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Sources of Multidrug Resistance in Patients With Previous Isoniazid-Resistant Tuberculosis Identified Using Whole Genome Sequencing: A Longitudinal Cohort Study

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Vijay, Srinivasan, Ha, Vu T N, Vinh, Dao N, Thai, Phan V K, Ha, Dang T M, Lan, Nguyen H, Hai, Hoang T, Walker, Timothy M, Thu, Do D A, Dunstan, Sarah J, Thwaites, Guy E, Ashton, Philip M, Caws, Maxine ORCID: https://orcid.org/0000-0002-9109-350X and Thuong, Nguyen T T (2020) 'Sources of Multidrug Resistance in Patients With Previous Isoniazid-Resistant Tuberculosis Identified Using Whole Genome Sequencing: A Longitudinal Cohort Study'. Clinical Infectious Diseases. (In Press)

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Abstract

Background
Meta-analysis of patients with isoniazid-resistant tuberculosis given standard first-line anti-tuberculosis treatment indicated an increased risk of multi-drug resistant tuberculosis (MDR-TB) emerging (8%), compared to drug-sensitive tuberculosis (0.3%). Here we use whole genome sequencing (WGS) to investigate whether treatment of patients with pre-existing isoniazid resistant disease with first-line anti-tuberculosis therapy risks selecting for rifampicin resistance, and hence MDR-TB.

Methods
Patients with isoniazid-resistant pulmonary TB were recruited and followed up for 24 months. Drug-susceptibility testing was performed by Microscopic observation drug-susceptibility assay (MODS), Mycobacterial Growth Indicator Tube (MGIT) and by WGS on isolates at first presentation and in the case of re-presentation. Where MDR-TB was diagnosed, WGS was used to determine the genomic relatedness between initial and subsequent isolates. De novo emergence of MDR-TB was assumed where the genomic distance was five or fewer single nucleotide polymorphisms (SNPs) whereas reinfection with a different MDR-TB strain was assumed where the distance was 10 or more SNPs.

Results
239 patients with isoniazid-resistant pulmonary tuberculosis were recruited. Fourteen (14/239, 5.9%) patients were diagnosed with a second episode of tuberculosis that was multi-drug resistant. Six (6/239, 2.5%) were identified as having evolved MDR-TB de novo and six as having been re-infected with a different strain. In two cases the genomic distance was between 5-10 SNPs and therefore indeterminate.

Conclusions
In isoniazid-resistant TB, de novo emergence and reinfection of MDR-TB strains equally contributed to MDR development. Early diagnosis and optimal treatment of isoniazid resistant TB are urgently needed to avert the de novo emergence of MDR-TB during treatment.

Item Type: Article
Subjects: QU Biochemistry > Genetics > QU 550 Genetic techniques. PCR. Chromosome mapping
QW Microbiology and Immunology > QW 45 Microbial drug resistance. General or not elsewhere classified.
WA Public Health > Statistics. Surveys > WA 950 Theory or methods of medical statistics. Epidemiologic methods
WF Respiratory System > Tuberculosis > WF 200 Tuberculosis (General)
Faculty: Department: Clinical Sciences & International Health > International Public Health Department
Digital Object Identifer (DOI): https://doi.org/10.1093/cid/ciaa254
Depositing User: Marie Hatton
Date Deposited: 17 Mar 2020 15:21
Last Modified: 31 Jul 2020 09:17
URI: https://archive.lstmed.ac.uk/id/eprint/13998

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