Skip to main content

Main menu

  • Home
  • Current issue
  • Early View
  • Archive
  • Authors/reviewers
    • Instructions for authors
    • Submit a manuscript
    • COVID-19 submission information
    • Institutional open access agreements
    • Peer reviewer login
  • Alerts
  • Subscriptions
  • ERS Publications
    • European Respiratory Journal
    • ERJ Open Research
    • European Respiratory Review
    • Breathe
    • ERS Books
    • ERS publications home

User menu

  • Log in
  • Subscribe
  • Contact Us
  • My Cart

Search

  • Advanced search
  • ERS Publications
    • European Respiratory Journal
    • ERJ Open Research
    • European Respiratory Review
    • Breathe
    • ERS Books
    • ERS publications home

Login

European Respiratory Society

Advanced Search

  • Home
  • Current issue
  • Early View
  • Archive
  • Authors/reviewers
    • Instructions for authors
    • Submit a manuscript
    • COVID-19 submission information
    • Institutional open access agreements
    • Peer reviewer login
  • Alerts
  • Subscriptions

Safety of prolonged treatment with bedaquiline in programmatic conditions

Dzmitriy Zhurkin, Elmira Gurbanova, Jonathon R. Campbell, Dick Menzies, Svetlana Setkina, Hennadz Hurevich, Varvara Solodovnikova, Dzmitry Viatushka, Alan Altraja, Alena Skrahina
ERJ Open Research 2022 8: 00685-2021; DOI: 10.1183/23120541.00685-2021
Dzmitriy Zhurkin
1Republican Scientific and Practical Center of Pulmonology and Tuberculosis, Minsk, Belarus
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Elmira Gurbanova
2Lung Clinic, University of Tartu, Tartu, Estonia
3WHO Collaborating Centre on TB in Prisons, Baku, Azerbaijan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: elmiragurbanova@gmail.com
Jonathon R. Campbell
4Dept of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Canada
5McGill International TB Centre, Montreal, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Jonathon R. Campbell
Dick Menzies
4Dept of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Canada
5McGill International TB Centre, Montreal, Canada
6Montreal Chest Institute, Montreal, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Svetlana Setkina
7Center for Examinations and Tests in Health Service, Minsk, Belarus
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hennadz Hurevich
1Republican Scientific and Practical Center of Pulmonology and Tuberculosis, Minsk, Belarus
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Varvara Solodovnikova
1Republican Scientific and Practical Center of Pulmonology and Tuberculosis, Minsk, Belarus
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Dzmitry Viatushka
1Republican Scientific and Practical Center of Pulmonology and Tuberculosis, Minsk, Belarus
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alan Altraja
2Lung Clinic, University of Tartu, Tartu, Estonia
3WHO Collaborating Centre on TB in Prisons, Baku, Azerbaijan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Alan Altraja
Alena Skrahina
1Republican Scientific and Practical Center of Pulmonology and Tuberculosis, Minsk, Belarus
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

Abstract

Bedaquiline is now considered a first-line medicine for treatment of rifampicin-resistant tuberculosis (RR-TB). We evaluated the safety of treatment with bedaquiline for longer than 190 days in individuals with RR-TB under programmatic conditions.

In a prospective cohort study enrolling pulmonary RR-TB patients, we initiated bedaquiline-based treatment at a tertiary hospital in Belarus. We defined standard bedaquiline use as <190 days and prolonged as ≥190 days. We recorded adverse events (AEs) and classified their seriousness and relation to bedaquiline. Our primary outcome in regression analyses was the incidence of serious AEs occurring within 5 months of bedaquiline cessation. We used generalised estimating equations to estimate the adjusted incidence rate ratio (aIRR) of serious AEs between the prolonged and standard bedaquiline groups.

We enrolled 113 patients, 83 (73%) of whom received standard and 30 (27%) received prolonged treatment. A total of 2030 AEs occurred during treatment. Of these, 63 (3.1%) were serious AEs occurring within 5 months of bedaquiline cessation; QTcF prolongation was the most common bedaquiline-related serious AE. The incidence of serious AEs per 100 person-months was 5.4 (3.9 to 7.2) in the standard group and 4.4 (2.6 to 7.0) in the prolonged group. In adjusted analyses, serious AEs were no different (aIRR: 0.82, 95% CI 0.42–1.61) in the prolonged group. One patient in the standard bedaquiline group died of acute cardiopulmonary failure deemed possibly related to bedaquiline.

Prolonged use of bedaquiline under programmatic conditions appears safe. Clinicians should carefully monitor QTcF interval since its prolongation was commonly observed.

Abstract

This study demonstrated that prolonged use of bedaquiline under programmatic conditions appears to be safe. However, clinicians should carefully monitor QTcF interval throughout treatment with bedaquiline due to proven risk of QTcF prolongation. https://bit.ly/36UHHc3

Introduction

Tuberculosis (TB) remains a major global health problem that is further complicated by the emergence of antimicrobial resistance. TB strains resistant to key drugs, such as rifampicin-resistant (RR)-TB or multidrug-resistant (MDR)-TB, substantially reduce the probability of treatment success. Strains with added resistances to second-line drugs, such as extensively drug-resistant (XDR)-TB, further limit treatment options and probability of success. The most recent data suggest a global treatment success rate of 59% for RR/MDR-TB [1].

