Dynamics of within-host Mycobacterium tuberculosis diversity and heteroresistance during treatment.
Adult
Antitubercular Agents
/ therapeutic use
Cohort Studies
Diarylquinolines
/ therapeutic use
Drug Resistance, Multiple, Bacterial
/ genetics
Female
Fluoroquinolones
/ therapeutic use
Gene Expression Regulation, Bacterial
Genes, Bacterial
Genetic Variation
Host-Pathogen Interactions
/ genetics
Humans
Male
Metabolic Networks and Pathways
/ genetics
Microbial Sensitivity Tests
Middle Aged
Mycobacterium tuberculosis
/ drug effects
Rifampin
/ therapeutic use
South Africa
Sputum
/ microbiology
Tuberculosis, Multidrug-Resistant
/ drug therapy
Tuberculosis, Pulmonary
/ drug therapy
Bedaquiline
Genetic diversity
Heteroresistance
Mycobacterium tuberculosis
TB
Whole genome sequencing
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
May 2020
May 2020
Historique:
received:
13
11
2019
revised:
02
03
2020
accepted:
19
03
2020
pubmed:
4
5
2020
medline:
2
4
2021
entrez:
4
5
2020
Statut:
ppublish
Résumé
Studying within-host genetic diversity of Mycobacterium tuberculosis (Mtb) in patients during treatment may identify adaptations to antibiotic and immune pressure. Understanding the significance of genetic heteroresistance, and more specifically heterozygous resistance-associated variants (RAVs), is clinically important given increasing use of rapid molecular tests and whole genome sequencing (WGS). We analyse data from six studies in KwaZulu-Natal, South Africa. Most patients (>75%) had baseline rifampicin resistance. Sputum was collected for culture at baseline and at between two and nine intervals until month six. Positive cultures underwent WGS. Mixed infections and reinfections were excluded from analysis. Baseline Mtb overall genetic diversity (at treatment initiation or major change to regimen) was associated with cavitary disease, not taking antiretroviral therapy if HIV infected, infection with lineage 2 strains and absence of second-line drug resistance on univariate analyses. Baseline genetic diversity was not associated with six-month outcome. Genetic diversity increased from baseline to weeks one and two before returning to previous levels. Baseline genetic heteroresistance was most common for bedaquiline (6/10 [60%] of isolates with RAVs) and fluoroquinolones (9/62 [13%]). Most patients with heterozygous RAVs on WGS with sequential isolates available demonstrated RAV persistence or fixation (17/20, 85%). New RAVs emerged in 9/286 (3%) patients during treatment. We could detect low-frequency RAVs preceding emergent resistance in only one case, although validation of deep sequencing to detect rare variants is required. In this study of single-strain Mtb infections, baseline within-host bacterial genetic diversity did not predict outcome but may reveal adaptations to host and drug pressures. Predicting emergent resistance from low-frequency RAVs requires further work to separate transient from consequential mutations. Wellcome Trust, NIH/NIAID.
Sections du résumé
BACKGROUND
BACKGROUND
Studying within-host genetic diversity of Mycobacterium tuberculosis (Mtb) in patients during treatment may identify adaptations to antibiotic and immune pressure. Understanding the significance of genetic heteroresistance, and more specifically heterozygous resistance-associated variants (RAVs), is clinically important given increasing use of rapid molecular tests and whole genome sequencing (WGS).
METHODS
METHODS
We analyse data from six studies in KwaZulu-Natal, South Africa. Most patients (>75%) had baseline rifampicin resistance. Sputum was collected for culture at baseline and at between two and nine intervals until month six. Positive cultures underwent WGS. Mixed infections and reinfections were excluded from analysis.
FINDINGS
RESULTS
Baseline Mtb overall genetic diversity (at treatment initiation or major change to regimen) was associated with cavitary disease, not taking antiretroviral therapy if HIV infected, infection with lineage 2 strains and absence of second-line drug resistance on univariate analyses. Baseline genetic diversity was not associated with six-month outcome. Genetic diversity increased from baseline to weeks one and two before returning to previous levels. Baseline genetic heteroresistance was most common for bedaquiline (6/10 [60%] of isolates with RAVs) and fluoroquinolones (9/62 [13%]). Most patients with heterozygous RAVs on WGS with sequential isolates available demonstrated RAV persistence or fixation (17/20, 85%). New RAVs emerged in 9/286 (3%) patients during treatment. We could detect low-frequency RAVs preceding emergent resistance in only one case, although validation of deep sequencing to detect rare variants is required.
INTERPRETATION
CONCLUSIONS
In this study of single-strain Mtb infections, baseline within-host bacterial genetic diversity did not predict outcome but may reveal adaptations to host and drug pressures. Predicting emergent resistance from low-frequency RAVs requires further work to separate transient from consequential mutations.
FUNDING
BACKGROUND
Wellcome Trust, NIH/NIAID.
Identifiants
pubmed: 32361247
pii: S2352-3964(20)30122-5
doi: 10.1016/j.ebiom.2020.102747
pmc: PMC7195533
pii:
doi:
Substances chimiques
Antitubercular Agents
0
Diarylquinolines
0
Fluoroquinolones
0
bedaquiline
78846I289Y
Rifampin
VJT6J7R4TR
Types de publication
Journal Article
Multicenter Study
Observational Study
Langues
eng
Sous-ensembles de citation
IM
Pagination
102747Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/P007597/1
Pays : United Kingdom
Organisme : NIAID NIH HHS
ID : R01 AI124413
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.
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