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Plasma CD163 independently predicts all-cause
mortality from HIV-1 infection
 
 
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"In conclusion, our study showed that sCD163 predicted all-cause mortality in antiretroviral treated individuals, suggesting the importance of monocyte/macrophage activation and a possible target for intervention. Further, our demonstration of a strong risk gradient in the highest quartile of patients suggests that elevated plasma sCD163 may help identifying a risk group requiring further work up and surveillance. Subjects with the highest sCD163 levels had a 165% increased risk of death compared to those with the lowest levels of sCD163........ In individuals receiving ART, low-level HIV replication, microbial translocation, viral coinfection (e.g. CMV or HCV), comorbidity and life style factors such as tobacco and alcohol use are believed to contribute to chronic inflammation (36)......Importantly, however, the predictive value of sCD163 was unchanged after adjustment for these important drivers of inflammation. Emerging data suggest that chronic immune activation may accelerate the burden of several age-related comorbidities in the HIV population (37)......Future studies should investigate a possible association between elevated sCD163 and diseases characterized by chronic inflammation such as cardiovascular disease, diabetes and cancer. The causes of death varied and included infection, cancer, cardiovascular, respiratory, hepatic and alimentary tract diseases......Future interventional studies using this drug or others that target pathways of sCD163 are required to determine if a strategy of monocyte/macrophage attenuation could reduce morbidity and mortality associated with HIV.......Individuals not receiving ART at baseline or who were not suppressed (HIV RNA ≥ 50 copies/mL) had higher sCD163 levels than individuals who were treated or who were suppressed (both P<0.0001). Individuals with a history of IDU or HCV antibody or HCV RNA positivity had higher sCD163 levels compared to individuals without (all P<0.0001). sCD163 increased with higher Charlson Comorbidity Index level (P=0.004) and was lower for never smokers compared to ever smokers or unknown smoking status (P=0.02).
 
There was a positive correlation between plasma sCD163 and plasma HIV RNA for all patients (r=0.40, P=0.0001) and for the subgroup of patients with detectable plasma HIV RNA (> 50 copies/ml) (r=0.36, P=0.0001). There was an inverse correlation between plasma sCD163 and blood CD4 T cell count (r=-0.25, P=0.0001) for all patients and for patients with detectable HIV RNA (r=-0.20, P=0.0001).
 
There were 167 (17.9%) deaths during 10.5 years of follow up. The median time to death was 4.5 (2.2-7.2) years. Plasma sCD163 was higher in non-survivors than in survivors (4.92 mg/L (3.29-8.65) vs. 3.16 mg/L (2.16-4.64), P=0.0001).
 
Further, age, race, comorbidity level, IDU, plasma HIV RNA level, blood CD4 T cell count and smoking status were associated with death during follow up. In adjusted analysis, the influence of plasma sCD163 levels on risk of death was attenuated (HR: 1.06 (95% CI: 1.03-1.09)). The adjusted HR of death per quartile increase of sCD163 was 1.35 (95% CI: 1.13-1.63) (95% CI: 1.13-1.63). Similarly, a strong risk gradient was evident for adjusted HRs for the fourth, third, and second quartiles of sCD163 compared to the first quartile of 2.65 (95% CI: 1.47-4.80, P<0.001), 1.77 (95% CI: 0.98-3.17, P=0.06) and 1.15 (0.62-2.11, P=0.66), respectively. By adjustment for individually relevant confounders, age, sex, race, transmission category, comorbidity, blood CD4 T cell counts and smoking status were each associated with death.”
 
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Plasma CD163 independently predicts all-cause mortality from HIV-1 infection
 
Troels Bygum Knudsen1, Gideon Ertner1, Janne Petersen2,3, Holger Jon Moller4, Soren K. Moestrup5,6, Jesper Eugen-Olsen7, Gitte Kronborg1,8, Thomas Benfield1,7,8
 
Journal of Infectious Diseases Advance Access published June 28, 2016
 
1Department of Infectious Diseases, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark; 2 Optimed, Clinical Research Centre, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark; 3 Section of Biostatistics, Department of Public Health, University of Copenhagen, Denmark; 4Department of Clinical Biochemistry, Aarhus University Hospital, Denmark; 5Department of Biomedicine, Aarhus University, Aarhus, Denmark; 6Institute of Molecular Medicine, University of Southern Denmark; 7 Clinical Research Centre, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark; 8Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
 
ABSTRACT
 
Background: CD163, a monocyte- and macrophage-specific scavenger receptor, is shed as soluble CD163 (sCD163) during the proinflammatory response. Here, we assessed the association of plasma sCD163 levels in HIV-1 infection to AIDS and all-cause mortality.
 
