its safety profile. [1][2][3] Previous studies that compared DR-TB regimens with and without Bedaquiline revealed the fastest conversion of culture result in a regimen with Bedaquiline and an increased recovery rate, while a significant difference in side effects was not found in both groups. [4][5][6] Bedaquiline is the main drug in the DR-TB regimen, with the addition of four other drugs based on the patient's sensitivity. 7,8 One of the side effects of Bedaquiline on the heart is the increasing QT interval prolongation incidence that can be seen on an electrocardiogram (ECG). QT intervals refer to ventricular systole cardiac electricity and combine measurement of heart depolarization and repolarization. The ventricle cardiac potential action phase described by ECG as the QT interval is measured from the beginning of the QRS complex to the end of the T wave when it returns to the isoelectric line. The normal value for QT interval in males ranges from 350-450 millisecond (ms) and in females ranges between 360-460 ms, while the normal value for QT corrected (QTc) in males ranges from 350-450 ms and in females from 360-460 ms. Prolongation of QT intervals of more than 500 ms will increase the risk by two until three times for torsade de pointes (TdP). This polymorphic interference of cardiac rhythm can be fatal for patients that can cause cardiac arrest. 9,10 Bedaquiline will be bonded with the main energy source enzyme of Mycobacterium tuberculosis (MTB), thus it has a bactericide effect. Action mechanisms against the target reduce cross potential resistance to anti-tuberculosis drugs (ATD). Commonly Bedaquiline is well tolerated, only a few cases where the treatment should be stopped due to bad tolerance and safety issue. 9,11,12 Pontali,et al. performed Bedaquiline safety aspect analysis towards cardiac based on 23 studies about Bedaquiline with 1,266 patients analyzed. Bedaquiline was stopped in 44 patients (3.5%) due to side effects. Only 8 from 1,266 (0.6%) patients experienced QT interval prolongation and stopped consuming Bedaquiline. Two of them restarted the treatment after the resolution of an acute episode. 9 A study by Brust, et al. about cardiac safety in 195 DR-TB patients using Bedaquiline-based treatment revealed that the mean QT interval prolongation between baseline to six months of treatment was 22.7 ms. Four patients experienced QT interval prolongation of more than 500 ms, and 19 patients experienced prolongation of more than 60 ms. This study also revealed that age correlated with QT interval prolongation, therefore conscientious observation is needed in elderly patients. 13 Bedaquiline has high efficacy in DR-TB treatment but also has QT interval prolongation side effects, thus serial ECG observation is needed. This side effect became a consideration for us to undergo a study to analyze whether there is a correlation between Bedaquiline treatment with QT interval prolongation in DR-TB patients at our center.

METHODS
This was a retrospective study using an observational design performed in April 2022 to see the variance of QT intervals in DR-TB patients treated with a regimen of Bedaquiline for zero, one, and six months at Arifin Achmad General Hospital,

RESULTS
The total samples were 65 DR-TB patients treated with Bedaquiline in the short treatment regimen, including the longer treatment regimen, but only 46 patients met the inclusion criteria. The patient characteristics of this study can be seen in Table 1.
The patient characteristics of this study were males (58.7%) compared to females (41.3%) with a mean age of 41.4 ± 13.2 years old. The electrolyte level in all patients was within normal (natrium 141.8 The mean baseline QT interval in the age group of >45 years old was longer than the group of <45 years old, but the difference was not statistically significant (445.5 ± 11.5 and 442.3 ± 9.1; p = 0.099). The female group had a longer mean baseline QT interval value than the male group, but the difference was also not statistically significant (446.9 ± 10.8 and 441.5 ± 9.3; p = 0.867). Patients with QT interval prolongation had lower serum kalium levels before the treatment than patients with no QT interval prolongation (3.7 ± 0.5 mmol/L and 4.1 ± 0.4 mmol/L), but the difference was not statistically significant (p = 0.205).
This study revealed that patients with baseline QT interval prolongation had lower mean body weight than patients with no QT interval prolongation, but it was not statistically significant. In contrast, patients who experienced QT interval prolongation after one and six months of therapy with Bedaquiline had higher mean body weight than patients with no QT interval prolongation, but the difference was insignificant. Table 3 shows that in the female group, the baseline QT interval was longer than the male group (446.9 ± 10.8 ms and 441.5 ± 9.3 ms; p = 0.867). After one month and six months of therapy, the female group also showed longer QT interval prolongation than the male group. The mean QT interval prolongation in the female group after one and six months of therapy compared to the baseline was 17.1 ms and 19.7 ms, while in the male group, the mean QT interval prolongation was 10.7 ms and 11.2 ms. These differences were not statistically significant.
In the male group, the mean QT interval after one month of therapy was longer than the baseline. This difference was statistically significant (p = 0.008).
In this study, there were prolongations found after six months of therapy compared to the baseline with a pvalue < 0.001. The prolongation of the mean QT interval after six months of therapy was longer than after one month of therapy, but this difference was not   Table 4 shows that the mean QT interval in patients who received regimen BDQ-LFX-CFZ was longer than in patients who received regimen BDQ-CFZ at baseline, after one month, and six months of therapy, although these differences were not statistically significant (p>0.05). Table 5 shows the mean QT interval prolongation with Bedaquiline regimen after one month and six months of therapy compared to the baseline (13.3 ms and 14.6 ms). The mean QT interval after six months of therapy was longer than after one month of therapy, but the difference was not statistically significant (p = 0.587).

