Dr. Longenecker is a cardiologist with a special interest in cardiovascular disease among people with HIV infection. Perhaps best known in the HIV community for his research on rosuvastatin in the SATURN-HIV trial, he works on more than a dozen research projects on cardiovascular disease and HIV infection in the United States and Uganda. Dr. Longenecker also conducts population-based research with an eye toward strengthening healthcare systems. With a medical degree from Ohio State University College of Medicine, he completed a residency in internal medicine at the University of California, San Francisco and a cardiology fellowship at Case Western Reserve University School of Medicine in Cleveland.
Mascolini: When should people with HIV be tested for dyslipidemia?
Longenecker: I think all patients with HIV need to be tested for dyslipidemia. Certainly HIV patients should be tested before starting antiretroviral therapy, then again after starting therapy because of the effects that some antiretrovirals can have. We know that uncontrolled HIV infection itself can cause lipid problems before starting ART. The chronic inflammation and immune activation that result from HIV infection can cause low HDL cholesterol and high triglycerides even before starting ART.1,2 So it's important to know those pretreatment levels and how they change with therapy. I would also add that the age and overall cardiovascular risk profile of a patient will determine when you start checking lipid panels: Older people with more cardiovascular risk will require more frequent monitoring.
Mascolini: For a 50-year-old without a lot of cardiovascular risk, once they start ART, how often would you recheck lipids?
Longenecker: You're going to get a sense of what antiretroviral therapy is doing to their lipids within the first 6 months or so. So it's reasonable to check within that time frame. For someone who's 50 years old, even without many cardiovascular risk factors, they may be close to having an indication for starting a statin. For someone who's on a statin, it's reasonable to check once initially 3 months after they start the statin then once a year thereafter. For someone who's younger, you won't have to check that often.
Lipid levels are determined primarily by the interaction of your genetics with your environment -- in other words, your diet and exercise plus medications including ART. One's genes obviously don't change, but if someone's diet and exercise pattern don't change, you wouldn't necessarily expect their lipid panel to change that much.
Practical Approaches to Diet and Exercise
Mascolini: What's the most important lipid-altering lifestyle change HIV clinicians should encourage?
Longenecker: This is a very important question. One of the cornerstones of lipid management in anybody is diet and lifestyle change. I think the most important thing is to emphasize moderation in diet and considering what we call the Mediterranean diet:3 lots of healthy plant oils, fish oils, plenty of dietary fiber, and less saturated fat and animal fat.
I think extreme diets are not particularly helpful for managing lipids. The best approach is moderation -- a dietary pattern that somebody can sustain over time -- rather than going on a rigid diet for a time then bouncing back to the opposite extreme. Also, we know that sugary drinks are bad for cardiovascular health and can potentially have an adverse effect on lipids. So that's one thing we can really target -- trying to reduce consumption of sugary drinks.
Combining exercise with a practical diet is also important. Exercise increases HDL cholesterol. Low HDL cholesterol is one of the hallmarks of HIV infection, and exercise can improve that. I really stress exercise with my patients. I think exercise will have much smaller effects on other lipids, but because of the exercise-induced cardiovascular risk reduction that goes beyond any effects on lipids, exercise is something that's very important to stress with our patients.
Mascolini: Have you had luck in getting your HIV patients to be more physically active? What seems to work for most people?
Longenecker: We deal with a challenging population here at University Hospitals in Cleveland. We're on the border with East Cleveland, so we have many patients of low socioeconomic status who live in "food deserts" where it's difficult to get healthy food. Sometimes it's difficult for them to exercise safely outside, and it's cold during the winter. So the HIV population here in Cleveland faces several healthy-lifestyle challenges.
Nevertheless, we work with people where they're at. And many of our patients can do beneficial exercises inside their apartments, such as strength training and yoga. Such exercise is not going to have much of an effect on their lipids, but it could be a good place to start. We also encourage incorporating exercise into their daily lives by walking, maybe parking farther out in the parking lot if they're going to the grocery store or walking up flights of stairs rather than taking the elevator.
