|Year : 2022 | Volume
| Issue : 4 | Page : 349-355
Scoping review: QT interval prolongation in regimen containing bedaquiline and delamanid in patients with drug-resistant tuberculosis
Oki Nugraha Putra1, Yulistiani Yulistiani2, Soedarsono Soedarsono3
1 Doctoral Program of Pharmacy, Faculty of Pharmacy, Airlangga University; Study Program of Pharmacy, Faculty of Medicine, Hang Tuah University, Surabaya, Indonesia
2 Faculty of Pharmacy, Airlangga University, Surabaya, Indonesia
3 Faculty of Medicine, Hang Tuah University; Department of Pulmonology and Respiratory Medicine, Dr. Soetomo Hospital, Surabaya, Indonesia
|Date of Submission||10-Jul-2022|
|Date of Decision||17-Sep-2022|
|Date of Acceptance||29-Oct-2022|
|Date of Web Publication||10-Dec-2022|
Dr. Ir. H. Soekarno, Surabaya, East Java
Source of Support: None, Conflict of Interest: None
Background: A regimen containing bedaquiline–delamanid is recommended in management of drug-resistant tuberculosis (DR TB) to increase a success rate. However, this regimen was rare in a clinical setting due to a potential risk of QT prolongation. Several studies have reported the incidence of QT prolongation after administration of this regimen, but the results are inconsistent due to different sample size, study design, and covariate. The aim of this review is to summarize and analyze the published articles related to QT prolongation of bedaquiline and delamanid in PubMed and ScienceDirect databases using a scoping review. Methods: This scoping review was conducted under PRISMA for scoping review. The outcomes of this review were incidence of QT prolongation and death. We found 8 articles to be included in this review. Results: The incidence of QT prolongation was higher for DR TB patients who received a regimen containing bedaquiline and delamanid. However, this review found no clinical symptoms, such as cardiac arrhythmias, torsade de pointes, or even death. DR TB patients, especially the elderly, were at risk for QT prolongation. Special consideration in patients with HIV and low level of potassium should be closely monitored for QT interval. Conclusion: The regular measurement of electrocardiography was highly recommended to evaluate QT interval. Generally, the use of individualized regimen containing bedaquiline and delamanid is relatively safe in DR TB patients.
Keywords: Bedaquiline, delamanid, drug-resistant tuberculosis, QT prolongation
|How to cite this article:|
Putra ON, Yulistiani Y, Soedarsono S. Scoping review: QT interval prolongation in regimen containing bedaquiline and delamanid in patients with drug-resistant tuberculosis. Int J Mycobacteriol 2022;11:349-55
|How to cite this URL:|
Putra ON, Yulistiani Y, Soedarsono S. Scoping review: QT interval prolongation in regimen containing bedaquiline and delamanid in patients with drug-resistant tuberculosis. Int J Mycobacteriol [serial online] 2022 [cited 2023 Jan 30];11:349-55. Available from: https://www.ijmyco.org/text.asp?2022/11/4/349/363166
| Introduction|| |
Drug-resistant tuberculosis (DR TB) is characterized by resistance to rifampicin or isoniazid with or without resistance to other antituberculosis drugs. Indonesia is among the ten largest countries worldwide with TB, TB/HIV, and DR TB burdens. The estimated DR TB cases in Indonesia are 2.4% of all new TB patients and 13% of TB patients who have been treated, with a total incidence of TB RO cases of 24,000 or 8.8/100,000 population. A recent study by Indarti et al. reported that the success rate in DR TB patients receiving bedaquiline and short-term regimen was 52.9% and 35.4%, respectively. It indicates that the main problem in DR TB treatment is a high failure and a low cure rate.
According to the WHO recommendations in 2020, treatment for DR TB currently uses a combination without injection drugs (kanamycin or capreomycin), and replaced by bedaquiline for shorter and longer regimen. Shorter regimen is intended for patients who have never received second-line antitubercular drugs for more than a month, have no resistance to shorter regimen, not severe TB or extrapulmonary TB, and not pregnant. Longer or individual regimen is indicated for preextended drug resistant (pre-XDR TB), and XDR TB, failed in shorter regimen, returned after treatment discontinuation, and relapsed DR TB patients.