Methods: Plasma sCD163 levels were measured in 933 HIV-1 infected individuals. Hazard ratios (HR) with 95% confidence intervals (95% CI) associated with mortality were computed by Cox proportional hazards regression.
 
Results: At baseline, 86% were on antiretroviral treatment, 73% had plasma HIV RNA < 50 copies/mL and the median CD4 T cell count was 503 cells/μl. During 10.5 years of follow up there were 167 (17.9%) deaths. Plasma sCD163 was higher in non-survivors than in survivors (4.92 mg/L (3.29-8.65) vs. 3.16 mg/L (2.16-4.64), P=0.0001). The cumulative incidence of death increased with increasing plasma sCD163 levels corresponding to a 6% or 35% increased risk of death for each mg/L or quartile increase in baseline plasma sCD163 (adjusted HR: 1.06 (95% CI: 1.03-1.09) and 1.35 (95% CI: 1.13-1.63), respectively).
 
Conclusion: Plasma sCD163 was an independent marker of all-cause mortality in a cohort of HIV-1 infected individuals suggesting that monocyte/macrophage activation may play a role in HIV pathogenesis and be a target of intervention.
 
INTRODUCTION
 
Immune activation and chronic inflammation is associated with disease progression in HIV infection. Although inflammation and immune activation is most profound during untreated HIV infection, virtually all components of innate and adaptive immunity remain dysfunctional despite antiretroviral treatment (ART). Consequently, many individuals experience persistent abnormalities of immune activation, inflammation and coagulation (1;2). T-cell activation rapidly declines following initiation of ART but changes in innate immune activation markers are more variable (3-5).. Selected markers of inflammation and coagulation have been correlated to HIV-associated outcomes (6-9).
 
CD163 is a haptoglobin-haemoglobin scavenger receptor expressed predominantly on monocytes and macrophages (10). CD163 is reported to be involved in erythroblast adhesion (11), immune sensing of bacteria (12), and binding of TWEAK (TNF-like weak inducer of apoptosis) (13). Upon proinflammatory stimuli such as Toll-like receptor (TLR) activation by lipopolysaccharide (LPS) or other microbial ligands, soluble CD163 (sCD163) is shed from monocytes by proteinase-mediated cleavage during the inflammatory response (14). The cleavage is mediated by ADAM-17, an inflammation-inducible enzyme that also leads to release of TNF-a, hence the alternative designation of ADAM17 as TNF-a-activating enzyme (TACE) (15;16).
 
The function of sCD163 is hitherto unknown but it is believed to be important in resolution of inflammation (17). Soluble CD163 has been associated with disease progression in viral hepatitis (18), and with increased mortality following sepsis and tuberculosis (19;20). Recent studies have shown that levels of sCD163 are elevated in HIV infected individuals and that sCD163 plasma levels remain elevated despite ART suggesting residual monocyte/macrophage activation after HIV suppression (21-25). Co-infection with hepatitis C virus, ongoing HIV replication and treatment with a protease inhibitor was associated with an attenuated decrease in plasma sCD163 in ART treated individuals (23). Further, elevated plasma sCD163 levels have been associated with coronary lesions and stenosis in HIV infected individuals receiving ART (21;24;26). Collectively, these studies indicate that plasma sCD163 levels are correlated with HIV-related morbidity. However, a role for sCD163 in disease progression and outcome has not been determined.
 
The objective of this study is to evaluate the influence of plasma sCD163 levels on progression to death and AIDS in a contemporary cohort of HIV infected individuals that were followed for more than 10 years.
 
RESULTS excerpted
 
Individuals not receiving ART at baseline or who were not suppressed (HIV RNA ≥ 50 copies/mL) had higher sCD163 levels than individuals who were treated or who were suppressed (both P<0.0001). Individuals with a history of IDU or HCV antibody or HCV RNA positivity had higher sCD163 levels compared to individuals without (all P<0.0001). sCD163 increased with higher Charlson Comorbidity Index level (P=0.004) and was lower for never smokers compared to ever smokers or unknown smoking status (P=0.02).
 
There was a positive correlation between plasma sCD163 and plasma HIV RNA for all patients (r=0.40, P=0.0001) and for the subgroup of patients with detectable plasma HIV RNA (> 50 copies/ml) (r=0.36, P=0.0001). There was an inverse correlation between plasma sCD163 and blood CD4 T cell count (r=-0.25, P=0.0001) for all patients and for patients with detectable HIV RNA (r=-0.20, P=0.0001).
 
There were 167 (17.9%) deaths during 10.5 years of follow up. The median time to death was 4.5 (2.2-7.2) years. Plasma sCD163 was higher in non-survivors than in survivors (4.92 mg/L (3.29-8.65) vs. 3.16 mg/L (2.16-4.64), P=0.0001).
 
