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J Basic Clin Physiol Pharmacol 2021; 32(4): 421–427

Denny Ardhianto, Suharjono*, Soedarsono and Umi Fatmawati

Analysis of the side effect of QTc interval


prolongation in the bedaquiline regimen in drug
resistant tuberculosis patients
https://doi.org/10.1515/jbcpp-2020-0415 prolongation occurred in most patients and also the onset
Received November 27, 2020; accepted February 23, 2021 was mostly one month after using BDQ regimen. The side
effects of QTc interval prolongation from groups of com-
Abstract bination and risk factors were no difference in each month
(p>0.05).
Objectives: Indonesia is one of the top 20 countries with
Conclusions: This study can be concluded that there were
the highest prevalence of drug resistant tuberculosis (DR-
no differences in the QTc prolongation between the groups
TB) worldwide with a percentage of new cases of 2.4% and
of BDQ regimen (BDQ, BDQ + LFX, BDQ + CFZ and
retreatment of 13%. Bedaquiline (BDQ) is one of the drugs
BDQ + LFX + CFZ) and the groups of risk factors.
that used in the individual long regimen treating DR-TB.
BDQ is also combined with levofloxacin (LFX) and/or clo- Keywords: bedaquiline; dr-tb; qt interval.
fazimine (CFZ) that can cause QTc interval prolongation.
The aim was to study the differences in the use of BDQ
regimens to the lengthening of the QTc interval and to
study risk factors (diabetes, hypokalemia, sex, BMI, and
Introduction
age) in BDQ regimen.
Along with the increasing rate of TB case detection in
Methods: This study was an observational retrospective
Indonesia, it is necessary to pay attention to the emergence
study with a total sampling method, which was conducted
of DR-TB cases among TB cases due to noncompliance to
at Dr. Soetomo General Hospital Surabaya. Samples from
medication and transmission from DR-TB patients. DR-TB
this study were patients diagnosed with DR-TB at Dr.
treatment aims to cure patients and reduce the trans-
Soetomo General Hospital Surabaya in the period of
mission of M. tuberculosis [1]. However, there are still ob-
January 2015–December 2019 who used BDQ regimen and
stacles to achieve this goal. This can be due to patient
met the inclusion criteria. The ECG data were analyzed
noncompliance in treatment, one of which is due to side
from the mean of each group (BDQ regimen and risk fac-
effects of drugs experienced by the patient. Every year
tors), also analyzed using statistical analysis.
there was an increase in the number of patients who
Results: Data obtained from total sample in this study
dropped out of treatment at Dr. Soetomo General Hospital
were 73 patients. The most widely used different regimens
Surabaya with a total number of 35 patients from January to
in this study were the combination of BDQ + LFX by 36
September 2018.
patients (49.3%), BDQ + LFX + CFZ by 16 patients (21.9%),
The treatment management of DR-TB is divided into two
BDQ by 11 patients (15.1%) and BDQ + CFZ 10 patients
types, namely short-term therapy (9–11 months) and long-
(13.7%). Out of 73 patients, 52 patients (71.2%) experienced
term therapy using an individual regimen (20–24 months).
lengthening of the QT interval and grade 1 of QTc interval
Patients who are intolerant and do not meet the criteria for
short-term therapy and are diagnosed with pre-extensively
drug resistant tuberculosis (pre XDR-TB) or extensively drug
resistant tuberculosis (XDR-TB) should apply long-term
*Corresponding author: Suharjono, Department of Clinical Pharmacy, therapy. Pre XDR-TB refers to TB that resistant to rifampicin
Faculty of Pharmacy, Universitas Airlangga, Surabaya, Indonesia, and isoniazid with one of the fluoroquinolones or one of the
Phone: +62 812 1733 877, E-mail: suharjono@ff.unair.ac.id second-line injectable drugs. XDR-TB involves resistance to
Denny Ardhianto, Department of Clinical Pharmacy, Faculty of rifampicin and isoniazid with one of the fluoroquinolones
Pharmacy, Universitas Airlangga, Surabaya, Indonesia
and one of the second-line injection drugs. The drugs used
Soedarsono, Department of Pulmonology and Respiratory Medicine,
Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
in individual therapy regimens are at least five effective
Umi Fatmawati, Department of Pharmacy, Dr. Soetomo General drugs. As a new drug, BDQ should be included in such
Hospital, Surabaya, Indonesia regimens plus four other drugs based on the sensitivity of
422 Ardhianto et al.: QTc interval prolongation in bedaquiline regimen