Bedaquiline is a drug with antituberculous bactericidal activity approved by the European Medicines Agency in 2013 for treatment of MDR-TB over a period of 24 weeks. It is now considered a first-line medicine for RR/MDR-TB treatment according to the World Health Organisation (WHO) [2, 3]. In 2020, the WHO allowed off-label prolonged use of bedaquiline, defined as longer than 24 weeks. This recommendation was based on analysis of data derived from the endTB observational study [4, 5]. Prolonged use of bedaquiline is frequently considered by clinicians owing to limited number of options available for treatment of patients with highly resistant TB. However, evidence of the safety of prolonged bedaquiline use under programmatic conditions is limited [6].

The primary objective of our study was to evaluate the safety of prolonged use of bedaquiline, defined as use for >190 days, under programmatic conditions. The secondary objective was to compare incidence of serious adverse events (AEs) and bedaquiline-related AEs experienced among individuals treated with standard and prolonged treatment with bedaquiline.

Material and methods

Study design and population

This was a prospective cohort study using data from a cohort event monitoring study combined with routine data of the programmatic management of drug-resistant TB, defined as all associated functions related to providing services in the country, based on the TB strategy to achieve the targets set for drug-resistant TB in the Global Plan to End TB [6, 7]. The study protocol was approved by the Ethics Committee at the Republican Scientific Practical Centre on Pulmonology and Phthisiatry (RSPCPP) of Belarus. All new and previously treated patients with bacteriologically confirmed pulmonary RR-TB initiating treatment with bedaquiline at RSPCPP, a tertiary care hospital, between March 2015 and June 2016 were consecutively included in the study. Successfully treated patients were followed-up for 24 months for possible recurrence of TB. Patients receiving delamanid concurrently with bedaquiline were excluded from this study.

Definitions

WHO definitions for drug resistance, patient registration groups and treatment outcomes from 2013 were used [8]. Patients with RR-TB, whose isolates were resistant to either a fluoroquinolone or to any of the second-line injectables, but not to both, were defined as having pre-XDR-TB. An adverse event was defined as any untoward medical occurrence that may present in a patient during treatment with TB drugs, but which does not necessarily have a causal relationship with this treatment [9]. A serious event was one which either led to death or a life-threatening experience, hospitalisation or prolongation of hospitalisation, persistent significant disability or a congenital anomaly/birth defect [10]. Severity of the event was classified as mild (grade 1), moderate (grade 2) and severe (grades 3 and 4) according to the Common Terminology Criteria for Adverse Events, version 5 [10, 11].

Study procedures

All bacteriological tests were performed at the Reference Laboratory of the National TB Centre in Minsk, Belarus, which was quality-assured by the Supranational Reference Laboratory in Milan, Italy [12]. Details of bacteriological tests are described in supplementary Appendix 1.

Treatment regimens were individually tailored according to the drug susceptibility profile and contained bedaquiline, linezolid and clofazimine, unless contraindicated. If confirmed susceptible, the regimens had one second-line injectable and/or a fluoroquinolone added to the regimen. Terizidone, pyrazinamide, imipenem-cilastatin with amoxicillin-clavulanate and/or ethionamide/protionamide were added to bring the total number of effective drugs (i.e., defined as drugs to which patient's isolates were not resistant to) in the treatment regimen to six.

The recommended standard duration of bedaquiline use is 24 weeks (168 days) [5]. However, this duration may vary owing to events, such as missed or cancelled clinic visits. Based on a histogram of the duration of bedaquiline use, we grouped the patients according to those who received bedaquiline for <190 days as receiving standard treatment with bedaquiline and those who received bedaquiline for ≥190 days as receiving prolonged treatment with bedaquiline (histogram presented in supplementary Appendix 2).

The decision to prolong treatment with bedaquiline was based on the following criteria: remaining sputum culture-positive after ≥3 months of treatment, but not meeting the criteria for treatment failure; fewer than four effective drugs remaining in the treatment regimen if bedaquiline was discontinued; and/or individual risk factors for poor outcomes, such as body mass index (BMI) <18.5 kg/m2, high pre-treatment sputum smear bacillary load defined semi-quantitatively as 2+ or 3+, HIV-positivity and extensive/advanced pulmonary disease [13]. Injectables were continued throughout the treatment, if tolerated. The overall treatment duration was at least 12 months after the culture conversion for a minimum total treatment duration of 18 months.

Treatment efficacy and safety monitoring was implemented through bacteriological, clinical and laboratory assessment. All assessments were performed at the start of treatment and monitored at least monthly during the treatment and semi-annually post treatment for 24 months (supplementary table S1). AEs were recorded and considered potentially bedaquiline treatment-related if they occurred either during treatment or up to 5 months after bedaquiline was stopped, in view of the prolonged terminal elimination half-life of bedaquiline [14].

The Belarussian national electronic TB registry and national pharmacovigilance electronic database were used for data collection. Pharmacovigilance specialists checked the contents of the data for completeness and accuracy and judged on the severity of all reported AE, as well as performed causality assessment for serious AE.

