Research progress of bedaquiline for the treatment of multidrug-resistant tuberculosis

doi:10.3969/j.issn.1000-6621.2021.06.017

Abstract

Abstract:

The emergence and spread of multidrug-resistant tuberculosis (MDR-TB) has become a major obstacle to the World Health Organization’s End TB Strategy by 2035. Some studies have shown that the treatment success rate of MDR-TB with second-line anti-TB drugs was lower, and it was even worse in the patients with extensive drug-resistant tuberculosis (XDR-TB). Therefore, there is an urgent need to develop new anti-tuberculosis drugs. Bedaquiline is the first drug approved for the treatment of MDR-TB in the past 50 years. It can significantly increase the cure rate of MDR-TB and shorten the treatment duration. In order to improve the clinical doctors’ understanding of bedaquiline on MDR-TB treatment, we wrote this paper by reviewing the status of bedaquiline in the treatment of MDR/XDR-TB, the clinical research progress and several relevant issues.

Key words: Tuberculosis,multidrug-resistant, Bedaquline, Clinical protocols, Research

LIAO Wei-ming, FU Liang, DENG Guo-fang, YUAN Xiao-liang. Research progress of bedaquiline for the treatment of multidrug-resistant tuberculosis[J]. Chinese Journal of Antituberculosis, 2021, 43(6): 619-624. doi: 10.3969/j.issn.1000-6621.2021.06.017

