title: 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.
abstract: 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.
authors.affiliation: Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine.
authors.forename: José Afonso
authors.initials: JA
authors.lastname: Guerra-Assunção
authors.affiliation: Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine.
authors.forename: Rein M G J
authors.initials: RM
authors.lastname: Houben
authors.affiliation: Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine Karonga Prevention Study, Malawi.
authors.forename: Amelia C
authors.initials: AC
authors.lastname: Crampin
authors.affiliation: Karonga Prevention Study, Malawi.
authors.forename: Themba
authors.initials: T
authors.lastname: Mzembe
authors.affiliation: Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine.
authors.forename: Kim
authors.initials: K
authors.lastname: Mallard
authors.affiliation: Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine.
authors.forename: Francesc
authors.initials: F
authors.lastname: Coll
authors.affiliation: Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine.
authors.forename: Palwasha
authors.initials: P
authors.lastname: Khan
authors.affiliation: Karonga Prevention Study, Malawi.
authors.forename: Louis
authors.initials: L
authors.lastname: Banda
authors.affiliation: Karonga Prevention Study, Malawi.
authors.forename: Arthur
authors.initials: A
authors.lastname: Chiwaya
authors.affiliation: Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine.
authors.forename: Rui P A
authors.initials: RP
authors.lastname: Pereira
authors.affiliation: Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine.
authors.forename: Ruth
authors.initials: R
authors.lastname: McNerney
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Harris
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Julian
authors.initials: J
authors.lastname: Parkhill
authors.affiliation: Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine.
authors.forename: Taane G
authors.initials: TG
authors.lastname: Clark
authors.affiliation: Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine.
authors.forename: Judith R
authors.initials: JR
authors.lastname: Glynn
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000627:therapeutic use; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D014644:Genetic Variation; D016680:Genome, Bacterial / Q000235:genetics*; D055106:Genome-Wide Association Study; D015658:HIV Infections / Q000150:complications / Q000453:epidemiology* / Q000821:virology; D006801:Humans; D007538:Isoniazid / Q000627:therapeutic use; D008295:Malawi / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000302:isolation & purification*; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D012008:Recurrence; D017422:Sequence Analysis, DNA; D014376:Tuberculosis / Q000188:drug therapy / Q000453:epidemiology* / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D007538:Isoniazid
keywords: HIV; RFLP; recurrence; reinfection; relapse; tuberculosis; whole-genome sequence