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Biomarkers of Inflammation and Cardiovascular Risk in HIV Positive Children

Children with HIV have higher levels of certain biomarkers of inflammation and endothelial dysfunction compared with healthy children, as well as coagulation abnormalities associated with higher risk of cardiovascular disease, according to 2 recently published studies. These findings, suggested to one study team, suggest that efforts to control cardiovascular risk factors should start early for HIV positive children.

Observational studies have found that HIV positive adults have a higher likelihood of cardiovascular disease and heart attacks than the general HIV negative population, but this link has not been extensively studied in children with HIV. The reason for this association is not fully understood, but inflammation and metabolic changes related to antiretroviral drugs appear to play a role.

Inflammation is a key feature of atherosclerosis, or "hardening of the arteries." As atherosclerosis progresses, arteries lose their elasticity and become filled with plaques made up of lipids, immune cells, and other material. Numerous signaling molecules are involved in this process, some of which can be measured in the blood as biomarkers of inflammation, coagulation (clotting), and endothelial (blood vessel lining) dysfunction.

Cardiovascular Biomarkers

In the first study, published in the June 7, 2010 advance online edition of the Journal of Acquired Immune Deficiency Syndromes, Tracie Miller from the University of Miami and colleagues compared biomarkers of vascular dysfunction among HIV-infected children and a demographically similar group of uninfected children:

  • Inflammation: C-reactive protein (CRP), interleukin-6 (IL-6), and monocyte chemoattractant protein 1 (MCP-1);
  • Coagulation: fibrinogen and P-selectin;
  • Endothelial dysfunction: soluble intracellular cell adhesion molecule 1 (ICAM-1), soluble vascular cell adhesion molecule 1 (VCAM-1), and E-selectin.
  • Metabolic dysfunction: leptin, a hormone produced by fat tissue.

The study included 106 HIV-infected children (average age 15 years) and 55 HIV negative control children (average age 12 years). Sex ratio and body mass index were similar in the 2 groups. In addition to biomarkers, the researchers also evaluated body composition, CD4 cell percentage, HIV viral load, and use of antiretroviral therapy.


  • Children with HIV had higher levels of ICAM-1, VCAM-1, MCP-1, IL-6, and fibrinogen compared with uninfected children.
  • There was a trend toward higher levels of E-selectin (P = 0.07) and CRP (P = 0.08) in the HIV group, but these differences did not reach statistical significance.
  • Levels of P-selectin and leptin were similar in the 2 groups. 
  • In a multivariate analysis that included only children with HIV, a higher waist-to-hip ratio was associated with increases in ICAM-1 (17% per 1 standard deviation in ratio), MCP-1 (19%), IL-6 (18%), and CRP (59%). 
  • CD4 percentage was inversely associated with VCAM-1, MCP-1, IL-6, fibrinogen, and CRP -- that is, biomarkers levels rose as immune function declined.

"HIV-infected children have higher levels of biomarkers of vascular dysfunction than healthy children," the study authors concluded. "Risk factors associated with these biomarkers include higher waist-to-hip ratios and HIV disease severity."

Coagulation Abnormalities

In the second study, reported in the May 15, 2010 issue of AIDS, Giuseppe Pontrelli and colleagues from Italy looked at coagulation abnormalities and their association with HIV viral load in HIV positive children and adolescents. Here too, the researchers measured several biomarkers associated with cardiovascular risk:

  • C-reactive protein: an acute-phase protein associated with inflammation;
  • Fibrinogen: an acute phase protein involved in coagulation;
  • Protein S and protein C: 2 anticoagulation proteins that help control blood clotting, or thrombosis;
  • Antithrombin: a molecule that inactivates several enzymes of the coagulation system;
  • D-dimer: a by-product of clot breakdown indicating increased coagulation;
  • Homocysteine: an amino acid associated with increased cardiovascular risk.

This study enrolled 88 HIV positive participants with an average age of 14 years. The mean CD4 percentage was 30%. The investigators compared biomarker levels in children with high and low viral load, adjusting for demographic, clinical, and treatment-related factors. About three-quarters had low viral load.


  • 51% of participants showed protein S deficiency and 8% had protein C deficiency, indicating increased thrombosis risk.
  • Children with high viral load had lower levels of protein S, protein C, and antithrombin, but an increase in D-dimer.
  • Lower protein S (?11.2%; P = 0.04) and higher D-dimer (+0.13 mcg/ml; P = 0.004) remained independently association with high viral load in a multivariate analysis controlling for other factors.

Based on these findings, the investigators concluded, "HIV-infected children and adolescents present high prevalence of thrombophilic abnormalities," with an elevated risk of coagulation.

"The multivariate model confirmed that high viral replication is independently associated with decrease of protein S and increase of D-dimer," they continued, "suggesting the advantage of suppressive therapy on coagulation homeostasis and the opportunity of an active control of cardiovascular risk factors starting at a younger age."

Investigator affiliations:

Miller study: Divisions of Pediatric Clinical Research, General Pediatrics, and Infectious Diseases and Immunology, Department of Pediatrics, Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL; Department of Epidemiology and Biostatistics, Harvard School of Public Health, Boston, MA.

Pontrelli study: Department of Public Health, Ospedale Pediatrico Bambino Gesu, Rome, Italy.



L Miller, G Somarriba, EJ Orav, and others. Biomarkers of Vascular Dysfunction in Children Infected With Human Immunodeficiency Virus-1. Journal of Acquired Immune Deficiency Syndromes (Abstract). June 7, 2010 (Epub ahead of print).

G Pontrelli, AM Martino, HK Tchidjou, and others. HIV is associated with thrombophilia and high D-dimer in children and adolescents. AIDS 24(8): 1145-1151 (Abstract). May 2010.