Recurrence due to relapse or reinfection with Mycobacterium tuberculosis: a whole-genome sequencing approach in a large, population-based cohort with a high HIV infection prevalence and active follow-up.

José Afonso Guerra-Assunção; Rein MGJ Houben ORCID logo; Amelia C Crampin ORCID logo; Themba Mzembe; Kim Mallard; Francesc Coll ORCID logo; Palwasha Khan ORCID logo; Louis Banda; Arthur Chiwaya; Rui PA Pereira; +5 more... Ruth McNerney; David Harris; Julian Parkhill; Taane G Clark ORCID logo; Judith R Glynn ORCID logo; (2014) Recurrence due to relapse or reinfection with Mycobacterium tuberculosis: a whole-genome sequencing approach in a large, population-based cohort with a high HIV infection prevalence and active follow-up. The Journal of infectious diseases, 211 (7). pp. 1154-1163. ISSN 0022-1899 DOI: 10.1093/infdis/jiu574
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BACKGROUND: Recurrent tuberculosis is a major health burden and may be due to relapse with the original strain or reinfection with a new strain. METHODS: In a population-based study in northern Malawi, patients with tuberculosis diagnosed from 1996 to 2010 were actively followed after the end of treatment. Whole-genome sequencing with approximately 100-fold coverage was performed on all available cultures. Results of IS6110 restriction fragment-length polymorphism analyses were available for cultures performed up to 2008. RESULTS: Based on our data, a difference of ≤10 single-nucleotide polymorphisms (SNPs) was used to define relapse, and a difference of >100 SNPs was used to define reinfection. There was no evidence of mixed infections among those classified as reinfections. Of 1471 patients, 139 had laboratory-confirmed recurrences: 55 had relapse, and 20 had reinfection; for 64 type of recurrence was unclassified. Almost all relapses occurred in the first 2 years. Human immunodeficiency virus infection was associated with reinfection but not relapse. Relapses were associated with isoniazid resistance, treatment before 2007, and lineage-3 strains. We identified several gene variants associated with relapse. Lineage-2 (Beijing) was overrepresented and lineage-1 underrepresented among the reinfecting strains (P = .004). CONCLUSIONS: While some of the factors determining recurrence depend on the patient and their treatment, differences in the Mycobacterium tuberculosis genome appear to have a role in both relapse and reinfection.


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