Data analysis

We compared individuals who received standard treatment with bedaquiline with those who received prolonged treatment. We described each group based on demographic, clinical and treatment-related factors and calculated the number and incidence of all AEs, serious AEs and bedaquiline-related events for each group. We compared groups using two-sided tests: Kruskal–Wallis test for medians, Pearson's chi square test for proportions and Fisher exact test for rates. Uncertainty in incidence rates was calculated using exact Poisson confidence intervals. We calculated the proportion of patients experiencing QTcF >500 ms or an increase by >60 ms from baseline during treatment with bedaquiline.

We then conducted regression analyses to compare patients who completed standard treatment with those who received prolonged treatment. We did this to minimise possible survivor bias from patients who died early in treatment or those who stopped bedaquiline due to a bedaquiline-related AE and therefore never had the opportunity to receive prolonged treatment. We used generalised estimating equations with a Poisson distribution and log-link to estimate incidence rate ratios and their 95% confidence intervals (using robust standard errors). The analyses accounted for clustering at the individual level and used an autoregressive correlation structure. The primary outcome was the incidence of serious AEs occurring within 5 months of bedaquiline cessation, and the secondary outcome was the incidence of serious AEs occurring during receipt of bedaquiline up to day 189.

To construct multivariate models, we first performed univariate analysis on various predictors of our outcomes. The predictors were selected a priori, based on the literature, as well as on what we perceived would be known by the treating clinicians [15]. The predictors included: sex (male or female), age (per 10-year increase), use of second-line injectable drugs (yes or no), number of concomitant TB medications (per additional drug), smear-positivity at treatment initiation (yes or no), cavitation on chest radiograph at treatment start (yes or no), BMI (<18.5 or ≥18.5 kg·m−2), QT interval corrected by the Fridericia's correction formula (QTcF) (per 10-ms increase), alcohol abuse disorder (defined as alcohol use leading to problems in relationships, health, employment or finances within the past year; yes or no), diabetes mellitus (yes or no) and HIV co-infection (yes or no). Multivariate models were constructed including group allocation (i.e., standard versus prolonged), age, sex and all predictors with p<0.2 in univariate analysis. We also conducted a sensitivity analysis that included all predictors in multivariate models to see if conclusions might differ.

We conducted a secondary analysis in the prolonged bedaquiline group. We compared the incidence of serious AEs in the first 189 days of treatment versus the incidence of serious AEs from day 190 up to 5 months after stopping bedaquiline.

We did a post hoc analysis to compare the time to first instance of QTcF prolongation by >60 ms between the standard and prolonged treatment groups among those who had both baseline and at least one QTcF measurement during the treatment. We considered the last QTcF measure as a censoring event. We used Cox proportional hazards model adjusted for the variables considered in our previous multivariate model to estimate the hazard ratio and 95% confidence interval for the incidence of QTcF prolongation by >60 ms between the groups.

All analyses were conducted with R software (version 4.0.0; The R Foundation, Vienna, Austria) using package geepack (version 1.3-1).

Results

Sociodemographic data and disease characteristics

A total of 120 RR-TB patients were treated at the RSPCPP during March 2015 through June 2016. Out of them, seven were excluded from the cohort: five because no bedaquiline was used and two because of getting delamanid in addition to bedaquiline. A total of 113 patients with pulmonary RR-TB were subjected to the analyses. Of these, 83 (73.5%) received standard treatment with bedaquiline and 30 (26.5%) received prolonged treatment. The proportion of patients who were smear-positive (p<0.01) at the start of treatment was higher among the patients who received prolonged treatment (table 1). Other characteristics did not significantly differ between the treatment groups.

View this table:
  • View inline
  • View popup
TABLE 1

Characteristics of patients on standard or prolonged treatment with bedaquiline

Treatment

Characteristics of the treatment regimen and outcomes are reported in table 2. The number of effective drugs included in the initial regimen was six in both groups. The median total treatment duration was 24.2 months among those who received prolonged treatment with bedaquiline and 23.7 months among those who received standard treatment (p<0.01). The median (IQR) duration of bedaquiline use among those receiving prolonged bedaquiline was 8.0 (7.3–9.2) months. The duration of receiving second-line injectables was also significantly longer among those receiving prolonged bedaquiline (median 13.8 months versus 5.3 months; p=0.02). Treatment success was equivalent between groups (92.8% among standard duration versus 96.7% among prolonged duration; p=0.92). There was no recurrent TB among successfully treated patients during the follow-up period of 24 months.

View this table:
  • View inline
  • View popup
TABLE 2

Regimen received and treatment outcomes among patients on standard and prolonged treatment with bedaquiline

Safety profile

Any adverse event

The most common AEs observed among patients were elevated liver enzymes, eosinophilia, ECG abnormalities including prolongation of the QTcF, electrolyte disorders, hyperuricaemia, hyperglycaemia, and elevated creatinine and alkaline phosphatase. Details of the AEs recorded during the treatment are presented in table 3, while the complete list of events and their classification as per system organ class and category is presented in supplementary Appendix 3.

