含贝达喹啉方案治疗耐多药/广泛耐药结核病的24周单组观察性研究

doi:10.3969/j.issn.1000-6621.2021.05.014

摘要/Abstract

摘要：

目的评价含贝达喹啉方案治疗耐多药结核病(multidrug-resistant tuberculosis,MDR-TB)/广泛耐药结核病(extensively drug-resistant tuberculosis,XDR-TB)的有效性和安全性。方法以2018年3月至2019年8月成都市公共卫生临床医疗中心收治的MDR-TB和XDR-TB患者为研究对象,给予含贝达喹啉的抗结核药物治疗方案。共纳入研究对象50例,包括MDR-TB患者8例(16.0%,8/50)、准广泛耐药结核病(Pre-XDR-TB)患者20例(40.0%,20/50)、XDR-TB患者22例(44.0%,22/50)。分析24周结核分枝杆菌痰培养阴转率和治疗转归以评估治疗的有效性,分析影响治疗成功的因素,记录不良事件发生情况,分析心电图QTcF(按Fridericia法校正的QT间期)的变化以评估安全性。结果 45例(90.0%,45/50)患者完成24周随访,失访3例,死亡2例。24周痰培养阴转率为84.2%(32/38),中位阴转时间为8(4,16)周。24周治疗成功率为84.0%(42/50),多因素logistic回归分析结果显示,BMI<18.5是影响24周治疗成功的独立危险因素(OR=0.070,95%CI=0.005~0.922)。24周内47例(94.0%,47/50)患者累积发生不良事件221次,其中严重不良事件5次(含2例死亡)。50例患者的基线心电图QTcF值中位数为397.5(385.0,411.0)ms;各监测时间[治疗4周为420.0(406.0,438.0)ms,治疗8周为434.0(403.0,445.0)ms,治疗12周为420.0(390.0,440.0)ms,治疗16周为420.0(400.0,439.0)ms,治疗20周为418.0(399.0,440.0)ms,治疗24周为417.0(402.0,440.0)ms] 的QTcF值分别与基线QTcF值比较,差异均有统计学意义(Z=-3.903,P<0.001;Z=-3.770,P<0.001;Z=-2.673,P=0.008;Z=-3.370,P=0.001;Z=-3.550,P<0.001;Z=-3.013,P=0.003)。24周内有6例患者(12.0%,6/50)出现过QTcF>500ms,因此停用贝达喹啉。结论含贝达喹啉的组合方案治疗MDR-TB/XDR-TB患者,24周时的结核分枝杆菌培养阴转率较高,患者耐受性相对良好。

关键词: 泛耐药结核病, 贝达喹啉, 药物评价, 观察性研究

Abstract:

Objective To evaluate the early effectiveness and safety of bedaquiline containing regimen in the treatment of multidrug-resistant (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB). Methods Patients were enrolled in Chengdu Public Health Clinical Medical Center from Mar. 2018 to Aug. 2019 and then were given bedaquiline containing anti-tuberculosis treatment. Fifty cases were enrolled, among which 8 (16.0%), 20 (40.0%), 22 (44.0%) patients were with multidrug-resistant, pre-extensively drug-resistant and extensively drug-resistant tuberculosis respectively. Within 24 weeks, Mycobacterium tuberculosis culture conversion rate and treatment outcome were analyzed to assess treatment effectiveness. Adverse events and QTcF were recorded to assess treatment safety. Results Forty-five (90.0%) cases completed follow-up at 24 weeks, 3 cases were lost, 2 cases died. 84.2% (32/38) of the patients with base-line sputum culture positive had achieved sputum culture conversion, the median time for culture conversion was 8 (4,16) weeks. 84.0% (42/50) of patients showed favorable outcomes. BMI <18.5 was an independent risk factor for treatment success (OR=0.070, 95%CI=0.005-0.922). A total of 221 adverse events occurred in 47 patients (94.0%, 47/50), and 5 severe adverse events occurred in 5 patients (including 2 deaths). The median QTcF value of 50 patients at baseline was 397.5 (385.0, 411.0) ms, which fluctuated between 417.0 (402.0, 440.0) ms (at 24 weeks) and 434.0 (403.0, 445.0) ms (at 8 weeks) after treatment (420.0 (406.0, 438.0) ms at 4 weeks, 420.0 (390.0, 440.0) ms at 12 weeks, 420.0 (400.0, 439.0) ms at 16 weeks, 418.0 (399.0, 440.0) ms at 20 weeks). There were statistically significant difference on QTcF value at each monitoring time compared with that at baseline (Z=-3.903, P<0.001, at 4 weeks; Z=-3.770, P<0.001, at 8 weeks; Z=-2.673, P=0.008, at 12 weeks; Z=-3.370, P=0.001, at 16 weeks; Z=-3.550, P<0.001, at 20 weeks; Z=-3.013, P=0.003, at 24 weeks, respectively). Six patients (12.0%, 6/50) permanently stopped using bedaquiline due to QTcF >500 ms. Conclusion Using bedaquiline containing anti-tuberculosis regimen could achieve high culture conversion rates in patients with MDR and XDR-TB, it was well tolerated too.