The individual regimen consists of three drugs from class A and two drugs from class B. If the number from both groups is insufficient to complete five drugs due to contraindications or adverse effects, one or more drugs can be added from group C to complete the regimen. Bedaquiline is strongly recommended to be given together with optimized background therapy to treat DR TB to increase sputum conversion and reduce the risk of death. Bedaquiline has high bactericidal activity, sterilization effect, and resistance prevention, however, mutation in atpE and Rv0678 genes are associated with bedaquiline resistance among DR TB patients. A cohort study conducted in several countries reported that DR TB patients who received a bedaquiline-based regimen had a success rate of 74.2%. Bedaquiline requires optimized background regimens to achieve success rates and prevent resistance, one of which is the addition of delamanid. Delamanid is one from class C drugs and belongs to the nitroimidazole group, with a nitro group on its side chain. Like bedaquiline, it has high bactericidal activity, good sterilization effect, and resistance prevention in cases of DR TB.
Delamanid has a different mechanism from bedaquiline, and regimen containing bedaquiline–delamanid is recommended to prevent acquired resistance and expected to reduce the resistance level, thereby increasing the cure rate. A recent study by Chesov et al. stated that at the beginning before treatment, all TB isolates were sensitive to bedaquiline. However, 15.3% of patients were resistant to bedaquiline during treatment, and 3.8% were reinfected with bedaquiline-resistant strains. A lower level of resistance to delamanid was reported by von Groote-Bidlingmaier et al., who stated that delamanid resistance was 0.39% before and 1.17% during therapy. Delamanid is active against both replicating and dormant TB bacteria. They become dormant through decreased metabolism in hypoxic conditions, one of the factors for resistance. Hypoxia in TB is caused by decreased oxygen supply in the pulmonary alveoli by type I alveolar cells mediated by hypoxia-inducible factor-1α. A recent in vitro study by Chen et al. stated that delamanid could reduce more than 50% of the bacterial load in actively replicating TB bacteria and control more than 80% of mycobacteria growth.
One of the factors that cause low sputum conversion and cure rate in DR TB patients is antitubercular drug resistance and type of DR TB. A recent study by Maretbayeva et al. stated that in DR TB patients who did not experience sputum culture conversion in the 6th month, 80% of them were XDR TB cases and had lung cavities. Therefore, the administration of delamanid is expected to suppress both active and dormant TB bacteria, thereby increasing the sputum conversion. if there is no contraindication or resistance to bedaquiline and/or delamanid, they are administered for 6 months in individual regimens. A study by Das et al., in India, stated that pre-XDR TB and XDR TB patients who received the bedaquiline–delamanid regimen together with standardized regimens, 81.2% of them experienced sputum conversion at 2122 weeks compared to those without delamanid. In addition to effectiveness, drug safety is an important aspect that needs to be concerned in DR TB patients. Bedaquiline and delamanid are reported to have side effects, one of them is QT prolongation. The QT interval on the surface electrocardiography (ECG) represents the summation of the myocyte ventricular action potentials.
A recent study by Dooley et al. reported that there were no cases of grade 3 and 4 QT prolongation in group receiving bedaquiline, delamanid, and both. In addition, the mean change in the QT interval from the initial value was 12.3 ms; 8.6 ms; and 20.7 ms in the group receiving bedaquiline, delamanid, and their combination at week 24, respectively. Another study by Olayanju et al. reported that of forty DR TB patients who received a combination of bedaquiline–delamanid together with other standard regimens, the number of patients who experienced at least one QT prolongation >450 ms was 19.5% in delamanid and 44.1% in bedaquiline–delamanid-based regimen (P < 0.001). The incidence of QT prolongation was observed more frequently at doses of 200 mg/day compared to 100 mg/day. However, the severity was classified as mild to moderate and not associated with syncope and arrhythmias. Patients with hypoalbuminemia (<2.8 g/dl), hypokalemia, and the elderly are risk factors for QT prolongation with delamanid. QT prolongation is associated with the main metabolite of bedaquiline and delamanid, M2, and DM-6705, respectively.
