Genetic variants and their association with phenotypic resistance to bedaquiline in Mycobacterium tuberculosis: a systematic review and individual isolate data analysis.
Genetic variants and their association with phenotypic resistance to bedaquiline in Mycobacterium tuberculosis: a systematic review and individual isolate data analysis.
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DOI：
10.1016/s2666-5247(21)00175-0
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发表时间：
2021-11
期刊：
影响因子：
--
通讯作者：
Van Rie A
中科院分区：
文献类型：
--
作者：
Ismail N;Rivière E;Limberis J;Huo S;Metcalfe JZ;Warren RM;Van Rie A
贝达喹啉是控制耐利福平结核病的关键药物。分子耐药分析有助于贝达喹啉的有效使用和耐药性监测。为了促进分子分析的发展，我们旨在鉴定贝达喹啉耐药的基因组标记。在这项系统评价和个体分离物分析中，我们检索了欧洲PubMed Central和Scopus从每个数据库建立到2020年10月19日发表的研究，这些研究评估了临床或非临床结核分枝杆菌分离物的基因型和表型贝达喹啉耐药性。所有报告了四个相关基因（Rv0678、atpE、pepQ和Rv1979c）变异评估以及临床和非临床样本中贝达喹啉表型数据的研究均被纳入。我们使用世卫组织认可的标准化方法，整理了来自符合条件的研究的单个分离物数据，以评估基因组变异与表型贝达喹啉耐药性之间的关系。提取数据的偏倚风险由两位作者使用临床研究诊断准确性研究质量评估工具和实验动物系统评价中心实验动物研究工具独立评估。主要结果是确定4个感兴趣基因（Rv0678、atpE、pepQ和Rv1979c）中与耐药相关的突变；对于每个基因组变异，计算比值比（OR）、95% CI和p值，以确定与贝达喹啉耐药相关的耐药标记。本研究注册号为PROSPERO， CRD42020221498。在确定的1367项研究中，有41项发表于2007年至2020年之间的研究符合纳入条件。我们提取了1708株分离株的数据：临床分离株1569株（91.9%），非临床分离株139株（8.1%）。我们在Rv0678中发现了237个独特的变异，在atpE中发现了14个，在pepQ中发现了28个，在Rv1979c中发现了11个。大多数临床分离的Rv0678（287个变体中229个[79%]）、atpE（16个变体中14个[88%]）、pepQ（32个变体中32个[100%]）或Rv1979c（119个变体中115个[98%]）对贝达喹啉表型敏感。除了atpE 187G→C （OR∞,[95% CI 13.28 -∞];p< 0.0001）和Rv0678 138_139insG （OR 6·91 [95% CI 1.16 - 47·38];p= 0.016）变异外，Rv0678、atpE、pepQ和Rv1979c中任何一个变异的表型-基因型相关性均不显著（p≥0.05）。贝达喹啉缺乏明确的基因型-表型关联使分子药敏试验的发展复杂化。迫切需要全球协调一致的努力来评估结核分枝杆菌分离株的基因型和表型药物敏感性，特别是在接受含贝达喹啉治疗不成功的患者中。治疗方案应设计为防止贝达喹啉耐药的出现，并应使用表型药敏试验来指导和监测治疗。法兰德斯研究基金会，南非医学研究理事会，科学与创新部-国家研究基金会，国家卫生研究所过敏和传染病研究所，多丽丝·杜克慈善基金会。
Bedaquiline is a crucial drug for control of rifampicin-resistant tuberculosis. Molecular drug resistance assays could facilitate effective use of bedaquiline and surveillance of drug resistance emergence. To facilitate molecular assay development, we aimed to identify genomic markers of bedaquiline resistance. In this systematic review and individual isolate analysis, we searched Europe PubMed Central and Scopus for studies published from the inception of each database until Oct 19, 2020, that assessed genotypic and phenotypic bedaquiline resistance in clinical or non-clinical Mycobacterium tuberculosis isolates. All studies reporting on the assessment of variants in the four genes of interest (Rv0678, atpE, pepQ, and Rv1979c) and phenotypic bedaquiline data in both clinical and non-clinical samples were included. We collated individual isolate data from eligible studies to assess the association between genomic variants with phenotypic bedaquiline resistance, using a standardised method endorsed by WHO. Risk of bias of the extracted data was independently assessed by two authors using the Quality Assessment of Diagnostic Accuracy Studies tool for clinical studies and Systematic Review Center for Laboratory Animal Experimentation tool for animal studies. The primary outcome was to identify mutations associated with resistance in four genes of interest (Rv0678, atpE, pepQ, and Rv1979c); for each genomic variant, the odds ratio (OR), 95% CI, and p value were calculated to identify resistance markers associated with bedaquiline resistance. This study is registered with PROSPERO, CRD42020221498. Of 1367 studies identified, 41 published between 2007 and 2020 were eligible for inclusion. We extracted data on 1708 isolates: 1569 (91·9%) clinical isolates and 139 (8·1%) non-clinical isolates. We identified 237 unique variants in Rv0678, 14 in atpE, 28 in pepQ, and 11 in Rv1979c. Most clinical isolates with a single variant reported in Rv0678 (229 [79%] of 287 variants), atpE (14 [88%] of 16 variants), pepQ (32 [100%] of 32 variants), or Rv1979c (115 [98%] of 119 variants) were phenotypically susceptible to bedaquiline. Except for the atpE 187G→C (OR ∞, [95% CI 13·28–∞]; p<0·0001) and Rv0678 138_139insG (OR 6·91 [95% CI 1·16–47·38]; p=0·016) variants, phenotypic–genotypic associations were not significant (p≥0·05) for any single variant in Rv0678, atpE, pepQ, and Rv1979c. Absence of clear genotypic–phenotypic associations for bedaquiline complicates the development of molecular drug susceptibility tests. A concerted global effort is urgently needed to assess the genotypic and phenotypic drug susceptibility of M tuberculosis isolates, especially in patients who have received unsuccessful bedaquiline-containing regimens. Treatment regimens should be designed to prevent emergence of bedaquiline resistance and phenotypic drug susceptibility tests should be used to guide and monitor treatment. Research Foundation Flanders, South African Medical Research Council, Department of Science and Innovation - National Research Foundation, National Institute of Health Institute of Allergy and Infectious Diseases, and Doris Duke Charitable Foundation.
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影响因子：
5.2
作者：
Degiacomi G;Sammartino JC;Sinigiani V;Marra P;Urbani A;Pasca MR
通讯作者：
Pasca MR
影响因子：
9.4
作者：
Kaniga, Kone;Aono, Akio;Omar, Shaheed, V
通讯作者：
Omar, Shaheed, V
影响因子：
158.5
作者：
Conradie, Francesca;Diacon, Andreas H.;Spigelman, Melvin
通讯作者：
Spigelman, Melvin
影响因子：
11.1
作者：
Ismail NA;Omar SV;Joseph L;Govender N;Blows L;Ismail F;Koornhof H;Dreyer AW;Kaniga K;Ndjeka N
通讯作者：
Ndjeka N
影响因子：
4.9
作者：
Ghodousi, Arash;Rizvi, Alamdar Hussain;Cirillo, Daniela Maria
通讯作者：
Cirillo, Daniela Maria