Evaluating the clinical impact of routine whole genome sequencing in tuberculosis treatment decisions and the issue of isoniazid mono-resistance
Author(s)
Park, Mirae
Lalvani, ajit
Satta, Giovanni
Kon, Onn Min
Type
Journal Article
Abstract
Background
The UK has implemented routine use of whole genome sequencing (WGS) in TB diagnostics. The WHO recommends addition of a fluoroquinolone for isoniazid mono-resistance, so early detection may be of use. The aim of this study was to describe the clinical utility and impact of WGS on treatment decisions for TB in a low incidence high resource clinical setting. The clinical turnaround time (TAT) for WGS was analysed in comparison to TB PCR using Xpert MTB/RIF (Cepheid, Sunnyvale, CA) results where available and subsequent phenotypic drug susceptibility testing (DST) when required.
Methods
This was a retrospective analysis of TB cases from January 2018 to March 2019 in London. Susceptibility and TAT by WGS, phenotypic DST, TB PCR using Xpert MTB/RIF were correlated to drug changes in order to describe the utility of WGS on treatment decisions on isoniazid mono-resistance in a low incidence high resource setting.
Results
189 TB cases were identified; median age 44 years (IQR 28–60), m:f ratio 112:77, 7 with HIV and 6 with previous TB. 80/189 cases had a positive culture and WGS result. 50/80 were fully sensitive to 1st line treatment on WGS, and the rest required additional DST. 20/80 cases required drug changes; 12 were defined by WGS: 8 cases had isoniazid mono-resistance, 2 had MDR-TB, 1 had isoniazid and pyrazinamide resistance and 1 had ethambutol resistance. The median TAT for positive culture was 16 days (IQR 12.5–20.5); for WGS was 35 days (IQR 29.5–38.75) and for subsequent DST was 86 days (IQR 69.5–96.75), resulting in non-WHO regimens for a median of 50.5 days (IQR 28.0–65.0). 9/12 has TB PCRs (Xpert MTB/RIF), with a median TAT of 1 day.
Conclusion
WGS clearly has a substantial role in our routine UK clinical settings with faster turnaround times in comparison to phenotypic DST. However, the majority of treatment changes defined by WGS were related to isoniazid resistance and given the 1 month TAT for WGS, it would be preferable to identify isoniazid resistance more quickly. Therefore if resources allow, diagnostic pathways should be optimised by parallel use of WGS and new molecular tests to rapidly identify isoniazid resistance in addition to rifampicin resistance and to minimise delays in starting WHO isoniazid resistance treatment.
The UK has implemented routine use of whole genome sequencing (WGS) in TB diagnostics. The WHO recommends addition of a fluoroquinolone for isoniazid mono-resistance, so early detection may be of use. The aim of this study was to describe the clinical utility and impact of WGS on treatment decisions for TB in a low incidence high resource clinical setting. The clinical turnaround time (TAT) for WGS was analysed in comparison to TB PCR using Xpert MTB/RIF (Cepheid, Sunnyvale, CA) results where available and subsequent phenotypic drug susceptibility testing (DST) when required.
Methods
This was a retrospective analysis of TB cases from January 2018 to March 2019 in London. Susceptibility and TAT by WGS, phenotypic DST, TB PCR using Xpert MTB/RIF were correlated to drug changes in order to describe the utility of WGS on treatment decisions on isoniazid mono-resistance in a low incidence high resource setting.
Results
189 TB cases were identified; median age 44 years (IQR 28–60), m:f ratio 112:77, 7 with HIV and 6 with previous TB. 80/189 cases had a positive culture and WGS result. 50/80 were fully sensitive to 1st line treatment on WGS, and the rest required additional DST. 20/80 cases required drug changes; 12 were defined by WGS: 8 cases had isoniazid mono-resistance, 2 had MDR-TB, 1 had isoniazid and pyrazinamide resistance and 1 had ethambutol resistance. The median TAT for positive culture was 16 days (IQR 12.5–20.5); for WGS was 35 days (IQR 29.5–38.75) and for subsequent DST was 86 days (IQR 69.5–96.75), resulting in non-WHO regimens for a median of 50.5 days (IQR 28.0–65.0). 9/12 has TB PCRs (Xpert MTB/RIF), with a median TAT of 1 day.
Conclusion
WGS clearly has a substantial role in our routine UK clinical settings with faster turnaround times in comparison to phenotypic DST. However, the majority of treatment changes defined by WGS were related to isoniazid resistance and given the 1 month TAT for WGS, it would be preferable to identify isoniazid resistance more quickly. Therefore if resources allow, diagnostic pathways should be optimised by parallel use of WGS and new molecular tests to rapidly identify isoniazid resistance in addition to rifampicin resistance and to minimise delays in starting WHO isoniazid resistance treatment.
Date Issued
2022-04-07
Date Acceptance
2022-03-23
Citation
BMC Infectious Diseases, 2022, 22 (349), pp.1-10
ISSN
1471-2334
Publisher
BioMed Central
Start Page
1
End Page
10
Journal / Book Title
BMC Infectious Diseases
Volume
22
Issue
349
Copyright Statement
© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the
original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or
other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line
to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory
regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this
licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativeco
mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the
original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or
other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line
to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory
regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this
licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativeco
mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
License URL
Sponsor
Imperial College Healthcare NHS Trust- BRC Funding
Identifier
https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-022-07329-y
Grant Number
RDA02
Subjects
Isoniazid mono-resistance
Treatment alteration
Tuberculosis
Turnaround times
Whole genome sequencing
Adult
Antitubercular Agents
Humans
Isoniazid
Microbial Sensitivity Tests
Mycobacterium tuberculosis
Retrospective Studies
Rifampin
Tuberculosis, Multidrug-Resistant
Whole Genome Sequencing
Humans
Mycobacterium tuberculosis
Tuberculosis, Multidrug-Resistant
Isoniazid
Rifampin
Antitubercular Agents
Microbial Sensitivity Tests
Retrospective Studies
Adult
Whole Genome Sequencing
Microbiology
0605 Microbiology
1103 Clinical Sciences
1108 Medical Microbiology
Publication Status
Published
Date Publish Online
2022-04-07