Although several studies have reported QT prolongation with a regimen containing bedaquiline–delamanid in DR TB patients, these studies have major differences in sample size, method and study design, presence of covariates or risk factors, and treatment. Other factors also contribute to the incidence of QT prolongation, and the results from the previous study cannot be directly interpreted in DR TB patients. Based on this background, a scoping review was carried out on several studies reporting QT interval prolongation using bedaquiline–delamanid in DR TB patients.
| Methods|| |
Search strategy and study selection
This review is a scoping review using the PRISMA extension for scoping review guidelines. We used secondary data from articles published from 2016 up to September 2022 in PubMed and ScienceDirect databases. The literature search keywords were “drug-resistant tuberculosis” (DR TB), “pre-XDR TB,” “XDR-TB,” “MDR-TB,” “bedaquiline,” “delamanid,” “cardiac safety,” “adverse events,” “QTc,” and “QT prolongation.” Boolean operators with “OR,” “AND,” and “NOT” are used to combine these keywords to search articles more specific.
The inclusion criteria for compiling this review were as follows: (a) articles written in English; (b) articles as original articles with randomized controlled trial (RCT), cohort, cross-sectional, or case–control study designs; (c) containing a regimen of bedaquiline–delamanid; (d) reporting QT interval; and (e) DR TB patients aged >18 years. The exclusion criteria were as follows: (a) the article was not in full text and (b) the article was written as a review, case report, or letter to the editor. Articles in full text that meet the inclusion criteria will be summarized, extracted, and analyzed. A significant of QT prolongation was defined when QT interval >500 ms or mean change >60 from baseline with clinical symptoms.
Each study that meets the inclusion criteria will be collected, extracted, and summarized including the author's name, year of publication, study design, sample size, type of DR TB, and summary of research findings. The results of the scoping review are presented as a descriptive or narrative synthesis due to the relatively heterogeneous study. Scoping review aimed to summarize several clinical evidence and identify the characteristics of the study, therefore we did not conduct a quality assessment of the included studies as in systematic review.
| Results|| |
In a total of 150 articles were identified using specific keywords. From this, 40 articles with duplicate records were removed. Of 110 articles remained, 75 of them were excluded due to irrelevant title and abstract, review/opinion/editorial, and case report or case series. Furthermore, from 35 eligible articles, 27 of them were excluded because QT prolongation was not reported after concomitant use of bedaquiline and delamanid. Finally, only 8 articles were included for scoping review reporting QT prolongation in a regimen containing bedaquiline and delamanid in DR TB. The PRISMA flowchart for article inclusion is shown in [Figure 1].
A total of 8 studies met the inclusion criteria and were included in this present review involving 1.174 DR TB patients. The characteristic of the included studies is summarized in [Table 1]. All of the included studies in this scoping review, two were experimental and six were observational studies.
| Discussion|| |
This present review has summarized and evaluated the available published literature analyzing the cardiac safety of regimen containing bedaquiline–delamanid in DR TB. Several studies have reported the efficacy of a regimen containing bedaquiline–delamanid in DR TB patients to increase the success rate of sputum conversion.,, However, the use of these regimens in clinical practice is rare. This cannot be separated from the safety issue, QT prolongation. QT interval is time for heart to repolarize after the depolarization process. The duration of QT interval is directly proportional to the heart rate. The faster the heart rate, the sooner the heart repolarizes, and the QT interval becomes shorter. On the other hand, when heart rate is slow, the need for rapid repolarization decreases and the QT interval will prolong. Therefore, it is known to calculate the QTc interval or the corrected QT interval, whose value is constant regardless of the heart rate. Prolonged and abnormal QT intervals increase the risk of potentially life-threatening ventricular arrhythmias, known as torsade de pointes (TdP). The normal value of QTc is 0.38-0.42 s or should not exceed 500 ms.
Evidence showed that the QT prolongation correlates with the plasma concentration of bedaquiline and delamanid and their main metabolite, M2 and DM-6705, respectively. Delamanid showed a dose–response relationship with an increase in QT from day 1 to day 56 with a mean change of 12 ms at a dose of 100 mg twice daily and 15 ms at a dose of 200 mg twice daily. However, there was no QT prolongation accompanied by syncope or clinically significant signs of arrhythmia, and TdP. Delamanid showed a nonlinear pharmacokinetic profile and its metabolite will be converted into several metabolites and their concentrations will rise to steady-state level for 6-10 weeks.
