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

• Published in: The Journal of infectious diseases Vol. 211; no. 7; pp. 1154 - 1163
• Main Authors: Guerra-Assunção, José Afonso, Houben, Rein M. G. J., Crampin, Amelia C., Mzembe, Themba, Mallard, Kim, Coll, Francesc, Khan, Palwasha, Banda, Louis, Chiwaya, Arthur, Pereira, Rui P. A., McNerney, Ruth, Harris, David, Parkhill, Julian, Clark, Taane G., Glynn, Judith R.
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01-04-2015
• Subjects: Adult; Antitubercular Agents - therapeutic use; BACTERIA; Cohort Studies; Female; Follow-Up Studies; Genetic Variation; Genome, Bacterial - genetics; Genome-Wide Association Study; HIV Infections - complications; HIV Infections - epidemiology; HIV Infections - virology; Human immunodeficiency virus; Humans; Isoniazid - therapeutic use; Major and Brief Reports; Malawi - epidemiology; Male; Middle Aged; Mycobacterium tuberculosis; 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; Malawi; recurrence; reinfection; HIV; relapse; whole-genome sequence; tuberculosis; RFLP
• ISSN: 0022-1899; 1537-6613; 1537-6613
• DOI: 10.1093/infdis/jiu574

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-nudeotide 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.