Distinguishing Relapse from Reinfection in Recurrent Tuberculosis: A Genomic and Epidemiologic Study in Brazil

Background: Tuberculosis recurrence accounts for a substantial proportion of incident tuberculosis in many settings. Distinguishing between its mechanisms can inform public health interventions for prevention. Methods: We conducted a retrospective study of individuals with multiple culture-confirmed TB episodes and available sequential isolates from 2012 to 2023 in Dourados and Campo Grande, Mato Grosso do Sul state, Brazil. Patients were classified as having recurrent TB after treatment completion or retreatment following non-curative outcomes. Whole-genome sequencing was used to assess pairwise genetic distances between isolates, classifying relapse or persistent infection ([≤]12 single-nucleotide polymorphisms [SNPs]) versus reinfection or retreatment with reinfection (>12 SNPs). Results: Among 9,293 individuals with TB, 772 recurrent or retreatment episodes were identified. Paired isolates from 82 individuals were available for comparisons. Among individuals who completed treatment, reinfection accounted for 74.1% (40/54) of recurrent episodes, while 25.9% (14/54) were classified as relapse. Among individuals with non-curative outcomes, persistent infection (53.6%, 15/28) and retreatment with reinfection (46.4%, 13/28) occurred at similar frequencies. Persistent infection and relapse occurred earlier after the initial episode, whereas reinfection and retreatment with reinfection predominated after two years. Incarceration history was strongly associated with reinfection after treatment completion (92.5%, p=0.012) and after non-curative outcomes (76.9%, p=0.016). Conclusions: In this high-burden setting, reinfection drives TB recurrence among individuals who complete treatment, particularly at longer intervals after initial disease, reflecting sustained exposure risk. Relapse and persistent infection remain clinically important, especially following non-curative outcomes. These findings underscore the need for integrated strategies combining adherence support to prevent treatment-related recurrence with interventions to reduce transmission, particularly in high-risk settings.