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The utility of T-cell interferon-γ (IFN-γ) responses to Mycobacterium tuberculosis specific antigens [interferon-γ release assays (IGRAs)] in high-burden settings remains unclear and there is growing evidence that IGRA performance varies across high tuberculosis (TB) burden vs. low TB burden settings. Here we review the evidence supporting the utility of IGRAs in specific subgroups and compare their performance in high-burden vs. low-burden settings.Although the IGRA, compared with the tuberculin skin test (TST), has greater specificity in BCG-vaccinated individuals, treatment of latent tuberculosis infection is not a priority in high-burden setting. Nevertheless, in high-burden settings, the TST performs reasonably well and correlates as well, or better, with proxy measures of exposure.IGRAs may still be useful in high-burden settings in specific subgroups at high risk of progression, including young children, HIV-infected individuals and healthcare workers, but this requires confirmation. Although the IGRAs cannot distinguish between latent and active TB, their utility as rule-out tests, when combined with smear microscopy or the TST, requires further study. Prospective studies are required in high-burden settings to confirm whether IFN-γ responses are predictive of high risk of progression to active TB, particularly in HIV-infected individuals.