Martin Hoenigl1,2,3, Carlee B Moser4, Nicholas Funderburg5, Ronald Bosch4, Amy Kantor4, Yonglong Zhang6, Jesper Eugen-Olsen7, Malcolm Finkelman6, Jochen Reiser8, Alan Landay9, Daniela Moisi10, Michael M Lederman10, Sara Gianella1. 1. Division of Infectious Diseases, Department of Medicine, University of California San Diego, Austria. 2. Section of Infectious Diseases and Tropical Medicine, Medical University of Graz, Austria. 3. Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, Austria. 4. Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. 5. Division of Medical Laboratory Science, School of Health and Rehabilitation Sciences, The Ohio State University, Columbus. 6. Associates of Cape Cod, Inc, Falmouth, Massachusetts. 7. Clinical Research Centre, Copenhagen University Hospital Hvidovre, Denmark. 8. Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois. 9. Division of Geriatrics and Palliative Care, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois. 10. Division of Infectious Diseases, Department of Medicine, Case Western Reserve University, Cleveland, Ohio.
Abstract
BACKGROUND: Despite effective antiretroviral therapy (ART), human immunodeficiency virus (HIV) infection remains associated with higher morbidity and mortality, driven, in part, by increased inflammation. Our objective was to identify associations between levels of plasma biomarkers of chronic inflammation, microbial translocation, and monocyte activation, with occurrence of non-AIDS events. METHODS: Participants (141 cases, 310 matched controls) were selected from a longitudinal observational trial; all were virally suppressed on ART at year 1 and thereafter. Soluble urokinase plasminogen activator receptor (suPAR), lipopolysaccharide binding protein (LBP), beta-D-glucan (BDG), intestinal fatty-acid binding protein, oxidized low-density lipoproteins, and soluble CD163 were measured pre-ART, after 1-year of ART, and pre-event. At each time point, conditional logistic regression analysis assessed associations of the biomarkers with events and adjusted for relevant covariates to calculate odds ratios (ORs) according to 1 interquartile range (IQR) difference. RESULTS: At all time points, higher levels of suPAR were associated with increased risk of non-AIDS events (OR per 1 IQR was 1.7 before ART-initiation, OR per 1 IQR was 2.0 after 1 year of suppressive ART, and OR 2.1 pre-event). Higher levels of BDG and LBP at year 1 and pre-event (but not at baseline) were associated with increased risk of non-AIDS events. No associations were observed for other biomarkers. CONCLUSIONS: Elevated levels of suPAR were strongly, consistently, and independently predictive of non-AIDS events at every measured time point. Interventions that target the suPAR pathway should be investigated to explore its role in the pathogenesis of non-AIDS-related outcomes in HIV infection.
BACKGROUND: Despite effective antiretroviral therapy (ART), human immunodeficiency virus (HIV) infection remains associated with higher morbidity and mortality, driven, in part, by increased inflammation. Our objective was to identify associations between levels of plasma biomarkers of chronic inflammation, microbial translocation, and monocyte activation, with occurrence of non-AIDS events. METHODS:Participants (141 cases, 310 matched controls) were selected from a longitudinal observational trial; all were virally suppressed on ART at year 1 and thereafter. Soluble urokinase plasminogen activator receptor (suPAR), lipopolysaccharide binding protein (LBP), beta-D-glucan (BDG), intestinal fatty-acid binding protein, oxidized low-density lipoproteins, and soluble CD163 were measured pre-ART, after 1-year of ART, and pre-event. At each time point, conditional logistic regression analysis assessed associations of the biomarkers with events and adjusted for relevant covariates to calculate odds ratios (ORs) according to 1 interquartile range (IQR) difference. RESULTS: At all time points, higher levels of suPAR were associated with increased risk of non-AIDS events (OR per 1 IQR was 1.7 before ART-initiation, OR per 1 IQR was 2.0 after 1 year of suppressive ART, and OR 2.1 pre-event). Higher levels of BDG and LBP at year 1 and pre-event (but not at baseline) were associated with increased risk of non-AIDS events. No associations were observed for other biomarkers. CONCLUSIONS: Elevated levels of suPAR were strongly, consistently, and independently predictive of non-AIDS events at every measured time point. Interventions that target the suPAR pathway should be investigated to explore its role in the pathogenesis of non-AIDS-related outcomes in HIV infection.
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