Key words: Extensively drug-resistant tuberculosis, Bedaquiline, Drug evaluation, Observational study

时正雨, 吴桂辉, 黄涛, 刘宇红, 高孟秋, 陈蕾, 李曦, 杨铭, 何畏, 陈艳, 鲁小莉, 高静韬, 李亮. 含贝达喹啉方案治疗耐多药/广泛耐药结核病的24周单组观察性研究[J]. 中国防痨杂志, 2021, 43(5): 487-494. doi: 10.3969/j.issn.1000-6621.2021.05.014

SHI Zheng-yu, WU Gui-hui, HUANG Tao, LIU Yu-hong, GAO Meng-qiu, CHEN Lei, LI Xi, YANG Ming, HE Wei, CHEN Yan, LU Xiao-li, GAO Jing-tao, LI Liang. Early effectiveness and safety of bedaquiline containing regimen in treatment of multidrug-resistant and extensively drug-resistant tuberculosis: An one arm observational study of 24 weeks[J]. Chinese Journal of Antituberculosis, 2021, 43(5): 487-494. doi: 10.3969/j.issn.1000-6621.2021.05.014

图/表 6

表1

表2

表3

表4

50例患者治疗转归影响因素的多因素logistic回归分析

因素	β值	s $x ˉ$ 值	Wald χ²值	P值	OR值	95%CI值
性别(男性)	0.767	0.921	0.692	0.405	2.152	0.354~13.097
年龄(40~63岁)	-1.448	1.229	1.389	0.239	0.235	0.021~2.612
BMI(<18.5)	-2.661	1.316	4.089	0.043	0.070	0.005~0.922
耐药类型
MDR-TB	-	-	0.898	0.638	-	-
Pre-XDR-TB	1.293	1.387	0.869	0.351	3.644	0.240~55.219
XDR-TB	0.632	1.090	0.337	0.562	1.882	0.222~15.926
常量	3.544	2.383	2.212	0.137	34.609	-

表4

图1~3

表5

参考文献 31

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类别	例数	构成比(%)
性别
男	36	72.0
女	14	28.0
年龄组(岁)^a
18~39	33	66.0
40~59	15	30.0
60~63	2	4.0
BMI
<18.5	13	26.0
≥18.5	37	74.0
并发症
糖尿病	6	12.0
乙型肝炎	5	10.0
HIV感染	1	2.0
累及部位
单纯肺部	36	72.0
肺部+其他部位	14	28.0
累及肺叶
单个肺叶	11	22.0
多个肺叶	39	78.0
类别	例数	构成比(%)
肺部空洞
无	9	18.0
有	41	82.0
耐药类型
MDR-TB	8	16.0
Pre-XDR-TB	20	40.0
Pre-XDR-TB耐氟喹诺酮类药物	17	34.0
Pre-XDR-TB耐二线注射类药物	3	6.0
XDR-TB	22	44.0
基线结核分枝杆菌培养
阳性	38	76.0
阴性	12	24.0

因素	治疗成功(42例)		不良转归(8例)		χ²值	P值
因素	例数	构成比(%)	例数	构成比例^a	χ²值	P值
性别					0.050	0.823
男	31	73.8	5	5/8
女	11	26.2	3	3/8
年龄组(岁)^b					0.001	0.999
18~39	28	66.7	5	5/8
40~63	14	33.3	3	3/8
BMI					4.530	0.033
<18.5	8	19.0	5	5/8
≥18.5	34	81.0	3	3/8
耐药类型					-	0.217^c
MDR-TB	6	14.3	2	2/8
Pre-XDR-TB	19	45.2	1	1/8
XDR-TB	17	40.5	5	5/8

变量	赋值
自变量
性别	女=0;男=1
年龄	18~39岁=0;40~63岁=1
BMI	≥18.5=0;<18.5=1
耐药类型	MDR-TB=1;Pre-XDR-TB=2;XDR-TB=3
因变量
24周治疗转归	不良转归=0; 治疗成功=1