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Special Focus Review

Clinical utility of biomarkers of endothelial activation and coagulation for prognosis in HIV infection

A systematic review

, &
Pages 564-571 | Received 09 Apr 2013, Accepted 30 May 2013, Published online: 24 Jun 2013

Abstract

Introduction: HIV infection is associated with vascular dysfunction and adverse cardiovascular outcomes. Our objective was to review the evidence regarding the clinical utility of endothelial activation and coagulation biomarkers for the prognosis of HIV-infected patients.

Methods: We searched PubMed and Embase for publications using the keywords “HIV” or “HIV infection” and “endothelium” or “coagulation”. We reviewed reference lists and hand-searched for additional relevant articles. All clinical studies that enrolled non-pregnant, HIV-infected adults, measured biomarkers reflecting endothelial activation or coagulation, and prospectively evaluated their associations with vascular dysfunction or clinical outcomes were included.

Results: Seventeen studies were identified that fulfilled the inclusion criteria, of which 11 investigated endothelial activation biomarkers and 12 investigated coagulation biomarkers. Biomarkers and outcomes varied widely across studies. Overall, published studies support an association between P-selectin and venous thromboembolism in HIV-infected patients, an association between tissue-type plasminogen activator and death, and associations between D-dimer and several clinical outcomes, including venous thromboembolism, cardiovascular disease, and all-cause mortality.

Conclusions: Several studies have demonstrated associations between biomarkers of endothelial activation and coagulation and clinically important outcomes in HIV-1 infection. Additional large-scale prospective investigations to determine the utility of endothelial activation and coagulation biomarkers for risk stratification and prediction of adverse outcomes are clearly warranted.

Introduction

Since effective antiretroviral therapy (ART) became widely available, the risks for morbidity and mortality due to opportunistic infections have greatly decreased for persons living with HIV infection.Citation1,Citation2 Unfortunately, recent evidence shows that HIV-infected persons are at higher risk for cardiovascular, renal, and hepatic disease, despite effective ART.Citation3-Citation6 Increasing evidence points to chronic inflammation among individuals who develop HIV-related end-organ disease and other complications.Citation7,Citation8 Such inflammation may activate the coagulation cascade, leading to a pro-thrombotic tendency in HIV-infected persons that could lead to arterial or venous thromboembolism (VTE).Citation9,Citation10

Subclinical atherosclerotic disease and vascular dysfunction have also been identified in HIV-infected individuals.Citation11 While traditional risk factors are still important, traditional risk assessments such as the Framingham Risk Score underestimate cardiovascular risk in HIV-infected persons.Citation12,Citation13 Inflammation, endothelial activation, and oxidative stress, all increased in HIV-1 infection, are known to be major driving forces for the initiation of coronary plaques, their progression to instability, and eventual plaque disruption.Citation14-Citation16 Indeed, several studies have demonstrated increased levels of biomarkers of endothelial activation (e.g., VCAM-1, ICAM-1, E-selectin) and coagulation (e.g., P-selectin, d-dimer, fibrinogen) in HIV-infected persons compared with healthy, uninfected controls.Citation17-Citation20

There are multiple mechanisms whereby HIV-1 proteins and antiretroviral drugs may lead to endothelial damage (reviewed in ref. Citation21). The HIV-1 envelope protein gp120 and the regulatory protein Tat are both associated with endothelial cell apoptosis and increased cellular adhesion molecules, adhesion, permeability, and reactive oxygen species (ROS). Tat is also associated with decreased endothelial relaxation, and increased monocyte chemoattractant protein-1, matrix metalloproteinase, chemotaxis, proliferation, and angiogenesis. Other accessory proteins may augment these effects: Nef and Vpr by increasing endothelial cell apoptosis, and Vpu by increasing expression of cellular adhesion molecules (Table 1 in ref. Citation21). Antiretroviral drugs may exacerbate HIV-1-related endothelial effects. Nucleoside or nucleotide reverse transcriptase inhibitors decrease mitrochondrial function, levels of reduced glutathione, and vasorelaxation, and increase ROS, vasoconstrictor release, endothelial proliferation, and vascular permeability. Protease inhibitors have been associated with decreased mitrochondrial function, endothelial nitric oxide synthase, vasorelaxation, and flow-mediated dilation, as well as increased ROS, mitochondrial DNA damage, vascular permeability, and carotid intima media thickness. There are no known endothelial effects of non-nucleoside reverse transcriptase inhibitors, integrase inhibitors, or entry inhibitors (Table 2 in ref. Citation21).