View this table:
  • View inline
  • View popup
TABLE 3

All adverse events registered during the treatment course among patients on standard and prolonged treatment with bedaquiline

More than 90% of patients in both groups experienced at least one AE during treatment with a total of 2030 events registered. There was no statistically significant difference in total incidence of any AE during treatment among patients who received the prolonged treatment with bedaquiline compared to those who received standard treatment (80.9 versus 80.1 per 100 person-months of treatment; p=0.83). However, when comparing those AEs that occurred within 5 months of cessation of bedaquiline, significantly more events occurred in the standard bedaquiline group than in the prolonged group (128.0 versus 114.2 per 100 person-months of treatment, respectively; p=0.04). The cumulative incidence of any AE appeared similar between the groups during treatment (figure 1a).

FIGURE 1
  • Download figure
  • Open in new tab
  • Download powerpoint
FIGURE 1

Cumulative rates of a) any and b) serious adverse events during treatment, stratified by the duration of bedaquiline (Bdq) exposure.

The incidence of any bedaquiline-related AE within 5 months of stopping bedaquiline was significantly higher among patients who received standard treatment versus those who received prolonged treatment with bedaquiline (3.0 versus 1.0 per 100 person-months, respectively; p=0.01). QTcF prolongation was the most common bedaquiline-related AE in both groups. This accounted for 72% of events in the standard treatment group (median time to event 102 days (IQR 35–142 days)) and 100% of the events in the prolonged treatment group (median time to event 112 days (IQR 109–135 days)). A total of six persons stopped bedaquiline due to a bedaquiline-related AE in the standard group, while no patients stopped bedaquiline due to a bedaquiline-related event in the prolonged group.

Serious adverse events

Serious AEs are described in table 4; the complete list of registered serious events occurring up to 5 months after bedaquiline cessation (n=63) are provided in supplementary table S2. We did not observe a significant difference in the incidence of serious AEs between the standard and prolonged bedaquiline groups during treatment (2.8 versus 3.6 per 100 person-months; p=0.30). This was consistently found when limiting analysis to the first 190 days of treatment (7.5 versus 5.4 per 100 person-months of treatment; p=0.07). There was no significant difference between the groups in serious AEs for up to 5 months after bedaquiline cessation (5.4 versus 4.4 per 100 person-months; p=0.48).

View this table:
  • View inline
  • View popup
TABLE 4

Serious adverse events registered during the treatment course among patients on standard and prolonged treatment with bedaquiline

Among patients who experienced a serious AE within 5 months of stopping bedaquiline, the median time to the first serious AE was 91 days in the standard treatment group and 112 days in the prolonged treatment group. The most common serious AEs among these persons in the standard treatment group were liver enzyme elevation (35.5%), eosinophilia (17.8%) and hypokalaemia (13.3%). In the prolonged treatment group, they were QTcF prolongation (27.8%) and hypokalaemia (22.2%). The cumulative incidence of serious AEs was lower in the prolonged group early in treatment but surpassed the standard group in ∼1 year.

The incidence of serious bedaquiline-related AEs did not differ between the standard and prolonged treatment groups (0.7 versus 0.2 per 100 person-months; p=0.22). The QTcF prolongation was the most common serious bedaquiline-related AE in both groups. One patient stopped bedaquiline due to a serious bedaquiline-related AE in the standard duration group.

QTcF changes throughout the treatment

Among the 108 patients with the baseline QTcF interval measurements available, the mean±sd estimate was 385.7±33.9 ms (table 5). After 1 month of treatment with bedaquiline, the QTcF intervals had increased by an average of 17.6±24.4 ms and appeared to continually increase throughout the treatment to reach a maximum of 61.9±49.1 ms in the 9th month of treatment. While the QTcF prolongations of 60 ms above the baseline were common, only one patient developed a prolongation of the QTcF interval up to >500 ms during the treatment. Monthly QTcF intervals were largely similar between standard and prolonged treatment groups (supplementary Appendix 3). When the prolonged and standard treatments were compared using Cox proportional hazard models, there was no significant difference for the rate of QTcF prolongation by >60 ms above the baseline between the standard group (10 events per 100 person-months) and the prolonged group (14.8 events per 100 person-months), with an adjusted hazard ratio of 1.16 (95% CI 0.56–2.42).

View this table:
  • View inline
  • View popup
TABLE 5

Change in mean QTcF interval by month of treatment#

Deaths

Four deaths occurred among the 113 patients, one in the prolonged group and three in the standard group. The death in the prolonged group occurred in a 31-year-old woman due to sudden death from a pulmonary thromboembolism and cardiac failure 350 days after initiating treatment. The patient had received 223 days of bedaquiline treatment; hence, the event was deemed unlikely to be related to bedaquiline.

Two deaths in the standard group were deemed unlikely to be related to bedaquiline. A 50-year-old woman received bedaquiline for 47 days, and on day 112 of treatment she died due to a pre-existing neoplasm. A 42-year-old man received bedaquiline for 175 days but died on day 799 of treatment as a result of respiratory failure owing to progression of tuberculosis.

One death in the standard group was deemed possibly related to bedaquiline. A 41-year-old man receiving a regimen of bedaquiline, pyrazinamide, linezolid, clofazimine, terizidone, imipenem-cilastatin and amoxicillin-clavulanate died 42 days after initiating treatment due to acute cardiopulmonary failure. The patient had ankylosing spondylitis and a history of alcohol abuse. The patient's QTcF measurement taken on the day of treatment initiation was 428 ms; the last QTcF measurement was performed 15 days before his death and the result was 441 ms.

