NIH Launches REPRIEVE, First Large-Scale Cardiac HIV Prevention Study

Over the past few years, studies have show that people with HIV are 50 to 100 percent more likely to develop cardiovascular disease, including myocardial infarctions and strokes. Now, the National Institutes of Health are launching REPRIEVE, a Randomized Trial to Prevent Vascular Events in HIV. This is a large study of HIV patients who don't have heart disease, but are at risk for it. Researchers hope to find a link between statin drugs and the reduction of heart-related disease in HIV.

"What's interesting is that the traditional factors like smoking, diabetes, hypertension, lipid dyslipidemia, elevated cholesterol and glucose contribute to cardiovascular disease, but don't account for the whole risk, only about 25 percent of the risk," said co-principal investigator of the REPRIEVE trial, Dr. Steven Grinspoon, Professor of Medicine at Harvard Medical School.

The problem, he said, is that HIV patients have a very high risk of heart attack and stroke. The NIH is attempting to come up with a strategy to prevent it in this group, before it happens.

"The logic is that once you have heart disease, the horse is out of the barn," said Grinspoon. "The key thing about REPRIEVE is that we take HIV patients who don't have heart disease but are at risk epidemiologically, and randomize them to statins. This includes people with any viral load who are on ARTs, who don't have known heart disease or such an elevated risk that they should go on the drug; those who are low- to moderate-risk. We think it may be useful because the statin drugs not only lower radical cholesterol, but are anti-inflammatory and reduce immune activation, which we think is contributing to heart disease."

Heart disease operates on a spectrum; you can have some element of heart disease that is subclinical. It has no symptoms, but is brewing under the surface, and the patient will not have the clinically identifiable disease. This study hopes to nip this in the bud.

"We would like to raise awareness that heart disease has increased among HIV patients, and that the NIH is funding the first large-scale trial to try and prevent heart disease," said Grinspoon.

The primary end point is studying MACE: Major Adverse Cardiovascular Events, meaning heart attack, stroke and angina. Grinspoon hypothesizes that patients on statins will have 30 percent fewer of these events than the non-statins placebo group.

Statins are used by 25 million -- or one in 12 people in the U.S. -- to lower cholesterol levels, while also decreasing inflammation in the heart's arteries. The 2013 U.S. Guidelines recommend statins for people who have known heart disease, very high cholesterol, diabetes, and/or many traditional risk factors for heart-related disease.

Statin therapy may also be well-suited to lower the risk of heart-related disease in HIV; statins lower traditional heart disease risk factors (high cholesterol) but also decrease HIV-associated inflammation.�Statins also decrease the amount of plaque in the heart's arteries among people living with HIV.

They are looking for 6,500 patients, and have already screened 900 and have 500 confirmed. They also need to establish 100 sites, and have 65 now. Those eligible are HIV-positive individuals between 40 and 75 years old, who have been on ART for at least six months before entering the study. They should have no history of cardiovascular disease and be at low risk to develop it, and should not be currently using a statin drug.

Grinspooon explains that it's a simple study: patients will come in three times a year, share their history and get pills -- either pitavastatin or a placebo -- to take once a day. They'll also give a little blood once a year during a quick visit to a doctor, who will screen for heart disease.

"This is a new statin that has no interaction with ARVs at all, which is very important," said Grinspoon. "Taking one extra pill a day has been very well-tolerated so far. It doesn't aggravate their glucose or anything."

He also hypothesizes that some patients might be helped with kidney function or liver disease, because of statin's anti-inflammatory effect. They will also be collecting info on those, in an 800-person sub-study within the main study. This group will get a coronary angiogram at the beginning and again at the two-year mark, as well as detailed inflammatory markers. They'll be followed for three to six years, but on average about four years.

"This sub-study group will get CAT scans of the arteries of their heart. We'll collect more blood, and use more sophisticated markers of immune activation," said Grinspoon. "We'll also look at the coronary arteries, see if the plaque situation has improved over time. Patients like this a lot. It is not really risky, because it's not a tube in their artery, it's just a virtual angiogram done mostly at the AIDS clinical sub-trial site."

What the REPRIEVE study is looking for is negative adverse affects: any affect on muscle function, because sometimes statins give muscle aches. They'll also look for elevations in liver enzymes, and make sure there is no elevated blood sugar, because some statins can slightly increase your blood glucose. They will also try to make sure patients' liver, muscle and glucose remain good.

Even those in the placebo group can benefit, because they will get lifestyle recognition and risk calculations at the beginning of the trial. Their risk will be assessed by the AHA's 2013 Risk Calculator; you enter the patient's age, cholesterol, hypertension, smoking, diabetes, and come up with your heart attack risk for the next 10 years.

For the study, they'll only accept those patients who are at a less than 10 percent risk, unless they have very good cholesterol levels. Grinspoon said some diabetic patients could even get in, if they had very low cholesterol.

In terms of compensation, those in the main study will get $25 per screening, and at each visit. Those in the sub-study will receive some additional compensation. REPRIEVE is seeking both men and women across the U.S., Thailand, Brazil, Canada and 80 U.S. domestic sites.

"We hope to show that statins are effective to prevent heart disease and are safe to use in the HIV-positive population," said Grinspoon. "If that's the case, I think it will become the standard of care to recommend statins to people who are not traditionally at risk for heart disease, but who could improve their standard of life by giving them statins early."

The REPRIEVE Trial is primarily funded by the NIH Heart Lung and Blood Institute (NHLBI) and supported by the NIH Division of AIDS (DAIDS), utilizing the ACTG and other trial networks.

To learn more about the REPRIEVE trial and how to sign up, visit www.reprievetrial.org or www.clinicaltrials.gov