Because endothelial activation and coagulation may each play key mechanistic roles leading to adverse outcomes in HIV-infected patients, biomarkers of these processes may prove valuable for the diagnosis, prognosis, or risk stratification of HIV-infected patients. In addition, a better understanding of the mechanisms leading to HIV-1-related vascular dysfunction may lead to specific treatments aimed at reducing endothelial activation or coagulopathy. Our objective was therefore to review the evidence regarding the clinical utility of biomarkers of endothelial activation and coagulation for prognosis in HIV-infected patients.

Results

Our search identified 1134 unique articles (see ). Of these, 55 studies met our initial screening criteria (i.e., studies of HIV-infected adults in which biomarkers were measured). After retrieval of the full-text publication, 38 studies were excluded for the following reasons: 25 studies were cross-sectional, 11 studies did not report a relevant outcome, and 2 studies were interventional trials: one study evaluated the short-term effect of vaccination on inflammatory biomarkers,Citation22 and the other study examined the effect of telmisartan on blood pressure and proteinuria.Citation23 The remaining 17 studies were included in our review. Four studies were randomized trials of interventions aimed at improving vascular function: salsalate,Citation24 pentoxifylline,Citation25 rosiglitazone,Citation26 and NRTI-sparing vs. standard triple PI-based ART.Citation27 All remaining studies were observational designs, two of which were secondary analyses of data collected during a prospective clinical trial.Citation10,Citation28

Figure 1. Study flow diagram.

Figure 1. Study flow diagram.

Biomarkers of endothelial activation

We identified 11 studies investigating associations between biomarkers of endothelial activation and vascular dysfunction or clinical outcomes in HIV infection (see ). Nine studies evaluated ICAM-1, 8 evaluated VCAM-1, 3 evaluated E-selectin, and one each evaluated ICAM-3, P-selectin, and VEGF, respectively. Two studies used nested case-control designs, and one used a retrospective case-control with prospective follow-up of cases. Five studies evaluated vascular function using measures including carotid intima-media thickness (c-IMT, n = 2), flow-mediated dilation (n = 2), arterial stiffness (n = 1), circulating endothelial cells (n = 1), finger arterial pulse wave amplitude (n = 1), and nitroglycerin-mediated dilation (n = 1). Six studies evaluated clinical outcomes, including CD4 count decline (n = 1), cytomegalovirus retinitis (n = 1), cardiovascular disease (CVD) events (n = 1), death (n = 1), Kaposi sarcoma (n = 1), and VTE (n = 1). The study of CVD events used a composite outcome including acute myocardial infarction, silent myocardial infarction, coronary revascularization, acute coronary syndrome, cerebrovascular accident, lower extremity revascularization, and sudden cardiac death.Citation29

Table 1. Biomarkers of endothelial activation

Only one study reported positive findings: in the study by Musselwhite et al., P-selectin levels were associated with VTE.Citation30 Two studies reported associations that were not significant in multivariable analysis. In one, higher ICAM-1 levels were associated with shorter time to death.Citation31 In the other, higher VCAM-1 levels were associated with CVD events.Citation29 The results of three studies suggested an indirect association between endothelial activation biomarkers and outcomes. In the first, VCAM-1 and ICAM-1 decreased over 24 mo of ART, while c-IMT increased and arterial stiffness decreased.Citation27 In the second, pentoxifylline reduced VCAM-1 levels and improved flow mediated dilation (FMD) over 8 weeks of follow-up.Citation25 In the third, VCAM-1 levels decreased to a greater extent among participants taking tenofovir-containing regimens, in whom endothelial function also improved to a greater extent than among participants taking abacavir-containing regimens.Citation32 In all three of these studies, no evaluation was presented to determine whether baseline biomarker levels predicted outcomes. Five studies demonstrated no difference between the outcome of interest and endothelial activation biomarkers.

Biomarkers of coagulation

We identified 12 studies investigating associations between biomarkers of coagulation and vascular dysfunction or clinical outcomes in HIV infection (see ). d-dimer was evaluated in seven studies and VWF in six studies, while fibrinogen, PAI-1, prothombin fragment 1+2, and tissue factor were evaluated in two studies each. Thrombomodulin and tPA were each evaluated in only one of these 12 studies. One study conducted an extensive coagulation work-up including activated protein C sensitivity ratio, endogenous thrombin potential, protein C, prothrombin, PT, PTT, thrombin-antithrombin complex, total and free protein S, as well as d-dimer and VWF.Citation33 Five studies used nested case-control designs. Four studies evaluated vascular function using measures including c-IMT (n = 3), arterial stiffness (n = 1), and FMD (n = 1). Eight studies evaluated clinical outcomes, including all-cause mortality (n = 3), CVD events (n = 1), deep venous thrombosis (n = 1), opportunistic infections (n = 1), and VTE (n = 1). One study evaluated HIV disease progression, defined as AIDS-defining illness, death, or a CD4 count <50 cells/μL.Citation34

