Pointers on Cardiovascular Disease Risk, Screening and Management in Patients With HIV

Dr. Stein is the Robert Turell Professor in Cardiovascular Research in the Department of Medicine, Division of Cardiovascular Medicine at the University of Wisconsin School of Medicine and Public Health in Madison, Wisconsin. He is Director of the Preventive Cardiology Program, Director of the Vascular Health Screening Program, and Associate Director of Adult Echocardiography at the University of Wisconsin Hospital and Clinics. Dr. Stein is heavily involved in research on cardiovascular disease in people with HIV infection.

Heart Risk Attributable to HIV and Antiretrovirals

Mascolini: Many people with HIV carry a high burden of classic cardiovascular risk factors. How much do HIV infection and antiretrovirals add to that risk?

Stein: The impact of traditional cardiovascular disease risk factors -- smoking, abnormal lipids, diabetes -- outweighs the impact of HIV infection itself and antiretroviral therapy. In people with HIV and a low overall risk of cardiovascular disease, HIV and antiretrovirals will not greatly increase their risk of heart disease. In HIV-positive people at moderate or higher risk, the excess risk associated with HIV and antiretrovirals can put them over the edge for having a heart attack or developing heart disease.

Data indicating that there's an increased risk of cardiovascular disease with HIV infection have only recently been appreciated. The kind of research studies that we do in the HIV community aren't really optimally designed to determine how much excess cardiovascular disease risk HIV infection confers.

In the HIV community we do a great job conducting antiretroviral studies and looking at how effective a new drug is in treating HIV. We also do a good job assessing the complications of antiretroviral therapy. But because cardiovascular disease takes decades to develop and manifest itself, the HIV community is only now starting to appreciate that risk and starting to study it in a really robust way.

Most of these studies suggest that the excess cardiovascular risk with HIV infection is about 50%.¹⁻⁴

Although 50% sounds high, it's a relative risk. If you're at low risk -- let's say your MI risk over the next decade is 2% -- and your risk goes up 50% to 3% over a decade, that's a pretty small increase. But if your 10-year risk is 20% or higher because you smoke and have high cholesterol, then that 50% increase with HIV raises your risk to 30% or more. At that point that excess risk with HIV becomes very important.

Mascolini: What about specific antiretrovirals? Should clinicians shy away from lopinavir or abacavir, for example, in people with an already high cardiovascular risk?

Stein: I don't think so. Taking care of patients with HIV infection is very complicated. But one principle overrides everything -- getting optimal viral suppression. And getting optimal control of HIV is the most important predictor of long-term survival. So as a cardiologist I would never tell an HIV treater or a patient with HIV infection that they can't start an antiretroviral because it raises their heart disease risk so much that it will overshadow the risk of uncontrolled HIV infection. There's no drug for treating HIV that I think is prohibitive from the standpoint of heart disease.

Having said that, I will add that there are certain protease inhibitors (ritonavir-boosted lopinavir and perhaps indinavir) and certain nucleoside reverse transcriptase inhibitors (abacavir and perhaps didanosine) that have been associated with heart disease. If everything is equal and the same amount of viral suppression can be obtained using a different agent, I would recommend staying away from those agents. But again the most important thing is to suppress the virus.

We and others have shown that obtaining adequate viral suppression is good for endothelial function -- it improves the ability of blood vessels to relax.⁵˒⁶ When you look at the overall data for cardiovascular disease risk in people with HIV, some data suggest that uncontrolled viremia or inadequate treatment of HIV increases cardiovascular risk.⁷⁻⁹ Start with controlling the virus; then we can address cardiovascular disease risk factors.

Cardiovascular Risk Screening in Adults and Children

Mascolini: Should everyone with HIV be screened regularly for cardiovascular disease?

Stein: All patients with HIV should be regularly screened for modifiable risk factors for cardiovascular disease, specifically smoking, high blood pressure, high cholesterol, diabetes mellitus, and poor lifestyle choices. In addition to smoking, those poor choices include not getting enough exercise and eating a diet of low nutritional quality. I don't think the next step of screening people with imaging tests usually is indicated. I don't think HIV-positive people routinely need stress tests or calcium scans or carotid ultrasounds. There are very specific indications for those tests.

Mascolini: Unlike US experts, the European AIDS Clinical Society (EACS) does recommend an annual ECG for people with HIV.¹⁰ What do you think about that?

Stein: We don't recommend screening electrocardiograms in the United States, mainly because they're not very sensitive in picking up disease. And whenever you screen people there's a chance that you'll falsely mislabel someone as having disease. So we try not to screen people with an ECG unless there's a reason. If a patient is having symptoms that are suggestive of heart disease -- shortness of breath or chest discomfort -- doing a 12-lead electrocardiogram would absolutely be indicated. But for someone who doesn't have any symptoms, doing a 12-lead ECG doesn't really have any benefits and has the potential for some harm.

