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. 2019 Jun 25;6(11):ofz303. doi: 10.1093/ofid/ofz303

Good Fences Make Good Neighbors: Human Immunodeficiency Virus and Vascular Disease

Elizabeth S Mayne 1,, Susan Louw 2
PMCID: PMC6847507  PMID: 31737735

Abstract

Cardiovascular disease, venous thrombosis, and microvascular disease in people with HIV (PWH) is predicted to increase in an aging HIV-infected population. Endothelial damage and dysfunction is a risk factor for cardiovascular events in PWH and is characterized by impaired vascular relaxation and decreased nitric oxide availability. Vascular disease has been attributed to direct viral effects, opportunistic infections, chronic inflammation, effects of antiretroviral therapy, and underlying comorbid conditions, like hypertension and use of tobacco. Although biomarkers have been examined to predict and prognosticate thrombotic and cardiovascular disease in this population, more comprehensive validation of risk factors is necessary to ensure patients are managed appropriately. This review examines the pathogenesis of vascular disease in PWH and summarizes the biomarkers used to predict vascular disease in this population.

Keywords: biomarkers, cardiovascular disease, endothelium, HIV, thrombosis

INTRODUCTION

Patients with human immunodeficiency viral (HIV) infection have an improved prognosis on antiretroviral therapy (ART) [1]. This is associated with a concomitant drop in the prevalence of opportunistic infections and a corresponding increase in life expectancy [1–3]. Noncommunicable diseases have become a major cause of morbidity and mortality in these patients, including large vessel disease (occlusive vasculitides and aneurysms), cardiovascular disease (CVD), and venous thromboembolism [4–13]. Thrombotic disease is pathological clotting in the vascular system. In arteries, abnormal clotting can result in peripheral vascular disease, myocardial infarction, and cerebrovascular accidents [8]. Venous clots can dislodge and travel to the pulmonary vasculature, a phenomenon known as pulmonary thromboembolism [11]. In the microvasculature system, small disseminated clots can be seen with microangiopathic thrombotic processes, including thrombotic thrombocytopaenic purpura (TTP), TTP-like syndrome, and disseminated intravascular coagulopathy (DIC) [14]. Abnormal clotting in the entire vascular tree occurs in people with HIV (PWH). Thrombotic risk in PWH has been attributed to a number of factors, including the presence of opportunistic infections, prolonged immobility, antiretroviral drugs and other treatments, comorbid conditions (including hypertension and diabetes), and the impact of HIV, itself, on the endothelium [15–17]. This review will look at the interaction between HIV, the vascular wall, and pathogenic thrombosis.

THE ENDOTHELIUM

The endothelium is a monolayer of cells that lines the blood vessels [18, 19]. It is a highly specialized organ that is responsible for control of both inflammation and coagulation. The endothelium-lining arteries, veins, and capillaries show differential response to stressors that are physiological adaptations to the anatomical location [19]. These stressors include differential shear stress (high in the arterial system and lower in the venous system) that can result in location-specific gene transcription [19].

Under normal conditions, the endothelium is a selectively permeable, anticoagulant surface. It produces a number of molecules that act to limit clotting by inhibiting both platelet activation and coagulation factors (Table 1).

Table 1.

Anticoagulant Factors and Vasodilators Produced by the Endothelium

Anticoagulant Factor Function
Heparan sulphate Combines with antithrombin and inactivates coagulation factors IIa and Xa [19]
Prostacyclin Platelet inhibition [19]
Cluster of differentiation (CD) [39] Scavenges adenosine diphosphate released by activated platelets to inhibit platelet aggregation [20]
Endothelial protein C receptor Binds activated protein C to potentiate its activity; complex also acts to protect endothelial cells through the activity on protease-activated receptor-1 and -2 [21]
Thrombomodulin Forms a complex with thrombin to activate protein C, which binds and inactivates factors V and VIII (with protein S as a cofactor) [22]
Tissue factor pathway inhibitor Inhibits the tissue factor-VIIa complex and factor Xa [23]
Primary vasodilator
Nitric oxide (endothelium-derived) Mediates vasodilation; inhibits platelet activation [24, 25]
Endothelium derived hyperpolarizing factor Mediates smooth muscle relaxation and causes vasodilation [26]

In response to pro-inflammatory stimuli or trauma, the endothelium upregulates cellular adhesion molecules and procoagulant factors and becomes more permeable (Table 2) [19]. This allows leukocytes to translocate across the endothelial surface and into the tissue. There is a local shift from an anticoagulant to a procoagulant surface [27]. Tissue factor may be exposed by trauma, secreted into the peri-endothelial space in endothelial vesicles, or upregulated on leukocytes (especially monocytes) [28, 29] and platelets, resulting in activation of the coagulation cascade and clot initiation. Platelets are activated by exposure to subendothelial tissue (primarily collagen) and provide a secondary surface for coagulation, resulting in clot propagation [30].

Table 2.

Procoagulant Substances Produced by the Endothelium [36]

Factor Site of Storage or Expression Function
Activation of the coagulation cascade
Tissue factor Subendothelial tissue including fibroblasts. Induced on endothelial cells in vivo. Expressed by leukocytes during inflammation (specifically monocytes) [31] Activates the extrinsic coagulation pathway resulting in thrombin generation [31]
Factor VIII Endothelial cells [32] Stabilizes factor IX [32]
Platelet activation
Collagen and subendothelial matrix Subendothelial tissue [33] Promotes platelet adhesion, activation, and aggregation [33]
Cellular adhesion molecules, including p-selectin and e-selectin, ICAM-1, and CXC12 [34] Endothelial cells [33] Promotes platelet adhesion, activation, and aggregation [33]
Von Willebrand Factor [35] Weibel-Palade bodies [35] Enables platelet adherence to exposed collagen through its interaction with platelet receptor Ib-V-IX (protects factor VIII from degradation [36, 37])
Eicosanoids, including prostaglandins and thromboxane A2 [38] Endothelial cells [38] Promotes platelet aggregation [38]
Vasoconstrictive agents
Endothelins (predominantly endothelin-1) [39] Endothelial cells, vascular smooth muscles cells, and reproductive system [39] Activates endothelin receptors, increases production of reactive oxygen species, and reduces bioavailability of nitric oxide [39]

Following endothelial injury, a number of processes are initiated to repair the damaged endothelium and allow for clot resorption [40]. Bone-marrow–derived endothelial progenitor cells home to sites of vascular injury and stimulate angiogenesis [40–42]. Platelets and endothelial cells secrete a number of growth factors (including vascular endothelial growth factor), cytokines (including TGF-beta), and chemokines (including CXCL-12 or stromal derived factor-1) that restore barrier function and stimulate endothelial cell proliferation [43–45]. Clot resolution occurs with activation of proteases, like plasmin (through the function of tissue plasminogen activator or tPA present on endothelial cells) [46], which break down fibrin clots with resulting production of fibrin degradation products (measured as D-dimers). This process reduces local hypoxia with stabilization of hypoxia-inducible factor-1, which also can contribute to repair [19].

ENDOTHELIAL DYSFUNCTION

Endothelial dysfunction is a state of aberrant endothelial cell activation that is associated with thrombosis [47]. Endothelial dysfunction classically is associated with arterial atherosclerosis, but it can be more broadly defined to include a prothrombotic state throughout the vasculature [48]. Multiple pathophysiological mechanisms contribute to a phenotype that is characterized by reduced dilatation, decreased arterial compliance, and local inflammation with reduced vascular repair and angiogenesis [19]. Bioavailability of nitric oxide, a key vasodilator and platelet inhibitor, is significantly reduced [25]. The pro-inflammatory mediators that are produced by the damaged endothelial tissue also act directly to upregulate tissue factor expression by leukocytes and to activate platelets [28, 49, 50]. Cyclo-oxygenase enzymatic activity is upregulated in response to various inflammatory stimuli and results in increased production of prostaglandin E2 and thromboxane A2, which stimulate platelet activation and aggregation [38, 51].

