Efficacy and safety of combination regimen containing betaquinoline in the treatment of multidrug-resistant tuberculosis_West China Medical Journal

Authors：

CHEN Yan ¹ , CHEN Zhu ^1,2 , HUANG Tao ³ , LU Xiaoli ³ , LI Peng ¹ , LIN Rui ¹ , CHEN Xiong ¹ , LIU Yuhong ⁴ , GAO Mengqiu ⁴ ,  WU Guihui ³ ,  LI Liang ⁴

1. Drug Clinical Trial Institution Office, Public Health Clinical Center of Chengdu, Chengdu, Sichuan 610066, P. R. China;
2. Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
3. Tuberculosis Department, Public Health Clinical Center of Chengdu, Chengdu, Sichuan 610066, P. R. China;
4. Tuberculosis Department, Beijing Chest Hospital, Capital Medical University, Beijing 101149, P. R. China;

Corresponding author：

WU Guihui, Email: wghwgh2584@sina.com; LI Liang, Email: t6611@sina.com

Keywords：

Tuberculosis; Drug resistance; Bedaquiline; Effectiveness; Safety

DOI：

10.7507/1002-0179.202006302

Video：

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Objective To study the efficacy and safety of combined anti-tuberculosis regimen containing bedaquiline in the treatment of multidrug-resistant tuberculosis (MDR-TB). Methods A total of 69 MDR-TB patients treated by joint regimen combined bedaquiline with other anti-tuberculosis drugs between March 2018 and August 2019 in Public Health Clinical Center of Chengdu were taken as the trial group, and 60 MDR-TB patients received treatment without bedaquiline between June 2016 and December 2017 in the same hospital were taken as the control group. The efficacy and safety of the two groups were compared. Results The 69 patients in the trial group included 44 males and 25 females, aged from 21 to 63 years, with an average of (34.6±11.0) years; 58 patients (84.1%) completed the 24-week treatment with bedaquiline, while 11 patients did not complete the treatment, including 3 deaths (4.3%), 1 loss of follow-up (1.4%), 1 withdrawal from the study (1.4%), and 6 discontinuation due to adverse events (8.7%). Among the 54 patients with positive results of tuberculosis on baseline sputum culture, 49 transformed to negative results within 24 weeks of treatment (the negative conversion rate was 90.7%), and the median negative conversion time was 13.0 weeks. The 60 patients in the control group included 45 males and 15 females, aged from 16 to 66 years, with an average of (35.5±13.2) years. Among the 53 patients with positive results of tuberculosis on baseline sputum culture, 30 transformed to negative results within 24 weeks of treatment (the negative conversion rate was 56.6%), and the median negative conversion time was 12.0 weeks. The negative conversion rate of sputum bacteria in the trial group was significantly higher than that in the control group (χ²=16.133, P<0.001). The most common adverse reactions in the trial group were liver function abnormalities (42 cases, 60.9%), prolonged QTc interval (37 cases, 53.6%), electrolyte disturbances (20 cases, 29.0%), and blood system damage (20 cases, 29.0%). In the 37 patients who experienced prolonged QTc interval, there were 8 patients with QTc intervals≥500 ms and 29 patients with QTc intervals ≥450 ms and <500 ms, with a median occurrence time of 16.0 weeks, among whom 25 patients experienced prolonged QTc interval in 4-48 weeks after the withdrawal of bedaquiline. Conclusion The negative conversion rate of tuberculosis sputum culture of patients with MDR-TB treated by bedaquiline combined with other anti- tuberculosis drugs is high, but electrocardiogram should be closely monitored during and after the treatment in order to guard against the potential cardiac toxic effects of bedaquiline.

