Copenhagen, Denmark - The use of protease inhibitors, a potent antiretroviral medication used in the treatment of human immunodeficiency virus (HIV), is associated with an increased risk of MI, a finding that is only partly explained by dyslipidemia [1]. There was, however, no such association with nonnucleoside reverse-transcriptase inhibitors (NNRTIs), although investigators caution that experience with these newer drugs remains limited.

"Using a data set that has accrued almost three times more end points in the three years of follow-up since the last report, we continue to observe an association between exposure to combination antiretroviral therapy and the risk of myocardial infarction," write the Data Collection on Adverse Events of Anti-HIV Drugs (DAD) study group in the April 26, 2007 issue of the New England Journal of Medicine. This relationship, write the authors, between exposure to protease inhibitors and MI remained significant after multivariable adjustment.

Dr James Stein (University of Wisconsin Medical School, Madison, WI), who wrote an editorial accompanying the DAD study [2], stressed that the protease inhibitors have had a profound effect on survival, turning HIV infection from a "short-term illness with a terrible prognosis to a chronic illness that people can live with for more than two decades."

However, when the protease inhibitors first came to market, there were several case reports of young patients with heart disease and stroke, as well as talk about an impending epidemic of cardiovascular disease in the HIV population, as these drugs are associated with central obesity, dyslipidemia, and insulin resistance.

"The question that physicians have struggled with for more than 10 years is just how big of a risk is this and how it affects our patients," Stein told heartwire. "The overriding principle, however, for any patient with HIV is that aggressive control of HIV is much more important than the risks of its treatment for cardiovascular disease."

The DAD study, led by steering committee chair Dr Jens Lundgren (University of Copenhagen, Denmark), is an international collaboration of investigators following 23 437 HIV-infected patients at 188 clinics in Europe, the US, and Australia. All participants are actively followed in their cohorts from the time of enrollment—December 1999 through April 2001—with an analysis assessing the risk of MI prespecified once sufficient events had accumulated.

From data collected through February 2005 from the observation cohorts, the analysis revealed that 345 patients had had an MI. The incidence of MI increased from 1.53 per 1000 person-years in those not exposed to protease inhibitors to 6.01 per 1000 person-years in those exposed to the drugs for more than six years.

After adjustment for exposure to the other drug class—patients are treated with more than one antiretroviral—and cardiovascular risk factors, excluding lipid levels, patients receiving protease inhibitors had an increase in the risk of MI of 16% per year, as compared with an increase of only 5% per year among those treated with NNRTIs. Further adjustment for serum lipid levels, hypertension, and diabetes mellitus reduced this risk to 10% per year for those treated with protease inhibitors and to zero among those treated with the NNRTIs.

Protease inhibitors are known to increase total cholesterol and LDL cholesterol to a greater extent than NNRTIs, the authors point out, whereas the NNRTIs are known to increase HDL cholesterol. However, the risk of MI associated with protease inhibitors was not fully explained by the lipid changes induced by the drug class.

"Thus, the full mechanism by which protease inhibitors may lead to increase rates of myocardial infarction remains to be elucidated," conclude the DAD investigators.

Stein, the NEJM editorialist, told heartwire that the magnitude of risk observed with protease inhibitors is not high, especially when compared with other cardiovascular risk factors. The risk, for example, is still less than being male, being a smoker, having diabetes mellitus, or having had a previous cardiovascular event.

Treatment leads to risk factors that need to be managed, but this shouldn't for one minute discourage people from treating HIV aggressively.

"The risk is there, but it's still very small," said Stein. "Treatment leads to risk factors that need to be managed, but this shouldn't for one minute discourage people from treating HIV aggressively. I would also say that there is not an epidemic of heart disease on the horizon. When you look at the absolute risks of the people in these studies—mostly men in their early 40s—the risk is low to moderate depending on how many risk factors they have. This risk is mostly attributable to their smoking, their male sex, and their history of heart disease. We can intervene on smoking as well as on lipids, so this should remain our focus."

New guidelines will soon be published by the HIV Medical Association, a branch of the Infectious Disease Society of America, for diagnosis and management of dyslipidemia in patients with HIV, said Stein.

Regarding the possibility that NNRTIs do not significantly increase the cardiovascular risk, Stein said it is interesting and plausible, although such a finding is not proven by this study. The drugs do have fewer adverse lipid effects than the protease inhibitors, but the limitations of the study prevent definitive conclusions. The main limitation is the person-years of exposure with the drugs, with just 63.7% patients exposed to the NNRTIs for a median of 2.6 years, as compared with 93.6% of patients exposed to the protease inhibitors for almost seven years.

"At this point, I don't think cardiovascular risk should be a deciding factor when an HIV doctor is choosing a class of drug for treatment," he said. "The overriding factor should be what the best drug is for their HIV."