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

Zürcher, Kathrin; Reichmuth, Martina L.; Ballif, Marie; Loiseau, Chloé; Borrell, Sonia; Reinhard, Miriam; Skrivankova, Veronika; Hömke, Rico; Sander, Peter; Avihingsanon, Anchalee; Abimiku, Alash'le G; Marcy, Olivier; Collantes, Jimena; Carter, E Jane; Wilkinson, Robert J; Cox, Helen; Yotebieng, Marcel; Huebner, Robin; Fenner, Lukas; Böttger, Erik C; ... (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. Elsevier 10.1016/S2666-5247(21)00044-6

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Social and Preventive Medicine (ISPM)

UniBE Contributor:

Zürcher, Kathrin; Reichmuth, Martina Larissa; Ballif, Marie; Whitesell, Veronika; Fenner, Lukas and Egger, Matthias

Subjects:

600 Technology > 610 Medicine & health
300 Social sciences, sociology & anthropology > 360 Social problems & social services

ISSN:

2666-5247

Publisher:

Elsevier

Funders:

[4] Swiss National Science Foundation

Language:

English

Submitter:

Doris Kopp Heim

Date Deposited:

07 Jan 2022 17:10

Last Modified:

21 Mar 2022 19:21

Publisher DOI:

10.1016/S2666-5247(21)00044-6

PubMed ID:

35252901

Additional Information:

Zürcher and Reichmuth contributed equally to this work.

BORIS DOI:

10.48350/164293

URI:

https://boris.unibe.ch/id/eprint/164293

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