Impact of Whole-Genome Sequencing of Mycobacterium Tuberculosis On Treatment Outcomes for MDR-TB/ XDR-TB: A Systematic Review Protocol

Abstract Background The emergence of drug-resistant tuberculosis (DR-TB) is a persistent threat to public health. The detection of DR-TB requires culture-based drug susceptibility testing (DST) or rapid molecular assays for targeted genes. The recent advances in Whole-genome sequencing (WGS) technology have offered a new capacity to identify resistance-conferring mutations in Mycobacterium tuberculosis (MTB). This study reviews and quantifies the emerging evidence on the association between genomic markers of drug resistance in MTB identified by WGS and treatment outcomes for DR-TB. Methods A literature search will be conducted in NCBI PubMed, Scopus, Cochrane Library, Web of Science, and CINAHL (Ebsco) to retrieve all the relevant original reports from 2000 onwards. Clinical trials and observational studies describing different applications of WGS to genotypic resistance testing for TB and detection of MDR-TB/ XDR-TB as well as treatment outcomes of the patients will be included. Two primary reviewers will separately screen and select papers for data extraction, risk of bias, and assess the quality. Any disagreement between the reviewers' will be clarified by a third reviewer. The I2 statistics will be used to assess the heterogeneity of the included studies and if the data are sufficiently homogenous, a meta-analysis will be performed. The Egger's test and visual representation of the funnel plot will be used to monitor for publication bias. Narrative data synthesis will be conducted for all the included studies if performing meta-analysis is not possible. Discussion This systematic review will examine the evidence on the feasibility and added value of WGS in improving treatment outcomes in DR-TB patients. The rapid detection of drug-resistance conferring mutations and selection of appropriate drug regimens is likely to improve the cure rates while minimizing adverse events and treatment costs. Hence, the outcome of this systematic review will inform policy-making and will guide clinical laboratory practice to improve drug resistance diagnostic capacity and treatment outcomes. Systematic review registration: PROSPERO CRD42020197099.

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Whole genome sequencing of Mycobacterium tuberculosis for detection of drug resistance: a systematic review

Clinical Microbiology and Infection ◽

10.1016/j.cmi.2016.09.008 ◽

2017 ◽

Vol 23 (2) ◽

pp. 61-68 ◽

Cited By ~ 39

Author(s):

D. Papaventsis ◽

N. Casali ◽

I. Kontsevaya ◽

F. Drobniewski ◽

D.M. Cirillo ◽

...

Keyword(s):

Systematic Review ◽

Drug Resistance ◽

Mycobacterium Tuberculosis ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Whole Genome

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Whole-Genome Sequencing Reveals Recent Transmission of Multidrug-Resistant Mycobacterium tuberculosis CAS1-Kili Strains in Lusaka, Zambia

Antibiotics ◽

10.3390/antibiotics11010029 ◽

2021 ◽

Vol 11 (1) ◽

pp. 29

Author(s):

Joseph Yamweka Chizimu ◽

Eddie Samuneti Solo ◽

Precious Bwalya ◽

Wimonrat Tanomsridachchai ◽

Herman Chambaro ◽

...

Keyword(s):

Drug Resistance ◽

Mycobacterium Tuberculosis ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Regulatory Region ◽