We have a program here run by one of the nursing faculty called System Change that aims to help our HIV patients develop ways to change their environment so they make healthy choices more automatically and don't have to rely on motivation to make a healthy choice. An example would be putting sugary drinks in the back of the refrigerator, behind more healthy options like a bottle of water. Or putting a note in the stairwell of your office encouraging you to take the stairs rather than take the elevator. Our patients do little experiments with themselves and report back to the group to share what's worked for them.
One of the things I'd like to stress about the HIV community in HIV clinics around the country is the strong sense of camaraderie. People identify with other people who have HIV, and getting HIV-positive people together in groups is a good thing. In our clinics we've run exercise groups, walking groups, yoga groups, that sort of thing. These groups help people at least take the first step to develop a healthy lifestyle.
We also have a community garden behind the clinic. Because there are many "food deserts" here in Cleveland, our patients can grow vegetables in these gardens then harvest some of the vegetables to use in their cooking. That has been a healthy thing for the patients, but also a community-building exercise. The bonds created by these types of group activities are something our HIV clinics should aim to foster.
Impact of HCV, TDF-to-TAF Switch, and Switching ART
Mascolini: Several studies found better lipid profiles with HCV/HIV coinfection than with HIV alone.4-7 Do these findings affect how clinicians should manage lipids in coinfected people?
Longenecker: We know that HCV infection is typically associated with lower LDL cholesterol, which has to do with how HCV affects the liver. But it's important to recognize that patients with hepatitis C infection are at increased risk of atherosclerotic vascular events, and people with HCV/HIV coinfection may be at higher risk than people with HIV monoinfection.8,9 Because of this higher cardiovascular disease risk, I think it's important to have different lipid targets with HCV-infected patients. Often we would prescribe a statin for an HCV-infected person to reduce cardiovascular risk, even if the lipid profile is not as abnormal as it is for other patients.
A general principle of cardiovascular risk reduction is that you want to treat patients who are at higher absolute risk regardless of what their lipids are because we know that the relative risk reduction with statins is consistent across all lipid levels. It's just that patients with lower lipid levels tend to have lower risk, so the absolute statin benefit may be less.
Mascolini: Tenofovir disoproxil fumarate (TDF) has a beneficial effect on lipids not seen with tenofovir alafenamide (TAF).10,11 As people switch from TDF to TAF regimens, should clinicians watch lipids more closely after people start TAF?
Longenecker: This issue is on the margins of clinically relevant, because the lipid differences between TDF and TAF are subtle. In the end it's going to be relatively uncommon that switching somebody from TDF to TAF puts them at a risk level that makes you recommend a statin. Our patients' cardiovascular risk profile is driven by many factors -- including smoking, hypertension, diabetes, age, race, and gender -- that are unrelated to lipids. So a minor change in LDL cholesterol really is not going to be that clinically relevant overall.
In a patient with familial hypercholesterolemia or a very bad lipid profile to start, the switch to TAF may be clinically relevant, so you have to evaluate the impact of switching TDF to TAF on a case-by-case basis. But overall that switch will not matter.
Mascolini: If a patient has taken a suppressive but dyslipidemic antiretroviral regimen for years, should the clinician stick with that regimen and treat the abnormal lipids or consider switching to a newer regimen?
Longenecker: Great question and one that is discussed a lot. I think it depends entirely on the patient-provider discussion about this. We know that switching antiretroviral regimens is associated with a small but quantifiable risk of virologic failure. So if an antiretroviral regimen is working for somebody and you can easily treat their lipids with a statin or other drugs -- and they don't seem to be at particularly high risk and they're not difficult to treat -- then I think it's fine to continue the antiretrovirals.
In situations where, for example, a person with very difficult-to-treat hypertriglyceridemia is taking a lipogenic protease inhibitor, it may be reasonable to try switching to something else. But that discussion must be had between the provider and the patient, because often the patient will feel very strongly about what to do.
