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Inflammatory Markers and Cardiovascular Risk in Treated and Untreated People with HIV

Two recently published studies shed further light on the relationship between inflammation and non-AIDS conditions in people with HIV. One study found that HIV positive people may have elevated levels of the inflammatory biomarker high-sensitivity C-reactive protein (CRP), even if they are on effective antiretroviral therapy (ART) and otherwise have a low cardiovascular risk. The second study found that people with untreated HIV infection had lower HDL (good) cholesterol and increased levels of inflammatory and coagulation markers compared with HIV negative individuals.

A growing body of evidence indicates that even low-level ongoing HIV infection can lead to persistent immune activation and inflammation, which may help explain why people with HIV are at higher risk for a variety of non-AIDS conditions such as cardiovascular disease, despite well-preserved immune function.

ART-treated Participants

In the first study, published in the December 2009 Journal of Acquired Immune Deficiency Syndromes, Michael Boger from Vanderbilt University School of Medicine and colleagues assessed relationships between blood levels of high-sensitivity CRP (hsCRP) and other metabolic parameters associated with cardiovascular risk over time in HIV positive people on ART.

In the general population, hsCRP is widely used as a predictor of future coronary artery disease (atherosclerosis leading to blockage of arteries that supply the heart). The American Heart Association recommends CRP measurement for people with intermediate cardiovascular risk, and the large JUPITER trial showed that the drug rosuvastatin (Crestor) reduced the risk of serious cardiovascular events in people with elevated CRP even if they had normal cholesterol levels. But the utility of CRP as a predictor of heart disease in people with chronic inflammatory conditions such as HIV infection is not clear.

Boger's team looked at prospective data from 94 HIV positive adults enrolled between June 2005 and July 2007. About three-quarters were men, the median age was 44 years, and 57% were white. Participants were on ART (54% taking a protease inhibitor), had HIV RNA < 10,000 copies/mL (median 50 copies/mL) and a median CD4 cell count of about 500 cells/mm3, and did not have diabetes or cardiovascular disease at baseline.

Results

  • At study entry, the median high-sensitivity CRP level was 2.94 mg/dL (1.0-3.0 is considered average).
  • 49% had hsCRP > 3 mg/dL, suggesting an increased risk of coronary artery disease.
  • The median Framingham risk score (calculated based on age, sex, total cholesterol, HDL cholesterol, systolic blood pressure, and smoking status)was 3, indicating a 10-year cardiovascular risk of 1%.
  • In a multivariate analysis, increased hsCRP was associated with:
    • Higher body mass index (BMI) (P = 0.001);
    • Higher non-HDL cholesterol (P = 0.013);
    • Lower HDL cholesterol (P = 0.015);
    • Elevated triglycerides (P = 0.017).
  • There was a trend toward an association between higher hsCRP and higher viral load, but this did not reach statistical significance.

"Among HIV-infected adults with low estimated cardiovascular disease risk and virologic suppression on ART, hsCRP was elevated and independently associated with BMI and lipid changes," the study authors concluded. "Future studies should assess associations between hsCRP and clinical outcomes."

"The most important finding of our study is that hsCRP was elevated in individuals with low Framingham risk score and correlated with changes in serum lipids and BMI over time," they elaborated in their discussion.

Studies of people with HIV "suggest that chronic ART exposure, uncontrolled HIV replication, or both, likely contribute to cardiovascular disease in HIV-infected patients," they continued. "hsCRP is a minimally invasive method for assessing risk of future acute coronary events in an HIV-negative population with intermediate risk as determined by traditional risk assessment. Ultimately, its use in HIV may allow practitioners to tailor ART and primary prevention strategies in at-risk individuals."

However, they added, the presence of lipodystrophy (body fat changes) and elevated hsCRP due to ongoing viral replication "may confound interpretation of hsCRP at assessing coronary risk" in the HIV positive population.

Finally, the researchers wrote, "These data are important because they suggest that inflammation is relevant to the pathophysiology of metabolic disturbances in chronically HIV-infected persons on treatment with minimal plasma HIV-1 replication, confirm that cardiovascular disease risk by traditional risk factors and risk of acute coronary syndrome by hsCRP are often discordant in HIV-infected persons, and that noninvasive inflammatory markers may be of utility."

