TY - JOUR
T1 - Mortality from drug-resistant tuberculosis in high-burden countries comparing routine drug susceptibility testing with whole-genome sequencing
T2 - a multicentre cohort study
AU - International epidemiology Databases to Evaluate AIDS
AU - Zürcher, Kathrin
AU - Reichmuth, Martina L.
AU - Ballif, Marie
AU - Loiseau, Chloé
AU - Borrell, Sonia
AU - Reinhard, Miriam
AU - Skrivankova, Veronika
AU - Hömke, Rico
AU - Sander, Peter
AU - Avihingsanon, Anchalee
AU - Abimiku, Alash'le G.
AU - Marcy, Olivier
AU - Collantes, Jimena
AU - Carter, E. Jane
AU - Wilkinson, Robert J.
AU - Cox, Helen
AU - Yotebieng, Marcel
AU - Huebner, Robin
AU - Fenner, Lukas
AU - Böttger, Erik C.
AU - Gagneux, Sebastien
AU - Egger, Matthias
N1 - Funding Information:
RJW reports grants from Wellcome, European and Developing Countries Clinical Trials Partnership, UK Research and Innovation, Cancer Research UK, and National Institutes of Health, during the conduct of the study. ECB reports personal fees from AID Diagnostika and COPAN, outside the submitted work. MY reports grants from US National Institutes of Health, during the conduct of the study. All other authors declare no competing interests.
Funding Information:
We thank all sites and patients who participated in this study. We are also grateful to the Tuberculosis Working Group of International epidemiology Databases to Evaluate AIDS (IeDEA) for helpful discussions. Calculations were done on UBELIX , the HPC cluster at the University of Bern. The IeDEA is supported by the US National Institutes of Health, National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Cancer Institute, the National Institute of Mental Health, the National Institute on Drug Abuse, the National Heart, Lung, and Blood Institute, the National Institute on Alcohol Abuse and Alcoholism, the National Institute of Diabetes and Digestive and Kidney Diseases, the Fogarty International Center, and the National Library of Medicine: Asia-Pacific, U01AI069907; CCASAnet, U01AI069923; Central Africa, U01AI096299; East Africa, U01AI069911; NA-ACCORD, U01AI069918; Southern Africa, U01AI069924; West Africa, U01AI069919. ME was supported by special project funding from the Swiss National Science Foundation ( grant number 17481 ). KZ, MB, CL, LF and ME were supported by the Swiss National Science Foundation ( grant number 320030_153442 ). SG, CL, SB, and MR were supported by the Swiss National Science Foundation (grant numbers 153442 , 310030_188888 , IZRJZ3_164171 , IZLSZ3_170834 and CRSII5_177163) and by the European Research Council ( grants 309540 and 883582 ). RJW received support from the Francis Crick Institute, which is funded by UK Research and Innovation, Cancer Research UK ( grant number FC0010218 ), and Wellcome ( grant numbers 104803, 203135 ). This work is solely the responsibility of the authors and does not necessarily represent the official views of any of the institutions mentioned above.
Funding Information:
We thank all sites and patients who participated in this study. We are also grateful to the Tuberculosis Working Group of International epidemiology Databases to Evaluate AIDS (IeDEA) for helpful discussions. Calculations were done on UBELIX, the HPC cluster at the University of Bern. The IeDEA is supported by the US National Institutes of Health, National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Cancer Institute, the National Institute of Mental Health, the National Institute on Drug Abuse, the National Heart, Lung, and Blood Institute, the National Institute on Alcohol Abuse and Alcoholism, the National Institute of Diabetes and Digestive and Kidney Diseases, the Fogarty International Center, and the National Library of Medicine: Asia-Pacific, U01AI069907; CCASAnet, U01AI069923; Central Africa, U01AI096299; East Africa, U01AI069911; NA-ACCORD, U01AI069918; Southern Africa, U01AI069924; West Africa, U01AI069919. ME was supported by special project funding from the Swiss National Science Foundation (grant number 17481). KZ, MB, CL, LF and ME were supported by the Swiss National Science Foundation (grant number 320030_153442). SG, CL, SB, and MR were supported by the Swiss National Science Foundation (grant numbers 153442, 310030_188888, IZRJZ3_164171, IZLSZ3_170834 and CRSII5_177163) and by the European Research Council (grants 309540 and 883582). RJW received support from the Francis Crick Institute, which is funded by UK Research and Innovation, Cancer Research UK (grant number FC0010218), and Wellcome (grant numbers 104803, 203135). This work is solely the responsibility of the authors and does not necessarily represent the official views of any of the institutions mentioned above.
Publisher Copyright:
© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license
PY - 2021/7
Y1 - 2021/7
N2 - 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.
AB - 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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U2 - 10.1016/S2666-5247(21)00044-6
DO - 10.1016/S2666-5247(21)00044-6
M3 - Article
AN - SCOPUS:85108981381
SN - 2666-5247
VL - 2
SP - e320-e330
JO - The Lancet Microbe
JF - The Lancet Microbe
IS - 7
ER -
