CVD prevention, treatment challenging as patients with HIV, HCV live longer

Due to successful treatment options, people with HIV and hepatitis C virus are living longer than before. However, these patients are at greater risk for various forms of heart disease than the general population.

An emerging field of research is focusing on how to prevent and treat heart disease in these patients.

“They’ll face many of the problems of heart failure and heart attacks that they wouldn’t have faced 20 years ago when they were dying from HIV and hepatitis C,” Carl Fichtenbaum, MD, associate chairman of medicine for translational research and professor of clinical medicine at the University of Cincinnati Medical Center, told Infectious Disease News.

What is known: Patients with HIV and HCV share many of the same risk factors as the general population, but have additional risk factors unique to their conditions. However, what is not known are the mechanisms underlying how patients with HIV and HCV acquire cardiovascular disease (CVD) at an early age and optimal prevention and treatment strategies.

“We don’t really quite understand the full pathogenesis — what’s happening in the immune system; what pathways are getting triggered. But what we do see is that there’s an increased amount of noncalcified plaque in the lining of the blood vessels so that people are developing the typical atherosclerosis but at an accelerated rate,” Judith A. Aberg, MD, chief of the infectious diseases division at Mount Sinai Hospital in New York, said in an interview.

There are few data from epidemiological studies in this population, except related to death and myocardial infarction (MI). Recent research established that many patients with HIV and HCV are at elevated risk for MI, heart failure (HF), metabolic syndrome and other cardiac conditions. The next phase of research might provide clues on how to mitigate these risks. Most prominently, REPRIEVE, the largest study to date of HIV-related CVD, was launched in April.

Photo courtesy of Shawn Rocco/Duke Medicine; printed with permission

Infectious Disease News spoke with cardiologists and infectious disease specialists about some of the possible reasons for the increased risk for CVD in patients with HIV and HCV, and the latest treatment strategies that are giving these patients a greater chance at survival.

Increased susceptibility

Several factors could possibly explain why HIV and HCV increase risk for CVD. As one example, these patients have a greater prevalence of traditional CVD risk factors compared with the general population.

“The prevalence of smoking in people with HIV infection is 60% to 80% in some studies, which is much higher than in the general population,” Chris T. Longenecker, MD, assistant professor of medicine and director of an HIV cardiometabolic risk clinic at Case Western Reserve University in Cleveland, told Infectious Disease News.

Abnormal lipid levels also are common in patients with HIV and HCV, according to Longenecker.

“HIV infection is associated initially with a decline in all lipoproteins. But then when one is started on antiretroviral therapy, LDL tends to return back to baseline levels and triglycerides can increase much more prominently. HDL, on the other hand, remains low. When you have high triglycerides and low HDL, that is a pattern that we see in other chronic inflammatory diseases, diabetes and so on. This is partly worsened by certain antiretroviral drugs,” he said.

In addition, “there seems to be a higher prevalence of comorbidities in HIV and HCV that are themselves associated with increased risk for CVD. In particular, chronic kidney disease and diabetes,” Longenecker said.

However, recent research suggests as much as 75% of all excess CVD in this population might be related to nontraditional risk factors, according to Steven K. Grinspoon, MD, professor of medicine at Harvard Medical School, director of the Massachusetts General Hospital Program in Nutritional Metabolism and co-director of the Nutrition Obesity Research Center at Harvard.

“HIV-infected patients have a number of metabolic abnormalities, body composition abnormalities and abnormalities in lipids and inflammatory pathways, which all contribute to CVD,” Grinspoon said. “They have excess visceral fat relative to subcutaneous [fat]. They have insulin resistance due in part to the virus and in part to specific medications that can affect GLUT4 glucose transport. They have significant abnormalities in inflammatory pathways, including activated monocyte pathways and T-cell pathways. There is also increased immune activation perhaps due to microbial translocation, HCV, cytomegalovirus or other pathways.

“Further, multiple epidemiological studies have suggested an increased risk for CVD of 50% to 100% compared with the general population. The studies suggest that increased inflammation can be associated with different types of plaque, and these patients often have arterial inflammation.”