Multidrug Resistant ◽

Epidemiological Methods ◽

Whole Genome ◽

Recent Transmission ◽

Mdr Tb

Globally, tuberculosis (TB) is a major cause of death due to antimicrobial resistance. Mycobacterium tuberculosis CAS1-Kili strains that belong to lineage 3 (Central Asian Strain, CAS) were previously implicated in the spread of multidrug-resistant (MDR)-TB in Lusaka, Zambia. Thus, we investigated recent transmission of those strains by whole-genome sequencing (WGS) with Illumina MiSeq platform. Twelve MDR CAS1-Kili isolates clustered by traditional methods (MIRU-VNTR and spoligotyping) were used. A total of 92% (11/12) of isolates belonged to a cluster (≤12 SNPs) while 50% (6/12) were involved in recent transmission events, as they differed by ≤5 SNPs. All the isolates had KatG Ser315Thr (isoniazid resistance), EmbB Met306 substitutions (ethambutol resistance) and several kinds of rpoB mutations (rifampicin resistance). WGS also revealed compensatory mutations including a novel deletion in embA regulatory region (−35A > del). Several strains shared the same combinations of drug-resistance-associated mutations indicating transmission of MDR strains. Zambian strains belonged to the same clade as Tanzanian, Malawian and European strains, although most of those were pan-drug-susceptible. Hence, complimentary use of WGS to traditional epidemiological methods provides an in-depth insight on transmission and drug resistance patterns which can guide targeted control measures to stop the spread of MDR-TB.

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Whole genome sequencing data of 1110 Mycobacterium tuberculosis isolates identifies insertions and deletions associated with drug resistance

BMC Genomics ◽

10.1186/s12864-018-4734-6 ◽

2018 ◽

Vol 19 (1) ◽

Cited By ~ 3

Author(s):

Xi Zeng ◽

Jamie Sui-Lam Kwok ◽

Kevin Yi Yang ◽

Kenneth Siu-Sing Leung ◽

Mai Shi ◽

...

Keyword(s):

Drug Resistance ◽

Mycobacterium Tuberculosis ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Whole Genome Sequencing Data ◽

Whole Genome ◽

Sequencing Data ◽

Insertions And Deletions

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Comprehensive Whole-Genome Sequencing and Reporting of Drug Resistance Profiles on Clinical Cases of Mycobacterium tuberculosis in New York State

Journal of Clinical Microbiology ◽

10.1128/jcm.00298-17 ◽

2017 ◽

Vol 55 (6) ◽

pp. 1871-1882 ◽

Cited By ~ 46

Author(s):

Joseph Shea ◽

Tanya A. Halse ◽

Pascal Lapierre ◽

Matthew Shudt ◽

Donna Kohlerschmidt ◽

...

Keyword(s):

New York ◽

Drug Resistance ◽

Mycobacterium Tuberculosis ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Predictive Value ◽

New York State ◽

Whole Genome ◽

Content Type ◽

York State

ABSTRACTWhole-genome sequencing (WGS) is a newer alternative for tuberculosis (TB) diagnostics and is capable of providing rapid drug resistance profiles while performing species identification and capturing the data necessary for genotyping. Our laboratory developed and validated a comprehensive and sensitive WGS assay to characterizeMycobacterium tuberculosisand otherM. tuberculosiscomplex (MTBC) strains, composed of a novel DNA extraction, optimized library preparation, paired-end WGS, and an in-house-developed bioinformatics pipeline. This new assay was assessed using 608 MTBC isolates, with 146 isolates during the validation portion of this study and 462 samples received prospectively. In February 2016, this assay was implemented to test all clinical cases of MTBC in New York State, including isolates and early positive Bactec mycobacterial growth indicator tube (MGIT) 960 cultures from primary specimens. Since the inception of the assay, we have assessed the accuracy of identification of MTBC strains to the species level, concordance with culture-based drug susceptibility testing (DST), and turnaround time. Species identification by WGS was determined to be 99% accurate. Concordance between drug resistance profiles generated by WGS and culture-based DST methods was 96% for eight drugs, with an average resistance-predictive value of 93% and susceptible-predictive value of 96%. This single comprehensive WGS assay has replaced seven molecular assays and has resulted in resistance profiles being reported to physicians an average of 9 days sooner than with culture-based DST for first-line drugs and 32 days sooner for second-line drugs.