each patient. The BDQ regimen used is generally combined used, laboratory examinations, and ECG examinations. The exclusion
with the drug class of fluoroquinolone and CFZ. criteria for this study were patients with a history of prolonged QTc
interval, patients who ever received moxifloxacin, delamanid, terfe-
One risk of Bedaquiline relates to the heart. It may
nadine, digoxin, amiodarone, or azole antifungals, new patients who
cause an increase in incidence of prolonged QTc interval on used BDQ for less than 6 months, the patients died or dropped out
the electrocardiogram [2, 3]. The drug in the class of fluo- during BDQ use and patients with a history of DCFC, atrial fibrillation,
roquinolone that is often used as a combination is LFX. CFZ acute coronary syndrome diagnosis.
and LFX used in combination also have a side effect of Descriptive analyzes for the prevalence of severity, incidence of
prolonged QTc interval, mean prolonged QTc interval, time of occur-
prolonged QTc interval. In TB treatment there are risk
rence of prolonged QTc interval and risk factors (age, sex, BMI, DM and
factors that can increase the potential for prolonged QTc
hypokalemia) were presented in table. Analysis of differences in the
interval such as age, sex, BMI, diabetes mellitus, electro- use of BDQ, BDQ + LFX combination, BDQ + CFZ combination and
lyte imbalance, especially low potassium levels which can BDQ + LFX + CFZ combination and BMI risk factor for the side effects of
also be caused by side effects of the OAT used [4]. prolonged QTc interval will use the one-way ANOVA statistical test if
An electrocardiogram (ECG) describes the phases of the data are normally distributed. If the data are not normally
distributed, the difference analysis will use the Kruskal-Wallis statis-
the atrial and ventricular action potentials. The QTc inter-
tical test. Then the risk factors for hypokalemia, sex, DM and age were
val can be measured as the interval from the start of the analyzed using the independent T sample test.
QRS complex to the end of the T wave when it returns to
baseline. The QTc interval represents the electrical ven-
tricular system and is a combined measure of cardiac de-
polarization and repolarization. QTc values are considered Results
normal for men when they are in the range between 350
and 450 ms and for women when they are between 360 and There were 155 patients who received the BDQ regimen
470 ms [3]. An increase in the QTc interval above 500 ms while 73 patients met the inclusion criteria. A total of 73
will lead to two to three times of the possibility of the DR-TB patients who were treated as outpatients at the
incidence of torsade de pointes, a polymorphic type of MDR-TB Polyclinic of Dr. Soetomo General Hospital, Sur-
heart rhythm disorder that is fatal to the patient, where the abaya and received the BDQ regimen were assigned into
heart may stop suddenly. Therefore, WHO recommends several diagnoses including MDR-TB 48 (65.7%), pre-XDR
caution when administering these drugs and recommends TB 24 (32.8%), and XDR-TB 1 (1.3%). The patients’ de-
to put strict monitoring procedures in place [5]. Dr. Soe- mographic data consisting of sex, age, and patient risk
tomo General Hospital is one of the referral hospitals factors were analyzed, and the results are listed in Table 1.
located in East Java Province that has MDR-TB Polyclinic. Based on the severity of the incidence of prolonged
Drugs for DR-TB therapy include BDQ, LFX and CFZ. This QTc interval mostly occurred in grade 1 in each month as
study aims to analyze the effect of differences in the use of presented in Table 2. Severity divided into three levels,
BDQ regimens (BDQ, BDQ + LFX, BDQ + CFZ, and grade 1 for normal QTc value – 480 ms, grade 2 for 481–
BDQ + LFX + CFZ) and risk factors (DM, hypokalemia, sex, 500 ms, grade 3 for above 500 ms. Furthermore, the onset
BMI, age) on prolonged QTc interval. of prolonged QTc interval was mostly found in the first

Table : Patient demographic.