Regression analyses

The regression analyses included 30 patients in the prolonged treatment group and 75 patients in the standard treatment group (table 6). Multivariate regression analyses showed that the persons who received prolonged treatment with bedaquiline versus those who received standard treatment did not experience a significantly different incidence in serious AEs either within the first 190 days of exposure to bedaquiline (incidence rate ratio (IRR) 0.73, 95% CI 0.33–1.61) or up to 5 months after the cessation of bedaquiline (IRR 0.82, 95% CI 0.42–1.61). Other factors associated with AEs for both primary and secondary outcomes are reported in supplementary tables S3 and S4. In our secondary analysis, we did not observe any significant difference in the incidence of serious AEs between the first 190 days of treatment and treatment after this time-point (IRR 0.75, 95% CI 0.30–1.88) among persons receiving prolonged bedaquiline treatment (supplementary table S5).

View this table:
  • View inline
  • View popup
TABLE 6

Primary and secondary multivariate analyses

Discussion

Our prospective study shows that the prolonged use of bedaquiline appears to be safe under programmatic conditions with rigorous oversight and pharmacovigilance. Multivariate statistical methods allowed us to control for concomitant anti-TB medication and to compare events associated with standard and/or prolonged use of bedaquiline. There was no significant difference identified in incidence of overall and bedaquiline-related serious events during treatment among the patients who received prolonged treatment with bedaquiline compared to those who received standard treatment. These findings concur with similar conclusions from retrospective studies using spontaneously reported cases [13, 16]. Considering the fact that the terminal half-life of bedaquiline has been estimated to be 5.5 months, we also identified that the incidence of serious events was not different when analysed within 5 months of bedaquiline cessation [17].

Bedaquiline was deemed to be related to <10% of all serious AEs registered in our study. However, bedaquiline was responsible for approximately half of all serious QTcF interval prolongations, and one death occurred in the standard group due to sudden death. In both groups, QTcF prolongation was the most common bedaquiline-related AE overall and bedaquiline-related serious event in particular. While increases in QTcF interval up to 20 ms have been commonly described, a continual increase throughout the treatment that surpassed 60 ms above the baseline by the 9th month of treatment has not been reported previously [24]. Although in the present study the risk of QTcF prolongation was not significantly higher in those patients who received bedaquiline for a prolonged period, the finding of a continual increase in QTcF may still be of concern in view of the number of patients who receive standard RR-TB regimens of a duration of 9 to 12 months with inclusion of bedaquiline throughout the whole course of the treatment [4]. Cardiotoxic effects of the currently recommended RR-TB treatments are potentially impacted by the concomitant use of fluoroquinolones and clofazimine [13, 18–24]. Moreover, there is a long list of auxiliary medicines that are associated with the QTcF interval prolongation [25]. The higher number of QTcF-prolonging anti-TB medicines used in the standard bedaquiline treatment group causing additive cardiotoxic action can explain the more frequent non-serious QTcF prolongation observed in this group of patients. Our current finding further emphasises the need for performing an ECG on a regular basis for strict monitoring of QTcF interval. This also supports the requirement for ECG monitoring in programmes that use bedaquiline for a prolonged period to ensure accessibility of cardioversion to manage torsades de pointes and cardiac arrest [3]. Hence, management of patients with prolonged QTcF interval requiring life-saving anti-TB treatment needs a multidisciplinary approach including meticulous revision of medicines used for concomitant diseases, as well as consultations with a cardiologist about the need for a temporary or permanent pacemaker to prevent deadly arrhythmias. According to available literature, alcohol abuse observed in our study population may also contribute to cardiotoxicity, necessitating joint intervention with services for addictive behaviours [26–30]. According to CTCAE 5.0, which is the currently recommended scale for grading AEs and is used for reporting within this study, QTc interval prolongation >60 ms compared to baseline is defined as grade 3 AE. At the same time, earlier studies reporting QTc interval prolongation use the older version of grading scale CTCAE 4.0, where prolongation >60 ms compared to baseline without Torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia was not considered to be an AE [13, 15]. This potentially caused underreporting of severe QTc prolongation.

The finding that the majority of patients in both groups of our study experienced at least one AE coincides with well-documented toxicity of long-term anti-TB treatment [15, 31, 32]. The most common serious AEs not necessarily related to bedaquiline were liver enzyme elevation, eosinophilia and hypokalaemia. In contrast to what was observed within the period of bedaquiline treatment, the number of total non-serious AEs within 5 months after cessation of bedaquiline was significantly higher in the standard bedaquiline group. This can be explained by earlier replacement of bedaquiline and longer use of other anti-TB medicines with worse safety profiles, such as thiamide, second-line injectables, P-aminosalicyclic acid (PAS), pyrazinamide or carbapenems, in the regimen [15, 18, 32–35].

We found that second-line injectables were strongly associated with serious AEs throughout treatment. Extreme toxicity of injectables has already triggered initiatives on fully oral RR-TB treatment, but there is still a lack of anti-TB medicines that could be used instead in highly resistant cases, urging further developments in the field [5, 36–38].

