Cover Story

Patients with HIV, hepatitis C present unique considerations for cardiologists

The link between CVD and HIV and hepatitis C virus is complex. Progress has been made in recent years regarding diagnosis and treatment, but unanswered questions remain. Patients with HIV and hepatitis C virus are living longer due to breakthroughs in treatment, leading cardiologists to play a larger role in the associated CVDs that may arise.

“The community is learning that HIV-infected individuals are living longer, and because of this, they’re developing a wide spectrum of CVD,” Priscilla Hsue, MD, FACC, professor of medicine at the University of California, San Francisco School of Medicine, told Cardiology Today.

Although there is more to discover about the link between CVD and HIV and hepatitis C virus (HCV), researchers have made significant strides into determining the specific CV conditions that are common in patients with HIV and HCV. Those with HIV are more likely to develop HF with reduced ejection fraction, HF with preserved ejection fraction and ischemic cardiomyopathy, whereas clinical outcomes including angina, atherosclerosis and MI are more common in patients with HCV.

Chris Longenecker, MD, from Case Western Reserve University, said more education about appropriate CVD treatment in HIV- and HCV-infected patients is necessary.
Chris Longenecker, MD, from Case Western Reserve University, said more education about appropriate CVD treatment in HIV- and HCV-infected patients is necessary.

Source: Jon Styer/Eastern Mennonite University; reprinted with permission.

The cause of increased CVD risk is still to be determined, although traditional risk factors and inflammation may play a vital role in the diagnosis of CVD in patients with HCV and HIV. Once the source of the inflammation is found, treating it may aid in reducing the risk for CVD. Modern antiretroviral therapy (ART) has been found to lower the risk for CVD in patients with HIV. Benefits from hepatitis C treatments regarding CVD have yet to be determined.

Safely and effectively treating patients with statin therapy has been a major focus in current studies, but determining which therapies will not cause adverse effects due to drug interactions is the next step.

The next studies conducted may solidify a path to help patients with HCV and HIV live a longer life than what can already be achieved with ART.

Risk factors for CVD

Many risk factors contribute to the increased risk for CVD in patients with HIV, which are linked to the virus itself or traditional risk factors. Smoking is one of the main traditional risk factors that is prevalent in patients with HIV. Regardless of which traditional risk factors are present, it is important to keep them in mind when treating patients with HIV and risk for CVD, experts told Cardiology Today.

Priscilla Hsue, MD, FACC
Priscilla Hsue

“There’s a huge emphasis on trying to reduce traditional risk factors because we know that works outside of HIV, but there’s also been a lot of emphasis on the best way to prevent and treat patients who are at risk for [CVD],” Hsue said. “This is a large area in the field: determining the best way to reduce [CV] risk in HIV-infected individuals and the best way to predict patients who might be at risk.”

Lifestyle changes and exercise can help reduce CVD risk in patients with HIV. Lifestyle change should be a team effort between the patient and the physician. Aggressively treating hypertension may also lower risk for CVD and HF in patients with HIV.

Traditional risk factors do not appear to tell the whole story, however, as inflammation has been cited as a mechanism for increased CVD risk in patients with HIV and HCV.

In the Veterans Aging Cohort Study, at a median follow-up of 7.1 years, veterans with HIV, compared with no HIV, had increased risk for HFpEF (HR = 1.21; 95% CI, 1.03-1.41) and HFrEF (HR = 1.61; 95% CI, 1.4-1.86), and the association between HIV and HF was present even in patients who never smoked (HR = 1.33; 95% CI, 1.05-1.7), according to data from Matthew S. Freiberg, MD, MSc, associate professor of cardiovascular medicine at Vanderbilt University School of Medicine in Nashville, Tennessee, and colleagues.

“From what we’re learning about HFpEF and the inflammatory biology that may underlie it, it makes sense that a chronic inflammatory disease such as HIV would be associated with an increased risk of HFpEF. This is an exciting area that merits future study for sure,” Chris Longenecker, MD, assistant professor of medicine at Case Western Reserve University in Cleveland and Cardiology Today Next Gen Innovator, said in an interview.