Materials and methods
Characteristics Total Percentage
This research has been accepted through an ethical process and has DR-TB type MDR TB  .
been approved by the Ethics Committee of Dr. Soetomo General Hos- Pre-XDR TB  .
pital, Surabaya as stated in a letter number 1803/KEPK/I/2020. This XDR TB  .
was an observational study with a cross sectional study design. Risk factor Sex Female  .
Retrospective data collection was carried out by observing the data on Male  .
the medical records of DR-TB patients at MDR-TB Polyclinic, Dr. Soe- Age Elderly (>)  
tomo General Hospital, Surabaya. The samples of the study were pa- Adult (–)  .
tients with a diagnosis of DR-TB according to the inclusion criteria and BMI Severe underweight (<)  .
underwent treatment at MDR-TB Polyclinic of Dr. Soetomo General Underweight (–.)  .
Hospital, Surabaya from January 2015 to December 2019. Normal (.–.)  .
The inclusion criteria for this study were DR-TB patients who Overweight (–.)  .
received the BDQ regimen from January 2015 to December 2019 at the DM  .
MDR TB Polyclinic of Dr. Soetomo General Hospital, Surabaya, and Hypokalemia  .
had a complete medical records which included patient profiles, drugs
Ardhianto et al.: QTc interval prolongation in bedaquiline regimen 423

month. Thus it can be said that prolonged QTc interval was other anti-TB drugs and a combination of BDQ LFX CFZ
mostly occurred in the first month after the patient received plus other anti-TB drugs.
the BDQ regimen. In the first month, prolonged QTc inter- The use of BDQ dosage in the first two weeks was
val was mostly found at grade 1 so that according to the 400 mg every day, and the following week until the 25th
management of side effects by USAID and KNCV, moni- week used 200 mg, three times a week. The dose of LFX
toring for electrolyte levels and electrolyte correction was administered is 750 mg daily. The dosage of CFZ adminis-
necessary so that QTc may not get worse [6]. tered was 100 –300 mg every day depending on body
Based on the results of this study, the onset of QTc weight for two months, after which the dosage was reduced
interval side effects showed the highest percentage in the to 100 mg per day. All drugs used were oral tablet of 100 mg
first month. Then based on the data on the level of severity, of BDQ tablets, 250 mg of LFX tablets and 100 mg of CFZ
grade 1 data was mostly found. Thus, it was indicated that tablets. The BDQ regimen that was most widely used in this
the percentage of the incidence of QTc interval side effects study was the BDQ + LFX combination for 36 patients
was mostly found under 480 ms. (49.3%).
One of the regimens used for DR-TB patients is the BDQ The patient’s ECG data that had been taken were then
regimen. The BDQ regimen administered in this study was statistically tested using one-way ANOVA for 6 months in
BDQ plus other anti-TB drugs, a combination of BDQ LFX each month (M1, M3, M4, and M5). The M2 and M6 data
plus other anti-TB drugs, a combination of BDQ CFZ plus were not normally distributed, so the Kruskal-Wallis test
was performed. Based on the statistical results presented in
Table 3, it can be concluded that there was no difference in
Table : QTc interval prolongation side effect.
the QTc interval for each regimen (p>0.05).
Statistical tests on risk factors for diabetes, hypokale-
QTc interval prolongation side effect Total, n Percentage, % mia, sex, and age did not show any differences (p>0.05).
Meanwhile, the BMI showed a difference in the third month
QTc interval prolongation occurred  .
Severity (p<0.05), but there was no difference in the other months.
M (Month ) The results of the analysis of differences for BDQ regimens
Grade   . and risk factors are shown in Table 3.
Grade   .
Grade   .
M (Month )
Grade   
Discussion
Grade   
Grade    Sampling was conducted in March 2020 at Dr. Soetomo
M (Month ) General Hospital, Surabaya, and obtained 155 DR-TB pa-
Grade   . tients who used the BDQ regimen, but only 73 people met
Grade   .
the inclusion criteria of this study and made as samples.
Grade   .
M (Month ) The BDQ regimen was only administered when patients
Grade   . previously received short-term therapy were not tolerant of
Grade   . more severe side effects such as prolonged QTc interval. QT
Grade   . interval can be affected by heart rate, so it is necessary to
M (Month )
use a formula to synchronize the QT interval with heart rate
Grade   
Grade   
[7]. In this study, the data taken were QTc interval corrected
Grade    using Bazett’s formula if the heart rate was normal and
M (Month ) Framingham if the heart rate was abnormal. Routine ECG
Grade   . examination was carried out every month at MDR-TB
Grade   . Polyclinic of Dr. Soetomo General Hospital.
Grade   .
The mechanism of prolonged QTc interval triggered by
Onset
M  . administration of drugs occurs due to blockade of voltage-
M  . gated potassium channels, especially the fast component
M  . of the delayed rectifier potassium current (IKr) released by
M  . hERG (the human ether-a-go-go-related gene) which re-
M  .
sults in the accumulation of potassium in myocytes which
M  .
may lead to delayed cardiac repolarization [8, 9].
424 Ardhianto et al.: QTc interval prolongation in bedaquiline regimen

