CROI: Heart attack risk elevated by protease inhibitor treatment but not NNRTIs

The increased risk of heart attack seen in patients taking antiretroviral therapy is caused by protease inhibitors and not non-nucleoside reverse transcriptase inhibitors (NNRTIs), according to an analysis of the D:A:D study presented today at the Thirteenth Conference on Retroviruses and Opportunistic Infections (CROI) in Denver. The study showed that this was partially due to the changes in blood fat levels caused by protease inhibitors.

The Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) is an observational study that set out to assess the long-term safety of HIV treatment. It involves over 23,000 HIV-positive people in eleven cohorts based in three continents. Last year, results from the study presented at CROI in Boston showed that the risk of heart attacks increased by 17% with every year a patient spent on antiretroviral therapy.

Now, the study has collected enough data to allow the detection of a difference between drug classes in the risk of heart attack, or ‘myocardial infarction'.

Dr Nina Friis-Møller of the Copenhagen HIV Programme presented the latest results based on follow-up to February 2005, explaining that a total of 345 study participants had a heart attack during the study. However, she showed that this incidence was small in relation to the 94,469 person-years of follow-up, resulting in an overall incidence rate of just 3.65 heart attacks for every 1000 person-years of treatment.

After adjusting this rate for known risk factors, such as gender, smoking, blood pressure and increasing age, this was equivalent to a 16% increase in risk per year of antiretroviral exposure (95% confidence interval: 9 – 23%). This is the same as a doubling of the risk in five years.

At the end of the follow-up period, 83% of the patients had taken protease inhibitors (PIs), for a median duration of three years. The investigators found that the risk of having a heart attack increased by 16% per year of exposure to PIs, after adjustment for known risk factors (p

In contrast, each year of NNRTI exposure did not cause a significant increase in the risk of heart attack, with an average 5% increase per year (p = 0.17). Seventy-nine per cent of the study participants had taken NNRTIs, for a median duration of three years.

When the investigators adjusted their analysis for blood fat (lipid) levels, the risk of PI treatment was reduced to 10%. This indicates that some of the risk posed by PIs is secondary to their effects on blood fat levels.

Correcting the NNRTI risk for blood fats did not affect the investigators’ findings.

There was also no effect of the nucleoside reverse transcriptase inhibitor (NRTI) backbone taken by the patients.

Although these findings link protease inhibitor treatment to an elevated risk of heart attack, the absolute risk remains low, at less than 0.4% per year of treatment. Despite its size, however, the D:A:D study still does not include enough patients to allow investigators to detect the role of individual protease inhibitors on the risk of cardiovascular disease.

A link to artery wall thickening?

In a second presentation at the Denver conference, Dr Judith Currier of the University of California, Los Angeles, reported the latest results from ACTG 5078, a study examining the effects of anti-HIV treatment on the thickness of artery walls.

The thickness of the walls or ‘intima media’ of the carotid artery in the neck can be measured with ultrasound scans. Previous studies have shown that increased wall thickness is linked to an increased risk of heart attack.

To assess the change in carotid intima media thickness over time, investigators analysed three groups: 44 HIV-positive people treated with protease inhibitors for at least three years, 46 HIV-positive people who had never received PIs, and 46 HIV-negative people.

After taking measurements at baseline and every 24 weeks, they found no statistically significant differences in the rate at which the artery wall became thicker between the three groups. Although much smaller than the D:A:D study, this study was designed to be large enough to detect a meaningful difference between the groups, if it really existed.

As the patients in the three groups were matched for the ‘classic’ risk factors for cardiovascular disease, the investigators suggest that these may play a more significant role than antiretrovirals in the increased incidence of heart attacks in HIV-positive patients.

However, when they looked at HIV-positive patients alone, the investigators did find a trend towards a more rapid increase in artery wall thickening in three groups: patients taking ritonavir (Norvir), patients who had spent longer on protease inhibitors and patients with higher blood sugar levels.

It is hoped that further data will help to confirm these trends and provide a link between the effects of HIV drugs on artery walls and the heart attack rates seen in D:A:D.