Houston, TX - University of Texas researchers say they have uncovered a key mechanism by which protease inhibitors promote atherosclerosis and cardiovascular disease in HIV+ patients [1]. Writing in the July 2007 issue of the American Journal of Pathology, Dr Xinwen Wang and colleagues (Baylor College of Medicine, Houston, TX) report that the protease inhibitor ritonavir (Norvir, Abbott Laboratories) inhibits cholesterol efflux from human macrophage-derived foam cells—the process that removes excess cholesterol from tissues and the arterial wall.

This is the first time scientists have identified a mechanism that clarifies how protease inhibitors increase the risk of cardiovascular disease, senior author Dr Johnny Chen told heartwire. "The findings of ritonavir-induced cholesterol efflux in vitro may be used to explain, at least in part, the clinical association of cardiovascular disease with ritonavir treatment in some HIV-infected patients," he said.

Wang et al's findings are based on cell-culture studies in which human THP-1 monocytes and peripheral blood mononuclear cells were incubated with cholesterol to form foam cells. When ritonavir was added to the cells, cholesterol efflux from the cells was reduced compared with control cells to which no ritonavir was added. Further experiments indicated that ritonavir decreased the expression of molecules that mediate cholesterol efflux and increase production of superoxide anion, a reactive oxygen species (ROS). Increased ROS generation and oxidative stress have been linked to elevated risk of atherosclerosis, MI, and angina, the authors note. Strikingly, when an antioxidant, selenium (seleno-L-methionine), was added, the ritonavir-induced decrease in cholesterol efflux was minimized.

"The findings of ritonavir-induced oxidative stress in vitro may imply that clinical usage of antioxidant therapy may be effective in minimizing the adverse effects of ritonavir," Chen commented. "Since many different types of antioxidants with different actions are available, it is likely that certain antioxidants may be more effective than others to minimize the adverse effects of ritonavir."

For now, says Chen, it's not possible to "overinterpret" findings based solely on in vitro experiments. "It is strongly warranted to further investigate these issues of cholesterol efflux and antioxidant therapy in animal models and clinical trials," he said. It is also possible that future HIV drugs might be able to minimize effects on cholesterol transport. In the meantime, Chen's group is planning a study in HIV+ patients taking ritonavir to see if the addition of an antioxidant supplement might minimize the vascular effects, as measured by an imaging test such as carotid IMT.

Commenting on the study, Dr Greg Bondy (St Paul's Hospital, Vancouver, BC), a cardiologist with expertise treating hyperlipidemia in HIV+ patients, said the results are novel but not totally surprising. "Proteases are involved in processing virtually every single signaling pathway in a cell and are important for cell structure and cell metabolism, so certainly this is a believable story, a believable mechanism."  

But Bondy also points out that the vascular risk associated with protease inhibitors should not be overstated. "I put anybody who has HIV in a 'moderate-risk' category, I don't put them in a high-risk category," he said. To do so would be "an overemphasis of the risk associated with highly active antiretroviral therapy [HAART]. . . . If you look at cohort studies of HIV patients, most of their vascular risk is still attributable to traditional risk factors, smoking, diabetes, hypertension. There is vascular risk associated with protease inhibitors, or even whole antiviral regimes, or HIV itself, but the particular contribution with regard to increased vascular risk of protease inhibitors I still feel is relatively small."

It's also a manageable risk, Bondy adds. "I tell my HIV-treating physicians to use the drug regime that they feel best keeps the virus down, and then if the patients develop metabolic issues, I can generally deal with them."

For this reason, Bondy says it's unlikely that drug development would ever be tailored to tweak the metabolic side effects of HIV medications. He also points out that the antioxidant hypothesis has not panned out for CVD prevention in the past, as witnessed by the meteoric rise and fall of vitamin E. "When you get activation of ROS, it does correlate with increased atherosclerosis, but no one has yet proven that if you lower that using a pharmacologic therapy that that leads to any benefit. The whole antioxidant theory really was a big bust."

But Chen, in response, argues that not all antioxidants are equal. For this study, he said, "We tested multiple antioxidants to see which one would be best at blocking the effects of ritonavir. Antioxidants block oxidative stress and free radicals, but there are different pathways to generate free radicals, and you need to know which pathway you want to block." His group is continuing to test which antioxidant may be best for attenuating the effects of ritonavir on cholesterol transport. Different protease inhibitors may also produce different degrees of oxidative stress or have different effects on cholesterol efflux, he adds.

Chen also insists that the relative contribution of protease inhibitors or HAART to cardiovascular risk should not be minimized, particularly since HIV+ patients are living longer and longer.

"Patients aren't dying any more, and they have to be maintained on their medications for life. . . . These drugs can manage the infection nicely, but we can't control the complications of either the infection or drugs on multiple organs."