PATHOPHYSIOLOGICAL MECHANISMS ASSOCIATED WITH DEVELOPMENT OF ENDOTHELIAL DYSFUNCTION IN PWH

Chronic Inflammation Caused by HIV Infection

HIV infection is a cause of chronic inflammation [49]. A detailed description of the causes of inflammation in PWH is outside the scope of this article. Briefly, rapid depletion of CD4+ T cells from the gut-associated lymphoid tissue and, especially, Th17 subsets disrupts the gastrointestinal barrier function with translocation of microbial products across the interface [49, 52]. This directly stimulates innate pattern recognition molecules, like toll-like receptors (TLRs), with activation of pro-inflammatory signaling pathways like NFκB. TLRs 7 and 9 also are activated directly by HIV, because low-grade viral replication persists even on therapy [49]. Innate immune effector cells activated through pattern recognition receptors produce pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β [53]. The presence of HIV DNA in the cytoplasm of target cells also activates caspase-1, resulting in increased apoptosis [54]. Chronic inflammation has been associated with functional and quantitative abnormalities in multiple leukocytes subsets. This includes monocyte and neutrophil activation, CD4+ T cell dysfunction and apoptosis, CD8+ T cell activation, and B cell activation [49].

Chronic inflammation results in a state of abnormal endothelial cell activation that has been compared to changes seen in aging [55]. This is characterized by reduced number and function of endothelial progenitor cells with reduced capacity to repair endothelial damage [40, 47, 56]. Damage to endothelium can result from the release of oxygen-free radicals by activated immune cells, including activated monocytes and lymphocytes. Pro-inflammatory cytokines like TNF-α bind specific endothelial receptors triggering endothelial apoptosis and activation [50]. Neutrophil activation may result in the production of cytotoxic neutrophils extravasation traps (NETs) that interact directly with coagulation activators and may promote leukocyte adherence [57]. In animal models, neutrophil activation and NETosis is associated with increased risk of thromboembolism [58].

Direct Effects of HIV on Endothelial Cells

The ability of HIV to infect endothelial cells directly is controversial. Small preliminary studies (in vitro) suggested that some endothelial cells could harbor infectious viruses, although larger scale studies have disputed this [59, 60]. It is clear, however, that HIV viral proteins can have a detrimental effect on the endothelium with subsequent dysfunction. Tat activates endothelial signaling pathways with downstream reduction in transcription of nitric oxide synthetase and upregulation of monocyte chemoattractant protein-1 (MCP-1) and cell adhesion molecules [61, 62]. This promotes both leukocyte activation and leukocyte adhesion to the endothelium. Nef activates pro-inflammatory pathways, including NF-κB and NFAT-1, in both endothelial cells and macrophages, promoting alterations in the monocyte phenotype towards pro-inflammatory cells and release of free radicals that can directly damage the endothelium [63]. In addition, Nef can affect cholesterol transport that predisposes to the formation of foam cells [63]. The HIV envelope proteins, gp-120/41, activate the p38 map kinase pathway that has been linked to increased endothelial permeability, endothelial cell apoptosis, and vasoconstriction [64].

Large Vessel Arteritis and Thrombosis in HIV

Aneurysmal disease and occlusive large vessel disease has been well-described in PWH. Histologically, this disease is pleomorphic with some studies reporting an appearance similar to panarteritis nodosa and others reporting transmural inflammation [65]. The pathogenesis of large cell arteritis is delineated incompletely. Upregulation of chemokine secretion can result in transmural cellular infiltrates with compromise of the vasa vasorum. A suggestion that HIV proteins may mimic arterial proteins with a subsequent cross-reactivity. Aside from direct effects on endothelial cells, studies suggest that arterial smooth muscle cells and fibroblasts may be susceptible to direct HIV infection [65-69]. This may result in weakening of the vascular wall and subsequent dilation [67, 70]. This area does, however, require further elucidation.

HIV-Associated Communicable Diseases

HIV-associated immunodeficiency increases the predisposition to and persistence of a number of infections. Chronic infections are associated with a number of changes, including upregulation of procoagulant factors and platelet activation, and mediate a direct effect on endothelial cells. Mycobacterium tuberculosis has been identified in endothelial cells in extrapulmonary infection [71]. Mycobacterial infection is an independent risk factor for thromboembolism and microvascular abnormalities [71, 72]. Parasitic infections like Toxoplasma gondii upregulate endothelial adhesion molecules to assist with invasion [73]. In addition, dysbiosis and microbiome perturbations in the gastrointestinal, respiratory, and urogenital tracts occurring in PWH are an independent risk factor for cardiovascular disease [74].

Endothelial cells are targets for Herpesviridae, including cytomegalovirus, Epstein-Barr virus, Kaposi-sarcoma herpes virus (KSHV), and varicella-zoster virus. Persistent infection with these viruses have been associated, especially in aging or otherwise immunodeficient patients, with an increased risk of vasculitis [75] and endothelial dysfunction [76], mediated through inflammatory signaling pathways [73] and through endothelial cell apoptosis [78]. KSHV, specifically, secretes cytokine homologs like viral IL-6 that have been implicated in both mediating a pro-inflammatory milieu and in atypical angiogenesis [79]. Herpes simplex viruses may infect the endothelium with subsequent apoptosis [76]. Finally, other concomitant viral infections (including persistent hepatitis C viral infection) have been linked to increased risk of cardiovascular disease [81, 82].

Traditional Risk Factors for Cardiovascular Disease in the ART HIV Era

Traditional risk factors for endothelial dysfunction include the presence of diabetes mellitus, hypertension, and hyperlipidaemia. These conditions contribute significantly to CVD risk in PWH [83, 84]. Chronic inflammation (with circulating pro-inflammatory cytokines) can predispose to insulin resistance through the phosphorylation of insulin receptor substrate-1 [85, 86]. Antiretroviral therapy is associated with lipid- abnormalities and dysregulation of glucose-processing pathways, which are independently associated with an increased risk of type 2 diabetes mellitus [85]. Hypertension in PWH is common and a number of potential pathogenic mechanisms have been identified, including lipodystrophy, a pro-inflammatory state associated with the secretion of cytokines and adipokines, and renal disease [87]. HIV protease is molecularly homologous to renin, and renin levels are often inappropriately high [88, 89]. Hypertension is exacerbated by worsening endothelial dysfunction [87]. Dyslipidaemia is a common complication of both treated and untreated HIV infection [90, 91]. In ART-naïve patients, this may be mediated by direct effects of the virus and the inflammatory milieu. Lipid processing and transportation is altered in PWH. Modified lipids may directly activate pattern recognition receptors [90]. Finally, substance use, especially tobacco use, is increased in PWH [88]. Risk of arterial disease is significantly higher in PWH who smoke and there is a concomitant increased mortality [6, 93].

Antiretroviral Drugs

Antiretroviral therapy has reduced the morbidity and mortality of HIV infection, affording improved life expectancy, but long-term therapy can result in endothelial toxicity and vascular dysfunction. This has been linked with a number of metabolic abnormalities, including lipid abnormalities and predominantly an increase in circulating low-density lipoprotein and cholesterol levels [94]. The classes of drugs most commonly implicated are protease inhibitors. The majority of inflammatory and cardiovascular disease biomarkers show a decline with effective therapy, however, confirming a benefit of ART even for cardiovascular disease outcomes [90, 95–97].

Clinical Biomarkers of Endothelial Dysfunction in PWH

Attempts have been made to identify appropriate biological markers to predict and monitor cardiovascular disease risk in PWH with varying results. Early findings from the SMART (strategic timing of antiretroviral treatment) trial suggested that elevated highly sensitive C-reactive protein (CRP) and D-dimer results correlated with cardiovascular mortality in HIV-infected patients [98]. Summary data on the findings of selected trials investigating biomarkers related to thrombosis and accelerated atherogenesis are presented in Table 3. The most commonly measured biomarkers included IL-6 [29, 53, 56, 97–108], highly sensitive CRP [7, 28, 98, 99, 101–104, 106, 108, 109] and D-dimer levels [7, 28, 98, 99, 101–104, 106, 108, 109]. In addition, a number of studies measured markers of endothelial adhesion or activation, or both, including soluble intercellular adhesion molecule-1 and soluble vascular cell adhesion molecule-1 [7, 15, 17, 50, 97, 106–108, 110–112], monocyte activation (sCD163, sCD14, or changes in monocyte phenotype) [15, 28, 29, 50, 56, 96, 97, 100, 107–114], and platelet activation (expression of s- and p-selectin) [30, 33, 115]. Limitations exist in many studies examining biomarkers for CVD outcomes. Confounding variables include the age of the patients at analysis, the treatment status of the patients, the ART drug regimen used, and the presence of concomitant diseases. Not all studies include an HIV-uninfected control group. There is significant variation in the selection of biomarkers, measurement modality, and timing of measurement. Prediction of CVD outcomes often is correlative looking at surrogate markers of arterial disease, like flow-mediated dilation and carotid intimal medial thickness. Importantly, in studies looking at PWH after ART initiation, however, biomarkers did not always fully normalize, which suggests ongoing inflammation [17, 49, 100]. Ongoing study protocols include combinations of these markers [116, 117].

