Targeted plasma proteomics reveals organ damage signatures of AIDS- and noncommunicable disease-related deaths in people with HIV.

Antiretroviral therapy (ART) is shifting the primary driver of mortality for people with HIV (PWH) from opportunistic infections to noncommunicable diseases (NCDs). Protein biomarkers differentiating both AIDS-related and NCDs-related deaths from PWH may help early and precise risk prediction and intervention. We conduct a nested case-control study where 126 HIV deaths, 162 age-sex-matched HIV survivors and 152 HIV-negative controls are analyzed with 92 protein biomarkers of the Olink Organ Damage panel by proximity extension assays (PEA). Using LASSO regression, logistic regression, and ROC analysis, twelve proteins are significantly associated with HIV death, of which six (SIRT5, PPM1B, PSMA1, GALNT10, VEGFC, PTN) are specifically associated with NCDs-related death, two (RCOR1, SERPINA9) are specifically associated with AIDS-related death, and four (CA12, CA14, RARRES1, EDIL3) are associated with both. Three of these proteins are replicable in the external validation sample. The adjusted protein panels consisting of significantly associated proteins selected through both LASSO and logistic regression model well predicted NCDs-related death (AUC = 0.970) and AIDS-related death (AUC = 0.960) in PWH. The selected proteins also displayed a significant correlation with traditional biomarkers of NCDs among PWH (P < 0.05). The potential clinical utility of these biomarkers could shed light on pathogenesis of end-stage organ dysfunction in PWH.