In another study, Rebeccah A. McKibben, MD, MPH, from the department of medicine at Johns Hopkins University, and colleagues found that patients with chronic HCV infection had a greater risk for any plaque (prevalence ratio [PR] = 1.26; 95% CI, 1.09-1.45), coronary artery calcium (PR = 1.29; 95% CI, 1.02-1.63) and noncalcified plaque (PR = 1.42; 95% CI, 1.16-1.75). The presence of any plaque was associated with both HIV and HCV infections.

Treatment options

Although more is still to be learned, options are available to effectively manage HIV in this patient population. ART has been shown to reduce risk for CVD by suppressing the immune response and inflammation caused by HIV.

“Although some of the ARTs have metabolic side effects, overall, the effect of treating HIV is likely beneficial. Now we recommend that patients be treated early with ART to prevent the uncontrolled viremia,” Wendy S. Post, MD, MS, professor of medicine and epidemiology, and cardiovascular fellowship research director at Johns Hopkins University School of Medicine, told Cardiology Today.

Wendy S. Post, MD, MS
Wendy S. Post

As more modern versions of ART become available, some patients are still taking older formulations that may cause lipodystrophy, glucose abnormalities and inflammation, which may contribute to CVD risk.

Currently available treatments for HCV do not generally confer increased risk for CVD, but CV benefits have not yet been determined, though some studies have suggested that fibrosis reductions conferred by direct-acting antiviral drugs may lead to CV benefits. Newer agents to treat HCV, while known to dramatically impact HCV, have only been on the market a short time.

“We need longer-term studies to understand that, since people are just being treated now over the past year or two with these newer HCV agents,” Chloe L. Thio, MD, professor of medicine and associate professor of molecular microbiology and immunology at the Johns Hopkins University School of Medicine, told Cardiology Today. “It’ll take several years to understand whether treating HCV has an impact on [CV] outcomes.”

Several studies have found that statin therapy may benefit patients with HIV. One such study is INTREPID, by Judith A. Aberg, MD, FIDSA, FACP, the Dr. George Baehr Professor of Medicine and chief of the division of infectious diseases at Icahn School of Medicine at Mount Sinai, and colleagues. At 12 weeks, patients with HIV treated with ART and dyslipidemia assigned pitavastatin 4 mg per day had a 31% reduction in LDL, and patients in the pravastatin 40 mg per day group had a 20.9% reduction. Glucose metabolism was not affected by either statin in this patient population.

Judith A. Aberg, MD, FIDSA, FACP
Judith A. Aberg

“Pitavastatin is a good option for our patients because of its potency and lack of drug interactions with ART. It’s a moderate-intensity statin, and the statins that are high-intensity may have drug interactions and have been associated with glucose intolerance, so we’re limited on how we can prescribe,” Aberg told Cardiology Today.

A larger study, REPRIEVE, with an estimated 6,500 patients is currently in progress. Researchers assigned patients without a clinical indication for a statin to pitavastatin or placebo, and they are reviewing whether the statin reduces CVD risk and overall mortality in patients with HIV who are on ART.

Even with these results, other statins such as atorvastatin and rosuvastatin should also be considered for the treatment of CVD in patients with HIV. The choice of statin should be made on a case-by-case basis, depending on diagnosis, symptoms and what is in the best interest of the individual being treated, Aberg said, noting drug tolerability, potential drug-drug interactions and access to medication all play major factors in statin selection.

Regardless of the treatment option that is selected for a patient with HIV and a diagnosis of or an increased risk for CVD, physicians should keep in mind that this patient population should be treated the same as the general population, despite a common misconception that they should be treated less aggressively.

“We need to do better at educating cardiologists and primary care providers on the appropriate treatment of HIV-infected patients. One example is the idea that, because of the drug interactions with ART, you should give all HIV-infected patients pravastatin and shy away from stronger statins like rosuvastatin or atorvastatin,” Longenecker said. “That does a disservice to those who truly merit a stronger statin, such as those with prior atherosclerotic [CV] events or very high-risk cholesterol or risk profile.”

