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Cardiovascular Disease

HIV Positive People with Elevated C-reactive Protein Have Higher Cardiovascular Risk, but It May Not Be a Good Predictor of Heart Disease

A widely used biomarker of inflammation, C-reactive protein (CRP), is associated with cardiovascular risk in people with HIV, according to a large study reported in the July 2009 Journal of Acquired Immunodeficiency Syndromes. HIV positive people with elevated CRP had more than 4 times the risk of acute myocardial infarction (MI) than HIV negative people with normal CRP. But two other recent general population studies suggest CRP may not be a causal factor or a good predictor of heart disease.

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GlaxoSmithKline Meta-analysis Does Not Show Elevated Cardiovascular Risk Associated with Use of Abacavir

Since the 2008 Conference on Retroviruses and Opportunistic Infections, researchers have presented conflicting findings concerning the association between use of abacavir (Ziagen, also in the Epzicom and Trizivir combination pills) and increased risk of cardiovascular events.

As reported in the May 1, 2009 Journal of Acquired Immune Deficiency Syndromes, an analysis of more than 50 clinical trials conducted by abacavir manufacturer GlaxoSmithKline (GSK) did not find an increase in heart attacks or other cardiovascular events.

At CROI 2008, researchers with the large D:A:D (Data Collection on Adverse Events of Anti-HIV Drugs) study reported that recent use of abacavir was associated with an unexpected 90% increase in the risk of myocardial infarction (MI), with the increase being most pronounced in individuals with underlying cardiovascular risk factors and diminishing after the drug was discontinued.

Similarly, at the International AIDS Conference the following summer, investigators with the large SMART treatment interruption trial reported that abacavir was associated with an increased risk of MI, stroke, and other cardiovascular events, as well as elevated levels of certain biomarkers of inflammation.

After the D:A:D results were first reported, GSK researchers performed an analysis of the company's past clinical studies to see if they could find a similar "signal" linking abacavir and cardiovascular disease. Results were first reported in part at the 2008 International AIDS Conference.

Using the GSK HIV Data Repository, the investigators compiled data from 52 company-sponsored clinical trials, encompassing all phases of drug development, in which adult participants received at least 24 weeks of combination antiretroviral therapy (2 pediatric studies were excluded from the analysis); 36 of these studies were randomized, including 12 trials in which 3263 patients were randomly assigned to receive abacavir versus a control drug or placebo.

In total, these trials included 9502 HIV positive adults who received abacavir (accounting for 7641 person-years [PY] of follow-up) and 4672 patients who did not take the drug (accounting for 4267 PY). About 60% were treatment-experienced, while 40% were treatment-naive. Overall, most participant (82%) were men, the median age was 37 years, and 10% had a prior AIDS diagnosis; in studies with available race/ethnicity data, 58% were white, 24% were black, and 14% were Hispanic.

The researchers searched adverse event reports for terms related to coronary artery disease (CAD), including coronary artery atherosclerosis or occlusion, myocardial ischemia or infarction, acute MI, angina pectoris, and unstable angina. In addition, they reviewed all fatal adverse events due to any cause.

Results

  • Baseline demographics and HIV disease characteristics -- including lipid and glucose levels -- were similar in abacavir recipients and patients not exposed to abacavir.
  • MI rates were statistically similar for patients exposed to abacavir and those who did not take the drug (intent-to-treat, switch included):
    • Abacavir: 16 MIs; 0.168%; 2.09 per 1000 PY.
    • Non-abacavir: 11 MIs, 0.235%; 2.57 per 1000 PY.
  • Results were consistent when the analysis was restricted to the 12 trials in which participants were randomized to receive abacavir or a control drug/placebo:
    • Abacavir: 4 MIs; 2.15 per 1000 PY;
    • Non-abacavir: 7 MIs; 4.10 per 1000 PY.

"In this pooled summary, we observed few MI events overall and no excess risk of MI with abacavir therapy," the investigators stated.

"It is unclear why results from this data set seem discrepant to the [D:A:D] data set, particularly, as the non-abacavir MI event rate is similar," they added. "Further data are needed to evaluate any association between abacavir and increased risk of MI."

In their discussion, the researchers acknowledged that the total number of study participants may have been too small -- and the follow-up periods too short (typically 24 or 48 weeks) -- to detect an increase in cardiovascular events.

Furthermore, given what was known at the time the studies were designed, they typically did not collect data about cardiovascular risk factors such as blood lipid levels or biomarkers such as C-reactive protein, and did not employ HLA-B*5701 screening for abacavir hypersensitivity.

