Endothelial dysfunction in Italian cohort caused by HIV, not antiretrovirals, researchers conclude

A retrospective cohort study has found evidence that HIV infection rather than HIV treatment triggers a condition that is a precursor of heart disease. The study, published in the March 13^th edition of AIDS, examined changes in markers of endothelial dysfunction, which is characterised by damage to the smooth layer of tissue lining the blood vessels.

After the antiretroviral treatment breakthroughs of the late 1990s greatly reduced HIV-related mortality in developed countries, the cardiovascular health of HIV-positive people became a major concern. HIV-positive people are at elevated risk of heart disease for reasons that are not well understood. There has been much debate about whether cardiovascular health is primarily jeopardised by certain antiretroviral drugs or by HIV itself.

The study of endothelial markers compared three groups: HIV-positive people initiating antiretroviral therapy, HIV-positive people who remained treatment-naive for the full study period, and HIV-negative controls. The two HIV-positive groups had higher levels of four markers at baseline than the control group, an indication that they were experiencing greater endothelial damage.

Over time, the antiretroviral therapy group had declines in three markers while the treatment-naive group stayed the same, leading researchers to attribute the baseline elevations in markers to HIV rather than to antiretroviral therapy.

The study enrolled 66 HIV-positive outpatients at an Italian clinic: 28 beginning non-nucleoside reverse transcriptase inhibitors (NNRTIs), 28 beginning protease inhibitors (PIs), and 10 not in need of antiretroviral therapy. The volunteers in the NNRTI group and PI group were matched for age and sex. The control arm, comprising 28 healthy HIV-negative volunteers, was matched for age, sex and smoking history.

The HIV-positive volunteers taking antiretroviral therapy provided plasma samples at baseline, three months, six months, and twelve months (all plus or minus one month). The antiretroviral-naive HIV-positive volunteers provided samples at baseline and after twelve months. The healthy controls provided a single round of plasma samples.

The study analysed eight markers of endothelial and platelet activation. The markers found to be significantly higher in HIV-positive people at baseline were soluble P-selectin (sP-sel), soluble vascular cell adhesion molecule-1 (sVCAM-1), monocyte chemoattractant protein-1 (MCP-1), and von Willebrand factor (VWF).

HIV-positive people taking antiretroviral therapy experienced gradual decreases in sVCAM-1, MCP-1 and VWF levels, with these changes first achieving statistical significance at six-month follow-up, i.e. six months after antiretroviral therapy was initiated. In the antiretroviral-naive group, no comparable decreases were observed.

In a subset of 20 people taking antiretroviral therapy, additional plasma samples were obtained after 24 months. By this time, levels of sVCAM-1 and MCP-1 (but not VWF) had decreased to the levels observed in healthy controls.

A comparison of people who took NNRTIs and those who took PIs was also informative. Some researchers have suspected PIs of harming the cardiovascular system because this class of drugs is associated with body-fat changes that are known to be risk factors for heart disease, such as increases in cholesterol and triglyceride levels. However, the endothelial markers for the PI group and NNRTI group did not differ significantly during follow-up. That is, the two groups experienced comparable declines in sVCAM-1, MCP-1, and VWF.

Interestingly, even while the PI group experienced these declines, it also had significant increases in cholesterol and triglyceride levels.

There were no relevant baseline differences between the PI group and the NNRTI group. Ninety-three per cent of the PI group took lopinavir/ritonavir (Kaletra), and seven per cent nelfinavir (Viracept). Eighty-six per cent of the NNRTI group took efavirenz (Sustiva), and 14% nevirapine (Viramune).

The researchers found further evidence of the impact of HIV infection when they compared viral load changes to sVCAM-1, MCP-1, and VWF changes in the study participants taking antiretroviral therapy. Decreases in viral load levels significantly correlated with the decreases in the endothelial markers.

The study results do not rule out the possibility that long-term use of antiretroviral therapy may harm the cardiovascular system. The D:A:D study, a large observational cohort study, linked protease inhibitor use to a slightly elevated risk of heart attack. The D:A:D study also found that each year of exposure to PIs further increased this risk.

The researchers conclude, “A prospective study to evaluate the long-term effects of different HAART regimens on endothelial activation appears to be warranted, given that a late, drug-related, increase of cardiovascular risk in the DAD study has been observed.”