Table 3.

Selected Studies of Biomarkers for Cardiovascular Disease in PWH

Author and Year Number of HIV-infected Participants and Treatment Status Number of Uninfected Controls Biomarkers and Measurement Modality Major Findings
2008 Von Hentig [33] 18 HIV-infected patients pre- and post-ART initiation Platelet activation: platelet expression of CD62P, CD40L, and CD41 (flow cytometry) Platelet function unaltered on PI-containing ART regimen; CD40L and CD41 both increased on PI regimen
2008 Kuller [98] 250 HIV-infected patients on continuous ART and 249 patients on drug interruption protocol Cytokines: IL-6
Inflammatory markers: hsCRP, amyloid-A, amyloid-P
Coagulation markers: D-dimers, PT fragment 1,2
IL-6, CRP, and D-dimers independently predicted all-cause mortality in HIV-infected patients
2009 Francisci [15] 56 HIV-infected patients pre- and post-ART treatment on PI or NNRTI and 10 patients not on ART 28 Cytokines: sCD40L, MCP-1
Endothelial markers: P-selectin, sVCAM-1
Coagulation markers: vWF, tPA
CD40L and tPA within normal limits in HIV-infected patients; p-selectin was elevated at baseline and remained elevated on treatment; vCAM-1, vWF, and MCP-1 decreased significantly on treatment irrespective of regimen
2010 Jong [118] 86 HIV-infected patients pre- and post-ART initiation 71 Coagulation markers: vWF PT fragment 1 and 2, TAT complex, endogenous thrombin potential, APC, protein-S and -C Significantly increased vWF and D-dimers, APC ratio, and decreased free and bound protein-C and -S in HIV-infected patients; all markers except APC ratio improved with ART initiation
2010 Funderburg [28] 60 HIV-infected patients, majority on ART 19 Microbial products: LPS
Monocyte activation: sCD14, TF expression by monocytes
Coagulation markers: D-dimers
Monocyte expression of TF correlated with sCD14 and markers of immune activation in HIV-infected patients
2012 Funderburg [29] 57 HIV-infected patients on ART 23 Microbial products: LPS
Monocyte activation: sCD14, monocyte CD62P and TF expression
Cytokines: IL-6
Inflammatory markers: hsCRP
HIV-infected patients showed increased frequency of non-classical and intermediate monocytes that resembled profiles in associated with acute coronary syndrome; these monocytes express CD62P and TF and are related to T-cell activation, IL-6 and viral load
2012 Mayne [115] 46 HIV-infected patients, 73% on ART 18 Platelet activation: patient P-selectin and TF expression HIV-infected patients showed higher levels of platelet activation
2012 Olmo [97] 54 HIV-infected patients—34 on continuous treatment and 20 with treatment interruption Cytokines: IL-6, IL8, sCD40L, MCP-1 Endothelial adhesion markers: sP-selectin, 1 sVCAM-1 sICAM-1 Coagulation: tPA MCP-1 and sVCAM-1 increased relative to baseline in with treatment-interruption; sCD40L, tPA, and sP-selectin increased in both treatment arms relative to baseline
2013 Ronsholt [17]l 70 HIV-infected patients on ART with viral suppression 16 Cytokines: IL-8, β2-MI TNF-α
Endothelial markers: sVCAM-1 sICAM-1, sE-selectin, sP-selectin
HIV-infected patients on long-term therapy showed increased levels of β2-MI, IL-8, and sICAM-1
2013 Baker [113] 163 HIV-infected patients—54 ART-naïve and 109 ART-treated Monocyte activation: Monocyte microparticles with TF expression Cytokines: IL-6 Coagulation markers: D-dimers, vWF Monocyte-microparticle TF expression correlated with inflammatory and coagulation biomarkers in HIV-infected patients
2013 Baker [119] 717 HIV-infected patients—500 on continuing ART and 271 with treatment interruption Coagulation markers: FVIII, AT, protein C Patients in the interrupted treatment wing had transient increases in procoagulant factors and decreases in anticoagulant factors, increasing thrombin generation potential
2015 Van den Dries [114] Retrospective review of Dutch HIV-infected cohort Markers of monocyte activation: sCD14, LPB Coagulation markers: vWF vWF increased in all HIV-infected patients but significantly higher in patients with first and recurrent venous thrombosis; higher risk of venous thrombosis in HIV-infected patients
2015 O’ Halloran [110] 25 HIV-infected patients pre and post-ART initiation 15 Monocyte activation markers: sCD14, sCD163 Cytokines: sCD40L
Endothelial adhesion markers: sP-selectin, 1 sVCAM-1 sICAM-1 Coagulation factors: vWF
All biomarkers were significantly higher pre-ART initiation compared with controls and reduced after therapy in HIV-infected patients; only GPVI reduced to levels comparable to controls
2015 Nkambule [30] 58 HIV-infected patients pre-ART initiation 38 Platelet activation: platelet aggregation and CD62P and CD36 expression on platelets Platelet expression of CD62P increased in HIV-infected patients; CD62P and CD36 expression correlated with viral load; response in keeping with hypersensitivity on platelet aggregation
2016 Siedner [120] 105 HIV-infected patients on ART 100 Cytokine: IL-6
Monocyte activation: Kyrenunine: tryptophan ratio, sCD14
Sonographic: Ankle-brachial index
Increased arterial stiffness in HIV-infected patients; declines in inflammatory markers (IL-6, KTR and sCD14s) predicted a lower CIMT and hence atherosclerotic burden
2016 Haissman [109] 50 untreated and 155 ART treated HIV-infectedpatients 105 Monocyte activation: sCD14 Coagulation markers: D-dimers Radiological: Myocardial perfusion defect, CIMT Other Asymmetric dimethylargininine Concentrations of ADMA in infected patients and higher levels in untreated individuals; ADMA associated with viral load, sCD14, D-dimers and low CD4+ T cell count but not with CIMT or subclinical atherosclerosis
2016 Grund [101] 3766 HIV-infected on ART Cytokines: IL-6
Coagulation: D-dimers Inflammatory: hsCRP
260 patients had significant non-AIDS events or death and this was independently associated with increased IL-6, D-dimers, and hsCRP levels
2016 Freiburg [102] 249 patients measured prior to seroconversion, prior to ART initiation and post ART initiation Cytokines: IL-6 Coagulation markers: D-dimers Increased IL-6 and D-dimer levels post-seroconversion; D-dimer levels remained elevated and were associated with non-AIDS related adverse events
2016 Borges [103] 4304 HIV-infected patients Cytokines: IL-6 Coagulation markers: D-dimers IL-6 better predictor with all-cause mortality and cardiovascular disease than D-dimers or hsCRP
2016 Kulkarni [50] 19 HIV infected patients on ART 49 Monocyte activation/adhesion markers: VLA-4, LFA-1, fractalkine, CD11c, sCD14, sCD163 Endothelial adhesion markers sICAM-1 sVCAM-1 Other: Lp-PLA2 Endothelial activation markers increased in HIV infected individuals; decreased levels of fractalkine expression and increased levels of LFA-1 expression on circulating monocytes
2017 Dysangco [111] 28 HIV-infected patients on ART and 44 HIV-infected patients ART-naive 39 Arterial dilatation endothelial markers: sVCAM-1 Monocyte activation: CD163 Inflammatory markers: β2-MI, IP10, TNFR2 HIV-infected ART naïve patients had higher levels of inflammatory and endothelial adhesion markers (including sCD163, TNFR2, TIM and VCAM-1), but there was no difference in FMD amongst the groups
2017 Baker [104] 4299 HIV-infected patients on immediate or deferred ART Cytokines: IL-6
Coagulation markers: D-dimers
Increased IL-6 and D-dimer levels consistently associated with AIDS– and non–AIDS related deaths
2017 Grome [112] 70 HIV-infected patients on ART T-cell activation, senescence, and exhaustion. Macrophage activation: sCD163, sCD14 Chemokines: MIP-1α Endothelial markers: sICAM-1 sVCAM-1 Radiological: Flow-mediate dilation Decreased flow mediated dilation was associated with CD8+ T cell activation sICAM-1 and sVCAM-1 were associated with soluble markers of monocyte activation
2017 Maggi [7] 119 ART-naïve HIV-infected patients stratified to receive efavirenz, atazanavir or darunavir based-regimens Endothelial adhesion: sVCAM-1 sICAM-1 Radiological: CIMT Coagulation markers: D-dimers Patients on Darunavir at higher risk of pathological intimal thickening; endothelial markers remained static, but D-dimer levels fell consistently
2018 Viskovic [105] 181 virally suppressed HIV-infected patients on ART Cytokines: CD40L,MCP-1,IL-8,IL-6 Inflammatory marker: hsCRP Endothelial markers: P-selectin, tPA Markers used to construct an inflammatory burden score (IBS), which correlated positively with the presence of dyslipidaemia (total cholesterol:HDL ratio)
2018 Seang [56] 57 HIV-infected patients on ART Endothelial progenitor cells Cytokine: IL-6 Monocyte activation: sCD163 Undetectable EPC levels associated with higher CVD risk, decreased IL-6 levels, and increased sCD163 (monocyte activation) in HIV-infected patients
2018 Rezer [53] 10 HIV-infected patients on long-term ART 10 Cytokines: IL-6, IFN-γ, IL-17, TNF-α, IL-2, IL-4, IL-10
Inflammatory markers: hsCRP
Cardiac markers: Troponin, CK-MB, LDH
Increased levels of IL-6 and IFN-γ in HIV-infected patients; no increases in levels of enzymatic cardiac markers in HIV-infected patients
2018 Peterson [106] 326 ART-naïve HIV-infected patients with CD4+ T cell count >500 Cytokines: IL-6, IL-27 Endothelial adhesion markers: sVCAM-1, sICAM-1 Inflammatory markers: hsCRP, serum amyloid A Coagulation: D-dimers Sonographic: Radial artery waveform Increased levels of IL-6 and hsCRP inversely related to small arterial elasticity in HIV-infected patients
2018 Mosepele [107] 112 HIV-infected patients with viral suppression on long-term ART 84 Cytokines: IL-6 Monocyte activation: sCD163 Endothelial adhesion: sVCAM-1 sICAM-1, sE-selectin Radiological: CIMT HIV infection increased levels of sICAM-1 and sVCAM-1 but not E-selectin; IL-6 showed no relationship with biomarkers of endothelial dysfunction
2019 Subramanya [108] 452 HIV-infected patients on ART 276 Cytokines: IL-6, TNF-α Endothelial markers: sICAM-1 Monocyte activation: sCD163 Inflammatory markers: CCL2, hsCRP, TNFR1, TNFR2 Coagulation: Fibrinogen, D-dimers Elevated CCL2, IL-6, sCD163, CRP increased risk of carotid plaque independent of cardiovascular risk factors sTNFR2, ICAM-1, and fibrinogen predicted CIMT in HIV uninfected men; 8 biomarkers increased significantly in HIV-infected patients