"Our initial intention was to supplement the descriptive data summaries presented in this article with a more sophisticated multivariate analysis, adjusting for available baseline cardiovascular risk factors," the authors wrote. "However, given the relatively small number of CAD and MI events observed and missing baseline CAD risk factor data for many individuals, this additional work was not viable."

"Whether abacavir has a role in coronary heart disease risk needs further clarification and understanding; however, it is clear that combination antiretroviral therapy overwhelmingly provides substantial survival benefit to patients with HIV," they concluded. "As with all medications, physicians and patients must weigh the risks of HIV disease against the overall benefits and risks of the antiretroviral medicines available."

GlaxoSmithKline Infectious Disease Medicine Development Center, Research Triangle Park, NC; GlaxoSmithKline Global Clinical Safety and Pharmacovigilance and Infectious Disease Medicine Development Center, Middlesex, UK; GlaxoSmithKline Worldwide Epidemiology, Upper Providence, PA.

5/19/09

Reference

CH Brothers, JE Hernandez, AG Cutrell, and others. Risk of myocardial infarction and abacavir therapy: no increased risk across 52 GlaxoSmithKline-sponsored clinical trials in adult subjects. Journal of Acquired Immune Deficiency Syndromes 51(1): 20-28. May 1, 2009.

Atherosclerosis and Endothelial Dysfunction Associated with HIV Infection and Antiretroviral Therapy

As people with HIV live longer thanks to effective antiretroviral therapy (ART), management of cardiovascular disease has become an important aspect of HIV care. Large cohort studies continue to indicate that certain antiretroviral drugs are associated with an elevated risk of myocardial infarction (heart attack), and there is growing evidence that HIV infection itself also plays a role.

Two recent journal articles looked at specific manifestations of cardiovascular damage in people with HIV.

Carotid IMT

In the first study, published in the February 2009 Journal of Acquired Immune Deficiency Syndromes, Marit van Vonderen and colleagues from the Netherlands aimed to identify the effects of HIV infection, ART, and lipodystrophy on carotid artery intima-media thickness (C-IMT) and arterial stiffness in the limbs.

Carotid IMT is a surrogate measure of atherosclerosis ("hardening of the arteries" and build-up of plaque) that gauges thickness of the lining of the arteries in the neck that supply the brain. Arterial stiffness, or loss of elasticity, is another marker of cardiovascular risk.

This case-control study included 77 HIV positive men and 52 HIV negative control subjects. Among the men with HIV, 55 were exposed to ART and 22 were ART-naive; 23 had lipodystrophy.

C-IMT was measured using ultrasound, while arterial stiffness was estimated by distensibility and compliance coefficients of the carotid, femoral (inner thigh), and brachial (inner upper arm) arteries. The investigators also assessed carotid Young elastic modulus and pulse wave velocity.

Results

  • After adjusting for known cardiovascular risk factors such as age, smoking, and obesity, HIV positive patients had a C-IMT 10.8% greater than that of control subjects (0.69 vs 0.62 mm; P = 0.001).
  • HIV positive participants had distensibility coefficients 13.6% lower for the carotid and 29.5% lower for the femoral arteries compared with HIV negative subjects, indicating greater stiffness.
  • The HIV positive group also had compliance coefficients 14.1% lower for the carotid and 31.0% lower for the femoral arteries compared with the HIV negative group.
  • Young elastic modulus and pulse wave velocity were similar in the HIV positive and HIV negative groups.
  • Within the HIV positive group, ART-exposed and ART-naive patients had similar C-IMT measurements.
  • However, the ART-exposed patients had a 25.9% lower distensibility coefficient and a 21.7% lower compliance coefficient of the femoral artery than the unexposed HIV patients.
  • Cumulative exposure to either protease inhibitors or nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) was associated with greater femoral artery stiffness.
  • Arterial properties did not differ between patients with and without lipodystrophy.
  • Arterial indicators also did not vary according to CD4 cell count or HIV viral load.

"HIV infection is independently associated with C-IMT and generally increased arterial stiffness," the study authors concluded. "ART use is associated with increased stiffness of the femoral artery."

In their discussion, the researchers suggested that chronic viral infection leading to ongoing inflammation may lead to damage of the of the blood vessel endothelium (lining) over time.