The underlying cause of death had been determined for 144 (86.2%) cases. Infection was the most common cause of death (n=54), followed by cancer (n=25), respiratory or cardiovascular disease (n=17), and alimentary tract disease (n=7). Accident or suicide (n=17) , other or unknown causes (n=14) accounted for the remaining deaths.
 
By univariate Cox analysis, there was an increased risk of death for each mg/L increase in plasma sCD163 at baseline (HR: 1.11 (95% CI: 1.08-1.13) (Table 2).
 
Further, age, race, comorbidity level, IDU, plasma HIV RNA level, blood CD4 T cell count and smoking status were associated with death during follow up. In adjusted analysis, the influence of plasma sCD163 levels on risk of death was attenuated (HR: 1.06 (95% CI: 1.03-1.09)). The adjusted HR of death per quartile increase of sCD163 was 1.35 (95% CI: 1.13-1.63) (95% CI: 1.13-1.63). Similarly, a strong risk gradient was evident for adjusted HRs for the fourth, third, and second quartiles of sCD163 compared to the first quartile of 2.65 (95% CI: 1.47-4.80, P<0.001), 1.77 (95% CI: 0.98-3.17, P=0.06) and 1.15 (0.62-2.11, P=0.66), respectively. By adjustment for individually relevant confounders, age, sex, race, transmission category, comorbidity, blood CD4 T cell counts and smoking status were each associated with death.
 
DISCUSSION
 
Here we show in a large contemporary cohort that high sCD163 levels were independently associated with an increased risk of all-cause mortality. The association was robust after controlling for factors traditionally associated with HIV outcomes, across different subgroups and was particularly high for HIV-infected individuals who acquired HIV heterosexually and for never smokers.
 
Subjects with the highest sCD163 levels had a 165% increased risk of death compared to those with the lowest levels of sCD163
 
Injecting drug users had a high risk of death and the highest sCD163 levels but sCD163 alone did not explain the increased risk of death associated with IDU. We speculate that this is likely a consequence of comorbidity, behavior and life style associated with IDU. The largest transmission category in our clinic (MSM) had an increased risk of death associated with sCD163 that was comparable to the overall cohort.
 
Similarly, the large groups of individuals on ART or who had undetectable HIV RNA, had sCD163 associated risks that were comparable to the cohort in general.
 
Other inflammatory biomarkers have been linked to an increased risk of HIV-related all-cause mortality. Interestingly, the strongest associations with mortality were seen in untreated individuals for IL-6, D-dimer and sCD14 and to a lesser extent in treated individuals (6;7). Plasma sCD163 levels, in contrast, were predictive of mortality in treated but not in untreated individuals indicating that sCD163 could be useful to identify individuals with ongoing inflammation despite being successfully treated with ART. During untreated HIV, inflammation and activation is driven by HIV replication. In individuals receiving ART, low-level HIV replication, microbial translocation, viral coinfection (e.g. CMV or HCV), comorbidity and life style factors such as tobacco and alcohol use are believed to contribute to chronic inflammation (36).
 
Beltran et al. showed that co-infection with HCV and ongoing HIV replication was associated with an attenuated decrease in plasma sCD163 after initiation of ART (23). In our study, we adjusted for both of these factors because they were associated with mortality in univariate analysis. Only HIV RNA level remained an independent predictor in adjusted analysis suggesting that HCV status is likely a marker of other unfavourable risks such as IDU. Comorbidity and smoking was high in our cohort and both predictably associated with outcome.
 
Importantly, however, the predictive value of sCD163 was unchanged after adjustment for these important drivers of inflammation. Emerging data suggest that chronic immune activation may accelerate the burden of several age-related comorbidities in the HIV population (37).
 
Future studies should investigate a possible association between elevated sCD163 and diseases characterized by chronic inflammation such as cardiovascular disease, diabetes and cancer. The causes of death varied and included infection, cancer, cardiovascular, respiratory, hepatic and alimentary tract diseases.
 
Obesity has recently been associated with high levels of sCD163 in HIV infection but information on body mass index was not available in our cohort (38). Causation cannot be inferred from nonrandomized studies. In this respect it is of interest that sCD163 levels were lowered by 20% after two-weeks of treatment with an antiemetic, aprepitant (39). Future interventional studies using this drug or others that target pathways of sCD163 are required to determine if a strategy of monocyte/macrophage attenuation could reduce morbidity and mortality associated with HIV.
 
In conclusion, our study showed that sCD163 predicted all-cause mortality in antiretroviral treated individuals, suggesting the importance of monocyte/macrophage activation and a possible target for intervention. Further, our demonstration of a strong risk gradient in the highest quartile of patients suggests that elevated plasma sCD163 may help identifying a risk group requiring further work up and surveillance.
 
 
 
 
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