Abbreviations: ADMA, asymmetric dimethylargininine; APC, activated protein C; ART, antiretroviral therapy; AT, antithrombin; â2MI, â2-microglobulin; CD, cluster of differentiation; CIMT, coronary artery intimal medial thickness; CK-MB, creatine kinase; hsCRP, highly sensitive C-reactive protein; LDH, lactate dehydrogenase; LFA-1, leukocyte functional adhesion molecule-1; IL, interleukin; IP10, interferon-ã induced protein 10; LPB, lipopolysaccharide binding protein; Lp-PLA2, lipoprotein-associated phospholipase A2; MCP, monocyte-chemoattractant protein-1; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; PT, prothrombin; sICAM-1, soluble intercellular adhesion molecule-1; sVCAM-1, soluble vascular cell adhesion molecule-1; TAT, thrombin-antithrombin complexes; TF, tissue factor; TNFR, tumour-necrosis Factor á receptor; tPA, tissue plasminogen activator; VLA-4, very late antigen-4; vWF, von Willebrand factor.

Few biomarkers have been studied in the ART era in the context of venous thrombosis or microvascular disease, and none have been conclusively linked to diagnosis or prognostication of occlusive vasculitis or aneurysmal disease [65]. This may represent a future study focus.

Clinical Scoring Systems

A number of clinical scoring systems exist to assess arterial, venous, and microvascular thrombosis risk (Table 4). Although thrombosis throughout the vascular tree is described in PWH, relatively few of these scoring systems have undergone validation in this patient cohort. No published performance evaluations of venous thromboembolic scoring systems or microvasculature scoring systems exist in PWH, although small case series have referenced these scores [14, 121–122]. Arterial scoring systems have been more extensively studied. The Framingham risk score, based on the ongoing Framingham heart study, was initially designed to look at heart disease in nondiabetic, Caucasian participants between the ages of 30 and 69 [123]. A number of modifications have been introduced, including an ART regimen specifically for PWH—the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D score) [123]. Other scoring systems that have been evaluated include the systematic coronary risk evaluation (SCORE), atherosclerotic cardiovascular disease risk score (ASCVD), and prospective cardiovascular munster (PROCAM) scores. In PWH, these scoring systems have shown variable performance across validation studies. The Framingham risk score has generally shown the best predictive value for CVD in PWH with D:A:D, with the ASCVD and SCORE systems showing more consistent under-prediction in large European and American cohorts [117, 124–125]. Only smaller cross-sectional evaluations have been undertaken in low and middle-income countries [123, 126–127]. Despite the relatively poor predictive power and data fit shown in many analyses, these scoring systems continue to form the basis of clinical trials in this cohort of patients.Modeling studies suggest a significant health economic burden of cardiovascular disease in PWH that is predicted to increase as the HIV-infected population ages [136–137]. Understanding the underlying pathogenesis, assessing risk, and identification and validation of appropriate biomarkers will be important. This includes the development of risk scores for microvascular and venous thrombosis. Cardiovascular disease risk is increased in patients who are untreated or who fail to achieve or maintain viral suppression, and early initiation of ART is the mainstay of therapy. In addition, traditional cardiovascular risk factors, including tobacco use, dyslipidaemia, hypertension, and diabetes should be aggressively managed in this population along with chronic infections that can cause chronic inflammation and predispose to vascular disease [138].

Table 4.

Scoring System Developer Parameters Studies in PLWH Utility
Cardiovascular disease
Framingham [123] National Heart Institute/Boston University Age, tobacco use, systolic blood pressure, total cholesterol, HDL cholesterol Modified Framingham scores generally outperformed other scoring systems in large cohorts [128] although systems often either overpredicted [129] or underpredicted [125] cardiovascular risk [123].SCORE generally performed least well [124]. SCORE and D:A:D consistently underestimated cardiovascular risk [117, 128] 10-year risk of coronary artery disease only
D:A:D* [123] D:A:D Study Group Modified Framingham incorporating previous tobacco use, family history, and previous or current idinavir and lopinavir treatment 5-year risk of coronary artery disease only
SCORE** [117] European Society of Cardiology Gender, age, systolic blood pressure, smoking status, and total cholesterol/HDL cholesterol ratio 10-year risk of coronary artery disease only
ASCVD*** [117] American Heart Association Age, gender, race, total cholesterol, HDL, blood pressure, and smoking 10-year risk of coronary artery disease or stroke
PROCAM**** [130] Institute of Atherosclerosis Research at the University of Munster, Germany Gender, age, serum HDL and LDL cholesterol and triglyceride levels, smoking status, diabetes, family history of coronary heart disease, and systolic blood pressure 10-year risk of coronary artery disease or stroke
Venous thromboembolic disease
Caprini Score [131] American College of Chest Physicians Age, planned surgery and type, immobility, inherited thrombophilic state, recent stroke, presence of a cast, serious comorbidity (including malignancy), chronic obstructive pulmonary disease, inflammatory bowel disease, central venous access, use of oral contraceptives, pregnancy or recent miscarriage, swollen legs, varicose veins, or morbid obesity Not assessed in PWH Thromboembolic disease, especially deep-vein thrombosis
Rogers Score (Patient Safety in Surgery Score) [132] Biochemical—albumin, bilirubin, sodium
Haematological—recent tranfusion and haematocrit
Patient factors—American Society Anesthesia risk, ventilation, respiratory distress
Surgical factors—type, infection, complexity and emergency
Thromboembolic disease, especially deep-vein thrombosis
Microvascular circulatory disease
DIC ISTH [14, 133] International Society of Thrombosis and Hemostasis Platelet count, D-dimers, and prothrombin time in correct clinical context Utilized as a diagnostic score in PWH [14, 121, 122], but there were no validation studies Disseminated intravascular coagulation
DIC—JSTH [134] Japanese Society of Thrombosis and Hemostasis Clinical features, platelet count, D-dimers, prothrombin time, and antithrombin Disseminated intravascular coagulation
DIC JAAM [134] Japanese Association for Acute Medicine Septic score, platelet count, D-dimers, amd prothrombin time Disseminated intravascular coagulation
PLASMIC [135] Harvard TMA Research Collaborative Clinical—no active cancer, no history of transplant Laboratory— platelet count, haemolysis, Mean Cell Volume, International normalized ratio, Creatinine Thrombotic thrombocytopaenic purpura

*Data Collection on Adverse Events of Anti-HIV Drugs, **Sytematic COronary Risk Evaluation ***Atherosclerotic cardiovascular disease risk equation ****Prospective Cardiovascular Munster

Acknowledgments

Author contributions. E.S.M. and S.J.L. wrote the review paper, contributed equally, and approve the submission.