Mascolini: Should HIV-positive children and adolescents be screened?

Stein: First a caveat: I don't treat children and teens because I'm an adult cardiologist. I do recommend that kids with HIV be screened for cardiovascular disease risk factors. Although there's even less data in children with HIV than in adults, it looks like traditional risk factors -- along with uncontrolled HIV -- do predict most of the blood vessel dysfunction seen in kids with HIV. I think controlling the virus is critical in children, then making sure they live a healthy lifestyle.

I would default to the general population recommendations for screening of blood pressure, cholesterol, and blood sugar. For kids probably the more important points are making sure they don't start smoking and making sure they get adequate exercise and eat a healthy diet. Although HIV infection seems to cause vascular damage, I don't think having HIV accelerates blood vessel damage so quickly that we need to treat a 12-year-old as if that child is 40.

Interpreting the Framingham Score in HIV Patients

Mascolini: Some research suggests the Framingham equation lacks sensitivity in predicting cardiovascular disease in HIV-positive people.¹¹˒¹² Should HIV clinicians use it or take a modified approach?

Stein: The Framingham risk score does a very good job at what it's meant to do, which is predicting 10-year risk of cardiovascular disease in otherwise healthy, predominantly white, young and middle-aged patients.¹ It's a little less accurate with certain ethnic minorities, and a European group has found that it's less accurate in patients with HIV.¹¹˒¹² But it's hard to know what to do with that information because the Framingham risk score is less accurate when used in Europeans because their lifestyle and genetic make-up are different from people in America.

What I say to patients and physicians is that the Framingham score is a good starting place for discussion and it tells you what's going to happen over 10 years. But it's not very precise and it doesn't tell you what's going to happen over your lifetime. We're developing lifetime cardiovascular risk calculators that I think will be more useful for clinicians, and we hope to see them within the next year. Updated lipid guidelines should also be coming out soon.

For now, clinicians should not hang their hat too much on any one number. If the MI risk over the next 10 years is 5%, that's a starting point for discussion. But then ask yourself what it is about the patient that might put them at higher or lower risk. With HIV, for example, that 5% risk over 10 years may be more like 7% or 8%. If a patient smokes 3 packs a day, the risk is probably higher than the Framingham score suggests because the score just counts a person as a smoker or a nonsmoker. On the other hand a patient may have a very healthy lifestyle -- may be lean and exercise regularly and have no one in the family with any heart problems. That profile moves a patient a little bit lower on the risk scale.

The Framingham score should be thought of as a starting point for discussion with recognition that there's error in it and that it's not perfect in people with HIV. It's also not perfect when you move away from the typical young or middle-aged white adult in the United States. For minorities and people of European, Asian, or South American descent, it becomes less accurate.

Lipid Targets: How Low Should You Go?

Mascolini: How aggressive should HIV clinicians be in pharmacologic management of abnormal lipids?

Stein: Let me start with what we know. We know that dyslipidemia predicts cardiovascular disease in patients with HIV. And we know that certain antiretroviral therapies and certain lifestyle habits add to that risk. Treating dyslipidemia in HIV patients is complicated because of the drug interactions between statins and antiretrovirals. Newer antiretroviral agents have less dyslipidemic effects, and some of these newer antiretrovirals have fewer drug interactions -- and that could make prescribing easier.

The question is how low you should go with lipid targets, and I think the answer depends on the patient's baseline cardiovascular disease risk. Patients with higher risk -- people who already have coronary disease, people with multiple risk factors -- need to be treated more aggressively. People who are younger and have a lower risk factor burden can be treated less aggressively.

I think clinicians treating people with HIV can default to the regular US guidelines for treating dyslipidemia¹⁴ but be a little bit more aggressive because of that excess risk with HIV infection. With someone at high risk, you're already going to treat them more aggressively, aiming at an LDL cholesterol below 100 mg/dL or even 70 mg/dL if they already have coronary disease. A patient who is solidly at low risk is still at low risk with HIV. It's those people in the middle -- those intermediate-risk patients -- where I'm inclined to be a little bit more aggressive, simply because they have HIV and that increases the risk by about 50%. That may put them over the threshold for treating them more aggressively.

Caution With Aspirin and Counsel on Smoking

Mascolini: Should HIV clinicians consider primary prevention with aspirin?

Stein: Again I would default to the regular recommendations for people without HIV infection [see box].¹⁵ Aspirin is not a benign drug. It can prevent heart attacks, especially in men. It seems to prevent more strokes in women than heart attacks. If your patient already has cardiovascular disease, aspirin is already indicated. And if your patient has diabetes mellitus, aspirin is probably indicated.