Mascolini: Is there a typical abnormal lipid profile in people with HIV?
Longenecker: One of the hallmarks of dyslipidemia in HIV is the phenomenon of low HDL with high triglycerides. We see this in other chronic inflammatory diseases and in metabolic diseases. In the metabolic syndrome, for example, two of the criteria are low HDL and high triglycerides. This is a very proatherogenic lipid profile. So regardless of what the LDL cholesterol is, if you have low HDL and high triglycerides, this will increase the amount of atherogenic lipid particles. For any given LDL cholesterol level, there will be more LDL particles that can cause disease.
It's nice to see that over the years, as antiretroviral therapy has improved and we've started treating people at higher CD4 counts, we've seen less of this low HDL/high triglyceride phenomenon. That is really encouraging and it makes lipid management a lot easier now than it was 15 years ago.
But occasionally I do see a patient with very high triglycerides and I think it's important to address factors besides just giving them lipid drugs -- the two most important factors being diabetes and alcohol use. Both diabetes and heavy drinking can make the triglycerides go way out of whack. If someone has high triglycerides it's very important to get them to quit drinking heavily, and if they have diabetes we should try to get their hemoglobin A1c better controlled. Then you can add a fibrate, fish oil, or niacin, but it's important to address the diabetes or drinking first.
Mastering the In's and Out's of Statin Use With HIV
Mascolini: Which HIV patients are candidates for statin therapy, and which might do better with a different antilipid agent?
Longenecker: I'll give you my take on this. There certainly is variation in practice around the country. Deciding which antilipid agent to use is something of an art because we don't have a lot of randomized trial data to tell us exactly what the lipid thresholds should be in HIV-infected patients.
With that said, I think there is much epidemiologic evidence that HIV is associated with a higher risk of atherosclerotic vascular events like myocardial infarction and stroke. And a recent study from the U.S. CNICS group12 suggests that the risk prediction tools we typically use, such as the Pooled Cohort Equation risk calculator from the ACC/AHA,13-15 are poorly calibrated in HIV. In other words these general-population tools underestimate absolute risk in our HIV patients.
With the 2013 guidelines, the ACC/AHA identified four statin benefit groups in the general population which I loosely apply to my HIV patients. The first group includes patients with atherosclerotic vascular disease who have had a prior MI or stroke. Those patients should all be on a high-intensity statin, so my patients with HIV with prior events are on a high-intensity statin, if they can tolerate it. The second benefit group includes those with an LDL cholesterol greater than 190 mg/dL. These patients, whether or not they have HIV, should be on a high-intensity statin.
The third group is patients with diabetes, and this is where the risk calculator comes in: Patients with diabetes who may be at lower risk, for example, patients in their younger 40s, may need only a moderate-intensity statin, whereas patients who are older and have a higher risk with diabetes should have a high-intensity statin (Table 1).
|Table 1. High-, Moderate- and Low-Intensity Statins for People With HIV*|
|High Intensity||Moderate Intensity||Low Intensity|
Atorvastatin 40-80 mg
Rosuvastatin 20-40 mg
Atorvastatin 10-20 mg
Pravastatin 40-80 mg
Rosuvastatin 5-10 mg
Pitavastatin 1 mg†
Pravastatin 10-20 mg
* Lists only statins routinely used in people with HIV infection.
† At doses of 2 to 4 mg, pitavastatin could be considered a moderate-intensity statin. See interview text.
Source: ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults.14
The fourth category is any other patient who has a calculated 10-year risk of atherosclerotic vascular events greater than 7.5%. Some people have advocated for a greater than 5% threshold. What that means practically in HIV infection -- considering the risk underestimation with these calculators -- is that I tend to use a lower statin threshold. So if someone has a calculated 10-year risk of 5%, I consider having the statin discussion with them. But I stress that the decision to start a statin must be based on discussion with the patient and individualized to the patient.