Financial support. This work is supported by the Discovery Foundation Award for Academic Excellence and the Thuthuka Grant (TTK20110801000022866) from the National Research Foundation of South Africa to E.S.M.

Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

References

  • 1. Katz IT, Maughan-Brown B. Improved life expectancy of people living with HIV: who is left behind? Lancet HIV 2017; 4:e324–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2. Althoff KN, Smit M, Reiss P, Justice AC. HIV and ageing: improving quantity and quality of life. Curr Opin HIV AIDS 2016; 11:527–36. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3. Hogg RS, Eyawo O, Collins AB, et al. ; Comparative Outcomes And Service Utilization Trends (COAST) study Health-adjusted life expectancy in HIV-positive and HIV-negative men and women in British Columbia, Canada: a population-based observational cohort study. Lancet HIV 2017; 4:e270–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4. Calmy A, Gayet-Ageron A, Montecucco F, et al. ; STACCATO Study Group HIV increases markers of cardiovascular risk: results from a randomized, treatment interruption trial. AIDS 2009; 23:929–39. [DOI] [PubMed] [Google Scholar]
  • 5. Auerbach E, Aboulafia DM. Venous and arterial thromboembolic complications associated with HIV infection and highly active antiretroviral therapy. Semin Thromb Hemost 2012; 38:830–8. [DOI] [PubMed] [Google Scholar]
  • 6. Rasmussen LD, Helleberg M, May MT, et al. . Myocardial infarction among Danish HIV-infected individuals: population-attributable fractions associated with smoking. Clin Infect Dis 2015; 60:1415–23. [DOI] [PubMed] [Google Scholar]
  • 7. Maggi P, Bellacosa C, Leone A, et al. . Cardiovascular risk in advanced naïve HIV-infected patients starting antiretroviral therapy: Comparison of three different regimens - PREVALEAT II cohort. Atherosclerosis 2017; 263:398–404. [DOI] [PubMed] [Google Scholar]
  • 8. Durand M, Chartrand-Lefebvre C, Baril JG, et al. ; investigators of the Canadian HIV and Aging Cohort Study The Canadian HIV and aging cohort study - determinants of increased risk of cardio-vascular diseases in HIV-infected individuals: rationale and study protocol. BMC Infect Dis 2017; 17:611. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9. Hyle EP, Mayosi BM, Middelkoop K, et al. . The association between HIV and atherosclerotic cardiovascular disease in sub-Saharan Africa: a systematic review. BMC Public Health 2017; 17:954. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10. Gutierrez J, Albuquerque ALA, Falzon L. HIV infection as vascular risk: A systematic review of the literature and meta-analysis. PLoS One 2017; 12:e0176686. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. Louw S, Jacobson BF, Büller H. Human immunodeficiency virus infection and acute deep vein thromboses. Clin Appl Thromb Hemost 2008; 14:352–5. [DOI] [PubMed] [Google Scholar]
  • 12. Eyal A, Veller M. HIV and venous thrombotic events. S Afr J Surg 2009; 47:54–6. [PubMed] [Google Scholar]
  • 13. Epaulard O, Foote A, Bosson JL. Chronic Infection and Venous Thromboembolic Disease. Semin Thromb Hemost 2015; 41:644–9. [DOI] [PubMed] [Google Scholar]
  • 14. Mayne ES, Mayne ALH, Louw SJ. Pathogenic factors associated with development of disseminated intravascular coagulopathy (DIC) in a tertiary academic hospital in South Africa. PLoS One 2018; 13:e0195793. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15. Francisci D, Giannini S, Baldelli F, et al. . HIV type 1 infection, and not short-term HAART, induces endothelial dysfunction. AIDS 2009; 23:589–96. [DOI] [PubMed] [Google Scholar]
  • 16. Graham SM, Mwilu R, Liles WC. Clinical utility of biomarkers of endothelial activation and coagulation for prognosis in HIV infection: a systematic review. Virulence 2013; 4:564–71. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. Rönsholt FF, Ullum H, Katzenstein TL, et al. . Persistent inflammation and endothelial activation in HIV-1 infected patients after 12 years of antiretroviral therapy. PLoS One 2013; 8:e65182. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18. Ince C, Mayeux PR, Nguyen T, et al. ; ADQI XIV Workgroup The endothelium in sepsis. Shock 2016; 45:259–70. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. Vanhoutte PM, Shimokawa H, Feletou M, Tang EH. Endothelial dysfunction and vascular disease - a 30th anniversary update. Acta Physiol (Oxf) 2017; 219:22–96. [DOI] [PubMed] [Google Scholar]
  • 20. Marcus AJ, Broekman MJ, Drosopoulos JH, et al. . The endothelial cell ecto-ADPase responsible for inhibition of platelet function is CD39. J Clin Invest 1997; 99:1351–60. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21. Griffin JH, Zlokovic BV, Mosnier LO. Activated protein C: biased for translation. Blood 2015; 125:2898–907. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22. Sadler JE. Thrombomodulin structure and function. Thromb Haemost 1997; 78:392–5. [PubMed] [Google Scholar]
  • 23. Funderburg NT, Lederman MM. Coagulation and morbidity in treated HIV infection. Thromb Res 2014; 133(Suppl 1):S21–4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24. Kline ER, Kleinhenz DJ, Liang B, et al. . Vascular oxidative stress and nitric oxide depletion in HIV-1 transgenic rats are reversed by glutathione restoration. Am J Physiol Heart Circ Physiol 2008; 294:H2792–804. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25. Garcia V, Sessa WC. Endothelial NOS: perspective and recent developments. Br J Pharmacol 2019; 176:189–96. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26. Sirugo G, Hennig BJ, Adeyemo AA, et al. . Genetic studies of African populations: an overview on disease susceptibility and response to vaccines and therapeutics. Hum Genet 2008; 123:557–98. [DOI] [PubMed] [Google Scholar]
  • 27. Zhang Y, Meng H, Ma R, et al. . Circulating microparticles, blood cells, and endothelium induce procoagulant activity in sepsis through phosphatidylserine exposure. Shock 2016; 45:299–307. [DOI] [PubMed] [Google Scholar]
  • 28. Funderburg NT, Mayne E, Sieg SF, et al. . Increased tissue factor expression on circulating monocytes in chronic HIV infection: relationship to in vivo coagulation and immune activation. Blood 2010; 115:161–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29. Funderburg NT, Zidar DA, Shive C, et al. . Shared monocyte subset phenotypes in HIV-1 infection and in uninfected subjects with acute coronary syndrome. Blood 2012; 120:4599–608. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30. Nkambule BB, Davison GM, Ipp H. The evaluation of platelet function in HIV infected, asymptomatic treatment-naïve individuals using flow cytometry. Thromb Res 2015; 135:1131–9. [DOI] [PubMed] [Google Scholar]
  • 31. Witkowski M, Landmesser U, Rauch U. Tissue factor as a link between inflammation and coagulation. Trends Cardiovasc Med 2016; 26:297–303. [DOI] [PubMed] [Google Scholar]
  • 32. Fang H, Wang L, Wang H. The protein structure and effect of factor VIII. Thromb Res 2007; 119:1–13. [DOI] [PubMed] [Google Scholar]
  • 33. von Hentig N, Förster AK, Kuczka K, et al. . Platelet-leucocyte adhesion markers before and after the initiation of antiretroviral therapy with HIV protease inhibitors. J Antimicrob Chemother 2008; 62:1118–21. [DOI] [PubMed] [Google Scholar]
  • 34. Calza L, Pocaterra D, Pavoni M, et al. . Plasma levels of VCAM-1, ICAM-1, E-Selectin, and P-Selectin in 99 HIV-positive patients versus 51 HIV-negative healthy controls. J Acquir Immune Defic Syndr 2009; 50:430–2. [DOI] [PubMed] [Google Scholar]
  • 35. Jong E, Louw S, Meijers JC, et al. . The hemostatic balance in HIV-infected patients with and without antiretroviral therapy: partial restoration with antiretroviral therapy. AIDS Patient Care STDS 2009; 23:1001–7. [DOI] [PubMed] [Google Scholar]
  • 36. Leebeek FW, Eikenboom JC. Von Willebrand’s disease. N Engl J Med 2016; 375:2067–80. [DOI] [PubMed] [Google Scholar]
  • 37. Sonneveld MA, Franco OH, Ikram MA, et al. . Von Willebrand factor, ADAMTS13, and the risk of mortality: the Rotterdam Study. Arterioscler Thromb Vasc Biol 2016; 36:2446–51. [DOI] [PubMed] [Google Scholar]