Not all ART interacts with statins. Further, patients with HIV who are taking ART that does have interactions can start on lower doses of atorvastatin that can be titrated up to submaximal doses while monitoring for LDL response and symptoms, he said. Longenecker also noted that evidence suggests a left ventricular assist device may be considered for patients with HIV and advanced HF.

The same treatment approach can also be applied to patients with HCV, as a mechanism has not been found to disprove otherwise, experts said. In this patient population, physicians should monitor and treat, if necessary, patients’ cholesterol, BP and diabetes to minimize their traditional CV risk factors.

Specialized clinics for patients with HIV and CVD are at the forefront of a new model of care, Hsue and Longenecker said, noting that their institutions have them. Hsue said it is “a great model to provide better care,” and Longenecker said the program at his institution offers group exercise interventions and a community garden to promote a healthy lifestyle.

Further research

The NIH and NHLBI have placed a greater focus on trying to understand CVD in patients with HIV.

The research has informed clinicians that patients with HIV and HCV should be treated in the same way as the general population, using the primary care and preventive medicine guidelines, regardless of their diagnosis. Even with that information, the question persists whether more aggressive treatment should be done in each of these patient populations.

Hossein Bahrami, MD, PhD, MPH, FAHA
Hossein Bahrami

“We have been investigating [CV] diseases in HIV patients for a while, but in the last few years, we have a relatively better understanding of the problem,” Hossein Bahrami, MD, PhD, MPH, FAHA, assistant professor of medicine (cardiology), radiology and preventive medicine at the University of Southern California Keck School of Medicine, told Cardiology Today. “We are now at the stage that we have had enough studies to allow us to plan next steps, including prevention and early detection of CAD as well as screening methods and even incorporating specific guidelines for [CAD] prevention in HIV patients.”

Aberg said “we’re understanding more, and we believe this persistent immune activation and effects on the immune system are driving this increased risk for CAD, but we don’t understand how we can intervene to change that. We can manage the lipids with a statin and we can treat diabetes, but we haven’t figured out a way to actually decrease that inflammation.”

Chloe L. Thio, MD
Chloe L. Thio

Image: Johns Hopkins Medicine; reprinted with permission.

The same can be said about patients with HCV. Although it is known that higher hepatitis C RNA levels have a stronger link with subclinical outcomes, the cause of it is unknown. “Is it because hepatitis C, the virus itself, is playing a direct role, or is it because if there’s more virus around, there’s more inflammation?” Thio said.

Once the mechanism behind inflammation in patients with HCV is discovered, researchers can learn more about targeted treatment options that confront both the risk for CVD and HCV itself, she said.

Aside from inflammation, hypotheses for the cause of CVDs in patients with HIV include fibrosis in the myocardium and the initial infection of HIV.

Biomarkers aid in CVD risk prediction for patients with HIV
Click here to view a larger image.

More patients are switching from older ART, which caused patients to develop lipid abnormalities and insulin resistance, to newer versions of the treatment with minimal adverse events. Although the benefits of newer ART are evident, Aberg asked, “Do you have regression then because you’ve switched [medications], or will you continue to have ongoing damage from the previous exposure of those medications?”

Whether HFrEF may be reversed after initiation of ART is another unanswered question, Longenecker said, noting that case reports and smaller case series are encouraging, but more rigorous observational studies have not been completed.

Now that patients with HIV are living longer due to ART, proper clinical outcomes trials are becoming more feasible.

“We’ll learn a lot more about interventions [and] the effectiveness of certain interventions in the future in the next 10 years or so,” Longenecker said.

Greater awareness

With the research that has been completed and the information that has been gleaned, one of the most important things that the clinical community has learned is how important it is to increase awareness in both their own community and the HIV and HCV patient communities.