You probably know that the REPRIEVE trial of pitavastatin in people with HIV began with an entry criterion of less than a 7.5% 10-year cardiovascular disease risk.16 That was recently changed to less than a 10% 10-year risk. That's a little bit in conflict with my clinical practice because I might recommend a statin for patients in that 5% to 10% 10-year risk range. But if a patient in this range wants to participate in a randomized placebo-controlled trial like REPRIEVE, I would also encourage them to participate if they want to.
It will be several years before REPRIEVE determines the relative risk reduction for major cardiovascular events with a moderate-intensity statin in this relatively low-risk population. I look forward to the results of that trial.
Mascolini: How do you differentiate between high-intensity and moderate-intensity statins?
Longenecker: This distinction is not widely understood. The 2013 ACC/AHA guidelines recommend low-, moderate- and high-intensity statins (Table 1).14 What qualifies as a high-intensity statin? Atorvastatin at 40 to 80 mg daily, or rosuvastatin at 20 to 40 mg daily. Our patients with prior cardiovascular events should be on one of these drugs. But using them in patients with HIV is complicated by the fact that both atorvastatin and rosuvastatin have slight interactions with protease inhibitors and particularly with the boosters ritonavir and cobicistat. So in my clinical practice I tend to use atorvastatin a lot in doses up to 40 mg, and generally that is well tolerated by patients even if they are taking protease inhibitors.
I think it's important that we use these high-intensity statins in patients who are at high risk because the days of using pravastatin, which is a weak statin, for everybody simply to avoid drug interactions have resulted in many people getting undertreated for their risk.
Pitavastatin at doses of 2 to 4 mg lowers LDL cholesterol by approximately 40% to 45%. This puts it in the moderate-intensity statin group, so it might have an important role to play as a safe alternative with no ART drug interactions in patients who do not need a high-intensity statin.
Mascolini: A few population studies have found that statins are less effective in HIV populations than in comparison groups without HIV. Is this a reason for HIV clinicians to be cautious about prescribing statins for people with HIV?
Longenecker: I would challenge that general assumption. I am aware of a few studies that have shown this.17-19 I'm also aware of a number of other studies that suggest the same statin effect in people with and without HIV. For example in our SATURN-HIV study here in Cleveland we found expected reductions in LDL cholesterol with rosuvastatin at 10 mg daily.20 And Matt Feinstein, the first author of a systematic review in the American Journal of Cardiology, found evidence that the LDL response to statins is generally similar with and without HIV across all the studies that were identified.21 Although I do admit there were a few studies that suggest the statin response is different with HIV, in my clinical practice I have not found that to be a major problem.
Subclinical Disease Suggests Need for Statin
Mascolini: Your SATURN trial20 and a trial at Massachusetts General22 found subclinical cardiovascular benefits in HIV-positive people who started a statin with low LDL. But whether statins will prevent cardiovascular events in such people is still being assessed.16 Where do you stand on recommending statins for such patients?
Longenecker: In interpreting those two studies,20,22 you have to start with the understanding that the imaging modalities they used are not commonly ordered in clinical practice. Steve Grinspoon's study used CT angiography,22 and we rarely order a CT coronary angiogram in someone who is asymptomatic. Similarly, carotid IMT, which we used in the SATURN study,20 is not paid for by insurance and we don't really use it clinically to detect subclinical atherosclerosis in asymptomatic patients. It's uncommon to be evaluating a patient who is clinically asymptomatic yet has imaging studies to suggest they have a significant burden of subclinical atherosclerosis.
At University Hospitals Cleveland Medical Center we do have a robust coronary calcium scoring program and offer this test free of charge to qualified individuals with cardiovascular disease risk factors.23,24 In cohort studies in the general population, coronary artery calcium has some additive value for risk discrimination, for example, in terms of reclassifying someone who is at intermediate risk into low- or high-risk categories for the purposes of deciding on statin therapy.
