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

J Infect Dis. 2015 Apr 1;211(7):1154-63. doi: 10.1093/infdis/jiu574. Epub 2014 Oct 21.


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.

Keywords: HIV; RFLP; recurrence; reinfection; relapse; tuberculosis; whole-genome sequence.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antitubercular Agents / therapeutic use
  • Cohort Studies
  • Female
  • Follow-Up Studies
  • Genetic Variation*
  • Genome, Bacterial / genetics*
  • Genome-Wide Association Study
  • HIV Infections / complications
  • HIV Infections / epidemiology*
  • HIV Infections / virology
  • Humans
  • Isoniazid / therapeutic use
  • Malawi / epidemiology
  • Male
  • Middle Aged
  • Mycobacterium tuberculosis / genetics
  • Mycobacterium tuberculosis / isolation & purification*
  • Polymorphism, Restriction Fragment Length
  • Polymorphism, Single Nucleotide
  • Prevalence
  • Recurrence
  • Sequence Analysis, DNA
  • Tuberculosis / drug therapy
  • Tuberculosis / epidemiology*
  • Tuberculosis / microbiology


  • Antitubercular Agents
  • Isoniazid