This was not a randomised study, and the results may have been biased by the fact that the decision to continue with prolonged use of bedaquiline might have been affected by better tolerability of bedaquiline by the respective patients and better survival during the first 190 days of treatment, as compared to those patients who did not continue with bedaquiline. However, efforts were made to mitigate this bias with the statistical analysis, as were groups similar for the majority of other parameters.

Conclusion

In conclusion, this study demonstrated that prolonged use of bedaquiline under programmatic conditions with pharmacovigilance appears to be safe. Clinicians should carefully monitor QTcF interval throughout treatment with bedaquiline because of the risk of QTcF prolongation. Further studies are needed to establish strategies to manage prolonged QTcF interval during prolonged treatment with bedaquiline.

Supplementary material

Supplementary Material

Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.

Supplementary material 00685-2021.SUPPLEMENT

Footnotes

  • Provenance: Submitted article, peer reviewed.

  • Conflict of interest: All authors declare no conflicts of interest.

  • Received December 5, 2021.
  • Accepted March 17, 2022.
  • Copyright ©The authors 2022
http://creativecommons.org/licenses/by-nc/4.0/

This version is distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0. For commercial reproduction rights and permissions contact permissions{at}ersnet.org

References

  1. ↵
    1. WHO
    . Global tuberculosis report 2019. Geneva, World Health Organization, 2021. www.who.int/teams/global-tuberculosis-programme/tb-reports Date last accessed: 16 October 2021.
  2. ↵
    1. CDC
    . Provisional CDC guidelines for the use and safety monitoring of bedaquiline fumarate (Sirturo) for the treatment of multidrug-resistant tuberculosis. MMWR Recomm Rep 2013; 62: 1–12.
    OpenUrlPubMed
  3. ↵
    1. WHO
    . The use of bedaquiline in the treatment of multidrug-resistant tuberculosis. https://apps.who.int/iris/bitstream/handle/10665/84879/9789241505482_eng.pdf;jsessionid=C5E18091A88E8E0935C6428AC15BFA3D?sequence=1
  4. ↵
    1. Khan U,
    2. Huerga H,
    3. Khan AJ, et al.
    The Endtb observational study protocol: treatment of MDR-TB with bedaquiline or delamanid containing regimens. BMC Infect Dis 2019; 19: 733. doi:10.1186/s12879-019-4378-4
    OpenUrl
  5. ↵
    1. WHO
    . WHO consolidated guidelines on tuberculosis. Module 4: Treatment – drug-resistant tuberculosis treatment. www.who.int/publications/i/item/9789240007048 Date last accessed: 16 October 2021.
  6. ↵
    1. WHO
    . Companion handbook to the WHO guidelines for the programmatic management of drug-resistant tuberculosis. https://apps.who.int/iris/bitstream/handle/10665/130918/9789241548809_eng.pdf Date last accessed: 16 October 2021.
  7. ↵
    1. Layton D,
    2. Shakir SA
    . Specialist cohort event monitoring studies: a new study method for risk management in pharmacovigilance. Drug Saf 2015; 38: 153–163. doi:10.1007/s40264-014-0260-x
    OpenUrlPubMed
  8. ↵
    1. WHO
    . Definitions and reporting framework for tuberculosis – 2013 revision. https://apps.who.int/iris/handle/10665/79199 Date last accessed: 16 October 2021.
  9. ↵
    1. WHO
    . A practical handbook on the pharmacovigilance of medicines used in the treatment of tuberculosis. Enhancing the safety of the TB patient. www.who.int/docs/default-source/documents/tuberculosis/a-practical-handbook-on-the-pharmacovigilance-of-medicines-used-in-the-treatment-of-tuberculosis.pdf?sfvrsn=6e5fc0cf_5
  10. ↵
    1. European Medicines Agency
    . Clinical safety data management: Definitions and standards for expedited reporting. www.ema.europa.eu/en/documents/scientific-guideline/international-conference-harmonisation-technical-requirements-registration-pharmaceuticals-human-use_en-15.pdf
  11. ↵
    1. National Institutes of Health
    . National cancer institute. Common terminology criteria for adverse events (ctcae) v5.0. U.S. Department of Health and Human Services. 2017. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcae_v5_quick_reference_8.5x11.pdf
  12. ↵
    1. Reider HL,
    2. Chonde TM,
    3. Myking H, et al.
    The Public Health Service. National Tuberculosis Reference Laboratory and the National Laboratory Network. Minimum Requirements, Role and Operation in a Low-Income Country. Paris, International Union Against Tuberculosis and Lung Disease, 1998.
  13. ↵
    1. Guglielmetti L,
    2. Jaspard M,
    3. Le Dû D, et al.
    Long-term outcome and safety of prolonged bedaquiline treatment for multidrug-resistant tuberculosis. Eur Respir J 2017; 49: 1601799. doi:10.1183/13993003.01799-2016
    OpenUrlAbstract/FREE Full Text
  14. ↵
    1. Mcleay SC,
    2. Vis P,
    3. Van Heeswijk RP, et al.
    Population pharmacokinetics of bedaquiline (tmc207), a novel antituberculosis drug. Antimicrob Agents Chemother 2014; 58: 5315–5324. doi:10.1128/AAC.01418-13
    OpenUrlAbstract/FREE Full Text
  15. ↵
    1. Lan Z,
    2. Ahmad N,
    3. Baghaei P, et al.
    Drug-associated adverse events in the treatment of multidrug-resistant tuberculosis: an individual patient data meta-analysis. Lancet Respir Med 2020; 8: 383–394. doi:10.1016/S2213-2600(20)30047-3
    OpenUrl
  16. ↵
    1. Jones J,
    2. Mudaly V,
    3. Voget J, et al.
