Starting combination antiretroviral therapy improves markers of endothelial function but not arterial thickness and stiffness regardless of regimen type, says a new study reported in the April 15th issue of the Journal of Infectious Diseases. The small study provides insight into the mechanisms underlying the cardiovascular diseases that are becoming increasingly common among people with HIV on effective antiretroviral therapy.
With the continued success of HIV therapy, the long-term effects of antiretroviral drugs are becoming manifest, including a potential increased risk of cardiovascular diseases such as heart attack and stroke. Researchers are searching to identify the underlying mechanisms of such diseases in people with HIV. Metabolic complications, including increases in blood levels of lipids and changes in lipid and sugar metabolism, are also common in people on therapy – these changes are associated with the narrowing and hardening of arteries often seen in cardiovascular disease.
In a study designed to elucidate the effect of combination antiretroviral therapy, and the effect of different classes of antiretroviral drugs, on early markers of cardiovascular disease in people with HIV, Dutch investigators drew a subset of 27 participants from the MEDICLAS study. MEDICLAS is a single-blinded, randomised trail of treatment-naive men in Europe, comparing the metabolic complications and changes in body fat between a regimen containing nucleoside reverse transcriptase inhibitors (NRTIs), specifically Kaletra (lopinavir/ritonavir) and Combivir (AZT plus 3TC, 19 participants), and an NRTI-sparing regimen of Kaletra and nevirapine (Viramune, 18 participants).
Overall, participants in the substudy had few risk factors for cardiovascular disease. People with a history of the cardiovascular disease risk factors of severe obesity, diabetes or high blood lipid levels were excluded and, among eligible participants, smoking was the most common risk factor, reported by 17 of the 27 participants. Five participants had a history of heart disease, but only one member of each group used medication to control blood pressure and none used lipid-lowering drugs.
Investigators measured arterial thickness and stiffness as well as several chemical markers of the function of the endothelial cells lining of the blood vessels in all participants. Tests were performed before starting antiretroviral therapy and at three, twelve and 24 months of therapy.
Measuring arterial thickness in the intima media layers of the carotid artery, investigators noted a gradual increase in thickness with ongoing therapy. By 24 months, the estimated mean increase was 0.06 mm (p < 0.001) in the NRTI-containing group and 0.04 mm (p = 0.01) in the NRTI-sparing group, and there was no difference between the groups. This rate, the investigators say, appears to suggest a higher progression rate than the approximately 0.01 mm/year reported in HIV-negative people.
Investigators then measured several indicators of arterial stiffness in the carotid, femoral and brachial arteries. Significant decreases in measures of elasticity were noted in the femoral artery for both regimens, though the NRTI-containing regimen seemed to have a slightly larger effect on stiffness than the NRTI-sparing regimen. It was in that the NRTI-containing arm, the investigators write, that they also noted the most treatment-related cardiovascular disease risk factors, including decreased insulin sensitivity, central fat accumulation and limb fat loss. Changes in fat distribution, also called lipodystrophy, have been associated with some NRTIs.
Activation of the endothelium lining blood vessels is thought to represent an early stage in the development of cardiovascular disease and increased levels of markers of endothelial function have been linked to untreated HIV infection. It is not clear whether activation is caused directly by HIV or indirectly through an inflammation caused by HIV. In the current study, investigators noted a significant reduction in levels several markers of endothelial activation with both regimens, including coagulation and adhesion molecules, indicating an improvement in endothelial function after the initiation of therapy.
In reviewing the results, the investigators highlight the apparent disconnect between the worsening of arterial stiffness and the improvement in endothelial function. These findings", they write, “may suggest that the microcirculation and large vessels respond differently in this setting. Another potential explanation may be that the increase in arterial stiffness is mediated by nonendothelial mechanisms.” They also acknowledge that the small sample size of their study made it difficult to identify differences between the two treatments, and that larger studies may reveal effects on the vasculature and metabolism.