“The clinical community needs to be aware and to treat individuals with HIV and [CHD] aggressively,” Aberg said. “Many of us believe that persons living with HIV have an increased risk for [CHD], so start screening at a younger age, and then using statins, for example, and referring to cardiology when necessary. Really hitting on the importance of healthy diet, exercise and lifestyle changes — especially getting patients to stop smoking — would have a tremendous impact in the reduction of [CHD].” – by Darlene Dobkowski

Disclosures: Aberg reports conducting multicenter trials for Bristol-Myers Squibb, Gilead and GlaxoSmithKline without direct support and serving on the scientific advisory board for Merck. Bahrami, Post and Thio report no relevant financial disclosures. Hsue reports receiving grant support from the NIH and Pfizer and honoraria from Gilead Sciences. Longenecker reports receiving honoraria from Gilead Sciences and a research grant from Medtronic Foundation.

The link between CVD and HIV and hepatitis C virus is complex. Progress has been made in recent years regarding diagnosis and treatment, but unanswered questions remain. Patients with HIV and hepatitis C virus are living longer due to breakthroughs in treatment, leading cardiologists to play a larger role in the associated CVDs that may arise.

“The community is learning that HIV-infected individuals are living longer, and because of this, they’re developing a wide spectrum of CVD,” Priscilla Hsue, MD, FACC, professor of medicine at the University of California, San Francisco School of Medicine, told Cardiology Today.

Although there is more to discover about the link between CVD and HIV and hepatitis C virus (HCV), researchers have made significant strides into determining the specific CV conditions that are common in patients with HIV and HCV. Those with HIV are more likely to develop HF with reduced ejection fraction, HF with preserved ejection fraction and ischemic cardiomyopathy, whereas clinical outcomes including angina, atherosclerosis and MI are more common in patients with HCV.

Chris Longenecker, MD, from Case Western Reserve University, said more education about appropriate CVD treatment in HIV- and HCV-infected patients is necessary.
Chris Longenecker, MD, from Case Western Reserve University, said more education about appropriate CVD treatment in HIV- and HCV-infected patients is necessary.

Source: Jon Styer/Eastern Mennonite University; reprinted with permission.

The cause of increased CVD risk is still to be determined, although traditional risk factors and inflammation may play a vital role in the diagnosis of CVD in patients with HCV and HIV. Once the source of the inflammation is found, treating it may aid in reducing the risk for CVD. Modern antiretroviral therapy (ART) has been found to lower the risk for CVD in patients with HIV. Benefits from hepatitis C treatments regarding CVD have yet to be determined.

Safely and effectively treating patients with statin therapy has been a major focus in current studies, but determining which therapies will not cause adverse effects due to drug interactions is the next step.

The next studies conducted may solidify a path to help patients with HCV and HIV live a longer life than what can already be achieved with ART.

Risk factors for CVD

Many risk factors contribute to the increased risk for CVD in patients with HIV, which are linked to the virus itself or traditional risk factors. Smoking is one of the main traditional risk factors that is prevalent in patients with HIV. Regardless of which traditional risk factors are present, it is important to keep them in mind when treating patients with HIV and risk for CVD, experts told Cardiology Today.

Priscilla Hsue, MD, FACC
Priscilla Hsue

“There’s a huge emphasis on trying to reduce traditional risk factors because we know that works outside of HIV, but there’s also been a lot of emphasis on the best way to prevent and treat patients who are at risk for [CVD],” Hsue said. “This is a large area in the field: determining the best way to reduce [CV] risk in HIV-infected individuals and the best way to predict patients who might be at risk.”

Lifestyle changes and exercise can help reduce CVD risk in patients with HIV. Lifestyle change should be a team effort between the patient and the physician. Aggressively treating hypertension may also lower risk for CVD and HF in patients with HIV.

Traditional risk factors do not appear to tell the whole story, however, as inflammation has been cited as a mechanism for increased CVD risk in patients with HIV and HCV.

In the Veterans Aging Cohort Study, at a median follow-up of 7.1 years, veterans with HIV, compared with no HIV, had increased risk for HFpEF (HR = 1.21; 95% CI, 1.03-1.41) and HFrEF (HR = 1.61; 95% CI, 1.4-1.86), and the association between HIV and HF was present even in patients who never smoked (HR = 1.33; 95% CI, 1.05-1.7), according to data from Matthew S. Freiberg, MD, MSc, associate professor of cardiovascular medicine at Vanderbilt University School of Medicine in Nashville, Tennessee, and colleagues.