Citation： CHEN Yan, CHEN Zhu, HUANG Tao, LU Xiaoli, LI Peng, LIN Rui, CHEN Xiong, LIU Yuhong, GAO Mengqiu, WU Guihui, LI Liang. Efficacy and safety of combination regimen containing betaquinoline in the treatment of multidrug-resistant tuberculosis. West China Medical Journal, 2021, 36(10): 1392-1398. doi: 10.7507/1002-0179.202006302 Copy

1.	Dheda K, Gumbo T, Gandhi NR, et al. Global control of tuberculosis: from extensively drug-resistant to untreatable tuberculosis. Lancet Respir Med, 2014, 2(4): 321-338.
2.	Daley CL, Caminero JA. Management of multidrug-resistant tuberculosis. Semin Respir Crit Care Med, 2018, 39(3): 310-324.
3.	Li Y, Sun F, Zhang W. Bedaquiline and delamanid in the treatment of multidrug-resistant tuberculosis: promising but challenging. Drug Dev Res, 2019, 80(1): 98-105.
4.	中华医学会结核病学分会. 中国耐多药和利福平耐药结核病治疗专家共识(2019年版). 中华结核和呼吸杂志, 2019, 42(10): 733-749.
5.	Van Deun A, Decroo T, Tahseen S, et al. WHO 2018 treatment guidelines for rifampicin-resistant tuberculosis: uncertainty, potential risks and the way forward. Int J Antimicrob Agents, 2020, 55(1): 105882.
6.	张丽帆, 边赛男, 刘晓清, 等. 利奈唑胺治疗广泛耐药结核研究进展. 中华实验和临床感染病杂志(电子版), 2016, 10(6): 649-653.
7.	World Health Organization. Global tuberculosis report 2019. Geneva: World Health Organization, 2019. (2019-10-15)[2020-06-01].https://www.who.int/publications-detail-redirect/9789241565714.
8.	闫丽萍, 吴哲渊, 张祖荣, 等. 初治耐多药肺结核患者采用初治标准方案治疗的前瞻性临床研究. 中国防痨杂志, 2017, 39(1): 33-38.
9.	Field SK. Bedaquiline for the treatment of multidrug-resistant tuberculosis: great promise or disappointment?. Ther Adv Chronic Dis, 2015, 6(4): 170-184.
10.	唐神结, 许绍发, 李亮. 耐药结核病学. 北京: 人民卫生出版社, 2014: 126-287.
11.	杨松, 严晓峰. 贝达喹啉治疗耐多药与广泛耐药结核病的现状和展望. 结核病与肺部健康杂志, 2019, 8(4): 249-252.
12.	Diacon AH, Pym A, Grobusch MP, et al. Multidrug-resistant tuberculosis and culture conversion with bedaquiline. N Engl J Med, 2014, 371(8): 723-732.
13.	Diacon AH, Pym A, Grobusch M, et al. The diarylquinoline TMC₂₀₇ for multidrug-resistant tuberculosis. N Engl J Med, 2009, 360(23): 2397-2405.
14.	中华医学会结核病学分会, 抗结核新药贝达喹啉临床应用专家共识编写组. 抗结核新药贝达喹啉临床应用专家共识. 中华结核和呼吸杂志, 2018, 41(6): 461-466.
15.	Olaru ID, Heyckendorf J, Andres S, et al. Bedaquiline-based treatment regimen for multidrug-resistant tuberculosis. Eur Respir J, 2017, 49(5): 1700742.
16.	中国防痨协会. 耐药结核病化学治疗指南(2019年简版). 中国防痨杂志, 2019, 41(10): 1025-1073.
17.	Mbuagbaw L, Guglielmetti L, Hewison C, et al. Outcomes of bedaquiline treatment in patients with multidrug-resistant tuberculosis. Emerg Infect Dis, 2019, 25(5): 936-943.
18.	Cohen K, Maartens G. A safety evaluation of bedaquiline for the treatment of multi-drug resistant tuberculosis. Expert Opin Drug Saf, 2019, 18(10): 875-882.
19.	Guglielmetti L, Le DD, Veziris N, et al. Is bedaquiline as effective as fluoroquinolones in the treatment of multidrug-resistant tuberculosis?. Eur Respir J, 2016, 48(2): 582-585.
20.	Andries K, Villellas C, Coeck N, et al. Acquired resistance of Mycobacterium tuberculosis to bedaquiline. PLoS One, 2014, 9(7): e102135.

