Some PIs have greater impact than others on heart disease

Patients on atazanavir had less heart problems

Recent research has highlighted the cardiovascular problems that some HIV patients have had while being treated with protease inhibitors (PIs), but it’s been difficult for physicians to determine exactly which drugs are causing the most trouble.

Now a new study, presented at the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), held Dec. 16-19, 2005, in Washington, DC, shows that there is a significant difference in coronary risk depending on which PI a patient takes.

Investigators found that patients receiving atazanavir had a significantly lower risk over a 10-year period of coronary heart disease than did patients receiving nelfinavir, and this lower risk remained statistically significant for patients who had other heart disease risk factors, including smoking, diabetes, and hypertension.1

"There are a million people in the United States who have HIV and probably about half of those people are under the age of 25 years of age," says Craig I. Coleman, PharmD, an assistant professor of pharmacy practice at the University of Connecticut School of Pharmacy and director of the pharmacoeconomics and outcomes studies group at Hartford Hospital in Hartford, CT.

"So that means there will be a lot of patients out there, particularly as HIV drugs improve, who will live longer and die from things other than HIV/AIDS," Coleman says.

For some time, clinicians have known that PIs can cause metabolic problems, including hypoglycemia, insulin resistance, hyperlipidemia, and this was generally thought to be an across-the-board problem, Coleman notes.

"Then in mid-2004, atazanavir came out, and it has the benefit of not causing the same abnormalities," he says. "In fact, it may even have a little better cholesterol value—going in the direction you want."

Investigators wanted to find out if the difference was significant, so they analyzed 48 weeks of data from phase II clinical trials by the drug’s manufacturer and compared 2 PIs, combined with didanosine and stavudine as part of a highly active antiretroviral treatment (HAART). They pulled data about patients’ LDL and HDL values and used those values to model what a patient’s 10-year risk of coronary artery disease would be on each of those different therapies, Coleman explains.

"Some of these patients are much younger and will live for those 10 years, so the complications become very important," Coleman says.

Using the Framingham risk equation, they determined the risks of patients having coronary heart disease and found that on the atazanavir regimen patients would have significantly less risk, he says.

"We were able to show that you’re relative risk of having a coronary heart disease event like a myocardial infarction [MI] or dying from an MI would be lowered by one-third in patients who were taking atazanavir instead of nelfinavir," Coleman says.

Even for the patients who were diabetics, smokers, and already at higher risk, there was a significantly lower risk of coronary heart disease if they were taking atazanavir, he says.

"If the person was a smoker, a diabetic, and had hypertension, it was a 29 percent risk reduction," Coleman says.

While it would be useful to conduct a randomized control trial to confirm the answer the model suggests, it would be extremely expensive to undertake such research, and it’s unlikely pharmaceutical companies would sponsor such investigation, Coleman says.

"You would have to follow patients for a very long period of time, because coronary artery disease doesn’t kill immediately," Coleman says. "It takes many years for arteries to clog and cause an event and death, so you can’t just give people the drug and do a study and follow-up."

Since such a study would take 10-15 years to complete, the data derived from the study model might be the best available, Coleman says.

"The study point was to demonstrate to clinicians that the choice they make in terms of the PI they use may have repercussions 10 years down the line," Coleman says. "Choosing a PI with less lipid abnormalities and which has the least negative effects may reap benefits down the line."

Of course, there are limitations to the model’s predictions. For instance, the model assumes patients would receive the same PI throughout the 10-year period, either nelfinavir or atazanavir, he says.

"And there are all kinds of problems with resistance, so will people be on the same regimen for years?" Coleman says.

"And beyond the lipid impact, these drugs could cause changes in body fat, redistributing it in the chest, losing it other places, and getting big humps on their backs, so there’s a lot of concerns with these drugs," Coleman says.

Still, clinicians might consider atazanavir for patients who are at high risk of coronary heart disease, Coleman suggests.

"It’s certainly one factor to keep in mind when you’re prescribing," Coleman says. "Whether patients are treatment-naïve or treatment-experienced, what other risks and resistance they have, and there are a number of issues that go into choosing an agent, so this is one they can consider."

Reference

  1. Gillespie EL, White CM, Coleman CI. Do Different Protease Inhibitors Used for Human immunodeficiency virus have varying effects on coronary heart disease risk? Presented at the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy, Dec. 16-10, 2005, in Washington, DC. Abstract: H-348.