含贝达喹啉方案治疗耐多药肺结核疗效与安全性的Meta分析

doi:10.19982/j.issn.1000-6621.20220012

摘要/Abstract

摘要： 目的系统评价含贝达喹啉方案治疗耐多药肺结核(multidrug-resistant pulmonary tuberculosis,MDR-PTB)的疗效与安全性。方法检索中文数据库,包括中国知网、万方、维普、中国生物医学文献数据库,以及英文数据库,包括The Cochrane Library、PubMed、Embase,搜集含贝达喹啉方案治疗MDR-PTB的随机对照试验,检索时限从建库至2021年12月,由2位研究人员独立筛选文献、提取数据、评价文献质量后,采用RevMan 5.4软件对纳入的数据进行异质性检验分析,对文章进行发表偏倚分析。结果研究纳入10篇文献,共802例患者。Meta分析结果显示,与常规抗结核治疗方案相比,含贝达喹啉方案治疗MDR-PTB可提高12周末痰菌阴转率(OR=3.17,95%CI:1.85~5.43,P<0.01)、治疗24周末痰菌阴转率(OR=4.09,95%CI:2.74~6.12,P<0.01)、空洞闭合率(OR=3.11,95%CI:1.68~5.74,P<0.01)、病灶吸收率(OR=4.44,95%CI:2.40~8.22,P<0.01)和临床治愈率(OR=4.15, 95%CI:2.27~7.58,P<0.01),降低病亡率(OR=5.22,95%CI:1.16~16.96,P<0.01);与常规抗结核治疗方案相比,含贝达喹啉方案治疗MDR-TB的8周末痰菌阴转率(OR=1.79,95%CI:0.98~3.26,P=0.06)、药物不良反应发生率(OR=2.72,95%CI:0.61~12.19,P=0.19)差异无统计学意义。结论与常规抗结核治疗方案相比,含贝达喹啉的化疗方案治疗MDR-PTB有助于加速痰菌阴转,提高患者临床疗效,不会增加不良反应,但仍需严密监测心电图,警惕贝达喹啉的心脏毒性。

关键词: 结核, 抗多种药物性, 治疗结果, 安全, Meta分析(主题), 贝达喹啉

Abstract:

Objective: To systematically evaluate the efficacy and safety of the treatment containing bedaquiline for multidrug-resistant pulmonary tuberculosis (MDR-PTB). Methods: Randomized controlled trials (RCTs) of bedaquiline-containing regimens for the treatment of MDR-PTB were searched and collected from Chinese databases (China National Knowledge Infrastructure (CNKI), Wanfang Data, VIP and China Biomedical Literature Database (CBM)) and English databases (The Cochrane Library, PubMed, Embase). The retrieval time was from the establishment of the database to December 2021. Two researchers independently screened the literature, extracted data, and evaluated the quality of the literature. RevMan 5.4 software was used to analyze the heterogeneity of the included data, and the publication bias. Results: A total of 802 patients were included in 10 articles. Meta-analysis results showed that compared with conventional anti-tuberculosis regimens, bedaquiline-containing regimens in the treatment of MDR-PTB could increase the negative conversion rate of sputum at the end of 12 weeks after treatment (OR=3.17, 95%CI: 1.85-5.43, P<0.01), improve the negative rate of sputum bacteria at the end of 24 weeks after treatment (OR=4.09, 95%CI: 2.74-6.12, P<0.01), the cavity closure rate (OR=3.11, 95%CI: 1.68-5.74, P<0.01), the absorption rate of lesions (OR=4.44, 95%CI: 2.40-8.22, P<0.01) and clinical cure rate (OR=4.15, 95%CI: 2.27-7.58, P<0.01), and reduce the level of mortality (OR=5.22, 95%CI: 1.16-16.96, P<0.01). However, there was no significant difference in sputum negative conversion rate at the end of 8 weeks after treatment (OR=1.79, 95%CI: 0.98-3.26, P=0.06) and incidence of adverse drug reactions (OR=2.72, 95%CI: 0.61-12.19, P=0.19) at the end of 8 weeks after treatment with bedaquiline-containing regimens for MDR-PTB. Conclusion: Compared with conventional anti-tuberculosis treatment, the chemotherapy regimens containing bedaquiline for MDR-PTB help to accelerate the negative conversion of sputum bacteria and improve the clinical efficacy, with no increase in adverse reactions; however, ECG should be closely monitored to be alert to the cardiotoxicity of bedaquiline.