1. Dheda K, Gumbo T, Gandhi NR, et al. Global control of tuberculosis: from extensively drug-resistant to untreatable tuberculosis. Lancet Respir Med, 2014, 2(4): 321-338.
2. Daley CL, Caminero JA. Management of multidrug-resistant tuberculosis. Semin Respir Crit Care Med, 2018, 39(3): 310-324.
3. Li Y, Sun F, Zhang W. Bedaquiline and delamanid in the treatment of multidrug-resistant tuberculosis: promising but challenging. Drug Dev Res, 2019, 80(1): 98-105.
4. 中华医学会结核病学分会. 中国耐多药和利福平耐药结核病治疗专家共识(2019年版). 中华结核和呼吸杂志, 2019, 42(10): 733-749.
5. Van Deun A, Decroo T, Tahseen S, et al. WHO 2018 treatment guidelines for rifampicin-resistant tuberculosis: uncertainty, potential risks and the way forward. Int J Antimicrob Agents, 2020, 55(1): 105882.
6. 张丽帆, 边赛男, 刘晓清, 等. 利奈唑胺治疗广泛耐药结核研究进展. 中华实验和临床感染病杂志(电子版), 2016, 10(6): 649-653.
7. World Health Organization. Global tuberculosis report 2019. Geneva: World Health Organization, 2019. (2019-10-15)[2020-06-01].https://www.who.int/publications-detail-redirect/9789241565714.
8. 闫丽萍, 吴哲渊, 张祖荣, 等. 初治耐多药肺结核患者采用初治标准方案治疗的前瞻性临床研究. 中国防痨杂志, 2017, 39(1): 33-38.
9. Field SK. Bedaquiline for the treatment of multidrug-resistant tuberculosis: great promise or disappointment?. Ther Adv Chronic Dis, 2015, 6(4): 170-184.
10. 唐神结, 许绍发, 李亮. 耐药结核病学. 北京: 人民卫生出版社, 2014: 126-287.
11. 杨松, 严晓峰. 贝达喹啉治疗耐多药与广泛耐药结核病的现状和展望. 结核病与肺部健康杂志, 2019, 8(4): 249-252.
12. Diacon AH, Pym A, Grobusch MP, et al. Multidrug-resistant tuberculosis and culture conversion with bedaquiline. N Engl J Med, 2014, 371(8): 723-732.
13. Diacon AH, Pym A, Grobusch M, et al. The diarylquinoline TMC₂₀₇ for multidrug-resistant tuberculosis. N Engl J Med, 2009, 360(23): 2397-2405.
14. 中华医学会结核病学分会, 抗结核新药贝达喹啉临床应用专家共识编写组. 抗结核新药贝达喹啉临床应用专家共识. 中华结核和呼吸杂志, 2018, 41(6): 461-466.
15. Olaru ID, Heyckendorf J, Andres S, et al. Bedaquiline-based treatment regimen for multidrug-resistant tuberculosis. Eur Respir J, 2017, 49(5): 1700742.
16. 中国防痨协会. 耐药结核病化学治疗指南(2019年简版). 中国防痨杂志, 2019, 41(10): 1025-1073.
17. Mbuagbaw L, Guglielmetti L, Hewison C, et al. Outcomes of bedaquiline treatment in patients with multidrug-resistant tuberculosis. Emerg Infect Dis, 2019, 25(5): 936-943.
18. Cohen K, Maartens G. A safety evaluation of bedaquiline for the treatment of multi-drug resistant tuberculosis. Expert Opin Drug Saf, 2019, 18(10): 875-882.
19. Guglielmetti L, Le DD, Veziris N, et al. Is bedaquiline as effective as fluoroquinolones in the treatment of multidrug-resistant tuberculosis?. Eur Respir J, 2016, 48(2): 582-585.
20. Andries K, Villellas C, Coeck N, et al. Acquired resistance of Mycobacterium tuberculosis to bedaquiline. PLoS One, 2014, 9(7): e102135.

West China Medical Journal

Efficacy and safety of combination regimen containing betaquinoline in the treatment of multidrug-resistant tuberculosis

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