Andrade, Bruno de Bezerril “Documento produzido em parceria ou por autor vinculado à Fiocruz, mas não consta à informação no documento”.High Impact Research grant to A.K. from the Ministry of Higher Education, Malaysia (UM.C/625/1/HIR/ MOHE/MED/01). H.Y.T. was funded by the Graduate Research Assistantship Schemes 2010-2012, University of Malaya. S.M.C. is supported by an Australian National Health and Medical Research Council (NHMRC) Principal Research Fellowship. The work of B.B.A. and I.S. is supported by the Intramural Research Program of NIAID/NIH and the study conducted on patients in the Chennai cohort was supported in part by the NIH Intramural-to-India Program 2008.Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a substantial problem in HIV/TB coinfected patients commencing antiretroviral therapy (ART). The immunopathogenesis of TB-IRIS includes increased production of proinflammatory chemokines and cytokines, including interleukin-18, which is a signature cytokine of the nucleotide-binding domain and leucine-rich repeat pyrin containing protein-3 inflammasome. We compared plasma levels of interleukin-18 and other biomarkers of monocyte/macrophage activation in the prediction and characterization of TB-IRIS. Methods: Biomarkers were assayed pre-ART and during TB-IRIS, or equivalent timepoint, in a case–control study of Malaysian HIV patients with paradoxical or unmasking TB-IRIS (n¼15), TB no IRIS (n¼14), and no TB or IRIS (n¼15). Findings for interleukin- 18 were verified in another cohort of patients with paradoxical TB-IRIS (n¼26) and their controls (n¼22) from India. Results: Interleukin-18 was higher in TB-IRIS patients pre-ART and during the event in both Malaysian patients (P<0.0001) and Indian patients (P<0.01). CXCL10 was higher pre-ART (P<0.001), mainly in paradoxical TB-IRIS patients, and during TB-IRIS (P<0.001), whereas CXCL8 was only higher during TB-IRIS (P<0.001). Soluble(s) CD14 was increased in all patients with HIV/TB coinfection pre-ART and during TB-IRIS or equivalent time-point, compared with patients without TB. In contrast, interferon-g was lower before and during TB-IRIS. By receiver operating curve analysis, CXCL10, and/or interleukin-18 pre-ART were predictive of TB-IRIS. Conclusion: Plasma interleukin-18 levels pre-ART are candidate biomarkers for predicting paradoxical and unmasking TB-IRIS and should be investigated for risk stratification and elucidation of disease pathogenesis.