(67.4%) patients with DR-TB experienced QT interval prolongation after receiving treatment with
Bedaquiline regimen. This study revealed QT interval of patients with Bedaquiline regimen after one month and six months of therapy had prolonged than baseline QT interval with a prolongation of as much as 13.3 ms and 14.6 ms (p < 0.001). These results were similar to a study by Isralls, et al., which involved 420 patients who showed that the mean baseline QT interval was 406.4 ms and prolonged to 430.5 ms (IQR= 414.4-445.1) after three months of therapy and 434.0 ms (IQR= 419.0-447.9) after six months of therapy. A study by Katrak, et al. aimed to see the QT interval value of patients at baseline after 2 weeks, 4 weeks, 8 weeks, 12 weeks, and 24 weeks of therapy. The QT interval prolongation happened on week 2 and 4, with a peak of prolongation on day 57. 14 QT interval prolongation occurred due to cellular mechanism IKr component blockage. IKr blockading will cause prolongation of ventricular action potential duration, thus natrium will enter the cell profusely and decline potassium level. Excess of positive ion causes prolongation of repolarization phase; thus, QT interval will be prolonged. M2 level influences QT interval prolongation. 15 Patients in the age group of >45 years old showed longer QT interval values at baseline, after one month, and six months of therapy than the age group of <45 years old. This is because QT interval biological base will be prolonged due to the difference between potassium flew in cardiac, which is the main determining repolarization phase of the cardiac action potential. 16 This study showed that the QT interval after one month of therapy was longer than after six months of therapy in the age group of >45 years old. This is influenced by Bedaquiline doses given; thereafter, the QT interval value changed. A higher dose was given in the first two weeks of the treatment, which was 400mg once a day, and continued with 200mg three times a day for 22 weeks. This will cause alternating QT intervals due to Bedaquiline M2 level being declined. A higher dose will cause the prolongation of QT interval to become longer. 17 This study revealed that patients with prolonged QT intervals had a lower potassium level than patients who did not have QT interval prolongation (3.7 ± 0.5 mmol/L and 4.1 ± 0.4 mmol/L), but it was not statistically significant. Hypokalemia can cause QT interval prolongation, therefore examining potassium levels is needed to eliminate the risk factor for QT interval prolongation occurring in patients who receive Bedaquiline regimen. 18 The renal function of the patients in this study was within normal limit. The mean serum creatinine level in this study was 0.7 ± 0.1 mg/dL, with a mean glomerular filtration rate of 113.6 ± 14.4 ml/min/1.73 m 2 . Renal malfunction can cause QT interval prolongation and increase mortality. The patient characteristics in this study showed that all serum creatinine levels were normal, thus it can reduce the bias of this study. This study showed that patients with prolonged QT intervals had a mean body weight of 48.2 kg, while patients with no prolonged QT interval had a mean body weight of 50.4 kg. The difference between this group was not statistically significant. Light body weight can cause QT interval prolongation to occur due to the disturbance of the potassium channel, therefore repolarization phase of cardiac potential action becomes prolonged. 19 This study found that female has a risk factor to experienced QT interval prolongation compared to male. The female group had longer baseline QT intervals than the male group, but it was not statistically significant (446.9 ± 10.8 ms and 441.5 ± 9.3 ms; p = 0.867). After one month and six months of therapy, the female group's QT interval value was longer than the male group. QT interval value in the female group was prolonged as much as 17.3 ms between baseline and after one month of therapy, which was statistically significant. Prolonged QT interval also occurred after one month and six months of therapy, which was 19.7 ms. This result was statistically significant. QT intervals after one month of therapy in the male group were prolonged as much as 10.7 ms from baseline. This difference was statistically significant. Prolonged QT interval occurred after receiving six months of therapy with a mean prolongation value of 11.2 ms. It was also statistically significant. Comparison between QT intervals after one and six months of therapy in this group showed no significant difference.
Patients with the BDQ-LFX-CFZ regimen showed longer QT intervals than the BDQ-CFZ regimen. The former group experienced QT interval prolongation of as much as 13.3 ms after one month of therapy and 14.6 ms after six months of therapy. The latter group experienced QT interval prolongation of as much as 12.4 ms after one month of therapy and only 2.3 ms after six months of therapy. Other ATDs known to cause QTc prolongations are Fluoroquinolone and Clofazimine. Administration of drugs which have a risk to cause QT interval prolongation simultaneously can increase the risk of prolonged QT intervals to occur. 9 A study by Udwadia, et al. showed the result of QT interval prolongation of as much as 49 ms in patients who received Bedaquiline and Clofazimine, but none of these patients had symptoms and needed to stop the therapy. 20 Another study by Guglielmetti, et

CONCLUSION
Bedaquiline caused QT interval prolongation. In this study, 13.3 ms QT interval prolongation occurred after receiving therapy for one month, and 4.6 ms prolongation occurred after six months of therapy. This QT interval prolongation was statistically significant.