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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].