Antiretroviral therapy carries same risk of ischaemic heart disease as 1-4 cigarettes a day, Danish study shows

Highly active antiretroviral therapy is linked with a moderate increase in the risk of ischaemic heart disease “of the same order as that introduced by smoking 1–4 cigarettes per day”, report a team led by Niels Obel of the University of Copenhagen, Denmark. However, contrary to previous reports, this study suggests that the risk does not increase with longer duration of therapy. The study is published in the June 15^th edition of Clinical Infectious Diseases.

Concerns have been raised about whether the lipid abnormalities induced by antiretroviral therapy could lead to an increased risk of ischaemic (meaning reduced blood supply) heart disease. Although studies on the coronary arteries of people on antiretroviral therapy have confirmed the possibility, cohort studies have found conflicting results. To overcome the methodological shortcomings of previous cohort studies, Obel with Danish and US colleagues used three nationwide databases to study the risk of ischaemic heart disease in HIV-positive people and the general population.

The researchers used the Danish HIV Cohort Study, which records data from the eight specialist centres that treat all Danish HIV-positive patients. From early 1995, to the end of, 2004, they identified 3,953 HIV-positive patients with a first hospitalisation for ischaemic heart disease. These participants were matched by gender, age, and residence to a population-based control group of 373, 856 participants, drawn from the Danish Civil Registration System. Data on hospitalisations for verified ischaemic heart disease, including heart attacks and coronary artery bypass grafting, were drawn from discharge diagnoses in the Danish National Hospital Registry.

During the period of time in which the HIV cohort was not on antiretroviral treatment, patients were slightly more likely to be hospitalised for the first time with ischemic heart disease than were control subjects (adjusted relative risk 1.39; 95% CI 0.81–2.33).

After highly active antiretroviral treatment was initiated, “the risk increase became substantially higher” compared with the general population (adjusted relative risk 2.12; 95% CI 1.62–2.76), as did the risk of dying in the first 30 days after hospitalisation (8.8% versus 3.8%). The risk was highest in the first 90 days after antiretroviral treatment was started.

Overall, the incidence of ischaemic heart disease increased with time in both cohorts but the relative risk for people on antiretroviral therapy remained stable compared with controls for up to eight years of treatment. Among HIV-positive people, the risk of ischaemic heart disease was higher in those with lower CD4 counts, higher viral loads, and a shorter time from diagnosis to treatment initiation. Sensitivity analyses, which looked at different diagnoses resulting from ischaemic heart disease, such as angina, suggested that these risk estimates were robust.

Contrary to the Data Collection on Adverse Events of Anti-HIV Drugs (DAD) study, this report suggests that risk of heart disease is not progressive with duration of antiretroviral therapy.

The current study benefits from having a long follow-up, a large population-based control group, and registry outcomes that are known to be highly valid, note the authors. But, they write: “An important study limitation is lack of data on certain risk factors for ischemic heart disease, such as smoking, which is presumed to be more frequent among HIV-infected patients than among the general population”. Failure to account for smoking may have led to an overestimation of the relative risk associated with highly active antiretroviral therapy.

The rapid increase following antiretroviral therapy initiation calls into question the mechanism of ischaemic heart disease in these patients, assuming that the risk is not simply due to measurement bias, with patients more likely to be monitored at this critical time.

A more gradual increase in the risk would be expected if lipid accumulation in atherosclerotic plaques were the main risk factor, say the authors. “Other mechanisms, such as inflammation or changes in platelet or endothelial function, must be considered as potential explanations for the sudden expansion and instability of the atherosclerotic plaques”, they note, pointing to the immune reconstitution syndrome that occurs in some patients at this time.

Further investigation is needed into the pathogenesis of ischaemic heart disease related to highly active antiretroviral therapy, especially since a recent report suggests an association with specific drug classes.