Table 2. Biomarkers of coagulation

Five studies demonstrated associations between endothelial activation and outcomes of interest, four of which involved d-dimer. In these four studies, d-dimer predicted all-cause mortality (n = 2),Citation10,Citation35 CVD events (n = 1),Citation29 and VTE (n = 1).Citation30 In the fifth positive study, tPA and CD4 count independently predicted death.Citation36 Results from two studies suggested an indirect association between biomarkers and outcomes. In the first, a marked rise in VWF levels was associated with disease progression, with a positive correlation between VWF levels and HIV-1 RNA levels.Citation34 There was not a direct evaluation of whether baseline VWF levels predicted disease progression. In the second study, VWF levels decreased while c-IMT increased and arterial stiffness decreased during ART.Citation27 Again, there was not a direct evaluation of whether baseline VWF levels predicted vascular function. Four studies reported no association between coagulation biomarkers and outcomes of interest. One study identified no outcomes, and so had no power to determine associations.Citation33

Discussion

We conducted a comprehensive systematic review of the clinical utility of biomarkers reflecting endothelial activation and coagulation in HIV-1 infection. Our objective in conducting this review has been to evaluate the status of work in this area and identify productive avenues for future research. Increased coagulation and endothelial activation biomarkers have been reported in a number of studies of HIV-infected adults, with decreases in these markers after ART initiation (reviewed in refs. Citation7, Citation21, and Citation37). However, only a small number of studies have evaluated the association of endothelial activation and coagulation with either vascular dysfunction (a surrogate marker of future adverse outcomes) or clinical outcomes in this patient population. Seventeen studies were identified that fulfilled the inclusion criteria, of which 11 investigated endothelial activation biomarkers and 12 investigated coagulation biomarkers. The biomarkers and outcomes studied varied widely. Sample sizes were relatively small, ranging from 9 to 499 HIV-infected participants, with the exception of one very large study of over 1300 participants.Citation35

Our review of endothelial activation biomarkers identified the platelet activation biomarker P-selectin as having clinical utility for the diagnosis of VTE.Citation30 Notably, P-selectin has been previously reported as a predictor of VTE in the general population,Citation38 and increased plasma levels of P-selectin have been reported among pregnant HIV-infected women who developed preeclampsia, compared with those who did not.Citation39 While higher ICAM-1 levels were associated with mortality in one study,Citation31 and higher VCAM-1 levels with CVD events in another,Citation29 neither finding was an independent predictor of outcomes. Other studies we identified failed to evaluate the prognostic value of endothelial activation biomarkers despite longitudinal follow-up.

Are biomarkers of endothelial activation therefore not useful for the prediction of outcomes other than VTE? We have recently published a prospective study of endothelial activation biomarkers in HIV-1 seroconverters that was not included in this review. In this study, we found that levels of ICAM-1 and VCAM-1 were persistently elevated from the date of HIV-1 acquisition and that plasma VCAM-1 levels measured during chronic infection were independently associated with time to HIV progression or death.Citation40 Our search did not identify eligible studies of several other biomarkers in this category, including Ang-1, Ang-2, ADMA, and the soluble forms of endocan, endothelin-1, Flt-1, and Tie2 receptor. Investigation of these biomarkers is recommended as holding promise. Indeed, we have found in a small study of Kenyan women initiating ART that soluble ICAM-1 and plasma Ang-2 levels decreased after ART initiation, with concomitant increases in the beneficial protein Ang-1. Although both biomarkers predicted mortality after ART initiation in this cohort, Ang-2 had better predictive value.Citation41

Our review of coagulation biomarkers showed that d-dimer is the most promising biomarker, given its associations with several clinical outcomes, including venous thromboembolism, cardiovascular disease, and all-cause mortality.Citation10,Citation29,Citation30,Citation35 Interestingly, d-dimer has been found to be a predictor of mortality in Crimean-Congo hemorrhagic fever,Citation42 suggesting the possibility that this biomarker may have utility in other viral infections as well. In addition, tPA was identified as a potential biomarker for mortality in HIV-infected patients.Citation36 Future studies of biomarkers in HIV-1 infection should include d-dimer and consider inclusion of tPA, in order to help establish the clinical utility of these biomarkers for risk stratification and the prediction of clinically relevant endpoints. Our search did not identify eligible studies of several other coagulation biomarkers, including ADAMTS13, factor VIII activity, soluble fibrin, and thrombospondin.

