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.	中華醫學會結核病學分會. 中國耐多藥和利福平耐藥結核病治療專家共識(2019年版). 中華結核和呼吸雜志, 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.	張麗帆, 邊賽男, 劉曉清, 等. 利奈唑胺治療廣泛耐藥結核研究進展. 中華實驗和臨床感染病雜志(電子版), 2016, 10(6): 649-653.
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8.	閆麗萍, 吳哲淵, 張祖榮, 等. 初治耐多藥肺結核患者采用初治標準方案治療的前瞻性臨床研究. 中國防癆雜志, 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.	唐神結, 許紹發, 李亮. 耐藥結核病學. 北京: 人民衛生出版社, 2014: 126-287.
11.	楊松, 嚴曉峰. 貝達喹啉治療耐多藥與廣泛耐藥結核病的現狀和展望. 結核病與肺部健康雜志, 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.	中華醫學會結核病學分會, 抗結核新藥貝達喹啉臨床應用專家共識編寫組. 抗結核新藥貝達喹啉臨床應用專家共識. 中華結核和呼吸雜志, 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.	中國防癆協會. 耐藥結核病化學治療指南(2019年簡版). 中國防癆雜志, 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. 中華醫學會結核病學分會. 中國耐多藥和利福平耐藥結核病治療專家共識(2019年版). 中華結核和呼吸雜志, 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. 張麗帆, 邊賽男, 劉曉清, 等. 利奈唑胺治療廣泛耐藥結核研究進展. 中華實驗和臨床感染病雜志(電子版), 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. 閆麗萍, 吳哲淵, 張祖榮, 等. 初治耐多藥肺結核患者采用初治標準方案治療的前瞻性臨床研究. 中國防癆雜志, 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. 唐神結, 許紹發, 李亮. 耐藥結核病學. 北京: 人民衛生出版社, 2014: 126-287.
11. 楊松, 嚴曉峰. 貝達喹啉治療耐多藥與廣泛耐藥結核病的現狀和展望. 結核病與肺部健康雜志, 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. 中華醫學會結核病學分會, 抗結核新藥貝達喹啉臨床應用專家共識編寫組. 抗結核新藥貝達喹啉臨床應用專家共識. 中華結核和呼吸雜志, 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. 中國防癆協會. 耐藥結核病化學治療指南(2019年簡版). 中國防癆雜志, 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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