  • 38. Caughey GE, Cleland LG, Penglis PS, et al. . Roles of cyclooxygenase (COX)-1 and COX-2 in prostanoid production by human endothelial cells: selective up-regulation of prostacyclin synthesis by COX-2. J Immunol 2001; 167:2831–8. [DOI] [PubMed] [Google Scholar]
  • 39. Unic A, Derek L, Hodak N, et al. . Endothelins – clinical perspectives. Biochem Med (Zagreb) 2011; 21:231–42. [DOI] [PubMed] [Google Scholar]
  • 40. Edwards N, Langford-Smith AWW, Wilkinson FL, Alexander MY. Endothelial progenitor cells: new targets for therapeutics for inflammatory conditions with high cardiovascular risk. Front Med (Lausanne) 2018; 5:200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41. Rodríguez-Carrio J, Prado C, de Paz B, et al. . Circulating endothelial cells and their progenitors in systemic lupus erythematosus and early rheumatoid arthritis patients. Rheumatology (Oxford) 2012; 51:1775–84. [DOI] [PubMed] [Google Scholar]
  • 42. Montoya JL, Iudicello J, Fazeli PL, et al. ; HIV Neurobehavioral Research Program (HNRP) Group Elevated markers of vascular remodeling and arterial stiffness are associated with neurocognitive function in older HIV+ adults on suppressive antiretroviral therapy. J Acquir Immune Defic Syndr 2017; 74:134–41. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43. Chatterjee M, Gawaz M. Platelet-derived CXCL12 (SDF-1α): basic mechanisms and clinical implications. J Thromb Haemost 2013; 11:1954–67. [DOI] [PubMed] [Google Scholar]
  • 44. Chatterjee M, von Ungern-Sternberg SN, Seizer P, et al. . Platelet-derived CXCL12 regulates monocyte function, survival, differentiation into macrophages and foam cells through differential involvement of CXCR4-CXCR7. Cell Death Dis 2015; 6:e1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45. Waldschmidt JM, Simon A, Wider D, et al. . CXCL12 and CXCR7 are relevant targets to reverse cell adhesion-mediated drug resistance in multiple myeloma. Br J Haematol 2017; 179:36–49. [DOI] [PubMed] [Google Scholar]
  • 46. Longstaff C, Kolev K. Basic mechanisms and regulation of fibrinolysis. J Thromb Haemost 2015; 13(Suppl 1):S98–105. [DOI] [PubMed] [Google Scholar]
  • 47. López M, San Román J, Estrada V, et al. . Endothelial dysfunction in HIV infection–the role of circulating endothelial cells, microparticles, endothelial progenitor cells and macrophages. AIDS Rev 2012; 14:223–30. [PubMed] [Google Scholar]
  • 48. Prasad M, McBane R, Reriani M, et al. . Coronary endothelial dysfunction is associated with increased risk of venous thromboembolism. Thromb Res 2016; 139:17–21. [DOI] [PubMed] [Google Scholar]
  • 49. Younas M, Psomas C, Reynes J, Corbeau P. Immune activation in the course of HIV-1 infection: causes, phenotypes and persistence under therapy. HIV Med 2016; 17:89–105. [DOI] [PubMed] [Google Scholar]
  • 50. Kulkarni M, Bowman E, Gabriel J, et al. . Altered monocyte and endothelial cell adhesion molecule expression is linked to vascular inflammation in human immunodeficiency virus infection. Open Forum Infect Dis 2016; 3:ofw224. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51. Caughey GE, Cleland LG, Gamble JR, James MJ. Up-regulation of endothelial cyclooxygenase-2 and prostanoid synthesis by platelets. Role of thromboxane A2. J Biol Chem 2001; 276:37839–45. [DOI] [PubMed] [Google Scholar]
  • 52. Mudd JC, Brenchley JM. Gut mucosal barrier dysfunction, microbial dysbiosis, and their role in HIV-1 disease progression. J Infect Dis 2016; 214(Suppl 2):S58–66. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53. Rezer JFP, Adefegha SA, Ecker A, et al. . Changes in inflammatory/cardiac markers of HIV positive patients. Microb Pathog 2018; 114:264–8. [DOI] [PubMed] [Google Scholar]
  • 54. Doitsh G, Galloway NL, Geng X, et al. . Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection. Nature 2014; 505:509–14. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55. van Baarle D, Tsegaye A, Miedema F, Akbar A. Significance of senescence for virus-specific memory T cell responses: rapid ageing during chronic stimulation of the immune system. Immunol Lett 2005; 97:19–29. [DOI] [PubMed] [Google Scholar]
  • 56. Seang S, Kelesidis T, Huynh D, et al. . Low levels of endothelial progenitor cells and their association with systemic inflammation and monocyte activation in older HIV-infected men. AIDS Res Hum Retroviruses 2018; 34:39–45. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57. Grässle S, Huck V, Pappelbaum KI, et al. . von Willebrand factor directly interacts with DNA from neutrophil extracellular traps. Arterioscler Thromb Vasc Biol 2014; 34:1382–9. [DOI] [PubMed] [Google Scholar]
  • 58. Grover SP, Mackman N. Neutrophils, NETs, and immunothrombosis. Blood 2018; 132:1360–1. [DOI] [PubMed] [Google Scholar]
  • 59. Poland SD, Rice GP, Dekaban GA. HIV-1 infection of human brain-derived microvascular endothelial cells in vitro. J Acquir Immune Defic Syndr Hum Retrovirol 1995; 8:437–45. [DOI] [PubMed] [Google Scholar]
  • 60. Steffan AM, Lafon ME, Gendrault JL, et al. . Primary cultures of endothelial cells from the human liver sinusoid are permissive for human immunodeficiency virus type 1. Proc Natl Acad Sci U S A 1992; 89:1582–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61. Naidoo NG, Beningfield SJ. Other manifestations of HIV vasculopathy. S Afr J Surg 2009; 47:46–53. [PubMed] [Google Scholar]
  • 62. Mishra R, Singh SK. HIV-1 Tat C modulates expression of miRNA-101 to suppress VE-cadherin in human brain microvascular endothelial cells. J Neurosci 2013; 33:5992–6000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63. Wang T, Green LA, Gupta SK, et al. . Transfer of intracellular HIV Nef to endothelium causes endothelial dysfunction. PLoS One 2014; 9:e91063. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64. Green LA, Yi R, Petrusca D, et al. . HIV envelope protein gp120-induced apoptosis in lung microvascular endothelial cells by concerted upregulation of EMAP II and its receptor, CXCR3. Am J Physiol Lung Cell Mol Physiol 2014; 306:L372–82. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65. Pillay B, Ramdial PK, Naidoo DP. HIV-associated large-vessel vasculopathy: a review of the current and emerging clinicopathological spectrum in vascular surgical practice. Cardiovasc J Afr 2015; 26:70–81. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66. Chetty R. Vasculitides associated with HIV infection. J Clin Pathol 2001; 54:275–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67. Chetty R, Batitang S, Nair R. Large artery vasculopathy in HIV-positive patients: another vasculitic enigma. Hum Pathol 2000; 31:374–9. [DOI] [PubMed] [Google Scholar]
  • 68. Nair R, Robbs JV, Chetty R, et al. . Occlusive arterial disease in HIV-infected patients: a preliminary report. Eur J Vasc Endovasc Surg 2000; 20:353–7. [DOI] [PubMed] [Google Scholar]
  • 69. Nair R, Chetty R, Woolgar J, et al. . Spontaneous arteriovenous fistula resulting from HIV arteritis. J Vasc Surg 2001; 33:186–7. [DOI] [PubMed] [Google Scholar]
  • 70. Robbs JV. Pathogenesis and pathology of HIV-related large-vessel disease. S Afr J Surg 2009; 47:44–5. [PubMed] [Google Scholar]
  • 71. Barrios-Payán J, Saqui-Salces M, Jeyanathan M, et al. . Extrapulmonary locations of mycobacterium tuberculosis DNA during latent infection. J Infect Dis 2012; 206:1194–205. [DOI] [PubMed] [Google Scholar]
  • 72. Janssen S, Schutz C, Ward AM, et al. . Hemostatic changes associated with increased mortality rates in hospitalized patients with HIV-associated tuberculosis: a prospective cohort study. J Infect Dis 2017; 215:247–58. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73. Harker KS, Ueno N, Wang T, et al. . Toxoplasma gondii modulates the dynamics of human monocyte adhesion to vascular endothelium under fluidic shear stress. J Leukoc Biol 2013; 93:789–800. [DOI] [PubMed] [Google Scholar]
