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.