Analysis of adverse reactions of bedaquiline containing regimen in the treatment of drug-resistant pulmonary tuberculosis

doi:10.19982/j.issn.1000-6621.20210702

Abstract

Abstract:

Objective: To analyze the adverse reactions of bedaquiline combined with conventional anti-tuberculosis drugs in the treatment of drug-resistant pulmonary tuberculosis, so as to provide basis for the safe use and monitoring of bedaquiline. Methods: A retrospective study was conducted in 127 patients with multidrug-resistant tuberculosis, pre-extensive drug-resistant pulmonary tuberculosis, extensively drug-resistant pulmonary tuberculosis and rifampicin-resistant pulmonary tuberculosis from the Drug-Resistant Tuberculosis Ward of Shandong Public Health Clinical Center. All of them completed 24-week treatment and follow-up from November 2018 to December 2020. And 66 patients treated with bedaquiline containing regimen were considered as the observation group, the other 61 patients treated without bedaquiline containing regimen were considered as the control group. Clinical data including age, gender, drug resistance type, whether or not complicated with diabetes mellitus, whether or not take other drugs that led to prolonged QTc interval, etc., were collected. The occurrence of adverse drug reactions in the treatment of the two groups was monitored, and the influencing factors of QTc interval prolongation (>450 ms) in the observation group were analyzed. Results: The incidence of QTc interval prolongation in the observation group was 48.5% (32/66), which was significantly higher than that in the control group (26.2% (16/61)) (χ²=6.678, P=0.001). There were 3 cases (4.5%) and 1 case (1.6%) with QTc interval >500 ms in the observation group and the control group, respectively. The difference was not statistically significant (Fisher exact probability method, P=0.143). There was no difference in the occurrence of other adverse drug reactions between the two groups. The QTc interval in the observation group gradually increased with the use time of the treatment regimen containing bedaquiline. At the end of the 4th week, the QTc interval was (435.1±28.8) ms, which was significantly higher than that in the baseline period ((419.0±23.2) ms) (t=3.477, P=0.001), and the peak appeared at the end of the 12th week ((439.5±30.7) ms). Multivariate analysis showed that, if treated with bedaquiline containing regimen, the risk of QTc interval prolongation in patients aged ≥45 years was 9.027 times (95%CI: 1.033-78.859) of that in patients aged 18-45 years; combined use of other drugs that can lead to QTc interval prolongation was also an independent risk factor for QTc interval prolongation (OR (95%CI)=9.033 (1.042-78.326)). Conclusion: The incidence of QTc interval prolongation increased in patients with drug-resistant pulmonary tuberculosis after treatment with bedaquiline containing regimen, but there was no serious adverse cardiac events. The incidence of adverse events in other systems did not increase. Elderly patients were at high risk of QTc interval prolongation.

Key words: Tuberculosis,pulmonary, Tuberculosis,multidrug-resistant, Drug toxicity, Bedaquiline

CLC Number:

R453
R521

ZHANG Yu-xia, XIONG Yu, CHANG Ting-ting, LIU Feng-xia. Analysis of adverse reactions of bedaquiline containing regimen in the treatment of drug-resistant pulmonary tuberculosis[J]. Chinese Journal of Antituberculosis, 2022, 44(3): 239-245. doi: 10.19982/j.issn.1000-6621.20210702

Figures/Tables 7

References 20

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特征	观察组(66例)	对照组(61例)	统计检验值	P值
年龄[岁,M(Q₁,Q₃)]	34.0(21,64)	41.5(22,70)	Z=-3.351	0.001
性别[例(构成比,%)]			χ²=0.375	0.540
男性	44(66.7)	38(62.3)
女性	22(33.3)	23(37.7)
耐药类型[例(构成比,%)]			χ²=5.911	0.052
广泛耐药	7(10.6)	4(6.6)
准广泛耐药	14(21.2)	4(6.6)
耐多药	44(66.7)	48(78.6)
利福平耐药	1(1.5)	5(8.2)
使用其他导致QTc间期延长药物[例(构成比,%)]			χ²=1.331	0.249
是	53(80.3)	45(73.8)
否	13(19.7)	16(26.2)

不良反应	观察组(66例)	对照组(61例)	χ²值	P值
QTc间期延长	32(48.5)	16(26.2)	6.678	0.001
QTc间期>500ms	3(4.5)	1(1.6)		0.143^a
血液系统损伤	12(18.2)	6(9.8)	1.815	0.178
神经系统损伤	12(18.2)	8(13.1)	0.613	0.433
肝损伤	10(15.2)	16(26.2)	2.389	0.122
胃肠道反应	2(3.0)	3(4.9)		0.671^a
肾功能损伤	1(1.5)	2(3.3)		0.608^a
精神异常	2(3.0)	3(4.9)		0.671^a
过敏反应	1(1.5)	3(4.9)		0.350^a
甲状腺功能紊乱	1(1.5)	0(0.0)		1.000^a

特征	例数	构成比(%)	QTc间期(ms,$\bar{x} \pm s$)	统计检验值	P值
年龄(岁)				t=1.151	0.254
18~44	55	83.3	418.2±23.1
≥45	11	16.7	427.0±23.5
性别				t=0.369	0.713
男性	44	66.7	418.8±24.5
女性	22	33.3	421.2±19.5
耐药类型				F=1.756	0.320
耐多药	7	10.6	420.5±20.3
准广泛耐药	14	21.2	419.6±22.7
广泛耐药	44	66.7	425.6±19.7
利福平耐药	1	1.5	440

治疗时间(周)	例数	基线期QTc间期(ms,$\bar{x} \pm s$)	瞬时QTc间期(ms,$\bar{x} \pm s$)	t值	P值
0	66	419.4±23.1
2	63	419.4±23.4	427.4±23.9	1.890	0.061
4	64	419.0±23.2	435.1±28.8	3.477	0.001
8	58	421.4±23.0	437.8±26.5	3.552	0.001
12	60	418.0±23.7	439.5±30.7	4.290	0.000
16	54	418.6±23.5	433.0±26.1	3.008	0.003
20	56	419.7±23.7	436.5±24.6	3.628	0.000
24	46	420.0±22.3	430.7±19.3	2.459	0.016

因素	例数	QTc间期延长 [例(发生率,%)]	χ²值	P值
年龄(岁)			0.039^a
18~44	55	23(41.8)
≥45	11	9(81.8)
性别			1.486	0.223
男性	44	19(43.2)
女性	22	13(59.1)
使用其他导致QTc间期延长药物			4.184	0.041
是	53	29(54.7)
否	13	3(23.1)
合并糖尿病			0.570	0.450
是	12	7(58.3)
否	54	25(46.3)
耐药类型				0.685^a
耐多药	44	24(54.5)
准广泛耐药	14	6(42.3)
广泛耐药	7	2(2/7)
利福平耐药	1	0(0.0)