Inflammation and immune activation may play key roles in the elevated risk in HIV and HCV patients, Judith Currier, MD, MPH, professor of medicine and chief of the division of infectious diseases at David Geffen School of Medicine at UCLA, told Infectious Disease News.

“One possible unifying feature of both of these chronic viral infections is that they are associated with inflammation and activation of certain parts of the immune system,” Currier said. “It could be that chronic inflammation is contributing to the excess rates of CVD. For HCV, which can now be cured with new therapies, one of the big questions is whether that risk will dissipate after people have been treated. But for HIV, while our treatments are excellent at controlling the virus and suppressing it, people still have residual inflammation even when they have been treated. Interactions between the host, the virus, the immune system and the treatments may all conspire to contribute to CV risk.”

These factors could explain why patients with HCV remain at increased risk for CVD despite the association of the virus with lower levels of LDL and total cholesterol, Longenecker said.

It was once assumed that the elevated CV risk had more to do with ART than with HIV alone or other factors. However, that thinking is changing, especially in light of the introduction of new ART that do not appear to be associated with increased CV risk, Grinspoon said.

“A number of years ago, the traditional party line was that the HIV antiretroviral therapies caused metabolic problems that contribute to CVD,” he said. “The party line would have been that they cause insulin resistance and dyslipidemia and contribute to body-composition abnormalities. More recently, though, the pendulum has swung to another way of thinking, elucidated by the SMART study.”

Researchers for the SMART study hypothesized that patients with HIV who received more significant and ongoing therapy would have more CVD related to the metabolic toxicities of the ART.

“In fact, they found the opposite,” Grinspoon said. “The patients who were on less antiretroviral therapy had more CVD. The researchers have subsequently gone on to hypothesize that perhaps the antiretroviral therapy lowers inflammation and immune activation, but that is a positive thing and may trump any negative effects of the drugs on traditional metabolic markers and pathways.”

Numerous conditions in play

Patients with HIV, and to a lesser extent those with HCV, have an elevated risk for a number of cardiac conditions. Examples in the literature include a study that reported HIV-infected veterans had a greater risk for acute MI compared with veterans without HIV (HR = 1.48; 95% CI, 1.27-1.72). Commenting on this study, Priscilla Hsue, MD, professor of medicine at the University of California, San Francisco, and cardiologist at San Francisco General Hospital, said, “even if you looked at the well-treated and suppressed HIV group, this excess risk remained. The risk associated with HIV was similar to that for diabetes, which we consider a risk equivalent outside the setting of HIV.”

In a similar study, HIV-infected veterans with a baseline HIV-1 RNA level of at least 500 copies/mL had increased risk for HF (HR = 2.28; 95% CI, 1.57-3.32) compared with veterans without HIV.

Ischemic heart disease, coronary artery disease and MI are among the most common cardiac conditions seen in this population, partly because the median age of people with HIV in the United States is approximately 50 years, according to Longenecker. However, “in the future, we will see more HF as the HIV-infected population ages. We just don’t see it as often now because they are younger.”

Stroke and hypertensive heart disease also are often seen in people with HIV, and HF and cardiomyopathy in people with HCV, he said.

Cardiac conditions affecting this population are not limited to those related to atherosclerosis, according to Hsue. “We are seeing a lot of other CV complications associated with HIV, including atrial fibrillation, diastolic dysfunction and sudden cardiac death,” she said. “The mechanisms are a subject of active investigation.”

The excess risk for sudden cardiac death in patients with HIV is concerning because these patients are usually asymptomatic, according to Grinspoon. “They have noncalcified vulnerable plaque morphology, which is vulnerable to rupture, and may be connected to the increased incidence of sudden cardiac death,” he said. “They don’t have a typical pattern of chronic angina seen in more elderly patients with typical risk factors and traditional lesions. In contrast, they have a pattern of high-risk plaque morphology that may be associated with a unique type of disease.”

However, some research points to improvements in CV health among those with HIV.

A recent study by Daniel B. Klein, MD, chief of infectious diseases at Kaiser Permanente San Leandro, California, and colleagues suggests there has been a virtual leveling of the risk for MI over the past 15 years between patients with and without HIV in California.

