世界卫生组织《结核分枝杆菌耐药相关基因突变目录(第2版)》解读

doi:10.19982/j.issn.1000-6621.20230450

摘要/Abstract

摘要：

耐药结核病是2035年实现全球终结结核病流行目标的巨大障碍。世界卫生组织(World Health Organization,WHO)倡导采用快速分子药物敏感性检测技术进行耐药结核病早期诊断,而覆盖全面可靠的耐药检测靶标是提高分子药物敏感性检测技术可靠性的关键。WHO于2023年11月发布《结核分枝杆菌耐药相关基因突变目录(第2版)》,目的是基于更广泛的全球数据汇总形成更为全面准确的耐药相关基因突变目录,为开发与完善基于测序或其他方法的新型分子药物敏感性检测技术提供支持。本文对第2版目录相较于第1版目录在分析流程与耐药突变等内容的更新进行了详细的解读,并对未来目录完善的方向进行了展望。

关键词: 分枝杆菌,结核, 抗药性,细菌, 微生物敏感性试验, 基因, 突变

Abstract:

Drug-resistant tuberculosis is a major obstacle to the achievement of the End TB Strategy by 2035. The World Health Organization (WHO) promotes the use of rapid molecular drug susceptibility testing technology for early diagnosis of drug-resistant tuberculosis. Covering comprehensive and reliable drug resistance-related mutations is the key to improving the reliability of molecular drug resistance diagnosis. WHO has released the second edition of the Catalogue of mutations in Mycobacterium tuberculosis complex and their association with drug resistance in November 2023. This catalogue described more comprehensive and accurate drug-resistance-related gene mutations based on the largest collection of multinational Mycobacterium tuberculosis complex isolates, so as to support the development and improvement of the molecular drug susceptibility testing technology. This article provides a detailed interpretation of the updates in the analysis process and drug-resistant mutations in the second edition of the catalogue compared with the first edition, and looks forward to the future direction of improving the catalogue.

Key words: Mycobacterium tuberculosis, Drug resistance, bacterial, Microbial sensitivity tests, Genes, Mutation

中图分类号:

R378.91
R446

裴少君, 欧喜超. 世界卫生组织《结核分枝杆菌耐药相关基因突变目录(第2版)》解读[J]. 中国防痨杂志, 2024, 46(3): 260-266. doi: 10.19982/j.issn.1000-6621.20230450

Pei Shaojun, Ou Xichao. Interpretation of the World Health Organization’s Catalogue of mutations in Mycobacterium tuberculosis complex and their association with drug resistance (2nd Edition)[J]. Chinese Journal of Antituberculosis, 2024, 46(3): 260-266. doi: 10.19982/j.issn.1000-6621.20230450