Untreated Participants

In the second study, described in the January 15, 2010 Journal of Infectious Diseases, Jason Baker from the University of Minnesota and colleagues evaluated several markers of cardiovascular risk in people with HIV who were not receiving antiretroviral drugs:

  • HDL cholesterol;
  • Inflammation biomarkers: high-sensitivity CRP and interleukin 6 (IL-6);
  • Markers of endothelial activation (blood vessel dysfunction): E-selectin and soluble intercellular adhesion molecule-1 (sICAM-1);
  • Markers of thrombotic activity (blood clotting): fibrinogen and D-dimer.

The analysis included 32 untreated HIV positive participants and 29 HIV negative individuals enrolled between March 2007 and June 2008. A slim majority of HIV positive participants (56%) had a CD4 cell count above the 350 cells/mm3 threshold for initiating ART according to treatment guidelines in effect at the time. Most (84%) had never received ART, and the 5 with prior ART experience had a mean HIV infection duration of 14 years and had been off ART for at least 2 years.

The investigators looked at differences in levels of blood lipids and biomarkers according to HIV status, before and after adjusting for age, sex, race/ethnicity, BMI, smoking status, and hepatitis C coinfection.

Results

  • Compared with HIV negative individuals, HIV positive participants had lower HDL cholesterol levels by 26%.
  • Overall HDL particle concentrations were lower (-21%), with reductions observed for both large (-50%) and small (-20%) particles (all P £0.01).
  • There were trends toward higher total cholesterol and triglyceride levels in the HIV positive group, but these did not reach statistical significance (P = 0.15 and 0.11, respectively).
  • Levels of IL-6, sICAM-1, and D-dimer were 65%-70% higher in HIV positive participants (all P £0.02).
  • Adjusting for covariates did not diminish these associations.
  • Among HIV positive participants, total HDL cholesterol and small HDL particle concentration tended to be inversely correlated with levels of:

o   IL-6 (P = 0.08 and 0.02);

o   sICAM-1 (P < 0.01 for both);

o   D-dimer (P = 0.03 and 0.01).

Based on these findings, the investigators concluded, "Persons with untreated HIV infection have lower HDL particle concentration (primarily large and small HDL particle concentration) and higher IL-6, sICAM-1, and D-dimer levels."

"[T]he relationship of these markers to HIV-mediated atherosclerotic risk requires further study," they added.

Assessment of cardiovascular disease risk traditionally involves measurement of HDL and LDL (bad) cholesterol, they explained in their discussion. But small HDL particles "may be particularly protective in terms of atherosclerotic risk, given anti-inflammatory properties and their preference over larger HDL as initial acceptors of cholesterol from peripheral cells in reverse cholesterol transport." Furthermore, small HDL particles "are primarily responsible for HDL’s anti-inflammatory properties and inhibition of endothelial activation."

In summary, the authors wrote, "The relationship between small HDL particle concentration, inflammation, thrombogenesis, and risk for premature atherosclerosis requires further examination in longitudinal studies involving persons with HIV infection."

Study 1: Department of Medicine, Division of Infectious Diseases; Department of Biostatistics; and Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN.

Study 2: Departments of Medicine and Biostatistics, University of Minnesota, and Hennepin County Medical Center, Minneapolis, MN; Department of Biochemistry, University of Vermont, Burlington, VT.

2/16/10

References

M Boger, A Shintani, LA Redhage, and others. Highly Sensitive C-Reactive Protein, Body Mass Index, and Serum Lipids in HIV-Infected Persons Receiving Antiretroviral Therapy: A Longitudinal Study. Journal of Acquired Immune Deficiency Syndromes 52(4): 480-487.

J Baker, W Ayenew, H Quick, and others. High-Density Lipoprotein Particles and Markers of Inflammation and Thrombotic Activity in Patients with Untreated HIV Infection. Journal of Infectious Diseases 201(2): 285-292. January 15, 2010.