Our study has several limitations. First, our search strategy was broad, but we may have missed some articles in which the biomarkers were not discussed in terms of their effects on endothelial activation or coagulation. We tried to address this by adding searches of biomarker names and by hand-searching the reference lists of identified studies. Second, many publications were produced by single-center teams or were retrospective analyses of previously collected specimens and data, limiting the generalizability to other populations or jurisdictions. Third, the identified studies included a wide range of biomarkers, and did not always evaluate the association of biomarkers with the later development of outcomes. In addition, the selection of outcomes varied across studies, and their definitions may have differed. Finally, because many of the biomarkers studied are not standardized, available literature can only report similarities in the direction and relative magnitude of associations across studies. We were unable to identify a sufficiently large number of adequately powered studies with prospective designs, careful selection of biomarkers, and standardized outcomes to confirm conclusively whether any of these biomarkers have clinical utility in most HIV-infected patient populations at the present time.

Materials and Methods

Data sources

We systematically and inclusively identified all studies that reported data on biomarkers of: (1) endothelial activation (including angiopoietin-1 [Ang-1], angiopoietin-2 [Ang-2], asymmetric dimethylarginine [ADMA], and the soluble forms of endocan, endothelin-1, E-selectin, FMS-like tyrosine kinase-1 [sFlt-1], intercellular adhesion molecule 1 [ICAM-1], ICAM-3, P-selectin, Tie2 receptor, vascular cell adhesion molecule 1 [VCAM-1], and vascular endothelial growth factor [VEGF]), and (2) coagulation (including ADAMTS13, antithrombin, d-dimer, factor VIII activity, fibrinogen, plasminogen activator-inhibitor 1 [PAI-1], protein C, protein S, prothrombin, prothrombin fragment 1+2, soluble fibrin, thrombin, thrombomodulin, thrombospondin, tissue-type plasminogen activator [tPA], tissue factor, and von Willebrand factor [VWF]) in HIV-infected adult patients. We electronically searched PubMed (1950 to Week 27, 2012) and Embase (1980 to Week 27, 2012) databases for all pertinent articles published in English (see Table S1).

Study selection methods

Study selection was performed independently by two reviewers (RM and SMG), with disagreement resolved through arbitration by a third reviewer (WCL). A study was included if it met the following criteria:

(1) Inclusion of non-pregnant, HIV-infected adults, aged 18 y or older;

(2) Measurement of any known biomarker of endothelial activation and/or coagulation; and

(3) Measurement of vascular dysfunction (e.g., carotid intima-media thickness) or a clinical endpoint (e.g., all-cause mortality).

Studies that included only children (i.e., <18 y of age), case reports, case series, and studies of interventions in which only short-term outcomes were evaluated (e.g., changes in blood pressure) were excluded. We excluded cross-sectional studies and prospective studies that only evaluated changes in biomarker levels, usually after ART initiation. Conference abstracts and publications in languages other than English were also excluded, as we were not able to fully assess these studies.

Study data extraction and analysis

For each of the selected studies, we extracted the biomarkers evaluated, study design, patient population, duration of follow-up, and details of the outcomes and findings. Results were tabulated for each type of biomarker (i.e., endothelial activation and coagulation) and compared across studies where appropriate. Due to broad study heterogeneity and disparate outcomes, we did not attempt to numerically combine or perform a metaanalysis of study results.

Conclusions

This systematic review of the published literature demonstrates that several biomarkers reflecting endothelial activation and coagulation, including d-dimer, P-selectin, and tPA, may represent potentially useful biomarkers for the prediction of clinical outcomes in HIV-infected patients. The clinical utility of these biomarkers is limited by the paucity and inconsistency of available evidence, the lack of standardized approaches to biomarker testing and assessment, and the lack of prospective validation in representative patient populations. Due to the increased risk of morbid outcomes in HIV-infected patients, additional large-scale prospective investigations to determine the utility of the most promising endothelial activation and coagulation biomarkers to stratify risk and predict adverse outcomes are clearly warranted. Such research has the potential to elucidate mechanisms of endothelial injury and has the potential to identify specific treatments aimed at reducing endothelial activation or reducing risk of thrombosis.

Supplemental material

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Acknowledgments

Special thanks go to Sherry A Dodson, Clinical Librarian, University of Washington Health Sciences Library for her assistance with our search strategies. This work was supported by a New Investigator Award to SMG from the University of Washington Center for AIDS Research, which is funded by the National Institutes of Health (NIH) (P30 AI027757) and is supported by the following NIH Institutes and Centers: National Institute of Allergy and Infectious Diseases; National Cancer Institute; National Institute of Mental Health; National Institute on Drug Abuse; National Institute of Child Health and Human Development; National Heart, Lung, and Blood Institute; and National Institute on Aging; by the NIH (AI-58698 and AI-38518); and by a Canada Research Chair in Infectious Diseases and Inflammation to WCL from the Canadian Institutes for Health Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Disclosure of Potential Conflicts of Interest

WCL is listed as a co-inventor on a patent applied for by the University Health Network (Toronto, ON Canada) to develop point-of-care tests for endothelial activation biomarkers in infectious diseases. All other authors report no conflict of interest.

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