    Adverse drug reactions in South African patients receiving bedaquiline-containing tuberculosis treatment: an evaluation of spontaneously reported cases. BMC Infect Dis 2019; 19: 544. doi:10.1186/s12879-019-4197-7
    OpenUrl
  17. ↵
    1. Center for Drug Evaluation and Research
    . Clinical review of anti-infective drugs advisory committee on bedaquiline: NDA 204 384. www.accessdata.fda.gov/drugsatfda_docs/nda/2012/204384Orig1s000MedR_.pdf
  18. ↵
    1. Borisov SE,
    2. Dheda K,
    3. Enwerem M, et al.
    Effectiveness and safety of bedaquiline-containing regimens in the treatment of MDR- and XDR-TB: a multicentre study. Eur Respir J 2017; 49: 1700387. doi:10.1183/13993003.00387-2017
    OpenUrlAbstract/FREE Full Text
    1. Pontali E,
    2. Sotgiu G,
    3. Tiberi S, et al.
    Cardiac safety of bedaquiline: a systematic and critical analysis of the evidence. Eur Respir J 2017; 50: 1701462. doi:10.1183/13993003.01462-2017
    OpenUrlAbstract/FREE Full Text
    1. Stahlmann R,
    2. Lode HM
    . Risks associated with the therapeutic use of fluoroquinolones. Expert Opin Drug Saf 2013; 12: 497–505. doi:10.1517/14740338.2013.796362
    OpenUrlCrossRefPubMed
    1. Briasoulis A,
    2. Agarwal V,
    3. Pierce WJ
    . QT prolongation and torsade de pointes induced by fluoroquinolones: infrequent side effects from commonly used medications. Cardiology 2011; 120: 103–110. doi:10.1159/000334441
    OpenUrlCrossRefPubMed
    1. Choudhri SH,
    2. Harris L,
    3. Butany JW, et al.
    Clofazimine induced cardiotoxicity: a case report. Lepr Rev 1995; 66: 63–68.
    OpenUrlPubMed
    1. Yoon HY,
    2. Jo KW,
    3. Nam GB, et al.
    Clinical significance of QT-prolonging drug use in patients with MDR-TB or NTM disease. Int J Tuberc Lung Dis 2017; 21: 996–1001. doi:10.5588/ijtld.17.0174
    OpenUrl
  19. ↵
    1. Guglielmetti L,
    2. Tiberi S,
    3. Burman M, et al.
    QT prolongation and cardiac toxicity of new tuberculosis drugs in Europe: A Tuberculosis Network European Trials group (TBNET) study. Eur Respir J 2018; 52: 1800537. doi:10.1183/13993003.00537-2018
    OpenUrlAbstract/FREE Full Text
  20. ↵
    1. Nachimuthu S,
    2. Assar MD,
    3. Schussler JM
    . Drug-induced QT interval prolongation: mechanisms and clinical management. Ther Adv Drug Saf 2012; 3: 241–253. doi:10.1177/2042098612454283
    OpenUrlCrossRefPubMed
  21. ↵
    1. Li Z,
    2. Guo X,
    3. Liu Y, et al.
    Relation of heavy alcohol consumption to QTc interval prolongation. Am J Cardiol 2016; 118: 1201–1206. doi:10.1016/j.amjcard.2016.07.033
    OpenUrl
    1. Rossinen J,
    2. Sinisalo J,
    3. Partanen J, et al.
    Effects of acute alcohol infusion on duration and dispersion of QT interval in male patients with coronary artery disease and in healthy controls. Clin Cardiol 1999; 22: 591–594. doi:10.1002/clc.4960220910
    OpenUrlCrossRefPubMed
    1. Otero-Antón E,
    2. González-Quintela A,
    3. Saborido J, et al.
    Prolongation of the QTc interval during alcohol withdrawal syndrome. Acta Cardiol 1997; 52: 285–294.
    OpenUrlPubMed
    1. Yamamoto T,
    2. Friedman SE
    . Torsades de pointes in severe alcohol withdrawal and cirrhosis: implications for risk stratification and management. Fed Pract 2017; 34: 38–41.
    OpenUrl
  22. ↵
    1. Santos-Silva AF,
    2. Migliori GB,
    3. Duarte R
    . Tuberculosis, alcohol and tobacco: dangerous liaisons. Rev Port Pneumol (2006) 2017; 23: 177–178.
    OpenUrl
  23. ↵
    1. Diacon AH,
    2. Pym A,
    3. Grobusch MP, et al.
    Multidrug-resistant tuberculosis and culture conversion with bedaquiline. N Engl J Med 2014; 371: 723–732. doi:10.1056/NEJMoa1313865
    OpenUrlCrossRefPubMed
  24. ↵
    1. Zhang Y,
    2. Wu S,
    3. Xia Y, et al.
    Adverse events associated with treatment of multidrug-resistant tuberculosis in China: an ambispective cohort study. Med Sci Monit 2017; 23: 2348–2356. doi:10.12659/MSM.904682
    OpenUrl
    1. Bastos ML,
    2. Lan Z,
    3. Menzies D
    . An updated systematic review and meta-analysis for treatment of multidrug-resistant tuberculosis. Eur Respir J 2017; 49: 1600803. doi:10.1183/13993003.00803-2016
    OpenUrlAbstract/FREE Full Text
    1. Wu S,
    2. Zhang Y,
    3. Sun F, et al.
    Adverse events associated with the treatment of multidrug-resistant tuberculosis: a systematic review and meta-analysis. Am J Ther 2016; 23: e521–e530. doi:10.1097/01.mjt.0000433951.09030.5a
    OpenUrlCrossRefPubMed
  25. ↵
    1. Borisov S,
    2. Danila E,
    3. Maryandyshev A, et al.
    Surveillance of adverse events in the treatment of drug-resistant tuberculosis: first global report. Eur Respir J 2019; 54: 1901522. doi:10.1183/13993003.01522-2019
    OpenUrlAbstract/FREE Full Text
  26. ↵
    1. Mase SR,
    2. Chorba T
    . Treatment of drug-resistant tuberculosis. Clin Chest Med 2019; 40: 775–795. doi:10.1016/j.ccm.2019.08.002
    OpenUrlCrossRef
    1. Reuter A,
    2. Tisile P,
    3. von Delft D, et al.
    The devil we know: is the use of injectable agents for the treatment of MDR-TB justified? Int J Tuberc Lung Dis 2017; 21: 1114–1126. doi:10.5588/ijtld.17.0468
    OpenUrl
  27. ↵
    1. Shibeshi W,
    2. Sheth AN,
    3. Admasu A, et al.
    Nephrotoxicity and ototoxic symptoms of injectable second-line anti-tubercular drugs among patients treated for MDR-TB in Ethiopia: a retrospective cohort study. BMC Pharmacol Toxicol 2019; 20: 31. doi:10.1186/s40360-019-0313-y
    OpenUrl
PreviousNext
Back to top
Vol 8 Issue 2 Table of Contents
ERJ Open Research: 8 (2)
  • Table of Contents
  • Index by author
Email