Key words: Tuberculosis, multidrug-resistant, Treatment outcome, Safety, Meta-analysis as topic, Bedaquiline

余春红, 刘幸, 沈凌筠, 李海雯, 李谢, 伍蓉霜, 李先蕊, 樊浩. 含贝达喹啉方案治疗耐多药肺结核疗效与安全性的Meta分析[J]. 中国防痨杂志, 2022, 44(7): 660-668. doi: 10.19982/j.issn.1000-6621.20220012

YU Chun-hong, LIU Xing, SHEN Ling-jun, LI Hai-wen, LI Xie, WU Rong-shuang, LI Xian-rui, FAN Hao. Meta analysis of efficacy and safety of the treatment containing bedaquiline for multidrug-resistant pulmonary tuberculosis[J]. Chinese Journal of Antituberculosis, 2022, 44(7): 660-668. doi: 10.19982/j.issn.1000-6621.20220012

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参考文献 24

[1]	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
[2]	竺丽梅. 全面完善我国结核病控制策略, 加速遏制结核病进程. 中国热带医学, 2020, 20(10):913-915. doi: 10.13604/j.cnki.46-1064/r.2020.10.01. doi: 10.13604/j.cnki.46-1064/r.2020.10.01
[3]	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(2020年更新版). 中华结核和呼吸杂志, 2021, 44(2):81-87. doi: 10.3760/cma.j.cn112147-20200714-00805. doi: 10.3760/cma.j.cn112147-20200714-00805
[4]	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 pmid: 15591164
[5]	World Health Organization. WHO Consolidated guidelines on tuberculosis. Module 4: treatment-drug-resistant tuberculosis treatment. Geneva: World Health Organization, 2020.
[6]	牟厚玲. 贝达喹啉治疗耐多药肺结核的疗效及安全性观察. 河北医药, 2021, 43(19):2955-2957,2961. doi: 10.3969/j.issn.1002-7386.2021.19.018. doi: 10.3969/j.issn.1002-7386.2021.19.018
[7]	常瑞霞, 可春梅. 贝达喹啉治疗耐多药结核病的疗效和安全性. 临床药物治疗杂志, 2021, 19(3):57-60. doi: 10.3969/j.issn.1672-3384.2021.03.011. doi: 10.3969/j.issn.1672-3384.2021.03.011
[8]	任娜, 胡善雷, 刘金瑾, 等. 富马酸贝达喹啉片治疗耐多药肺结核的疗效观察. 临床肺科杂志, 2021, 26(7):1047-1051. doi: 10.3969/j.issn.1009-6663.2021.07.018. doi: 10.3969/j.issn.1009-6663.2021.07.018
[9]	凌慧琪, 陈伟杰, 何显科. 富马酸贝达喹啉片治疗耐多药肺结核的临床疗效分析. 广西医科大学学报, 2021, 38(7):1442-1447. doi: 10.16190/j.cnki.45-1211/r.2021.07.032. doi: 10.16190/j.cnki.45-1211/r.2021.07.032
[10]	陈艳, 陈竹, 黄涛, 等. 含贝达喹啉的联合方案治疗耐多药结核病的疗效及安全性研究. 华西医学, 2021, 36(10):1392-1398. doi: 10.7507/1002-0179.202006302. doi: 10.7507/1002-0179.202006302
[11]	班立芳, 马峥, 孔庆飞, 等. 贝达喹啉对耐多药肺结核患者免疫功能及细胞因子的影响. 检验医学与临床, 2020, 17(16):2292-2294. doi: 10.3969/j.issn.1672-9455.2020.16.006. doi: 10.3969/j.issn.1672-9455.2020.16.006
[12]	吴浩宇. 贝达喹啉联合常规抗结核药物治疗耐多药肺结核的效果观察. 中国医药指南, 2020, 18(29):48-49. doi: 10.15912/j.cnki.gocm.2020.29.022. doi: 10.15912/j.cnki.gocm.2020.29.022
[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. doi: 10.1056/NEJMoa0808427. doi: 10.1056/NEJMoa0808427 URL
[14]	Diacon AH, Donald PR, Pym A, et al. Randomized pilot trial of eight weeks of bedaquiline (TMC207) treatment for multidrug-resistant tuberculosis: long-term outcome, tolerability, and effect on emergence of drug resistance. Antimicrob Agents Chemother, 2012, 56(6): 3271-3276. doi: 10.1128/AAC.06126-11. doi: 10.1128/AAC.06126-11 pmid: 22391540
[15]	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. doi: 10.1056/NEJMoa1313865. doi: 10.1056/NEJMoa1313865 URL
[16]	卢春容, 房宏霞, 陆普选, 等. WHO 2021年全球结核病报告: 全球与中国关键数据分析. 新发传染病电子杂志, 2021, 6(4): 368-372. doi: 10.19871/j.cnki.xfcrbzz.2021.04.023. doi: 10.19871/j.cnki.xfcrbzz.2021.04.023
[17]	Collaborative Group for the Meta-Analysis of Individual Patient Data in MDR-TB treatment-2017, Ahmad N, Ahuja SD, 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
[18]	Gao M, Gao J, Xie L, et al. Early outcome and safety of bedaquiline-containing regimens for treatment of MDR- and XDR-TB in China: a multicentre study. Clin Microbiol Infect, 2020, 27(4):597-602. doi: 10.1016/j.cmi.2020.06.004. doi: 10.1016/j.cmi.2020.06.004 URL
[19]	World Health Organization. The use of bedaquiline in the treatment of multidrug-resistant tuberculosis: Interim policy guidance[M/OL]. [2021-12-06].
[20]	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. doi: 10.3969/j.issn.2095-3755.2019.04.004. doi: 10.3969/j.issn.2095-3755.2019.04.004
[21]	谢莉, 高静韬, 马丽萍, 等. 含贝达喹啉方案治疗耐多药肺结核对患者心电图QT间期的影响. 中国防痨杂志, 2020, 42(7):687-694. doi: 10.3969/j.issn.1000-6621.2020.07.009. doi: 10.3969/j.issn.1000-6621.2020.07.009
[22]	Pontali E, Sotgiu G, Tiberi S, et al. Cardiac safety of bedaquiline: a systematic and critical analysis of the evidence. Eur Respir J, 2017, 50(5):1701462. doi: 10.1183/13993003.01462-2017. doi: 10.1183/13993003.01462-2017 URL
[23]	Meyvisch P, Kambili C, Andries K, et al. Evaluation of six months sputum culture conversion as a surrogate endpoint in a multidrug resistant-tuberculosis trial. PLoS One, 2018, 13(7): e200539. doi: 10.1371/journal.pone.0200539. doi: 10.1371/journal.pone.0200539
[24]	胡春梅, 方刚, 张向荣, 等. 贝达喹啉联合常规抗结核药物治疗耐多药肺结核患者的长期疗效及安全性观察. 国际医药卫生导报, 2018, 24(5):711-715. doi: 10.3760/cma.j.issn.1007-1245.2018.05.028. doi: 10.3760/cma.j.issn.1007-1245.2018.05.028