Figures/Tables 1

References 35

[1]	World Health Organization. Global tuberculosis report 2020. Geneva: World Health Organization, 2020.
[2]	World Health Organization. WHO consolidated guidelines on tuberculosis. Module 4: treatment-drug-resistant tuberculosis treatment. Geneva: World Health Organization, 2020.
[3]	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. doi: 10.3969/j.issn.1000-6621.2019.10.001. doi: 10.3969/j.issn.1000-6621.2019.10.001
[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. doi: 10.3760/cma.j.issn.1001-0939.2019.10.006. doi: 10.3760/cma.j.issn.1001-0939.2019.10.006
[5]	Ghajavand H, Kargarpour Kamakoli M, Khanipour S, et al. High Prevalence of Bedaquiline Resistance in Treatment-Naive Tuberculosis Patients and Verapamil Effectiveness. Antimicrob Agents Chemother, 2019,63(3):e02530-18. doi: 10.1128/AAC.02530-18. doi: 10.1128/AAC.02530-18
[6]	Andries K, Verhasselt P, Guillemont J, et al. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science, 2005,307(5707):223-227. doi: 10.1126/science.1106753. doi: 10.1126/science.1106753 URL
[7]	Huitric E, Verhasselt P, Andries K, et al. In vitro antimycobacterial spectrum of a diarylquinoline ATP synthase inhibitor. Antimicrob Agents Chemother, 2007,51(11):4202-4204. doi: 10.1128/AAC.00181-07. doi: 10.1128/AAC.00181-07 URL
[8]	Koul A, Vranckx L, Dhar N, et al. Delayed bactericidal response of Mycobacterium tuberculosis to bedaquiline involves remodelling of bacterial metabolism. Nat Commun, 2014,5:3369. doi: 10.1038/ncomms4369. doi: 10.1038/ncomms4369 URL
[9]	Mase S, Chorba T, Lobue P, et al. 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(RR-09):1-12. doi: 10.1186/1472-6874-13-41. doi: 10.1186/1472-6874-13-41
[10]	World Health Organization. The use of bedaquiline in the treatment of multidrug-resistant tuberculosis. Geneva: World Health Organization, 2014.
[11]	Ndjeka N, Hughes J, Reuter A, et al. Implementing novel regimens for drug-resistant TB in South Africa: what can the world learn? Int J Tuberc Lung Dis, 2020,24(10):1073-1080. doi: 10.5588/ijtld.20.0174. doi: 10.5588/ijtld.20.0174 URL
[12]	Ahmad N, Ahuja SD, Akkerman OW, et al. Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis. Lancet, 2018,392(10150):821-834. doi: 10.1016/S0140-6736(18)31644-1. doi: 10.1016/S0140-6736(18)31644-1 URL
[13]	World Health Organization. Global tuberculosis report 2018. Geneva: World Health Organization, 2018.
[14]	World Health Organization. Global tuberculosis report 2019. Geneva: World Health Organization, 2019.
[15]	Pontali E, Raviglione MC, Migliori GB, et al. Regimens to treat multidrug-resistant tuberculosis: past, present and future perspectives. Eur Respir Rev, 2019,28(152):190035. doi: 10.1183/16000617.0035-2019. doi: 10.1183/16000617.0035-2019 URL
[16]	World Health Organization. Rapid communication: Key changes to the treatment of dru-resistant tuberculosis. Geneva: World Health Organization, 2019.
[17]	World Health Organization. Consolidated guidelines on drug-resistant tuberculosis treatment. Geneva: World Health Organization, 2019.
[18]	World Health Organization. WHO operational handbook on tuberculosis. Module 4: treatment-drug-resistant tuberculosis treatment. Geneva: World Health Organization, 2020.
[19]	Lee A, Xie YL, Barry CE, et al. Current and future treatments for tuberculosis. BMJ, 2020,368:m216. doi: 10.1136/bmj.m216. doi: 10.1136/bmj.m216
[20]	Moodley R, Godec TR, STREAM Trial Team. Short-course treatment for multidrug-resistant tuberculosis: the STREAM trials. Eur Respir Rev, 2016,25(139):29-35. doi: 10.1183/16000617.0080-2015. doi: 10.1183/16000617.0080-2015 pmid: 26929418
[21]	International Union Against Tuberculosis and Lung Disease. The evaluation of a standard treatment regimen for anti-tuberculosis drugs for patients with MDR-TB (STREAM) stage 2[EB/OL]. [2020-12-15]. https://clinicaltrials.gov/ct2/show/study/NCT02409290.
[22]	Conradie F, Diacon AH, Ngubane N, et al. Treatment of Highly Drug-Resistant Pulmonary Tuberculosis. N Engl J Med, 2020,382(10):893-902. doi: 10.1056/NEJMoa1901814. doi: 10.1056/NEJMoa1901814 URL
[23]	University of Cape Town. Evaluating a new treatment regimen for patients with MDR-TB (NEXT)[EB/OL]. [2020-12-15]. https://clinicaltrials.gov/ct2/show/NCT02454205.
[24]	Médecins Sans Frontières. Pragmatic clinical trial for a more effective concise and less toxic MDR-TB treatment regimen (TB-PRACTECAL)[EB/OL]. [2020-12-15]. https://clinicaltrials.gov/ct2/show/NCT02589782.
[25]	Médecins Sans Frontières. Evaluating newly approved drugs for MDR-TB (endTB)[EB/OL]. [2020-12-15]. https://clinicaltrials.gov/ct2/show/NCT02754765.
[26]	Seung KJ, Khan U, Varaine F, et al. Introducing new and repurposed TB drugs: the endTB experience. Int J Tuberc Lung Dis, 2020,24(10):1081-1086. doi: 10.5588/ijtld.20.0141. doi: 10.5588/ijtld.20.0141 URL
[27]	Médecins Sans Frontières. Evaluating Newly Approved Drugs in Combination Regimens for Multidrug-Resistant TB with Fluoroquinolone Resistance (endTB-Q) [EB/OL]. [2020-12-15]. https://clinicaltrials.gov/ct2/show/study/NCT03896685.
[28]	Global Alliance for TB Drug Development. Trial to Evaluate the Efficacy, Safety and Tolerability of BPaMZ in Drug-Sensitive (DS-TB) Adult Patients and Drug-Resistant (DR-TB) Adult Patients [EB/OL]. [2020-12-15]. https://clinicaltrials.gov/ct2/show/NCT03338621.
[29]	Tweed CD, Dawson R, Burger DA, et al. Bedaquiline, moxifloxacin, pretomanid, and pyrazinamide during the first 8 weeks of treatment of patients with drug-susceptible or drug-resistant pulmonary tuberculosis: a multicentre, open-label, partially randomised, phase 2b trial. Lancet Respir Med, 2019,7(12):1048-1058. doi: 10.1016/S2213-2600(19)30366-2. doi: 10.1016/S2213-2600(19)30366-2 URL
[30]	Wits Health Consortium(Pty) Ltd. Building Evidence for Advancing New Treatment for Rifampicin Resistant Tuberculosis (RR-TB) Comparing a Short Course of Treatment (Containing Bedaquiline, Delamanid and Linezolid) with the Current South African Standard of Care[EB/OL]. [2020-12-15]. https://www.clinicaltrials.gov/ct2/show/NCT04062201.
[31]	深圳市第三人民医院. 中国耐多药结核病全口服短程抗结核方案和宿主导向治疗的前瞻性对照临床试验 [EB/OL]. [2020-12-15]. http://www.chictr.org.cn/showproj.aspx?proj=52620.
[32]	深圳市第三人民医院. 全口服短程方案治疗氟喹诺酮类敏感性耐多药结核病的多中心随机撤药试验 [EB/OL]. [2020-12-15]. http://www.chictr.org.cn/showproj.aspx?proj=66452.
[33]	上海市公共卫生临床中心. 树突细胞联合含贝达喹啉的抗结核新方案干预治疗难治性耐多药结核患者的Ⅰ期临床研究[EB/OL]. [2020-12-15]. http://www.chictr.org.cn/showproj.aspx?proj=57588.
[34]	上海市公共卫生临床中心. 贝达喹啉在MDR/RR肺结核儿童中的安全性及初步有效性试验研究方案[EB/OL]. [2020-12-15]. http://www.chictr.org.cn/showproj.aspx?proj=53053.
[35]	首都医科大学附属北京胸科医院. 含贝达喹啉治疗耐多药结核病短程新方案的多中心随机对照研究[EB/OL]. [2020-12-15]. http://www.chictr.org.cn/showproj.aspx?proj=47842.