Klein and colleagues evaluated MI risk in patients enrolled in Kaiser Permanente’s Northern California and Southern California health plans from 1996 to 2011. Their analysis included 24,768 HIV patients and 257,600 demographically matched patients without HIV.

The findings of that study, published in Clinical Infectious Diseases, showed that the adjusted MI rate ratio for HIV status declined from 1.8 (95% CI, 1.3-2.6) in 1996-1999 to 1.0 (95% CI, 0.7-1.4) in 2010-2011.

“For providers, aggressive conventional risk factor reduction efforts are clearly warranted, coupled with early initiation of antiretroviral treatments to preserve immune function, which can translate into reduced heart disease for patients,” Klein told Infectious Disease News shortly after the study was published.

Aberg said infectious disease physicians are in agreement.

“We are well aware of our patients’ risk for having heart disease, so we are very aggressively screening for that risk and then starting people on statins or whatever other medications they may need,” Aberg said. “We may be reducing the incidence of the actual heart attacks.”

Management strategies

Now that more people with HIV and HCV are living to an age at which they are susceptible to cardiac conditions, more attention must be paid to how they should be managed.

“Aggressive primary prevention is important,” Hsue said. “Smoking cessation is critical, as is management of BP, monitoring of lipids and, for appropriate patients, aspirin therapy.”

What is missing, however, is a validated risk calculator applicable to this population, according to Hsue.

“We are beginning to recognize as a field that some of the things we use to monitor which individuals may be at risk, such as the Framingham risk calculator, may not be applicable in the HIV patient population,” Hsue said. “It does not capture aspects of antiretroviral therapy, duration of HIV infection or immune suppression, all of which may be linked to CV risk. Also, some recent studies in HIV have showed that the new American College of Cardiology/American Heart Association Pooled Cohort Equations CV Risk Calculator, when applied to HIV infection, would likely underestimate CVD risk in the HIV-infected population.”

HIV-specific risk calculators have been developed by the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) investigators to detect CV risk in patients with HIV, but they have not yet been validated in an independent cohort, she said.

“Chronic inflammation persists in the setting of treated and suppressed HIV infection and is independently predictive of CVD and other non-AIDS conditions,” Hsue said. “Intensification of HIV therapy in treated HIV patients does not seem to lower inflammation, and an active area of investigation in the field is identifying biomarkers that are predictive of CVD in HIV as well as therapies designed to lower inflammation and in turn impact CVD.”

There is a similar concern in patients with HCV, according to Currier. “Cholesterol levels can be lower due to liver disease and can make people look like they are at lower risk than they might really be,” she said.

Complicating matters further, many statin therapies are known to interact with antiretroviral drugs, according to Pamela S. Douglas, MD, who holds the Ursula Geller professorship for research in cardiovascular diseases at Duke Clinical Research Institute, Duke University School of Medicine. “There is no reason to withhold lipid-lowering treatment in patients with conventional indications for that, although it can be difficult to manage the polypharmacy associated with it,” she said.

Although attention must be paid to potential drug-drug interactions, Currier noted that, to date, “there is no evidence that the standard therapies do not work as well” in patients with HIV and HCV. “It is about making sure that people who are receiving treatments for HIV and HCV are having [CV risk] factors considered in their overall management, and we are not just focused on treating the viral infection and forgetting that if the person is going to be living a long time, then these other problems need to be attended to,” she said.

Some preliminary studies suggest aspirin may not be effective for CVD prevention in patients with HIV, and other research has reported lower aspirin use among people with HIV compared with those without HIV, particularly in those at elevated risk for coronary heart disease (CHD) and in those with known CHD, Grinspoon said.

Exercise also may be beneficial for this population in several ways, according to Longenecker. “Exercise is an area that’s emerging as a therapy or lifestyle modification that can reduce CV risk through traditional mechanisms, but also by reducing inflammation and immune activation,” he said.

Financial burden

The potential strain on the health care system in terms of providing cardiovascular services and medications for the aging HIV and HCV patient populations is likely to be significant, according to Fichtenbaum.