This lends support to the argument that maximally suppressive antiretroviral therapy, started before significant immune deficiency occurs, may help maintain cardiovascular health -- outweighing the potential negative effects of antiretroviral drugs themselves -- though clinicians increasing recognize the importance of assessing individual cardiovascular risk factors when making treatment decisions.

Department of Internal Medicine and Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, Netherlands; Department of Internal Medicine and cardiovascular research institute, University hospital Maastricht, Maastricht, Netherlands; Department of Clinical Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, Netherlands; Department of Infectious Diseases, Tropical Medicine, and AIDS, Center for Infection and Immunity and Center for Poverty-related Communicable Disorders, Academic Medical Center, Amsterdam, Netherlands.

Endothelial Dysfunction

In the second study, which appeared in the January 27, 2009 advance online edition of AIDS, Daniela Francisci and colleagues from Italy looked at endothelial dysfunction and activation of platelets (cell fragments involved in blood clotting) as markers of atherosclerosis and their association with HIV infection and its treatment.

This retrospective cohort study included 56 HIV positive participants evaluated before and 3, 6, 12, and 24 months after starting HAART, half including a protease inhibitors and half including a non-nucleoside reverse transcriptase inhibitor (NNRTI).

The HIV positive patients were compared against 28 healthy HIV negative control subjects matched for age and sex, and 10 HIV positive ART-naive patients studied at the time of diagnosis and after 12 months of untreated infection. Soluble endothelial and platelet activation markers were measured in plasma by flow cytometry.

Results

  • Levels of soluble P-selectin, soluble vascular cell adhesion molecule-1, monocyte chemoattractant protein-1, and von Willebrand factor were all significantly higher in HIV positive patients compared with HIV negative control subjects.
  • Soluble CD40 ligand and tissue type plasminogen activator, in contrast, were within the normal range in the HIV positive group.
  • During follow-up, levels of soluble vascular cell adhesion molecule-1, monocyte chemoattractant protein-1, and von Willebrand factor -- but not soluble P-selectin -- decreased progressively in the treated HIV patients.
  • Decreases were similar in patients treated with protease inhibitors and NNRTIs.
  • The untreated ART-naive HIV patients had elevated plasma markers of endothelial dysfunction at diagnosis, but these did not change over the 12 months of follow-up.

Based on these findings, the investigators concluded, "Chronic HIV infection, and not its pharmacological treatment, induces alterations of markers of endothelial function."

"Short-term treatment with HAART reduces some markers of endothelial dysfunction, with no differences between protease inhibitors and non-nucleoside reverse transcriptase inhibitors," they added.

Division of Infectious Diseases, Department of Experimental Medicine and Biochemical Sciences, Italy; Division of Internal and Cardiovascular Medicine, Department of Internal Medicine, University of Perugia, Perugia, Italy.


Monitoring and Risk Reduction

Much remains to be learned about cardiovascular disease in people with HIV. The persisting conflict between studies that find a solid link between heart disease and ART, and others that observe no association, remains unexplained.

Taken together, however, these 2 recent studies underlining the importance of cardiovascular risk assessment and ongoing monitoring of HIV patients on ART, as well as the need for risk-reduction measures such as smoking cessation, healthy diet, adequate exercise, and -- if needed -- lipid-lowering medications.

2/10/09

References

MG Van Vonderen, YM Smulders, CD Stehouwer, and others. Carotid Intima-Media Thickness and Arterial Stiffness in HIV-Infected Patients: The Role of HIV, Antiretroviral Therapy, and Lipodystrophy. Journal of Acquired Immune Deficiency Syndromes 50(2): 153-161. February 2009. (Abstract).

D Francisci, S Giannini , F Baldelli, and others. HIV type 1 infection, and not short-term HAART, induces endothelial dysfunction. AIDS. January 27, 2009 [Epub ahead of print].

CROI 2009: Elevated Rate of Heart Attacks and Strokes in HIV Patients on HAART Begins to Decline at California Kaiser Permanente

As HIV positive people began to live longer thanks to the development of effective antiretroviral therapy, cardiovascular disease became a growing concern, especially given evidence that HIV infection itself and the drugs used to treat it can increase cardiovascular risk.

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ICAAC 2008: Atherosclerosis, Coronary Plaques, and Heart Rhythm Changes in People with HIV

Cardiovascular disease is a growing concern as people with HIV live longer, but the complex relationship between HIV infection itself, immune activation triggered by the virus, and antiretroviral drugs used to treat it remains poorly understood. Three studies presented at the 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2008) in late October shed further light on factors associated with cardiovascular risk in HIV positive patients.

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