研究名称药品组合	研究内容	疗程	阶段性成果
EndTB
Bdq-Lzd-Mfx-PZA	MDR-TB	9个月	无
Bdq-Lzd-Mfx-Cfz-PZA	MDR-TB	9个月	无
Bdq-Lzd-Mfx-Dlm-PZA	MDR-TB	9个月	无
Lzd-Mfx-Dlm-Cfz-PZA	MDR-TB	9个月	无
Mfx-Dlm-Cfz-PZA	MDR-TB	9个月	无
EndTB-Q
Bdq-Lzd-Dlm-Cfz	氟喹诺酮类药品耐药性;MDR-TB	6~9个月	无
研究名称药品组合	研究内容	疗程		阶段性成果
Nix-TB
Bdq-Lzd-Ptm	MDR-TB	6~9个月		90%的患者获得良好治疗结局(治疗成功,且无复发)
SimpliciTB
INH-RFP-PZA-EMB/INH-RFP	DS-TB	6个月		无
Bdq-Ptm-Mfx-PZA	DS-TB	4个月		8周杀菌活性良好
Bdq-Ptm-Mfx-PZA	MDR-TB	6个月		无
STREAM Ⅱ
2011 WHO MDR-TB治疗方案^a	MDR-TB	18~20个月		无
Km-INH-Pto-Mfx-Cfz-EMB-PZA/Mfx-Cfz-EMB-PZA	MDR-TB	强化期16周/巩固期24周		无
Bdq-INH-Pto-Lfx-Cfz-EMB-PZA/Bdq-Lfx-Cfz-EMB-PZA	MDR-TB	强化期16周/巩固期24周		无
Bdq-Km-INH-Lfx-Cfz-PZA/Bdq-Lfx-Cfz-PZA	MDR-TB	强化期8周/巩固期20周		无
BEAT TB
Bdq-Dlm-Lzd-Lfx-Cfz	MDR-TB	6个月		无
Bdq-INH-EMB-PZA-Lzd-Cfz-Lfx	RR-TB	9个月		无
TB-PRACTECAL
Bdq-Ptm-Lzd	MDR/XDR-TB	6个月		无
Bdq-Ptm-Lzd-Lfx	MDR/XDR-TB	6个月		无
Bdq-Ptm-Lzd-Cfz	MDR/XDR-TB	6个月		无
NeXT
PZA-Pto-Trp-Mfx-Km	MDR-TB	21~24个月		无
Bdq-Pto/INH^h-Lzd-Lfx-PZA	MDR-TB	6~9个月		无