文献来源	样本量(男/女,例)		平均年龄(岁)		平均病程(年)		干预措施		疗程 (周)	观察指标
文献来源	C	T	C	T	C	T	C	T	疗程 (周)	观察指标
牟厚玲 2021^[6]	31 (24/7)	32 (21/11)	34.25± 2.01	34.35± 1.95	2.59± 0.51	2.61± 0.48	个体化治疗方案+Bdq	个体化治疗方案	24	③④⑦
常瑞霞 2021^[7]	45 (31/14)	45 (29/16)	51.6± 4.7	52.2± 4.4	7.0± 1.4	6.8± 1.6	个体化治疗方案+Bdq	个体化治疗方案	24	③⑤⑥⑦
任娜 2021^[8]	30 (19/11)	30 (17/13)	47.12± 12.33	46.85± 13.01	8.27± 5.57	8.08± 5.27	个体化治疗方案+Bdq	个体化治疗方案	24	③④⑤ ⑥⑦
凌慧琪 2021^[9]	32 (18/14)	32 (19/13)	45.35± 4.61	45.27± 4.59	1.19± 0.13	1.20± 0.12	个体化治疗方案+Bdq	个体化治疗方案	24	②③④ ⑤⑥⑦
陈艳 2021^[10]	69 (44/25)	60 (45/15)	34.6± 11.0	35.5± 13.82	-	-	个体化治疗方案+Bdq	个体化治疗方案	24	①②③⑧
班立芳 2020^[11]	53 (31/22)	52 (32/20)	42.65± 5.35	43.02± 5.40	2.96± 0.56	2.97± 0.58	个体化治疗方案+Bdq	个体化治疗方案	24	③
吴浩宇 2020^[12]	34 (19/15)	34 (20/14)	41.02± 3.55	40.11± 3.82	6.03± 2.15	5.97± 2.71	个体化治疗方案+Bdq	个体化治疗方案	24	②③④ ⑥⑦
Diacon 2009^[13]	23 (18/5)	24 (17/7)	33	33	-	-	个体化治疗方案+Bdq	个体化治疗方案	24	①⑧
Diacon 2012^[14]	21 (16/5)	23 (16/7)	33	33	-	-	个体化治疗方案+Bdq	个体化治疗方案	24	①⑧
Diacon 2014^[15]	66 (45/21)	66 (40/26)	32	34	-	-	个体化治疗方案+Bdq	个体化治疗方案	24	③⑧

纳入研究	随机方法	分配隐藏	盲法	结果数据的完整性	选择性报告研究结果	其他偏倚风险来源
牟厚玲2021^[6]	门诊单双号	不清楚	不清楚	是	是	不清楚
常瑞霞2021^[7]	患者意愿	不清楚	不清楚	是	是	不清楚
任娜2021^[8]	随机数字表	不清楚	不清楚	是	是	不清楚
凌慧琪2021^[9]	随机	不清楚	不清楚	是	是	不清楚
陈艳2021^[10]	入院时间	不清楚	不清楚	是	是	不清楚
班立芳2020^[11]	随机	不清楚	不清楚	是	是	不清楚
吴浩宇2020^[12]	数字随机表	不清楚	不清楚	是	是	不清楚
Diacon2009^[13]	随机	恰当	双盲	是	是	不清楚
Diacon2012^[14]	随机	恰当	双盲	是	是	不清楚
Diacon2014^[15]	随机	恰当	双盲	是	是	不清楚