Elevated Zonulin‐1 is Associated With an Increased Risk of Non‐AIDS‐Defining Cancers in People With HIV With Suboptimal Immune Recovery: A Case‐Cohort Study

People with HIV (PWH) on antiretroviral therapy (ART) exhibit a heightened risk of non-AIDS-defining cancers (NADCs), linked to chronic inflammation driven by microbial translocation. We investigated whether plasma biomarkers of gut barrier dysfunction are associated with NADC risk, hypothesizing this association is modified by immune status. We conducted a case-cohort study nested within the Spanish CoRIS cohort. Plasma levels of zonulin-1, lipopolysaccharide, LPS-binding protein, and flagellin were measured in 71 incident NADC cases and a 261-individuals subcohort. Multivariable Cox proportional hazards models were used to estimate NADC risk, testing for effect modification by baseline CD4 + T-cell count. Zonulin-1 was not independently associated with NADC risk. However, a strong statistical interaction with baseline CD4 + T-cell count was detected (p = 0.001). Among individuals with suboptimal immune recovery (defined as CD4 + T-cell count < 500 cells/mm³), higher zonulin-1 levels were associated with a nearly threefold increased NADC risk (aHR = 2.94 (1.28-6.76)). Conversely, no association was observed in those with robust immune reconstitution (≥ 500 cells/mm³; aHR= 0.84 (0.41-1.72)). Other biomarkers showed no association. This supports a "two-hit" model of carcinogenesis where a compromised gut barrier and impaired immune competence are associated with an increased risk of cancer. Zonulin-1 is a key biomarker for identifying this high-risk phenotype, suggesting targeted cancer prevention strategies restoring gut integrity.