As reported by Kim et al., Dooley et al., and Olayanju et al., in this review, we found that DR-TB patients who received regimen containing delamanid were more likely to have an increase in QT from baseline compared to those without delamanid although not statistically different. It may be explained by the decreased effect of the metabolites of both drugs on potassium channel receptors. Metabolites of each drug were found responsible for drug-associated QT prolongation. The final drug effect model includes competitive interactions between M2 and DM-6705, which act on the same cardiac receptors and thereby reduce the potency of each other by 28% for M2 and 33% for DM-6705, resulting from the combined effect is not greater but close to “additivity” in the analyzed concentration range. Metabolites M2 and DM-6705 act on human ether-a-go-go-related gene (hERG) receptor by binding and blocking the hERG potassium channel) with different affinities. Therefore, each metabolite reduces the other metabolite's potency. Furthermore, a recent study by Tanneau et al. reported that concomitant administration of delamanid with bedaquiline did not alter the pharmacokinetic profile of either delamanid or its metabolite, DM-6705. It indicates that bedaquiline does not increase the exposure effect of DM-6705. Thus, concurrent use of bedaquiline with delamanid does not increase the effect of QT prolongation.
According to the Ministry of Health of Indonesia Republic for DR TB, for individual regimen, bedaquiline was given at a dose of 400 mg for the first 2 weeks and then 200 mg thrice weekly for 22 weeks. Meanwhile, delamanid was given 2 × 100 mg daily for 24 weeks. Several studies reported the use of bedaquiline and delamanid, either sequentially or concurrently.,, Delamanid is available at a dose of 50 mg per tablet. The recommended daily dose of delamanid is 100 mg twice daily. The study by Mallikaarjun et al. reported that delamanid given at a dose of 100 mg twice a day and 200 mg once a day gave a cumulative fraction of response above 90%. Furthermore, a dose of 200 mg once daily had a smaller effect on QT prolongation than a dose of 100 mg twice daily. A dose of 200 mg once daily would be more advantageous for DR TB patients, given the complexity of the regimen, and therefore could improve patient compliance.
As reported by Kim et al., two patients discontinued bedaquiline/delamanid due to QT prolongation >500 ms. One patient used bedaquiline/delamanid sequentially and received clofazimine, while the rest received concomitantly and used clarithromycin, which potentially caused QT prolongation. A study by Polgreen et al. reported that the use of clarithromycin was significantly associated with atrial fibrillation with an adjusted odd ratio (aOR) of 1.70, P = 0.0011. Therefore, the selection of antibiotics in DR TB patients for other infectious diseases must consider the safety aspect that does not potentially cause QT prolongation. A study by Dooley et al. reported that although the mean QTc changes were greatest in group receiving bedaquiline and delamanid, there were no patients with QT prolongation level 3 (QTc >500 ms) or level 4 (life-threatening conditions, such as TdP). However, this study did not include DR TB patients taking clofazimine. As we know, clofazimine is used in individual regimens and is one of the class B drugs, together with cycloserine.
A recent study by Darmayani et al. reported that of 105 DR TB patients receiving bedaquiline in two hospitals in Indonesia, 37.1% of patients had clinically significant QT prolongation and 15.2% of them temporarily discontinued bedaquiline therapy. The mean difference in QT interval was greatest in the 3rd month after the administration of bedaquiline. Furthermore, only one patient received bedaquiline and delamanid concomitantly. However, this study did not analyze the QT prolongation that can also be caused by other DR TB therapies such as levofloxacin, moxifloxacin, clofazimine, and delamanid.
One of the drugs used in individual regimens is levofloxacin or moxifloxacin. Both drugs also have an impact on QT prolongation. However, a recent study conducted by Kusmiati et al. reported that there was no association between moxifloxacin concentrations and QT interval. It indicates that moxifloxacin is relatively safe for heart in DR TB patients. However, this study was conducted in DR TB patients on a short-term regimen in which moxifloxacin was administered for 9 months. Conversely, in individualized regimens, levofloxacin or moxifloxacin are administered for up to 20-24 months. Therefore, further studies are needed to clarify the relationship between moxifloxacin concentration and QT interval in DR TB patients with individual regimens.
