Abstract
Bedaquiline and delamanid are effective and might be safe in patients with chronic kidney or liver disease. MDR-TB patients with these comorbidities receiving bedaquiline and/or delamanid have poor treatment outcomes, probably owing to the comorbidities. https://bit.ly/3NyDD15
To the Editor:
Each year, ∼500 000 people worldwide suffer from rifampin-resistant tuberculosis (RR-TB) or multidrug-resistant tuberculosis (MDR-TB; resistance to both rifampin and isoniazid) [1]. Bedaquiline and delamanid are newly developed anti-TB drugs and their efficacies in the treatment of MDR/RR-TB have been well documented in both randomised controlled trials [2, 3] and cohort studies [4, 5]. As these new drugs have become widely used, evidence regarding their efficacy and safety in patients with chronic kidney or liver disease is needed urgently, as these organ impairments can affect drug metabolism or pharmacokinetics [6]. However, as bedaquiline and delamanid received accelerated approval based on phase 2 clinical trials, their effects in patients with comorbidities have not been fully evaluated [2, 3]. Therefore, this study aimed to assess the treatment profiles and outcomes in patients with MDR-TB receiving bedaquiline and/or delamanid in South Korea.
In September 2016, a national TB expert review committee (NTBERC) was launched by the Korea Disease Control and Prevention Agency (KDCA). The NTBERC decided whether to approve the use of bedaquiline and/or delamanid, and suggests appropriate companion drugs based on 2016 the World Health Organization [7] and 2017 Korean [8] guidelines. The main criterion for use of bedaquiline or delamanid was “an effective regimen cannot be composed from other conventional drugs”, usually encountered in patients with extensively drug-resistant tuberculosis (XDR-TB), pre-XDR-TB, pyrazinamide resistance or resistance to at least two second-line oral drugs. Bedaquiline and delamanid were prescribed at the same dose for all patients regardless of their comorbidities (bedaquiline 400 mg once daily for 2 weeks, followed by 200 mg three times a week for 22 weeks; delamanid 100 mg twice daily for 24 weeks) [7, 8].
This is a retrospective, nationwide cohort study of patients with MDR-TB in whom bedaquiline and/or delamanid was newly started from September 2016 to December 2019. Between 2017 and 2019, 1879 patients were newly diagnosed with MDR-TB in South Korea [9]. During the study period, bedaquiline and/or delamanid use was requested for 816 patients with pulmonary MDR-TB in 83 hospitals in South Korea. Among them, 741 adult patients were approved by the NTBERC and included in this study. Patients with chronic kidney and/or liver disease according to the duty physician's report were enrolled in the comorbidity group. Clinical data of patients were provided and anonymised by the KDCA. The study protocol was approved by the institutional review board of Asan Medical Center (approval number 2021–1730). The requirement for informed consent was waived because of the retrospective study design and use of anonymised data. The present study complied with the Declaration of Helsinki and all methods were performed in accordance with the relevant guidelines.
Treatment outcomes were divided into five categories: cured, treatment completed, treatment failed, died and lost to follow-up. Treatment success was defined as the sum of the cured and treatment-completed patients [10]. Culture conversion was defined as two consecutive negative cultures, collected ⩾30 days apart, in a patient with a positive culture at baseline. Time to culture conversion was defined as the time from the date of initiation of bedaquiline and/or delamanid to the first negative culture specimen collection date in patients with culture conversion.
The mean age of all patients was 52.1 years, and 510 (68.8%) patients were men (table 1). 83 (11.2%) patients with chronic kidney and/or liver disease were classified in the comorbidity group. Among them, 43 and 44 had chronic kidney and liver disease, respectively, and diabetic nephropathy (27.9%) and hepatitis B virus infection (54.5%) were the most prevalent confirmed aetiologies, respectively. Serum creatinine level was a median 1.89 mg·dL−1 in patients with chronic kidney disease. However, insufficient source data made it impossible to derive liver functional scores, including Model for End-Stage Liver Disease score.
Regarding initial new drugs, 376 (50.7%), 336 (45.3%) and 29 (3.9%) patients were prescribed bedaquiline, delamanid and both drugs, respectively. The comorbidity group had shorter duration of treatment with new drugs (median 167.0 versus 168.0 days, p=0.028) and total treatment (median 577.0 versus 615.0 days, p=0.004) than the control group. Treatment with any fluoroquinolone (67.5% versus 63.2%) and treatment with linezolid (57.8% versus 58.8%) were not different between groups.