Table : Statistical analysis to BDQ regimen and risk factors. group. This could increase the risk of prolonged QTc in-
terval due to synergistic drug interactions [10]. Hypergly-
Group Prolongation QTc mean, Month p- cemic condition will lead to overproduction of reactive
mean, ms ms Value
oxygen species resulting in reduced activity in the IKr ion
Regimen channels [11, 12].
M .
Hypokalemia is a risk factor for prolonged QTc interval
BDQ . ±. . ±. M .
through a mechanism to reduce IKr activity or so called a
BDQ + LFX . ±. . ±. M .
BDQ + CFZ . ±. . ±. M . hERG channel with excessive inactivation and block of
BDQ + LFX + CFZ . ±. . ±. M . sodium channels [13–15]. The highest mean prolonged QTc
M . interval in the hypokalemia group was 19.8 ± 15.6 ms
DM compared to the non hypokalemia group. The highest
M .
mean QTc was found in the hypokalemia group, namely
M .
DM . ± . . ± . M . 447.1 ± 13.4 ms compared to the non hypokalemia group.
Non DM . ± . . ± . M . The number who experienced prolongation was greater in
M . the hypokalemia group as many as 16 patients (88.9%)
M . compared to the non hypokalemia group of 37 patients
Hypokalemia
(66.1%). This suggested that the risk factor of hypokalemia
M .
could increase the QTc interval.
M .
Hypokalemia . ± . . ± . M . The presence of comorbidities such as diabetes mel-
Non hypokalemia . ± . . ± . M . litus was more prevalent among male respondents of 27
M . patients (65.9%) compared to female respondents of 15
M . patients (46.9%) wherein sex was a risk factor for pro-
Sex
longed QTc interval. Another risk factor was the presence
M .
M . of hypokalemia. It was found more in the male group of 10
Male . ± . . ± . M . patients (24.4%) compared to the female group of seven
Female . ± . . ± . M . patients (21.9%). However, based on the mean QTc in-
M . terval, the highest value was found among women of
M .
445.9 ± 20.3 ms while for men it was 438.1 ± 20.2 ms. This
BMI
is due estrogen hormone which can prolong the QTc in-
M .
Severe . ± . . ± . M . terval through a suppression mechanism on the rapid
underweight (IKr), slow (IKs), and inward rectifier (IK1) ion channels so
Underweight . ± . . ± . M . as to extend the action potential and consequently pro-
Normal . ± . . ± . M . long the QTc interval [16]. In addition to this, male pa-
Overweight . ± . . ± . M .
tients have a greater tendency to have smoke habits than
M .
Age female patients. One study stated that smoking increased
M . the risk of prolonged QTc interval and there was a sig-
M . nificant difference in QTc interval between before smok-
Elderly . ± . . ± . M . ing and after smoking [17]. One of the components of
Adult . ± . . ± . M .
cigarettes is nicotine, which is known as an inhibitor of
M .
non specific potassium ion channels, so that the potas-
M .
sium ion rate is inhibited and causes prolongation of the
QTc interval [18, 19]. In the male group, the mean age was
50.5 years, while in the female group the mean age was
The mean QTc interval in the group without diabetes 46.3 years. Older patients have the potential to experience
mellitus was slightly longer than the group with diabetes a decrease in several body functions such as excretion, so
mellitus. This could be possible because there were more that the drugs or metabolites that should be excreted are
female patients in the non-DM group by 17 (54.8%), still remain in the body and cause more potential side
whereas there were 15 female patients (35.7%) in the DM effects [20].
group. In addition, in the non-DM group, the number of Increasing BMI will increase the risk of prolonged QTc
patients who were administered a combination of three interval. This could be due to reduced ventricular repolari-
drugs, namely BDQ + LFX + CFZ, was more than the DM zation [21]. The incidence of prolonged QTc interval among
Ardhianto et al.: QTc interval prolongation in bedaquiline regimen 425