“The financial burden is going to be pretty incredible because there are lots of patients who are getting stents, there are lots of patients who have to use other medications when they develop [heart disease], like Plavix [clopidogrel bisulfate, Bristol-Myers Squibb and Sanofi], and these things are costly. Getting older is way more expensive, and that’s when we spend a lot more on health care,” he said.

More efficient treatments upfront may have the potential to save costs while improving the quality of life for HIV and HCV patients, according to Aberg, who is past chair of the HIV Medicine Association.

“If heart disease is accelerated in HIV, and you’re going to be treating individuals who are younger with heart disease, then you can imagine there will be additional costs to the health care system,” she said.

“When somebody says, ‘What’s the cost to treat hepatitis C?’ my comment always is, ‘What’s the cost not to treat?’ People are living longer, they’re healthier, they’re being productive in the workforce, the quality of life is improved and overall, you’re reducing medical costs by doing cardio prevention.”

Focus on statins

In the coming years, more light will be shed on the effectiveness of statins for CVD prevention in patients with HIV.

The first paper to show an effect of statins on plaque and HIV was published in The Lancet HIV in January. In a study of 40 patients with HIV randomly assigned atorvastatin or placebo, Grinspoon and colleagues found that statin therapy reduced noncalcified plaque volume and high-risk coronary plaque features.

The largest effort to date is the REPRIEVE trial. Researchers plan to randomly assign 6,500 patients with HIV aged 40 to 75 years who are taking antiretroviral drugs and do not meet current U.S. guidelines for statin therapy to a daily dose of Livalo (pitavastatin, Kowa Pharmaceuticals) or placebo. Pitavastatin was chosen because, unlike most other statins, it has not been shown to interact with ART. The study, which also will include a mechanistic substudy, is being funded by the NIH and Kowa.

Douglas, a co-principal investigator of REPRIEVE along with Grinspoon, said investigators hope to learn “how to think about and treat patients who are at a higher risk for CVD, but don’t necessarily fit in current treatment guidelines. We are also hoping to learn about atherosclerosis and mechanisms of atherosclerosis in this population. We will have the clinical phenotype and the events, but also the anatomic phenotype in great detail with [computed tomography angiography] and high-risk plaque, as well as a full profile of molecular biomarkers.”

According to Grinspoon, REPRIEVE could answer “a very interesting question for patients who have relatively minimal traditional disease, are relatively young, and do not qualify for regular treatment based on traditional algorithms, but who may have excess risk. It is the first study that is going to test the question of whether a prevention strategy in that asymptomatic group without traditional risk factors can prevent disease.”

Participants will be followed for up to 6 years for assessment of major adverse CV events. Researchers also will study the safety of statin therapy and its impact on cholesterol levels, immunologic parameters and serious non-CVD events such as new-onset diabetes, according to the NIH.

More to be learned

As helpful as the REPRIEVE findings might be, more research in many related areas is necessary in the near future, according to experts.

“There needs to be some implementation science done to determine how to incorporate multiple approaches to CV risk reduction into clinical practice — for example, including not only medical therapies but also diet and exercise and smoking cessation programs,” Longenecker said. “There is a long tradition of integrated clinical care for patients with HIV, so there are HIV clinics that do a good job of following their patients.

“I run an integrated HIV cardiometabolic risk clinic where I see patients alongside their primary HIV provider and nurses. We are finding that it is effective, but we need the implementation science to tell us exactly what programs work and don’t work.”

Another investigation, led by Janet Lo, MD, from the Program in Nutritional Metabolism at Massachusetts General Hospital, is assessing whether “leaky gut and impaired mucosal immune function in the gut are allowing bacteria to translocate, activating immune activation and causing CVD,” Grinspoon said. “Lo is aiming to use some strategies to ameliorate gut barrier dysfunction and decrease microbial translocation in the gut to alter CVD.”

Other promising areas are “alternative approaches to reduce chronic inflammation,” Hsue said. Studies are under way to evaluate low-dose methotrexate and interleukin-1 beta inhibition for reduction of inflammation in patients with CVD.

