Abstract
BACKGROUND: Tuberculosis recurrence represents 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 paired isolates collected between 2012 and 2023 in Dourados and Campo Grande, Mato Grosso do Sul, 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 were available for 82 individuals. Among those who completed treatment, reinfection accounted for 74.1% (40/54) of recurrent episodes, while 25.9% (14/54) were 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. Relapse and persistent infection occurred earlier after the initial episode, whereas reinfection predominated after two years. Incarceration history was strongly associated with reinfection both after treatment completion (92.5%, p=0.012) and non-curative outcomes (76.9%, p=0.016). CONCLUSIONS: In this high-burden setting, reinfection is the main driver of TB recurrence after treatment completion, particularly at longer intervals, indicating ongoing transmission. 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. SUMMARY: Whole-genome sequencing revealed that tuberculosis recurrence in Brazil is predominantly driven by reinfection, especially after treatment completion and at longer intervals, while relapse and persistent infection occur earlier and are linked to incomplete treatment, highlighting the need for combined treatment and transmission-control strategies.