If someone has a high coronary artery calcium score but low predicted risk by a risk equation, I do consider starting a statin in that patient. If someone does get a coronary angiogram for some reason and they have subclinical disease in their left anterior descending artery, which is arguably the most important coronary artery, then I do feel strongly about starting a statin in those patients to reduce their risk. Ultimately many patients who present with myocardial infarction did not have a high calculated risk before the MI. So if a patient has subclinical disease, I think it's appropriate to treat.
Common Mistakes and Coming Opportunities
Mascolini: What are the biggest mistakes clinicians make in managing dyslipidemia in people with HIV?
Longenecker: As I've already mentioned, a persisting problem is not using higher-dose statins for fears of safety concerns (Table 1). In our clinical practice here in Cleveland and at many other clinics around the country, HIV clinicians have been successfully using high-dose statins in recent years by being mindful of drug interactions and monitoring patients carefully. Encouraging clinicians to be a little less hesitant to use atorvastatin and rosuvastatin, which are now generic, is one of the most important things we can do.
All of the nonstatin treatments for dyslipidemia are less effective at reducing cardiovascular risk, except perhaps for the new class of drugs called PCSK9 inhibitors,25 which are wildly expensive and may be used only in selected patients with HIV. It's important to focus on getting patients on statins, which have the best track record of actual clinical benefits in the general population.
In patients who have high triglycerides as their primary lipid abnormality, it's reasonable to start a fibrate to try to get the triglycerides below 500 mg/dL before starting a statin. This is in addition to managing their diabetes and alcohol use, as already mentioned. But even in these patients, if their cardiovascular risk is high, they often merit statin treatment.
Mascolini: Are there any other issues concerning lipid management in people with HIV that you'd like to discuss?
Longenecker: The new PCSK9 inhibitors25 are an exciting development in lipid management, and I think they will have utility in certain HIV-infected patients. We do have some data from Priscilla Hsue's group at UCSF to suggest that HIV-infected patients have higher levels of PCSK9 in the blood.26 Those patients may benefit from PCSK9 inhibitors, which increase the amount of LDL receptors on the liver surface so the liver takes more LDL out of the blood and excretes it from the body. I think the unanswered questions are whether these drugs will have any adverse effects in the HIV population and whether they will be effective in reducing clinical events.
- Grunfeld C, Kotler DP, Hamadeh R, Tierney A, Wang J, Pierson RN. Hypertriglyceridemia in the acquired immunodeficiency syndrome. Am J Med. 1989;86:27-31.
- Grunfeld C, Pang M, Doerrler W, Shigenaga JK, Jensen P, Feingold KR. Lipids, lipoproteins, triglyceride clearance and cytokines in human immunodeficiency virus infection and the acquired immunodeficiency syndrome. J Clin Endocrinol Metab. 1992;74:1045-1052.
- Mayo Clinic. Nutrition and healthy eating. Mediterranean diet: a heart-healthy eating plan. 2016. www.mayoclinic.org/healthy-lifestyle/nutrition-and-healthy-eating/in-depth/mediterranean-diet/art-20047801
- Diong C, Raboud J, Li M, Cooper C; Ontario HIV Treatment Network Cohort Study Team. HIV/hepatitis C virus and HIV/hepatitis B virus coinfections protect against antiretroviral-related hyperlipidaemia. HIV Med. 2011;12:403-411.
- Bedimo R, Ghurani R, Nsuami M, et al. Lipid abnormalities in HIV/hepatitis C virus-coinfected patients. HIV Med. 2006;7:530-536.
- Collazos J, Mayo J, Ibarra S, Cazallas J. Hyperlipidemia in HIV-infected patients: the protective effect of hepatitis C virus co-infection. AIDS. 2003;17: 927-929.
- Polgreen PM, Fultz SL, Justice AC, et al. Association of hypocholesterolaemia with hepatitis C virus infection in HIV-infected people. HIV Med. 2004;5:144-150.
- Gillis J, Smieja M, Cescon A, et al. Risk of cardiovascular disease associated with HCV and HBV coinfection among antiretroviral-treated HIV-infected individuals. Antivir Ther. 2014;19:309-317.