Thank you for your interest in spreading the word on European Respiratory Society .

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Safety of prolonged treatment with bedaquiline in programmatic conditions
(Your Name) has sent you a message from European Respiratory Society
(Your Name) thought you would like to see the European Respiratory Society web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Print
Citation Tools
Safety of prolonged treatment with bedaquiline in programmatic conditions
Dzmitriy Zhurkin, Elmira Gurbanova, Jonathon R. Campbell, Dick Menzies, Svetlana Setkina, Hennadz Hurevich, Varvara Solodovnikova, Dzmitry Viatushka, Alan Altraja, Alena Skrahina
ERJ Open Research Apr 2022, 8 (2) 00685-2021; DOI: 10.1183/23120541.00685-2021

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Safety of prolonged treatment with bedaquiline in programmatic conditions
Dzmitriy Zhurkin, Elmira Gurbanova, Jonathon R. Campbell, Dick Menzies, Svetlana Setkina, Hennadz Hurevich, Varvara Solodovnikova, Dzmitry Viatushka, Alan Altraja, Alena Skrahina
ERJ Open Research Apr 2022, 8 (2) 00685-2021; DOI: 10.1183/23120541.00685-2021
del.icio.us logo Digg logo Reddit logo Technorati logo Twitter logo CiteULike logo Connotea logo Facebook logo Google logo Mendeley logo
Full Text (PDF)

Jump To

  • Article
    • Abstract
    • Abstract
    • Introduction
    • Material and methods
    • Results
    • Discussion
    • Supplementary material
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • PDF

Subjects

  • Respiratory infections and tuberculosis
  • Tweet Widget
  • Facebook Like
  • Google Plus One

More in this TOC Section

Original research articles

  • Biomarkers and low-dose CT in hospitalised AECOPD
  • Lung function in young adulthood
  • CT on lung cancer screening
Show more Original research articles

Tuberculosis

  • Latent tuberculosis screening and treatment in HIV
  • Programme costs of longer/shorter TB regimens and drug import
Show more Tuberculosis

Related Articles

Navigate

  • Home
  • Current issue
  • Archive

About ERJ Open Research

  • Editorial board
  • Journal information
  • Press
  • Permissions and reprints
  • Advertising

The European Respiratory Society

  • Society home
  • myERS
  • Privacy policy
  • Accessibility

ERS publications

  • European Respiratory Journal
  • ERJ Open Research
  • European Respiratory Review
  • Breathe
  • ERS books online
  • ERS Bookshop

Help

  • Feedback

For authors

  • Instructions for authors
  • Publication ethics and malpractice
  • Submit a manuscript

For readers

  • Alerts
  • Subjects
  • RSS

Subscriptions

  • Accessing the ERS publications

Contact us

European Respiratory Society
442 Glossop Road
Sheffield S10 2PX
United Kingdom
Tel: +44 114 2672860
Email: journals@ersnet.org

ISSN

Online ISSN: 2312-0541

Copyright © 2022 by the European Respiratory Society