Statin Therapy Reduces Heart Artery Plaque Size and Number in People With HIV

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.

How the Study Worked

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.

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.

What the Study Found

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.

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.

What the Results Mean for You

This well-planned trial produced strong evidence that 1 year of statin therapy can have a positive impact on coronary artery plaques and cholesterol in people with HIV. Plaque build-up and rising cholesterol can both lead to serious heart disease. Plaques shrank in two thirds of people taking atorvastatin for 1 year compared with only 1 in 5 people taking placebo, an inert pill made to look like atorvastatin. The results are strong because of the study design -- having a comparison group taking placebo and not telling participants or providers who got atorvastatin and who got placebo.

The study did not find that atorvastatin lowered coronary artery inflammation measured by FDG-PET scans. But the researchers could measure inflammation changes in the same region of the aorta in only 21 people in this study. In contrast, they could measure plaque with coronary CT angiography in all 37 people who completed the study. Lp-PLA, a signal of blood vessel inflammation, did decrease significantly after 1 year of atorvastatin therapy.

Why are these findings important? Several studies show that people with HIV have higher rates of serious cardiovascular disease than people without HIV. Comparing almost 4000 HIV-positive people with 1 million HIV-negative people, the same Boston researchers who conducted the atorvastatin study found that HIV-positive men had a 40% higher heart attack rate than HIV-negative men, while HIV-positive women had a 3 times higher rate than HIV-negative women.⁹ A nationwide French study found remarkably similar results when comparing heart attack risk in people with and without HIV.¹⁰ Combined analysis of results from 20 individual studies figured that antiretroviral-treated people with HIV had a twice higher risk of cardiovascular disease than people in the general population.¹¹

The atorvastatin study suggests that statins could be one way to lower the risk of cardiovascular disease in people with HIV. Although participants had healthy LDL cholesterol levels when they entered this trial, they had atherosclerosis (plaque build-up) that had not started causing symptoms yet. Symptom-free atherosclerosis is not rare in people with HIV -- more than half of the middle-aged HIV-positive adults screened for this trial had hidden atherosclerosis. Earlier study by the same researchers2 and by a British group¹² also found high rates of hidden atherosclerosis in people with HIV.

US Health Resources and Services Administration 2014 guidelines for HIV care recommend statins as first-line therapy for HIV-positive people with (1) high LDL cholesterol alone or (2) high LDL cholesterol plus triglycerides between 200 and 500 mg/dL.¹³ Current general-population guidelines recommend statins for people over 20 years old with an LDL cholesterol at or above 190 mg/dL.

Researchers who ran this study cautioned that their findings do not prove that statins will prevent coronary heart disease, only that they have a positive impact on plaques and cholesterol. Larger, longer studies, they say, are needed to determine whether those positive effects translate into lower heart disease rates in people with HIV. But the Boston team believes evidence that atherosclerosis gets worse faster in people with HIV "suggests the need for more aggressive treatment with statins" in HIV-positive people.

Your HIV provider can explain whether statin therapy is right for you based on your cholesterol and triglyceride levels, your potential for responding to diet and exercise therapy, and the antiretrovirals you are taking. The next article in this issue of HIV Treatment Alerts describes a study that found improvements in hip bone density after 48 weeks of treatment with another statin, rosuvastatin.¹⁴

References

1. Lo J, Lu MT, Ihenachor EJ, et al. Effects of statin therapy on coronary artery plaque volume and high-risk plaque morphology in HIV-infected patients with subclinical atherosclerosis: a randomised, double-blind, placebo-controlled trial. Lancet HIV. 2015;2:e52-e63.

2. Lo J, Abbara S, Shturman L, et al. Increased prevalence of subclinical coronary atherosclerosis detected by coronary computed tomography angiography in HIV-infected men. AIDS. 2010;24:243-253.

3. Post WS, Budoff M, Kingsley L, et al. Associations between HIV infection and subclinical coronary atherosclerosis. Ann Intern Med. 2014;160:458-467.

4. Fitch KV, Srinivasa S, Abbara S, et al. Noncalcified coronary atherosclerotic plaque and immune activation in HIV-infected women. J Infect Dis. 2013;208:1737-1746.

5. Mihaylova B, Emberson J, Blackwell L, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012;380:581-590.

6. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383-1389.

7. Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA. 2006;295:1556-1565.

8. Nicholls SJ, Ballantyne CM, Barter PJ, et al. Effect of two intensive statin regimens on progression of coronary disease. N Engl J Med. 2011;365:2078-2087.

9. Triant VA, Lee H, Hadigan C, Grinspoon SK. Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease. J Clin Endocrinol Metab. 2007;92:2506-2512.

10. Lang S, Mary-Krause M, Cotte L, et al. Increased risk of myocardial infarction in HIV-infected patients in France, relative to the general population. AIDS. 2010;24:1228-1230.

11. Islam FM, Wu J, Jansson J, Wilson DP. Relative risk of cardiovascular disease among people living with HIV: a systematic review and meta-analysis. HIV Med. 2012;13:453-468.

12. Post WS, Budoff M, Kingsley L, et al. Associations between HIV infection and subclinical coronary atherosclerosis. Ann Intern Med. 2014;160:458-467.

13. US Department of Health and Human Services Health Resources and Services Administration. Guide for HIV/AIDS Clinical Care. April 2014.

14. Erlandson KM, Jiang Y, Debanne SM, McComsey GA. Effects of randomized rosuvastatin compared with placebo on bone and body composition among HIV-infected adults. AIDS. 2015;29:175-182.