For everyone else you really have to look at the balance of bleeding and cardiovascular disease prevention. I think defaulting to the usual guidelines is the way to go -- use the Framingham risk score and look at the age and sex of your patient to determine if aspirin is needed. GI bleeding is a real problem. The rare but more feared complication is intracranial bleeding. We can't just give patients aspirin and think it's a completely benign drug.

Mascolini: Everyone knows smoking has a huge impact on cardiovascular risk, but physicians often throw up their hands in despair when you suggest they get their patients to quit. How do you recommend HIV clinicians approach this challenge?

Stein: The first way they approach the challenge is by doing an attitude adjustment. If the clinician doesn't think it's going to work, the patient will pick up on that. Then you go through this empty ritual of telling the patient to quit smoking when you don't think it's going to work and they don't think it's going to work. And when they leave the office and fail to quit you have a self-fulfilling but very dysfunctional prophesy.

Cigarette smoking is the single most powerful modifiable risk factor for cardiovascular disease. It's incontrovertible. We're fortunate enough to live in an era in which we have multiple options for help with smoking cessation, ranging from counseling and lifestyle intervention through dual pharmacologic therapy. I'm not going to say it's easy to quit smoking. It's not easy for patients; it's not easy for clinicians working with patients. But for all our worry over nutritional supplements and LDL targets and baseline ECG screening, the single most important thing would be to help people quit smoking.

I recommend that clinicians approach smoking cessation with a positive attitude and realize that it takes the average patient six or seven quit attempts before they're successful. Clinicians have to work with patients to develop a strategy for quitting based on how addicted to cigarettes they are, previous experiences with quit attempts, and concurrent medications, because polypharmacy is an issue for people with HIV.

In our research in people without HIV we have found that dual nicotine replacement therapy with a nicotine patch supplemented with a lozenge is the most effective strategy.¹⁶ But of course it has to be personalized. If someone has failed nicotine replacement therapy they could use bupropion (Wellbutrin, Zyban) or they could use varenicline (Chantix). But there's some art in dealing with the drug interactions.

If a physician doesn't have the time or interest in working with patients on smoking cessation, they should refer patients to a preventive cardiology clinic, or to a smoking cessation clinic, or to a clinical trial that will enroll people with HIV infection.

I think that smoking cessation in people with HIV is an untapped research need. I would much rather see some research money invested in helping people with HIV quit smoking than in worrying more about LDL cholesterol targets. That's how important it is.

References

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2. 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.

3. Obel N, Thomsen HF, Kronborg G, et al. Ischemic heart disease in HIV-infected and HIV-uninfected individuals: a population-based cohort study. Clin Infect Dis. 2007;44:1625-1631.

4. Freiberg MS, Chang CC, Kuller LH, et al. HIV infection and the risk of acute myocardial infarction. JAMA Intern Med. 2013;173:614-622.

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6. Arildsen H, Sørensen KE, Ingerslev JM, østergaard LJ, Laursen AL. Endothelial dysfunction, increased inflammation, and activated coagulation in HIV-infected patients improve after initiation of highly active antiretroviral therapy. HIV Med. 2013;14:1-9.

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8. Triant VA, Regan S, Lee H, Sax PE, Meigs JB, Grinspoon SK. Association of immunologic and virologic factors with myocardial infarction rates in a US healthcare system. J Acquir Immune Defic Syndr. 2010;55:615-619.

9. Marin B, Thiébaut R, Bucher HC, et al. Non-AIDS-defining deaths and immunodeficiency in the era of combination antiretroviral therapy. AIDS. 2009;23:1743-1753.

10. Lundgren JD, Battegay M, Behrens G, et al. European AIDS Clinical Society (EACS) guidelines on the prevention and management of metabolic diseases in HIV. HIV Med. 2008;9:72-81.

11. Law MG, Friis-Møller N, El-Sadr WM, et al. The use of the Framingham equation to predict myocardial infarctions in HIV-infected patients: comparison with observed events in the D:A:D Study. HIV Med. 2006;7:218-230.

12. Friis-Møller N, Thiébaut R, Reiss P, et al; for the DAD study group: Predicting the risk of cardiovascular disease in HIV-infected patients: the Data Collection on Adverse Effects of Anti-HIV Drugs Study. Eur J Cardiovasc Prev Rehabil. 2010;17:491-501.

13. Framingham Heart Study. Hard coronary heart disease (10-year risk). www.framinghamheartstudy.org/risk/hrdcoronary.html and http://hp2010.nhlbihin.net/atpiii/calculator.asp

14. National Heart, Lung, and Blood Institute. Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). 2004.

15. U.S. Preventive Services Task Force. Aspirin for the Prevention of Cardiovascular Disease. March 2009.

16. Piper ME, Smith SS, Schlam TR, et al. A randomized placebo-controlled clinical trial of 5 smoking cessation pharmacotherapies. Arch Gen Psychiatry. 2009;66:1253-1162.