“I am interested in using those kinds of non-HIV targets for inflammation and seeing how that impacts both chronic inflammation as well as HIV disease,” Hsue said. “Are those agents safely tolerated? Interestingly, if you target chronic inflammation in HIV, some HIV investigators think you may have an impact in curing HIV itself. There are also newer lipid-lowering agents developed in the non-HIV population — proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors — that may be a method to lower lipids in HIV without potential drug-drug interactions.”

Fichtenbaum said ID physicians need to educate themselves on the latest treatment options, and to establish themselves as “partners in health” with their HIV and HCV patients.

“You have to be a strong patient advocate. You have to keep yourself educated and up-to-date to be able to provide state-of-the-art care,” he said. “It’s very complicated treating coinfected individuals, and you can’t use every regimen, and you need to know what are the most effective ones and how to use them in combination with antiretroviral therapy. We need to make sure that the right pills and the best pills are available for people for their HIV, and we need that for hepatitis C. To live in relative comfort in their golden years, we need to cure their hepatitis C now.” – by Erik Swain and David Jwanier

• References:
• Butt AA, et al. Arch Intern Med. 2011;doi:10.1001/archinternmed.2011.151.
• Freiberg MS, et al. JAMA Intern Med. 2013;doi:10.1001/jamainternmed.2013.3728.
• Klein DB, et al. Clin Infect Dis. 2015;doi:10.1093/cid/civ014.
• Lo J, et al. Lancet HIV. 2015;doi:10.1016/S2352-3018(14)00032-0.
• Paula AA, et al. AIDS Res Ther. 2013;doi:10.1186/1742-6405-10-32.
• Schambelan M, et al. Circulation. 2008;doi:10.1161/CIRCULATIONAHA.107.189627.
• Suchindran S, et al. Open Forum Infect Dis. 2014;doi:10.1093/ofid/ofu076.
• The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. N Engl J Med. 2006;doi:10.1056/NEJMoa062360.
• Tseng ZH, et al. J Am Coll Cardiol. 2012;doi:10.1016/j.jacc.2012.02.024.

• For more information:
• Judith A. Aberg, MD, can be reached at the Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1090, New York, NY 10029; email: judith.aberg@mssm.edu.
• Judith Currier, MD, MPH, can be reached at UCLA Division of Infectious Diseases, Center for Health Sciences, 37-121, 10833 Le Conte Ave., Los Angeles, CA 90095; email: jscurrier@mednet.ucla.edu.
• Pamela S. Douglas, MD, can be reached at 2400 Pratt St., Durham, NC 27715; email: pamela.douglas@duke.edu.
• Carl Fichtenbaum, MD, can be reached at UC Health Holmes Hospital, Room 3114, Cincinnati, OH 45219; email: carl.fichtenbaum@uc.edu.
• Steven K. Grinspoon, MD, can be reached at Massachusetts General Hospital, 55 Fruit St., LON 207, Boston, MA 02114; email: sgrinspoon@partners.org.
• Priscilla Hsue, MD, can be reached at Room 5G1 Cardiology SFGH, 1001 Potrero Ave., San Francisco, CA 94110; email: priscilla.hsue@ucsf.edu.
• Chris T. Longenecker, MD, can be reached at 11100 Euclid Ave., Mail Stop Lakeside 5038, Cleveland, OH 44106; email: chris.longenecker@uhhospitals.org.

Disclosures: Aberg reports being co-vice chair for the REPRIEVE trial, which is being funded in part by Kowa Pharmaceuticals, and serving on scientific advisory boards for Janssen, Merck and ViiV Healthcare. Currier reports being an investigator for the REPRIEVE trial. Douglas and Grinspoon are co-principal investigators for the REPRIEVE trial. Fichtenbaum reports being the principal investigator for research grants to his institution from Cubist, Gilead Sciences and Pfizer. Hsue reports receiving honoraria from Amgen, Bristol-Myers Squibb and Gilead Sciences. Longenecker reports receiving salary support through a grant from Medtronic Philanthropy and receiving prior research funding from Bristol-Myers Squibb.