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

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.

Figure 1:. Distribution of diagnosed drug resistance between whole-genome sequencing and local drug susceptibility testing

The categories include pan-susceptible, monoresistant (any monoresistance), multidrug-resistant, pre-XDR or XDR, any isoniazid-resistant, or any rifampicin-resistant tuberculosis. Due to rounding, some group percentage totals are more than 100%. XDR=extensively drug-resistant.

Figure 2:. Mortality according to drug resistance, concordance of diagnosis, and treatment appropriateness

Mortality data are shown based on drug resistance (A), concordance of diagnosis (B), and treatment appropriateness (C). Appropriateness was considered according to WHO guidelines (appendix pp 6–7). Error bars are SEs. Analysis based on 530 patients with complete data. Mortality was calculated by dividing deaths by the number of patients in the respective category. MDR=multidrug-resistant. XDR=extensively drug-resistant.

Figure 3:. Logistic regression models to assess the effect of any drug resistance, drug resistance categories, diagnosis discordance, and treatment appropriateness on mortality

The models were adjusted for sex, age, HIV status, history of tuberculosis, and sputum microscopy, and country of participating site was included as random effect on the intercept. Appropriateness was considered according to WHO guidelines (appendix pp 6–7). XDR=extensively drug-resistant.