Electrolyte balance, especially potassium, plays an important role in QT interval. Several studies have reported that hypokalemia is a risk factor for QT prolongation. The potassium level was significantly lower in QT prolongation compared to those with normal QTc (P < 0.001). A study by Li et al. reported that when the QT interval was prolonged in DR TB patients receiving bedaquiline, potassium levels decreased by 10.71%, while sodium levels increased by 1.07% from baseline. Furthermore, a lower level of potassium (3.7 ± 0.5 mmol/L) was found in DR TB patients with QT prolongation compared to those without (4.1 ± 0.4 mmol/L), although it was statistically not significant. Therefore, electrolyte measurement is highly recommended for early detection of QT prolongation.
Concomitant use of antiretroviral therapy with bedaquiline makes possible interaction. Lopinavir–ritonavir reduces the clearance of bedaquiline, leading to an approximately twofold increase in steady-state concentrations, but the clinical implications of this interaction remain unclear. The study by Brust et al. reported that DR TB patients receiving bedaquiline and lopinavir/ritonavir did not find significant QT prolongation compared to those who did not receive lopinavir/ritonavir. It is because lopinavir–ritonavir has minimal effect on plasma concentrations of the metabolite bedaquiline, M2, which is responsible for QT prolongation. This is confirmed by Isralls et al., who reported that lopinavir/ritonavir had no association with QT interval >500 ms (P = 0.53, aOR: 0.79, 95% confidence interval [CI]: 0.371.68).
Interestingly, a study by Isralls et al. reported that other therapies used in DR patients, including levofloxacin, moxifloxacin, clofazimine, and delamanid, did not affect QT interval >500 ms (P > 0.05). Particular attention was paid to delamanid because only 12 out of 420 (2.85%) DR TB patients received delamanid, resulting in no statistically significant effect on the QT interval. Compared to delamanid with the highest incidence of patients with QT interval >500 ms of 33.3%, smaller number was shown in levofloxacin, moxifloxacin, and clofazimine; 26.3%, 14.3%, and 26.3%, respectively.
A study by Ferlazzo et al. reported that four patients had a QT prolongation of more than 60 ms from baseline. One patient received bedaquiline, delamanid, clofazimine, and moxifloxacin. The remaining three patients received bedaquiline, delamanid, and clofazimine. However, patients continued bedaquiline and delamanid and no cardiac arrhythmias were detected. However, the main limitations of this study were the relatively small number of samples and the absence of a comparison group, which make the results of this study must be interpreted with caution.
Another finding by Olayanju et al. showed that age was significantly associated with at least one QTc >450 ms, with HR 1.039. This finding was similar to the study by Brust et al. reported that age was significantly associated with QT interval >450 ms in DR TB patients receiving bedaquiline-based regimen. Age over 50 years was reported to be 8.3 times more likely to cause QT prolongation than age 2130 years. In addition, Primadana et al. have reported that DR TB patients with age more than 45 years, QT interval was longer at baseline, 1 month, and after 6 months compared to those <45 years. Aging processes may affect the molecular determinants of the QT interval or alter the myocardium with an increase in myocardial fibrosis. Aging is also associated with alterations in the amount of sympathetic and parasympathetic tone, which can alter myocardial repolarization and the duration of QT interval.
Regular ECG monitoring is highly recommended to detect any possible QT prolongation >500 ms as soon as possible. The study by van Beek et al., who performed modeling simulations between M2 level and QTc, reported that most patients with QTc >500 ms were identified at week 12. Monitoring therapy of QT interval until twelve weeks was required, particularly in concurrent use with clofazimine). In this review, although QT prolongation was found with bedaquiline and delamanid, it was not clinically significant in causing TdP or death. Although regimens containing bedaquiline and delamanid are effective to increase of success treatment, the safety aspect should take into account. All health-care team involved in treating DR TB patients must collaborate to ensure their safety and effectiveness.
| Conclusion|| |
The use of regimens containing bedaquiline and delamanid in individualized regimens for DR TB patients is relatively safe. Although more patients with QT prolongation were treated with bedaquiline and delamanid, there were no cardiac arrhythmias, TdP, or death cases. Regular ECG monitoring is highly recommended, especially in those with risk factors for QT prolongation.
Limitation of study
This review's limitation is the limited number of articles that meet the inclusion criteria. In addition, two studies did not include a comparison group and not each study reported any treatment other than bedaquiline and delamanid used in DR TB patients.
Since the present study was a scoping review, ethical approval was not applicable.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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