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Deciphering drug resistance in Mycobacterium tuberculosis using whole-genome sequencing: progress, promise, and challenges

Genome Medicine ◽

10.1186/s13073-019-0660-8 ◽

2019 ◽

Vol 11 (1) ◽

Cited By ~ 10

Author(s):

Keira A. Cohen ◽

Abigail L. Manson ◽

Christopher A. Desjardins ◽

Thomas Abeel ◽

Ashlee M. Earl

Keyword(s):

Drug Resistance ◽

Mycobacterium Tuberculosis ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Whole Genome

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Whole genome sequencing of clinical strains of Mycobacterium tuberculosis from Mumbai, India: A potential tool for determining drug-resistance and strain lineage

Tuberculosis ◽

10.1016/j.tube.2017.08.002 ◽

2017 ◽

Vol 107 ◽

pp. 63-72 ◽

Cited By ~ 17

Author(s):

Anirvan Chatterjee ◽

Kayzad Nilgiriwala ◽

Dhananjaya Saranath ◽

Camilla Rodrigues ◽

Nerges Mistry

Keyword(s):

Drug Resistance ◽

Mycobacterium Tuberculosis ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Whole Genome ◽

Clinical Strains ◽

Potential Tool

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Whole genome sequencing of Mycobacterium tuberculosis for detection of recent transmission and tracing outbreaks: A systematic review

Tuberculosis ◽

10.1016/j.tube.2016.02.009 ◽

2016 ◽

Vol 98 ◽

pp. 77-85 ◽

Cited By ~ 53

Author(s):

Vlad Nikolayevskyy ◽

Katharina Kranzer ◽

Stefan Niemann ◽

Francis Drobniewski

Keyword(s):

Systematic Review ◽

Mycobacterium Tuberculosis ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Whole Genome ◽

Recent Transmission

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Whole genome sequencing of Mycobacterium tuberculosis for prediction of drug resistance

Epidemiology and Infection ◽

10.1017/s095026882100279x ◽

2022 ◽

pp. 1-26

Author(s):

Luqi Wang ◽

Jinghui Yang ◽

Liang Chen ◽

Weibing Wang ◽

Fangyou Yu ◽

...

Keyword(s):

Drug Resistance ◽

Mycobacterium Tuberculosis ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Whole Genome

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Use of a whole genome sequencing-based approach for Mycobacterium tuberculosis surveillance in Europe in 2017–2019: an ECDC pilot study

European Respiratory Journal ◽

10.1183/13993003.02272-2020 ◽

2020 ◽

Vol 57 (1) ◽

pp. 2002272

Author(s):

Elisa Tagliani ◽

Richard Anthony ◽

Thomas A. Kohl ◽

Albert de Neeling ◽

Vlad Nikolayevskyy ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Pilot Study ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Surveillance System ◽

European Economic Area ◽

Whole Genome ◽

Cross Border ◽

Lessons Learnt ◽

Mdr Tb

Whole genome sequencing (WGS) can be used for molecular typing and characterisation of Mycobacterium tuberculosis complex (MTBC) strains. We evaluated the systematic use of a WGS-based approach for MTBC surveillance involving all European Union/European Economic Area (EU/EEA) countries and highlight the challenges and lessons learnt to be considered for the future development of a WGS-based surveillance system.WGS and epidemiological data of patients with rifampicin-resistant (RR) and multidrug-resistant (MDR) tuberculosis (TB) were collected from EU/EEA countries between January 2017 and December 2019. WGS-based genetic relatedness analysis was performed using a standardised approach including both core genome multilocus sequence typing (cgMLST) and single nucleotide polymorphism (SNP)-based calculation of distances on all WGS data that fulfilled minimum quality criteria to ensure data comparability.A total of 2218 RR/MDR-MTBC isolates were collected from 25 countries. Among these, 56 cross-border clusters with increased likelihood of recent transmission (≤5 SNPs distance) comprising 316 RR/MDR-MTBC isolates were identified. The cross-border clusters included between two and 30 resistant isolates from two to six countries, demonstrating different RR/MDR-TB transmission patterns in Western and Eastern EU countries.This pilot study shows that a WGS-based surveillance system is not only feasible but can efficiently elucidate the dynamics of in-country and cross-border RR/MDR-TB transmission across EU/EEA countries. Lessons learnt from this study highlight that the establishment of an EU/EEA centralised WGS-based surveillance system for TB will require strengthening of national integrated systems performing prospective WGS surveillance and the development of clear procedures to facilitate international collaboration for the investigation of cross-border clusters.

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