Among 603 patients with initial sputum-positive culture, 592 (98.2%) achieved culture conversion. At initiation of new drugs, 284 remained culture positive and 273 (96.1%) achieved culture conversion. The rate of culture conversion (96.3% versus 96.1%) and the time to culture conversion (median 41.0 versus 43.0 days) from the initiation of new drugs did not differ between groups.
Among all patients, 425 (57.4%) were cured and 169 (22.8%) completed treatment. The overall treatment success rate was 80.2%, and it was lower (66.3% versus 81.9%, p=0.001) in the comorbidity group. The comorbidity group had a lower cure rate (37.3% versus 59.9%, p<0.001), and higher death rate (21.7% versus 9.3%, p=0.002). TB-related death was not different when compared with respect to the comorbidities (4.8% versus 2.9%).
We analysed predictors for treatment success using multivariate logistic regression. Chronic kidney disease (adjusted odds ratio (aOR) 0.419, p=0.019), and chronic liver disease (aOR 0.369, p=0.009) were independently associated with lower treatment success after adjusting for age, sex, body mass index, history of MDR-TB treatment, radiological severities, positive acid-fast bacilli smear at treatment initiation and other underlying diseases.
20 patients discontinued bedaquiline and/or delamanid because of adverse drug reactions. Six (0.8%) had gastrointestinal disturbance, and five (0.7%) had prolongation of Fridericia-corrected QT interval; however, there was no significant difference between groups. Among patients with chronic kidney disease, three were temporarily haemodialysed owing to acute kidney injury, of whom two cases were related to second-line injectable drugs, and one was related to hepatorenal syndrome due to underlying liver cirrhosis and hepatocellular carcinoma.
It is well known that sputum culture conversion within 2 months of treatment may be an early predictor of treatment success in patients with MDR-TB [11]. Here, culture conversion rate and time to culture conversion were not different in the comorbidity group. Bedaquiline and delamanid could be used effectively in patients with chronic kidney or liver disease.
The treatment success rate of 80.2% is comparable to those of other studies in patients with MDR-TB treated with bedaquiline or delamanid [12, 13]. The comorbidity group had a lower treatment success rate, probably because of the higher death rate, or lower exposure to bedaquiline and/or delamanid owing to altered drug metabolism or pharmacokinetics [6]. However, TB-related death was not increased in the comorbidity group, and the higher death rate may have resulted from their comorbidities. In the literature, the treatment success rate was lower and the death rate was higher in TB patients with underlying diseases [14, 15]. Since patients with MDR-TB are treated for a long period of 18–24 months compared to patients with drug-sensitive TB, who are treated for 6 months [7, 8], they are more likely to die of underlying diseases in the meantime, which may have caused the lower treatment success rate. Therefore, if short-term treatment with new drugs was administered even to patients with underlying diseases, the treatment success rate could be further improved.
The limitations include a retrospective study design, and lack of detailed information regarding comorbidities, including their nature and severity.
In conclusion, this real-world population analysis suggests that chronic kidney and liver disease are predictors of poor treatment outcome in patients with MDR-TB receiving bedaquiline and/or delamanid. Nevertheless, our results indicate that bedaquiline and delamanid are effective and might be safe in patients with chronic kidney or liver disease.
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Acknowledgements
We thank Sung-Cheol Yun from the Division of Biostatistics at Asan Medical Center (Seoul, Republic of Korea) for advice on the statistical analyses.
Footnotes
Author contributions: Chiwook Chung and Tae Sun Shim conceived and designed the study. Chiwook Chung and Jung Eun Shin collected the data and contributed to data analysis. Chiwook Chung, Jung Eun Shin and Tae Sun Shim drafted the manuscript. All authors have revised and approved the final manuscript. All authors take responsibility for the accuracy of the content of the final manuscript.
Conflict of interest: Jae-Joon Yim received donations of linezolid (Zyvox) from Pfizer, Inc., and delamanid (Deltyba) from Otsuka Pharmaceutical Co. for the clinical trials for which he served as a principal investigator. All other authors report no potential conflicts of interest.
Support statement: This work was supported by the research programme funded by the Korea Disease Control and Prevention Agency (grant number: 20210323410-00). Funding information for this article has been deposited with the Crossref Funder Registry.
- Received April 19, 2022.
- Accepted June 3, 2022.
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