- Bedimo R, Westfall AO, Mugavero M, Drechsler H, Khanna N, Saag M. Hepatitis C virus coinfection and the risk of cardiovascular disease among HIV-infected patients. HIV Med. 2010;11:462-468.
- Sax PE, Zolopa A, Brar I, et al. Tenofovir alafenamide vs. tenofovir disoproxil fumarate in single tablet regimens for initial HIV-1 therapy: a randomized phase 2 study. J Acquir Immune Defic Syndr. 2014;67:52-58. 11.
- rilpivirine and emtricitabine in virally suppressed adults with HIV-1 infection: a randomised, double-blind, multicentre, phase 3b, non-inferiority study. Lancet HIV. 2017;Mar 1;pii:S2352-3018(17)30031-0.
- Feinstein MJ, Nance RM, Drozd DR, et al. Assessing and refining myocardial infarction risk estimation among patients with human immunodeficiency virus: a study by the Centers for AIDS Research Network of Integrated Clinical Systems. JAMA Cardiol. 2017; 2:155-162.
- Goff DC, Lloyd-Jones DM, Bennett G, et al. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the assessment of cardiovascular risk. Circulation. 2013;01 cir.0000437741.48606.98. http://circ.ahajournals.org/content/129/25_suppl_2/S49.long
- Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(suppl 2):S1-S45. http://circ.ahajournals.org/content/129/25_suppl_2/S1.long
- ACC/AHA ASCVD Risk Calculator. www.cvriskcalculator.com
- ClinicalTrials.gov. Evaluating the use of pitavastatin to reduce the risk of cardiovascular disease in HIV-infected adults (REPRIEVE). Clinical Trial Identifier NCT02344290. www.clinicaltrials.gov/ct2/show/NCT02344290
- Silverberg MJ, Leyden W, Hurley L, et al. Response to newly prescribed lipid-lowering therapy in patients with and without HIV infection. Ann Intern Med. 2009;150:301-313.
- Townsend ML, Hollowell SB, Bhalodia J, Wilson KH, Kaye KS, Johnson MD. A comparison of the effectiveness of lipid-lowering therapy between HIV- and non-HIV-infected subjects with hyperlipidaemia. Int J STD AIDS. 2007;18:851-855.
- Johns KW, Bennett MT, Bondy GP. Are HIV positive patients resistant to statin therapy? Lipids Health Dis. 2007;24;6:27.
- Longenecker CT, Sattar A, Gilkeson R, McComsey GA. Rosuvastatin slows progression of subclinical atherosclerosis in patients with treated HIV infection. AIDS. 2016;30:2195-2203.
- Feinstein MJ, Achenbach CJ, Stone NJ, Lloyd-Jones DM. A systematic review of the usefulness of statin therapy in HIV-infected patients. Am J Cardiol. 2015;115:1760-1766.
- 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.
- RadiologyInfo.org. Cardiac CT for calcium scoring. www.radiologyinfo.org/en/info.cfm?pg=ct_calscoring
- Metkus TS, Brown T, Budoff M, et al. HIV infection is associated with an increased prevalence of coronary noncalcified plaque among participants with a coronary artery calcium score of zero: Multicenter AIDS Cohort Study (MACS). HIV Med. 2015;16:635-639.
- Everett BM, Smith RJ, Hiatt WR. Reducing LDL with PCSK9 inhibitors -- the clinical benefit of lipid drugs. N Engl J Med. 2015;373: 1588-1591. www.nejm.org/doi/full/10.1056/NEJMp1508120#t=article
- Kohli P, Ganz P, Ma Y, et al. HIV and hepatitis C-coinfected patients have lower low-density lipoprotein cholesterol despite higher proprotein convertase subtilisin kexin 9 (PCSK9): an apparent "PCSK9-lipid paradox." J Am Heart Assoc. 2016;5:pii:e002683.