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Mortality from drug-resistant tuberculosis in high-burden countries comparing routine drug susceptibility testing with whole-genome sequencing: a multicentre cohort study


Zürcher, K; Reichmuth, M L; Ballif, M; Loiseau, C; Borrell, S; Reinhard, M; Skrivankova, V; Hömke, R; Sander, P; Avihingsanon, A; Abimiku, A G; Marcy, O; Collantes, J; Carter, E Jane; Wilkinson, R J; Cox, H; Yotebieng, M; Huebner, R; Fenner, L; Böttger, E C; Gagneux, S; Egger, M (2021). Mortality from drug-resistant tuberculosis in high-burden countries comparing routine drug susceptibility testing with whole-genome sequencing: a multicentre cohort study. The Lancet Microbe, 2(7):e320-e330.

Abstract

Background

Drug resistance threatens global tuberculosis control. We aimed to examine mortality in patients with tuberculosis from high-burden countries, according to concordance or discordance of results from drug susceptibility testing done locally and whole-genome sequencing (WGS).
Methods

In this multicentre cohort study, we collected pulmonary Mycobacterium tuberculosis isolates and clinical data from individuals with tuberculosis from antiretroviral therapy programmes and tuberculosis clinics in Côte d'Ivoire, Democratic Republic of the Congo, Kenya, Nigeria, Peru, South Africa, and Thailand, stratified by HIV status and drug resistance. Sites tested drug susceptibility using routinely available methods. WGS was done on Illumina HiSeq 2500 in the USA and Switzerland, and TBprofiler was used to analyse the genomes. We included individuals aged 16 years or older with pulmonary tuberculosis (bacteriologically confirmed or clinically diagnosed). We analysed mortality in multivariable logistic regression models adjusted for sex, age, HIV status, history of tuberculosis, and sputum positivity.
Findings

Between Sept 1, 2014, and July 4, 2016, of 634 patients included in our previous analysis, we included 582 patients with tuberculosis (median age 33 years [IQR 27–43], 225 [39%] women, and 247 [42%] HIV-positive). Based on WGS, 339 (58%) isolates were pan-susceptible, 35 (6%) monoresistant, 146 (25%) multidrug-resistant, and 24 (4%) pre-extensively drug-resistant (pre-XDR) or XDR. The analysis of mortality was based on 530 patients; 63 (12%) died and 77 (15%) patients received inappropriate treatment. Mortality ranged from 6% (18 of 310) in patients with pan-susceptible tuberculosis to 39% (nine of 23) in patients with pre-XDR or XDR tuberculosis. The adjusted odds ratio for mortality was 4·92 (95% CI 2·47–9·78) among undertreated patients, compared with appropriately treated patients.
Interpretation

In seven countries with a high burden of tuberculosis, we observed discrepancies between drug resistance patterns obtained locally and WGS. The underdiagnosis of drug resistance resulted in inappropriate treatment and higher mortality. WGS can provide accurate and detailed drug resistance information required to improve the outcomes of drug-resistant tuberculosis in high-burden settings. Our results support WHO's call for point-of-care tests based on WGS.
Funding

National Institutes of Allergy and Infectious Diseases, Swiss National Science Foundation, and Swiss National Center for Mycobacteria.

Abstract

Background

Drug resistance threatens global tuberculosis control. We aimed to examine mortality in patients with tuberculosis from high-burden countries, according to concordance or discordance of results from drug susceptibility testing done locally and whole-genome sequencing (WGS).
Methods

In this multicentre cohort study, we collected pulmonary Mycobacterium tuberculosis isolates and clinical data from individuals with tuberculosis from antiretroviral therapy programmes and tuberculosis clinics in Côte d'Ivoire, Democratic Republic of the Congo, Kenya, Nigeria, Peru, South Africa, and Thailand, stratified by HIV status and drug resistance. Sites tested drug susceptibility using routinely available methods. WGS was done on Illumina HiSeq 2500 in the USA and Switzerland, and TBprofiler was used to analyse the genomes. We included individuals aged 16 years or older with pulmonary tuberculosis (bacteriologically confirmed or clinically diagnosed). We analysed mortality in multivariable logistic regression models adjusted for sex, age, HIV status, history of tuberculosis, and sputum positivity.
Findings

Between Sept 1, 2014, and July 4, 2016, of 634 patients included in our previous analysis, we included 582 patients with tuberculosis (median age 33 years [IQR 27–43], 225 [39%] women, and 247 [42%] HIV-positive). Based on WGS, 339 (58%) isolates were pan-susceptible, 35 (6%) monoresistant, 146 (25%) multidrug-resistant, and 24 (4%) pre-extensively drug-resistant (pre-XDR) or XDR. The analysis of mortality was based on 530 patients; 63 (12%) died and 77 (15%) patients received inappropriate treatment. Mortality ranged from 6% (18 of 310) in patients with pan-susceptible tuberculosis to 39% (nine of 23) in patients with pre-XDR or XDR tuberculosis. The adjusted odds ratio for mortality was 4·92 (95% CI 2·47–9·78) among undertreated patients, compared with appropriately treated patients.
Interpretation

In seven countries with a high burden of tuberculosis, we observed discrepancies between drug resistance patterns obtained locally and WGS. The underdiagnosis of drug resistance resulted in inappropriate treatment and higher mortality. WGS can provide accurate and detailed drug resistance information required to improve the outcomes of drug-resistant tuberculosis in high-burden settings. Our results support WHO's call for point-of-care tests based on WGS.
Funding

National Institutes of Allergy and Infectious Diseases, Swiss National Science Foundation, and Swiss National Center for Mycobacteria.

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Additional indexing

Contributors:International epidemiology Databases to Evaluate AIDS
Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Medical Microbiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Health Sciences > Infectious Diseases
Health Sciences > Microbiology (medical)
Life Sciences > Microbiology
Life Sciences > Virology
Language:English
Date:July 2021
Deposited On:21 Oct 2021 15:51
Last Modified:25 Jun 2024 01:45
Publisher:Elsevier
ISSN:2666-5247
OA Status:Gold
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/S2666-5247(21)00044-6
  • Content: Published Version
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)