Soluble Urokinase Plasminogen Activator Receptor Is Predictive of Non-AIDS Events During Antiretroviral Therapy-mediated Viral Suppression

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.

Keywords: beta-D-glucan; lipopolysaccharide binding protein; non-AIDS mortality; suPAR; viral suppression.

Figure 1.

Distribution of soluble markers of inflammation and coagulation among cases (blue) and controls (black) in specimens obtained at the visit before antiretroviral therapy (ART) initiation (baseline), the visit approximately 1 year after ART initiation (year 1), and the visit immediately preceding the non–AIDS-defining event (pre-event). Jitter blots including median and interquartile range are displayed. For controls, all differences between baseline and year-1 were significant (ie, P < .05) except for soluble urokinase plasminogen activator receptor. Abbreviations: BDG, beta-D-glucan; I-FABP, intestinal fatty acid binding protein; LBP, lipopolysaccharide binding protein; oxLDL, oxidized low-density lipoproteins; sCD163, soluble CD163; suPAR, soluble urokinase plasminogen activator receptor.

Figure 2.

Heat map of Spearman correlations between biomarkers in controls. P values <.05 are indicated with a dot. Abbreviations: BDG, beta-D-glucan; I-FABP, intestinal fatty acid binding protein; LBP, lipopolysaccharide binding protein; oxLDL, oxidized low-density lipoproteins; sCD163, soluble CD163; suPAR, soluble urokinase plasminogen activator receptor.

Figure 3.

Biomarker levels at baseline and odds ratios of having a non–AIDS-defining event. Unadjusted analyses adjusted for the matching factors only. Adjusted analyses controlled also for concurrent log10 baseline human immunodeficiency virus RNA load or smoking. Abbreviations: BDG, beta-D-glucan; CI, confidence interval; HIV, human immunodeficiency virus; I-FABP, intestinal fatty acid binding protein; IQR, interquartile range; LBP, lipopolysaccharide binding protein; MI, myocardial infarction; OR, odds ratio; oxLDL, oxidized low-density lipoproteins; sCD163, soluble CD163; suPAR, soluble urokinase plasminogen activator receptor. *.01 ≤ P value < .05.

Figure 4.

Biomarker levels obtained at the visit approximately 1 year after antiretroviral therapy initiation (year 1) and odds ratios of having a non–AIDS-defining event. Unadjusted analyses adjusted for the matching factors only. Adjusted analyses controlled also for concurrent CD4+ T-cell count (adjustment includes quadratic and cubic terms) or smoking. Abbreviations: BDG, beta-D-glucan; CI, confidence interval; HIV, human immunodeficiency virus; I-FABP, intestinal fatty acid binding protein; IQR, interquartile range; LBP, lipopolysaccharide binding protein; MI, myocardial infarction; OR, odds ratio; oxLDL, oxidized low-density lipoproteins; sCD163, soluble CD163; suPAR, soluble urokinase plasminogen activator receptor. *.01 ≤ P value < .05, **P value < .01.

Figure 5.

Biomarker obtained at the visit immediately preceding the non–AIDS-defining event (pre-event) and odds ratios of having a non–AIDS-defining event. Adjusted analyses controlled also for concurrent CD4+ T-cell count (adjustment includes quadratic and cubic terms) or smoking. Abbreviations: BDG, beta-D-glucan; CI, confidence interval; HIV, human immunodeficiency virus; I-FABP, intestinal fatty acid binding protein; IQR, interquartile range; LBP, lipopolysaccharide binding protein; MI, myocardial infarction; OR, odds ratio; oxLDL, oxidized low-density lipoproteins; sCD163, soluble CD163; suPAR, soluble urokinase plasminogen activator receptor. *P = .01 to <.05; **P < .01.