Friis-Møller et al report that 126 people had MIs over a period of 36 199 person-years of follow-up. Strikingly, the longer a person was on antiretrovirals, the greater the risk of MI (p for trend <0.001), while people who had never taken antiretrovirals had a significantly lower risk of MI than people who had been on the drugs.

"Although the absolute event rate was low, combination antiretroviral therapy was associated with a 26% relative increase in the rate of myocardial infarction per year of exposure during the first four to six years of use," the investigators write.

In an editorial accompanying the study, Drs Peter Sklar (Drexel University, Philadelphia, PA) and Henry Masur (National Institutes of Health, Bethesda, MD) point out that the contradictory results from major studies on this topic likely stem in part from their short follow-up and lack of non-HIV-infected controls.2 As well, they note, it is difficult to know for certain that the increased cardiovascular risk arises from the treatment or from HIV infection. "Is it plausible that HIV infection itself could promote atherosclerosis through a proinflammatory effect on endothelial cells, much like the mechanism that has been hypothesized for other infectious agents such as cytomegalovirus, herpes simplex virus, or chlamydia?" they ask. Both HIV infection and antiretroviral drugs are known to produce changes in lipid profiles.

"Taken in aggregate," Sklar and Masur write, "the weight of evidence suggests that HIV-infected patients treated with combination antiretroviral regimens are at increased risk for the development of premature atherosclerotic complications." More evidence is needed, however, before physicians start tampering with what have proved to be highly successful treatments in HIV-infected patients. A "logical" first step, they say, will be for physicians to recommend lifestyle changes and lipid lowering, through drugs and dietary changes. "Antiretroviral therapies have been among the miracles of recent decades, yet we must work toward mitigating the toxic effects that have the potential to diminish the quality and duration of patients' survival over the long term," they conclude.

Commenting on the study for heartwire, International AIDS Society council member Dr Julio Montaner (British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC) downplayed the differences between the various studies examining CVD rates in patients on antiretroviral therapy. The overarching message is the same, he says, namely, that the effect of HIV drugs on CVD "doesn't even come close" to touching the dramatic drop they produce in morbidity and mortality from any cause. "There is a slight, increased risk of CVD, and there is reason to be concerned, but lacking comparator data, it is difficult to know how significant drug-related changes in lipid profiles will prove over time," he said. Distinguishing drug effects from inflammatory effects caused by HIV is also a challenge, he added, and requires further study. For example, CRP levels in HIV patients are "sky high" regardless of whether the patient has or has not started HAART.

Additional considerations are the other risk factors in the HIV+ population generally, Montaner points out. "If you look at the social-demographic characteristics of people with HIV as a whole, their profiles may be such that you would expect a high prevalence of risk factors," he said. "If you try to match my patients for age and gender with the Framingham 'normals,' you may be making a mistake, because smoking, obesity, and cocaine and other drug use may be overrepresented in my population, and all of those can be independent markers for cardiovascular risk."