  • 74. El-Far M, Tremblay CL. Gut microbial diversity in HIV infection post combined antiretroviral therapy: a key target for prevention of cardiovascular disease. Curr Opin HIV AIDS 2018; 13:38–44. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75. Nagel MA, Bubak AN. Varicella zoster virus vasculopathy. J Infect Dis 2018; 218:107–12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 76. Gombos RB, Brown JC, Teefy J, et al. . Vascular dysfunction in young, mid-aged and aged mice with latent cytomegalovirus infections. Am J Physiol Heart Circ Physiol 2013; 304:H183–94. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 77. Gaitzsch E, Czermak T, Ribeiro A, et al. . Double-stranded DNA induces a prothrombotic phenotype in the vascular endothelium. Sci Rep 2017; 7:1112. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 78. Xiong A, Clarke-Katzenberg RH, Valenzuela G, et al. . Epstein-Barr virus latent membrane protein 1 activates nuclear factor-kappa B in human endothelial cells and inhibits apoptosis. Transplantation 2004; 78:41–9. [DOI] [PubMed] [Google Scholar]
  • 79. Morris VA, Punjabi AS, Wells RC, et al. . The KSHV viral IL-6 homolog is sufficient to induce blood to lymphatic endothelial cell differentiation. Virology 2012; 428:112–20. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 80. Zhang X, Tang Q, Xu L. Herpes simplex virus 2 infects human endothelial ECV304 cells and induces cell apoptosis synergistically with ox-LDL. J Toxicol Sci 2014; 39:909–17. [DOI] [PubMed] [Google Scholar]
  • 81. Osibogun O, Ogunmoroti O, Michos ED, et al. . HIV/HCV coinfection and the risk of cardiovascular disease: a meta-analysis. J Viral Hepat 2017; 24:998–1004. [DOI] [PubMed] [Google Scholar]
  • 82. Osibogun O, Ogunmoroti O, Michos ED, et al. . A systematic review of the associations between HIV/HCV coinfection and biomarkers of cardiovascular disease. Rev Med Virol 2018; 28. [DOI] [PubMed] [Google Scholar]
  • 83. Mathabire Rücker SC, Tayea A, Bitilinyu-Bangoh J, et al. . High rates of hypertension, diabetes, elevated low-density lipoprotein cholesterol, and cardiovascular disease risk factors in HIV-infected patients in Malawi. AIDS 2018; 32:253–60. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 84. Rao SG, Galaviz KI, Gay HC, et al. . Factors associated with excess myocardial infarction risk in HIV-infected adults: a systematic review and meta-analysis. J Acquir Immune Defic Syndr 2019; 81:224–30. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 85. Pedro MN, Rocha GZ, Guadagnini D, et al. . Insulin resistance in HIV-patients: causes and consequences. Front Endocrinol (Lausanne) 2018; 9:514. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 86. Psomas C, Younas M, Reynes C, et al. . One of the immune activation profiles observed in HIV-1-infected adults with suppressed viremia is linked to metabolic syndrome: the ACTIVIH study. EBioMedicine 2016; 8:265–76. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 87. Fahme SA, Bloomfield GS, Peck R. Hypertension in HIV-infected adults: novel pathophysiologic mechanisms. Hypertension 2018; 72:44–55. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 88. Chandel N, Ayasolla K, Lan X, et al. . Renin modulates HIV replication in T cells. J Leukoc Biol 2014; 96:601–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 89. Srinivasa S, Burdo TH, Williams KC, et al. . Effects of sodium restriction on activation of the renin-angiotensin-aldosterone system and immune indices during HIV infection. J Infect Dis 2016; 214:1336–40. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 90. Funderburg NT, Mehta NN. Lipid abnormalities and inflammation in HIV inflection. Curr HIV/AIDS Rep 2016; 13:218–25. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 91. Maggi P, Di Biagio A, Rusconi S, et al. . Cardiovascular risk and dyslipidemia among persons living with HIV: a review. BMC Infect Dis 2017; 17:551. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 92. Raposeiras-Roubín S, Abu-Assi E, Iñiguez-Romo A. Tobacco, illicit drugs use and risk of cardiovascular disease in patients living with HIV. Curr Opin HIV AIDS 2017; 12:523–7. [DOI] [PubMed] [Google Scholar]
  • 93. Helleberg M, Afzal S, Kronborg G, et al. . Mortality attributable to smoking among HIV-1-infected individuals: a nationwide, population-based cohort study. Clin Infect Dis 2013; 56:727–34. [DOI] [PubMed] [Google Scholar]
  • 94. Botha S, Fourie CM, van Rooyen JM, et al. . Cardiometabolic changes in treated versus never treated HIV-infected black South Africans: the PURE study. Heart Lung Circ 2014; 23:119–26. [DOI] [PubMed] [Google Scholar]
  • 95. Funderburg NT, Xu D, Playford MP, et al. . Treatment of HIV infection with a raltegravir-based regimen increases LDL levels, but improves HDL cholesterol efflux capacity. Antivir Ther 2017; 22:71–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 96. Višković K, Židovec Lepej S, Gorenec A, et al. . Cardiovascular markers of inflammation and serum lipid levels in HIV-infected patients with undetectable viremia. Sci Rep 2018; 8:6113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 97. Olmo M, Saumoy M, Alonso-Villaverde C, et al. . Impact of antiretroviral therapy interruption on plasma biomarkers of cardiovascular risk and lipids: 144-week final data from the STOPAR study. HIV Med 2012; 13:488–98. [DOI] [PubMed] [Google Scholar]
  • 98. Kuller LH, Tracy R, Belloso W, et al. ; INSIGHT SMART Study Group Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med 2008; 5:e203. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 99. Baker JV. Chronic HIV disease and activation of the coagulation system. Thromb Res 2013; 132:495–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 100. Siedner MJ, Kim JH, Nakku RS, et al. . Persistent immune activation and carotid atherosclerosis in HIV-infected Ugandans receiving antiretroviral therapy. J Infect Dis 2016; 213:370–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 101. Grund B, Baker JV, Deeks SG, et al. ; INSIGHT SMART/ESPRIT/SILCAAT Study Group Relevance of Interleukin-6 and D-Dimer for serious non-AIDS morbidity and death among HIV-positive adults on suppressive antiretroviral therapy. PLoS One 2016; 11:e0155100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 102. Freiberg MS, Bebu I, Tracy R, et al. ; Infectious Disease Clinical Research Program HIV Working Group D-Dimer levels before HIV seroconversion remain elevated even after viral suppression and are associated with an increased risk of non-AIDS events. PLoS One 2016; 11:e0152588. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 103. Borges ÁH, O’Connor JL, Phillips AN, et al. ; INSIGHT SMART Study and ESPRIT Groups Interleukin 6 is a stronger predictor of clinical events than high-sensitivity C-reactive protein or D-Dimer during HIV infection. J Infect Dis 2016; 214:408–16. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 104. Baker JV, Sharma S, Grund B, et al. ; INSIGHT START (Strategic Timing of AntiRetroviral Treatment) Study Group Systemic inflammation, coagulation, and clinical risk in the START trial. Open Forum Infect Dis 2017; 4:ofx262. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 105. Viskovic K, Zidovec-Lepej S, Gorenec L, et al. . Cardiovascular markers of inflammation and serum lipid levels in HIV-infected patients with undetectable viraemia. J Int AIDS Soc 2014; 17:19548. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 106. Peterson TE, Huppler Hullsiek K, Wyman Engen N, et al. ; INSIGHT START (Strategic Timing of AntiRetroviral Treatment) Study Group Inflammation associates with impaired small arterial elasticity early in HIV disease. Open Forum Infect Dis 2018; 5:ofy117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 107. Mosepele M, Mohammed T, Mupfumi L, et al. . HIV disease is associated with increased biomarkers of endothelial dysfunction despite viral suppression on long-term antiretroviral therapy in Botswana. Cardiovasc J Afr 2018; 29:155–61. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 108. Subramanya V, McKay HS, Brusca RM, et al. . Inflammatory biomarkers and subclinical carotid atherosclerosis in HIV-infected and HIV-uninfected men in the Multicenter AIDS Cohort Study. PLoS One 2019; 14:e0214735. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 109. Haissman JM, Haugaard AK, Knudsen A, et al. . Marker of endothelial dysfunction asymmetric dimethylarginine is elevated in HIV infection but not associated with subclinical atherosclerosis. J Acquir Immune Defic Syndr 2016; 73:507–13. [DOI] [PubMed] [Google Scholar]