DR-TB patients at Dr. Soetomo General Hospital was mostly In this study, the highest mean prolonged QTc interval
found in the overweight group, namely 27.6 ± 22.9 ms. The in the BDQ group was 26.5 ± 21.6 ms, comorbids such as
highest mean QTc interval was also found in the overweight diabetes mellitus could increase the effect of prolonged
group, namely 447.6 ± 25.9 ms. In the overweight BMI group, QTc interval. There were seven patients with diabetes
all patients had risk factors for diabetes mellitus (100%), mellitus in the BDQ group (63.6% of patients in the BDQ
while risk factors for hypokalemia found in two patients group). In addition to the comorbid factor of diabetes
(20%). BDQ and CFZ are lipophilic drugs which are stored in mellitus, four patients (36.3%) in the BDQ group had a
fatty tissue [22]. In general, fat-soluble drugs can pass higher risk of hypokalemia than the other groups.
through cell membranes faster than water-soluble drugs Furthermore, the mean prolonged QTc interval in the
[23]. The drug, which accumulates in the fatty tissue, passes BDQ + LFX + CFZ group was the highest, followed by the
out of the tissue slowly so that it circulates in the blood- BDQ + CFZ and BDQ + LFX group. A study stated that the
stream for several days even after a person stops taking the addition of OAT CFZ significantly increased the incidence
drug [24]. Therefore, in the overweight group who had a of a side effect of prolonged QTc interval [27]. The highest
higher lipid concentration and took the drug, the maximum mean QTc interval for the BDQ + LFX + CFZ combination
QTc would take longer to appear. The buildup of concen- group was 446.2 ± 24.4. This is consistent with previous
tration when the drug from the fat is released and the new study which stated that the addition of a drug that had a
drug is introduced will further increase the risk of prolonged side effect of prolonged QTc interval would provide a
QTc interval. This was presented in the results of this study greater prolongation effect [28].
where the highest number of QTc above 500 ms was found Based on the data of this study, there was a fluctuation
among three patients (30%). After statistical test using one- in the average QTc interval on ECG examination every
way ANOVA was conducted, it was found that there was a month that can be seen in Figure 1. There were patients who
difference at the third month. After that, further test was experienced an increase in the QTc interval in M2 then did
carried out using post hoc and it was found that there were not experience a prolongation in the following month, after
differences in the data of the severe underweight, under- that there was an increase in the QTc interval in the
weight, and overweight groups (p<0.05). Based on the mean following month. This can be caused by the factor of po-
QTc interval in the third month, there was an increase in the tassium levels in these patients. When the QTc interval was
QTc interval with the highest increased in the overweight prolonged, the patient’s potassium level was lower
group. Thus, it can be said that a concomitant increase in (2.8 mmol/l) than before (3.8 mmol/l). Besides, the patient
BMI had the potential to prolong the patient’s QTc interval. also had hyperglycemia or an increase in blood sugar levels
There was no difference in normal group since the mean in during the month when the QTc interval was prolonged
this group was less than the underweight group. This can be (blood sugar of 228 mg/dl). The incidence of prolonged QTc
due to the smaller number of female respondents (35.9%) interval decreased as the blood sugar levels decreased from
compared to other groups. Besides, it could also be caused a previously high levels (blood sugar of 138 mg/dl).
by less number of patients who experienced hypokalemia
(17.9%). BDQ Regimen
The elderly are more at risk of experiencing prolonged
470
QTc interval with a mean prolongation of 21.39 ± 12.49 ms,
460
while in the adult age group it was 19.5 ± 16.3 ms. There was
a higher mean QTc interval in the elderly, namely 450
QTc interval (ms)

