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

Kathrin Zürcher,Chloé Loiseau,Helen Cox,Jimena Collantes,Matthias Egger,Lukas Fenner,Miriam Reinhard,Rico Hömke,Marie Ballif,Veronika Skrivankova,Peter Sander,Marcel Yotebieng,Anchalee Avihingsanon,Olivier Marcy,E Jane Carter,Robin E Huebner ,Martina L Reichmuth ,Sébastien Gagneux ,Sònia Borrell ,Erik C Böttger ,Robert J Wilkinson ,Alash’le Abimiku

doi:10.1016/s2666-5247(21)00044-6

Abstract

SummaryBackgroundDrug 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).MethodsIn 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.FindingsBetween 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.InterpretationIn 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.FundingNational Institutes of Allergy and Infectious Diseases, Swiss National Science Foundation, and Swiss National Center for Mycobacteria.

Highlights

Tuberculosis is caused by bacteria of the Mycobacterium tuberculosis complex and is the leading cause of death by a single infectious agent worldwide.[1]
We aimed to compare the drug resistance patterns routinely obtained in seven countries with a high tuberculosis burden with the results from Whole-genome sequencing (WGS), and examined the mortality associated with discordant resistance profiles using WGS as the reference
We showed that mortality among undertreated patients remained higher than among appropriately treated patients after excluding patients with Pre-extensively drug-resistant (pre-XDR) or XDR tuberculosis

Summary

Introduction

Tuberculosis is caused by bacteria of the Mycobacterium tuberculosis complex and is the leading cause of death by a single infectious agent worldwide.[1] In 2019, ten million people were estimated to have developed active tuberculosis, of whom 8% had HIV. The emergence of drug-resistant M tuberculosis strains threatens tuberculosis control. In 2019, 3% of new tuberculosis cases worldwide were estimated to be multidrug-resistant (MDR) tuberculosis, and 18% of individuals who had been previously treated had MDR tuberculosis.[1] People with HIV are at greater risk of acquiring MDR tuberculosis than people who are HIV-negative.[3] treatment outcomes in people with HIV and MDR tuberculosis are worse than among HIVnegative patients with MDR tuberculosis.[3] Pre-extensively drug-resistant (pre-XDR) or XDR tuberculosis poses additional challenges for treatment and control of the disease.[4] Strategies to control and prevent drug-resistant tuberculosis include surveillance, rapid drug susceptibility

Objectives

Methods

Conclusion