  • 110. O’Halloran JA, Dunne E, Gurwith M, et al. . The effect of initiation of antiretroviral therapy on monocyte, endothelial and platelet function in HIV-1 infection. HIV Med 2015; 16:608–19. [DOI] [PubMed] [Google Scholar]
  • 111. Dysangco A, Liu Z, Stein JH, et al. . HIV infection, antiretroviral therapy, and measures of endothelial function, inflammation, metabolism, and oxidative stress. PLoS One 2017; 12:e0183511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 112. Grome HN, Barnett L, Hagar CC, et al. . Association of T cell and macrophage activation with arterial vascular health in HIV. AIDS Res Hum Retroviruses 2017; 33:181–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 113. Baker JV, Huppler Hullsiek K, Bradford RL, et al. . Circulating levels of tissue factor microparticle procoagulant activity are reduced with antiretroviral therapy and are associated with persistent inflammation and coagulation activation among HIV-positive patients. J Acquir Immune Defic Syndr 2013; 63:367–71. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 114. van den Dries LW, Gruters RA, Hövels-van der Borden SB, et al. . von Willebrand Factor is elevated in HIV patients with a history of thrombosis. Front Microbiol 2015; 6:180. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 115. Mayne E, Funderburg NT, Sieg SF, et al. . Increased platelet and microparticle activation in HIV infection: upregulation of P-selectin and tissue factor expression. J Acquir Immune Defic Syndr 2012; 59:340–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 116. Strijdom H, De Boever P, Walzl G, et al. . Cardiovascular risk and endothelial function in people living with HIV/AIDS: design of the multi-site, longitudinal EndoAfrica study in the Western Cape Province of South Africa. BMC Infect Dis 2017; 17:41. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 117. Krikke M, Hoogeveen RC, Hoepelman AI, et al. . Cardiovascular risk prediction in HIV-infected patients: comparing the Framingham, atherosclerotic cardiovascular disease risk score (ASCVD), Systematic Coronary Risk Evaluation for the Netherlands (SCORE-NL) and Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) risk prediction models. HIV Med 2016; 17:289–97. [DOI] [PubMed] [Google Scholar]
  • 118. Jong E, Louw S, van Gorp EC, et al. . The effect of initiating combined antiretroviral therapy on endothelial cell activation and coagulation markers in South African HIV-infected individuals. Thromb Haemost 2010; 104:1228–34. [DOI] [PubMed] [Google Scholar]
  • 119. Baker JV, Brummel-Ziedins K, Neuhaus J, et al. ; INSIGHT SMART Study Team HIV replication alters the composition of extrinsic pathway coagulation factors and increases thrombin generation. J Am Heart Assoc 2013; 2:e000264. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 120. Siedner MJ, Kim JH, Nakku RS, et al. . HIV infection and arterial stiffness among older-adults taking antiretroviral therapy in rural Uganda. AIDS 2016; 30:667–70. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 121. Louw SJ, Mayne ALH, Mayne ES. Evaluation of the diagnostic utility of individual parameters in the disseminated intravascular coagulation (DIC) panel for use in underresourced settings. Int J Lab Hematol 2018; 40:e46–8. [DOI] [PubMed] [Google Scholar]
  • 122. Louw S, Gounden R, Mayne ES. Thrombotic thrombocytopenic purpura (TTP)-like syndrome in the HIV era. Thromb J 2018; 16:35. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 123. Noumegni SR, Ama VJM, Assah FK, et al. . Assessment of the agreement between the Framingham and DAD risk equations for estimating cardiovascular risk in adult Africans living with HIV infection: a cross-sectional study. Trop Dis Travel Med Vaccines 2017; 3:12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 124. Thompson-Paul AM, Lichtenstein KA, Armon C, et al. . Cardiovascular disease risk prediction in the HIV outpatient study. Clin Infect Dis 2016; 63:1508–16. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 125. Triant VA, Perez J, Regan S, et al. . Cardiovascular risk prediction functions underestimate risk in HIV infection. Circulation 2018; 137:2203–14. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 126. Mosepele M, Hemphill LC, Palai T, et al. . Cardiovascular disease risk prediction by the American College of Cardiology (ACC)/American Heart Association (AHA) Atherosclerotic Cardiovascular Disease (ASCVD) risk score among HIV-infected patients in sub-Saharan Africa. PLoS One 2017; 12:e0172897. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 127. Kumar D, Bohra GK, Agarwal M, et al. . Prediction of cardiovascular disease risk using framingham and data on adverse effect of antiretroviral drugs risk equation in relation to lipodystrophy in HIV patients on highly active antiretroviral therapy. J Glob Infect Dis 2018; 10:182–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 128. Dhillon S, Sabin CA, Alagaratnam J, et al. ; Pharmacokinetic and Clinical Observations in People over Fifty (POPPY) study Level of agreement between frequently used cardiovascular risk calculators in people living with HIV. HIV Med 2019; 20:347–52. [DOI] [PubMed] [Google Scholar]
  • 129. Herrera S, Guelar A, Sorlì L, et al. . The Framingham function overestimates the risk of ischemic heart disease in HIV-infected patients from Barcelona. HIV Clin Trials 2016; 17:131–9. [DOI] [PubMed] [Google Scholar]
  • 130. Barros ZM, de Alencar Ximenes RA, Miranda-Filho DB, et al. . Comparison between the Framingham and prospective cardiovascular of Münster scores for risk assessment of coronary heart disease in human immunodeficiency virus-positive patients in Pernambuco, Brazil. Metab Syndr Relat Disord 2010; 8:489–97. [DOI] [PubMed] [Google Scholar]
  • 131. Grant PJ, Greene MT, Chopra V, et al. . Assessing the caprini score for risk assessment of venous thromboembolism in hospitalized medical patients. Am J Med 2016; 129:528–35. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 132. Rogers SO Jr, Kilaru RK, Hosokawa P, et al. . Multivariable predictors of postoperative venous thromboembolic events after general and vascular surgery: results from the patient safety in surgery study. J Am Coll Surg 2007; 204:1211–21. [DOI] [PubMed] [Google Scholar]
  • 133. Taylor FB Jr, Toh CH, Hoots WK, et al. ; Scientific Subcommittee on Disseminated Intravascular Coagulation (DIC) of the International Society on Thrombosis and Haemostasis (ISTH) Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost 2001; 86:1327–30. [PubMed] [Google Scholar]
  • 134. Wada H, Matsumoto T, Yamashita Y. Diagnosis and treatment of disseminated intravascular coagulation (DIC) according to four DIC guidelines. J Intensive Care 2014; 2:15. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 135. Jamme M, Rondeau E. The PLASMIC score for thrombotic thrombocytopenic purpura. Lancet Haematol 2017; 4:e148–9. [DOI] [PubMed] [Google Scholar]
  • 136. Smit M, van Zoest RA, Nichols BE, et al. ; Netherlands AIDS Therapy Evaluation in The Netherlands (ATHENA) Observational HIV Cohort Cardiovascular disease prevention policy in human immunodeficiency virus: recommendations from a modeling study. Clin Infect Dis 2018; 66:743–50. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 137. Smit M, Cassidy R, Cozzi-Lepri A, et al. . Projections of non-communicable disease and health care costs among HIV-positive persons in Italy and the U.S.A.: a modelling study. PLoS One 2017; 12:e0186638. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 138. Hatleberg CI, Lundgren JD, Ryom L. Are we successfully managing cardiovascular disease in people living with HIV? Curr Opin HIV AIDS 2017; 12:594–603. [DOI] [PubMed] [Google Scholar]

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