Background.  While inflammation predicts mortality in treated human immunodeficiency virus (HIV) infection, the prognostic significance of gut barrier dysfunction and phenotypic T-cell markers remains unclear.

Methods.  We assessed immunologic predictors of mortality in a case-control study within the Longitudinal Study of the Ocular Complications of AIDS (LSOCA), using conditional logistic regression. Sixty-four case patients who died within 12 months of treatment-mediated viral suppression were each matched to 2 control individuals (total number of controls, 128) by duration of antiretroviral therapy–mediated viral suppression, nadir CD4⁺ T-cell count, age, sex, and prior cytomegalovirus (CMV) retinitis. A similar secondary analysis was conducted in the SCOPE cohort, which had participants with less advanced immunodeficiency.

Results.  Plasma gut epithelial barrier integrity markers (intestinal fatty acid binding protein and zonulin-1 levels), soluble CD14 level, kynurenine/tryptophan ratio, soluble tumor necrosis factor receptor 1 level, high-sensitivity C-reactive protein level, and D-dimer level all strongly predicted mortality, even after adjustment for proximal CD4⁺ T-cell count (all P ≤ .001). A higher percentage of CD38⁺HLA-DR⁺ cells in the CD8⁺ T-cell population was a predictor of mortality before (P = .031) but not after (P = .10) adjustment for proximal CD4⁺ T-cell count. Frequencies of senescent (defined as CD28⁻CD57⁺ cells), exhausted (defined as PD1⁺ cells), naive, and CMV-specific T cells did not predict mortality.

Conclusions.  Gut epithelial barrier dysfunction, innate immune activation, inflammation, and coagulation—but not T-cell activation, senescence, and exhaustion—independently predict mortality in individuals with treated HIV infection with a history of AIDS and are viable targets for interventions.