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Mortality from drug-resistant tuberculosis in high-burden countries comparing routine drug susceptibility testing
Kathrin Zürcher1, Martina L Reichmuth1, Marie Ballif1
1Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland (K Zürcher MSc, M L Reichmuth MSc, M Ballif PhD, V Skrivankova PhD, Prof L Fenner MD, Prof M Egger MD); Swiss Tropical and Public Health Institute, Basel, Switzerland (C Loiseau PhD, S Borrell PhD, M Reinhard, Prof S Gagneux PhD); University of Basel, Basel, Switzerland (C Loiseau, S Borrell, M Reinhard, Prof S Gagneux); Institute of Medical Microbiology, University of Zurich, Zurich, Switzerland (R Hömke, P Sander MD, Prof E C Böttger MD); Swiss National Center for Mycobacteria, Zurich, Switzerland (R Hömke, P Sander, Prof E C Böttger); The HIV Netherlands Australia Thailand Research Collaboration, Thai Red Cross AIDS Research Centre and Tuberculosis Research Unit, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand (A Avihingsanon MD); Institute of Human Virology Nigeria, Abuja, Nigeria (Prof A G Abimiku PhD); Centre de Prise en Charge de Recherche et de Formation, Yopougon, Abidjan, Côte d'Ivoire (O Marcy MD); Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Peru (J Collantes MSc); Department of Medicine, Moi University School of Medicine, and Moi Teaching and Referral Hospital, Eldoret, Kenya (Prof E J Carter MD); Brown University School of Medicine, Providence, RI, USA (Prof E J Carter); Wellcome Centre for Infectious Diseases Research in Africa (Prof R J Wilkinson PhD, Prof H Cox PhD), Institute for Infectious Disease and Molecular Medicine (Prof H Cox), and Centre for Infectious Disease Epidemiology and Research, Faculty of Health Sciences (Prof M Egger), University of Cape Town, Cape Town, South Africa; Department of Infectious Diseases, Imperial College London, London, UK (Prof R J Wilkinson); The Francis Crick Institute, London, UK (Prof R J Wilkinson); National TB Lab, Kinshasa, Democratic Republic of the Congo (Prof M Yotebieng MD); Albert Einstein College of Medicine, New York, NY, USA (Prof M Yotebieng); National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA (R Huebner PhD).
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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