图/表 3

表1

表2

表3

世界卫生组织《结核分枝杆菌耐药相关基因突变目录(第2版)》基因型耐药预测效能

药物	1组(耐药相关突变)	2组(暂定与耐药相关)	1组+2组
利福平
敏感度(%,95%CI)	92.1(91.7~92.5)	1.1(1.0~1.3)	93.3(92.9~93.7)
特异度(%,95%CI)	97.1(96.9~97.3)	99.8(99.8~99.9)	96.9(96.7~97.1)
阳性预测值(%,95%CI)	94.5(94.2~94.9)	76.5(70.8~81.6)	94.2(93.9~94.6)
异烟肼
敏感度(%,95%CI)	89.6(89.2~90.0)	2.0(1.8~2.2)	91.6(91.2~92.0)
特异度(%,95%CI)	98.2(98.1~98.4)	99.7(99.6~99.7)	97.9(97.8~98.1)
阳性预测值(%,95%CI)	97.5(97.2~97.7)	82.5(78.9~85.7)	97.1(96.8~97.3)
乙胺丁醇
敏感度(%,95%CI)	81.1(80.3~81.9)	0.0	81.1(80.3~81.9)
特异度(%,95%CI)	91.6(91.3~91.9)	100.0(100.0~100.0)	91.6(91.3~91.9)
阳性预测值(%,95%CI)	71.9(71.0~72.8)	0.0	71.9(71.0~72.8)
吡嗪酰胺
敏感度(%,95%CI)	63.5(62.0~64.9)	14.6(13.5~15.6)	78.0(76.8~79.2)
特异度(%,95%CI)	98.6(98.5~98.8)	99.2(99.1~99.3)	97.9(97.6~98.1)
阳性预测值(%,95%CI)	92.4(91.4~93.4)	82.9(80.1~85.5)	90.5(89.5~91.4)
左氧氟沙星
敏感度(%,95%CI)	83.6(82.6~84.5)	1.2(1.0~1.6)	84.8(83.9~85.7)
特异度(%,95%CI)	97.3(97.0~97.5)	99.6(99.6~99.7)	96.9(96.7~97.1)
阳性预测值(%,95%CI)	89.2(88.4~90.0)	48.3(40.1~56.6)	88.1(87.3~89.0)
莫西沙星
敏感度(%,95%CI)	84.8(83.7~85.9)	0.9(0.6~1.2)	85.7(84.6~86.8)
特异度(%,95%CI)	94.0(93.6~94.3)	99.5(99.4~99.6)	93.5(93.2~93.9)
阳性预测值(%,95%CI)	75.2(73.9~76.4)	29.5(21.6~38.4)	74.0(72.7~75.2)
贝达喹啉
敏感度(%,95%CI)	26.3(23.7~29.1)	23.0(20.5~25.7)	49.4(46.3~52.5)
特异度(%,95%CI)	99.4(99.3~99.5)	99.3(99.1~99.4)	98.7(98.5~98.9)
阳性预测值(%,95%CI)	78.2(73.5~82.4)	72.0(66.8~76.8)	75.2(71.8~78.4)
利奈唑胺
敏感度(%,95%CI)	27.3(22.8~32.1)	6.7(4.4~9.7)	34.0(29.2~39.0)
特异度(%,95%CI)	99.8(99.8~99.9)	100.0(99.9~100.0)	99.8(99.7~99.9)
阳性预测值(%,95%CI)	78.5(70.4~85.2)	78.1(60.0~90.7)	78.4(71.3~84.5)
氯法齐明
敏感度(%,95%CI)	4.3(2.9~6.1)	12.7(10.3~15.4)	17.0(14.2~20.0)
特异度(%,95%CI)	99.8(99.7~99.8)	98.9(98.7~99.1)	98.7(98.5~98.9)
阳性预测值(%,95%CI)	46.0(33.4~59.1)	36.0(29.9~42.4)	38.1(32.6~43.8)
德拉马尼
敏感度(%,95%CI)	0.0(0.0~1.5)	14.7(10.6~19.7)	14.7(10.6~19.7)
特异度(%,95%CI)	100.0(100.0~100.0)	99.9(99.8~99.9)	99.9(99.8~99.9)
阳性预测值(%,95%CI)	0.0	72.5(58.3~84.1)	72.5(58.3~84.1)
阿米卡星
敏感度(%,95%CI)	68.9(67.0~70.7)	4.0(3.2~4.8)	72.8(71.0~74.6)
特异度(%,95%CI)	99.2(99.0~99.3)	99.2(99.0~99.3)	98.3(98.1~98.5)
阳性预测值(%,95%CI)	90.1(88.7~91.4)	34.3(28.8~40.1)	82.8(81.2~84.4)
链霉素
敏感度(%,95%CI)	72.1(71.2~72.9)	7.6(7.1~8.1)	79.7(78.9~80.5)
特异度(%,95%CI)	97.6(97.4~97.8)	96.5(96.2~96.8)	94.1(93.7~94.4)
阳性预测值(%,95%CI)	95.2(94.7~95.7)	58.8(56.1~61.4)	89.9(89.3~90.5)
乙硫异烟胺
敏感度(%,95%CI)	45.8(44.4~47.1)	29.1(27.8~30.3)	74.8(73.6~76.0)
特异度(%,95%CI)	94.0(93.6~94.3)	91.9(91.5~92.3)	85.9(85.3~86.4)
阳性预测值(%,95%CI)	71.7(70.1~73.2)	54.6(52.7~56.4)	63.9(62.7~65.1)
卡那霉素^a
敏感度(%,95%CI)	74.4(73.0~75.9)	0.4(0.3~0.7)	74.9(73.4~76.3)
特异度(%,95%CI)	96.7(96.5~97.0)	100.0(99.9~100.0)	96.7(96.4~96.9)
阳性预测值(%,95%CI)	79.4(78.0~80.8)	66.7(44.7~84.4)	79.3(77.9~80.7)
卷曲霉素^a
敏感度(%,95%CI)	61.2(59.1~63.3)	4.9(4.0~6.0)	66.2(64.1~68.2)
特异度(%,95%CI)	98.0(97.8~98.2)	99.8(99.7~99.9)	97.8(97.6~98.1)
阳性预测值(%,95%CI)	80.4(78.4~82.3)	76.1(68.0~83.1)	80.1(78.1~81.9)

表3

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第2版	第1版
第2版	1组	2组	3组	4组	5组	无
1组	167	53	18	0	0	8
2组	9	880	107	0	0	126
3组	4	7(98)^a	12581	3	8	21178
4组	0	(1)^a	7	20	29	1(12358)^b
5组	0	0	36	5	136	182(126)^b