447.4 ± 23.3 ms, while in adults it was 441.4 ± 20.3 ms. 440

According to a previous study, the older you are, the higher 430
the risk of having a prolonged QTc interval [25]. Age affects 420
the function of the autonomic nerves, namely increasing
410
sympathetic nerve activity and decreasing para-
400
sympathetic activity which can change the pattern of
repolarization in the heart [26]. The highest number of 390
M M1 M2 M3 M4 M5 M6
prolonged QTc interval was found in the elderly group,
BDQ BDQ+LFX BDQ+CFZ BDQ+LFX+CFZ
namely 10 patients (90.9%), followed by adults of 42
patients (67.7%). Likewise, QTc above 500 ms was mostly Figure 1: QTc interval mean of BDQ regimen every month, M,
found in the elderly group of three patients (27.3%), and baseline; M1, first month; M2, second month; M3, third month; M4,
among adults of 14 patients (23.3%). fourth month; M5: fifth month; M6: sixth month.
426 Ardhianto et al.: QTc interval prolongation in bedaquiline regimen

This study had several limitations, namely the small 5. WHO. The use of bedaquiline in the treatment of multidrug-
number of samples taken which were not in balance with resistant tuberculosis Interim policy guidance. Geneva: World
Health Organization; 2013:30 p.
other groups and could not describe the incidence of side
6. USAIDKNCV. Guide for QTc monitoring and management of drug-
effects throughout Indonesian society. Then, the data resistant TB patients with QT-Prolonging Agents, vol 7. Amerika:
taken for this study were only during the use of BDQ for six KNCV Tuberculosis Foundation; 2018.
months due to the use of BDQ in individual DR-TB therapy 7. Luo S, Michler K, Johnston P, Macfarlane PW. A comparison of
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Dr. Soetomo General Hospital director, SMF Pulmonology Neurosci 2000;3:429–30.
15. Kallergis EM, Goudis CA, Simantirakis EN, Kochiadakis GE,
and Respiration Medicine and Tahir Professorship for their
Vardas PE. Mechanisms, risk factors, and management of
technical and administrative support to conduct this
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Research funding: None declared. 16. Sedlak T, Shufelt C, Iribarren C, Merz CN. Sex hormones and the
Author contributions: All authors have accepted QT interval: a review. J Womens Health (Larchmt). 2012;21:
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17. Akbarzadeh MA, Yazdani S, Ghaidari ME, Asadpour-Piranfar M,
approved its submission.
Bahrololoumi-Bafruee N, GolabchiA, et al. Acute effects of
Competing interests: Authors state no conflict of interest. smoking on QT dispersion in healthy males. ARYA Atheroscler
Informed consent: Not applicable. 2014;10:89–93.
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stress and endothelial dysfunction: say NO to cigarette smoking!
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