Treatment with atorvastatin, a drug aimed at lowering cholesterol, reduced coronary artery plaque volume and number in HIV-positive people who took it for 1 year.1 Plaques are built-up fat and cholesterol deposits in arteries (Figure 1) that can eventually block the artery and cause myocardial infarction (heart attack). This is the first study comparing a statin to placebo (a dummy pill) that shows statin therapy can control plaque in people with HIV.
Heart disease, including coronary artery disease, has become a major cause of sickness and death in people with HIV infection. Recent studies show a higher rate of hidden atherosclerosis (plaque build-up) and potentially dangerous noncalcified plaque in people with HIV than in HIV-negative people.2-4 Finding ways to prevent and control coronary artery disease has become a priority in people with HIV.
In the general population, statins proved effective in lowering rates of cardiovascular disease5 and death. Research also shows that statins can slow or reverse coronary artery atherosclerosis.6-8 In studies of people with HIV infection, statins lowered cholesterol and triglyceride levels and reduced signals of inflammation. But no studies in HIV-positive people directly compared a statin with placebo to assess the impact of statins on coronary artery inflammation or plaque. Researchers in Boston conducted this study to address those questions.
The research team recruited HIV-positive men and women between 18 and 60 years old who were not taking a statin and did not meet US guidelines for starting a statin. No one ever had cardiovascular disease, and no one had cardiovascular disease symptoms. All study participants did have evidence of symptom-free coronary artery atherosclerosis on coronary CT angiography, a type of scan. FDG-PET, another type of scan, indicated artery inflammation in all study participants.
Everyone had a low-density lipoprotein ("bad") cholesterol level between 70 and 130 mg/dL (1.81 and 3.37 mmol/L), which are healthy levels. Everyone was taking antiretroviral therapy, and no one had changed antiretrovirals in the past 6 months.
The researchers randomly assigned 40 study participants to start atorvastatin or placebo (a dummy pill). No study participants or researchers knew which people were getting atorvastatin and which were getting placebo. This type of trial -- a randomized, double-blind, placebo-controlled trial -- is the strongest trial design for determining the impact of a treatment like statin therapy. People assigned to take atorvastatin started at a dose of 20 mg daily then increased the dose to 40 mg daily if they tolerated the drug well for the first 3 months. Participants took atorvastatin or placebo for 1 year.
All study participants had an FDG-PET scan when the study began and after 1 year of atorvastatin or placebo to measure changes in inflammation of the aorta, the main artery coming out of the heart (Figure 1). Participants also had coronary CT angiography to assess changes in coronary artery plaque volume, number, and features. The researchers determined whether coronary artery plaques were calcified or noncalcified, because noncalcified plaques have a higher risk of rupture. They also determined whether plaques had other established high-risk features.
Figure 1. Treatment of HIV-positive people with a statin for 1 year had no measurable impact on inflammation of the aorta (left). But statin therapy did reduce coronary artery plaque volume and number (right). (Illustrations from Servier PowerPoint image bank.)
Changes in inflammation and plaque volume, number, and features were the main goals of the trial. The researchers used standard statistical methods to determine whether any of these changes differed significantly after 1 year in people taking atorvastatin compared with those taking placebo.
The study ran from November 2009 to January 2014 at a single center in Boston. Researchers randomly assigned 21 people to take placebo and 19 to take atorvastatin. Thirty-two study participants (80%) were men, 26 (65%) were white, and 6 (15%) were black. Study participants averaged 51 years in age. They had an average CD4 count around 550, and everyone had an undetectable viral load or a very low viral load. The atorvastatin group and the placebo group were similar in age, gender, race, CD4 count, viral load, and other study-entry measures like cholesterol, hypertension, and signals of inflammation. The atorvastatin group and the placebo group did not differ in coronary artery inflammation or plaque volume; they did not differ in plaque danger signals.
During the study period, only two people dropped out of the atorvastatin group and one dropped out of the placebo group.
After 1 year of atorvastatin or placebo, average change in inflammation of the aorta measured by FDG-PET did not differ substantially between groups. Neither did average change in inflammation of the most diseased segment of the aorta. However, Lp-PLA, a marker of blood vessel inflammation, decreased significantly more after 1 year of atorvastatin than after 1 year of placebo.
Coronary CT angiography scans showed that average coronary plaque volume decreased in the atorvastatin group while increasing in the placebo group (Figure 2). This difference was statistically significant, meaning the difference cannot be explained by chance. Volume of dangerous noncalcified plaques decreased in the atorvastatin group while increasing in the placebo group, also a significant difference (Figure 2). The average number of two types of dangerous plaques (low-attenuation plaques and positively remodeled plaques) dropped among people taking atorvastatin while rising among those taking placebo (Figure 2), and these differences were also statistically significant.
Figure 2. A trial that randomly assigned HIV-positive people to a statin or placebo (a dummy pill) for 1 year found that the statin decreased total plaque volume in heart arteries and dangerous noncalcified plaque volume, while those volumes rose in people taking placebo. After 1 year people taking the statin had lower average numbers of low-attenuation plaques and positively remodeled plaques in heart arteries, while people taking placebo had higher numbers of those plaques.
Total plaque volume declined in 11 of 17 people taking atorvastatin for 1 year versus 4 of 20 taking placebo (65% versus 20%). Total plaque volume increased in 6 of 17 people taking atorvastatin and 16 of 20 taking placebo (35% versus 80%). These differences were statistically significant. Coronary arteries narrowed in a clinically meaningful way in 3 people taking placebo and none taking atorvastatin.
Total cholesterol and "bad" LDL cholesterol decreased significantly in people taking atorvastatin for 1 year while increasing slightly among people taking placebo. During the 1-year study period, changes in CD4 count, viral load, body mass index, or belly fat did not differ significantly between the atorvastatin group and the placebo group.
No study participants had treatment-related problems that forced them to drop out of the trial. Two people taking atorvastatin and 1 taking placebo had a serious adverse event during the study. Six people taking atorvastatin and 5 taking placebo had myalgia (muscle pain, a well-recognized statin side effect) during the study. One person in the atorvastatin group switched to a lower dose of atorvastatin because of myalgia, and 1 person in the placebo group switched to a lower dose because of a liver function test abnormality; both people completed the study. Atorvastatin did not cause blood sugar abnormalities in this study.
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