“From what we’re learning about HFpEF and the inflammatory biology that may underlie it, it makes sense that a chronic inflammatory disease such as HIV would be associated with an increased risk of HFpEF. This is an exciting area that merits future study for sure,” Chris Longenecker, MD, assistant professor of medicine at Case Western Reserve University in Cleveland and Cardiology Today Next Gen Innovator, said in an interview.

In another study, Rebeccah A. McKibben, MD, MPH, from the department of medicine at Johns Hopkins University, and colleagues found that patients with chronic HCV infection had a greater risk for any plaque (prevalence ratio [PR] = 1.26; 95% CI, 1.09-1.45), coronary artery calcium (PR = 1.29; 95% CI, 1.02-1.63) and noncalcified plaque (PR = 1.42; 95% CI, 1.16-1.75). The presence of any plaque was associated with both HIV and HCV infections.

PAGE BREAK

Treatment options

Although more is still to be learned, options are available to effectively manage HIV in this patient population. ART has been shown to reduce risk for CVD by suppressing the immune response and inflammation caused by HIV.

“Although some of the ARTs have metabolic side effects, overall, the effect of treating HIV is likely beneficial. Now we recommend that patients be treated early with ART to prevent the uncontrolled viremia,” Wendy S. Post, MD, MS, professor of medicine and epidemiology, and cardiovascular fellowship research director at Johns Hopkins University School of Medicine, told Cardiology Today.

Wendy S. Post, MD, MS
Wendy S. Post

As more modern versions of ART become available, some patients are still taking older formulations that may cause lipodystrophy, glucose abnormalities and inflammation, which may contribute to CVD risk.

Currently available treatments for HCV do not generally confer increased risk for CVD, but CV benefits have not yet been determined, though some studies have suggested that fibrosis reductions conferred by direct-acting antiviral drugs may lead to CV benefits. Newer agents to treat HCV, while known to dramatically impact HCV, have only been on the market a short time.

“We need longer-term studies to understand that, since people are just being treated now over the past year or two with these newer HCV agents,” Chloe L. Thio, MD, professor of medicine and associate professor of molecular microbiology and immunology at the Johns Hopkins University School of Medicine, told Cardiology Today. “It’ll take several years to understand whether treating HCV has an impact on [CV] outcomes.”

Several studies have found that statin therapy may benefit patients with HIV. One such study is INTREPID, by Judith A. Aberg, MD, FIDSA, FACP, the Dr. George Baehr Professor of Medicine and chief of the division of infectious diseases at Icahn School of Medicine at Mount Sinai, and colleagues. At 12 weeks, patients with HIV treated with ART and dyslipidemia assigned pitavastatin 4 mg per day had a 31% reduction in LDL, and patients in the pravastatin 40 mg per day group had a 20.9% reduction. Glucose metabolism was not affected by either statin in this patient population.

Judith A. Aberg, MD, FIDSA, FACP
Judith A. Aberg

“Pitavastatin is a good option for our patients because of its potency and lack of drug interactions with ART. It’s a moderate-intensity statin, and the statins that are high-intensity may have drug interactions and have been associated with glucose intolerance, so we’re limited on how we can prescribe,” Aberg told Cardiology Today.

A larger study, REPRIEVE, with an estimated 6,500 patients is currently in progress. Researchers assigned patients without a clinical indication for a statin to pitavastatin or placebo, and they are reviewing whether the statin reduces CVD risk and overall mortality in patients with HIV who are on ART.

Even with these results, other statins such as atorvastatin and rosuvastatin should also be considered for the treatment of CVD in patients with HIV. The choice of statin should be made on a case-by-case basis, depending on diagnosis, symptoms and what is in the best interest of the individual being treated, Aberg said, noting drug tolerability, potential drug-drug interactions and access to medication all play major factors in statin selection.

Regardless of the treatment option that is selected for a patient with HIV and a diagnosis of or an increased risk for CVD, physicians should keep in mind that this patient population should be treated the same as the general population, despite a common misconception that they should be treated less aggressively.

“We need to do better at educating cardiologists and primary care providers on the appropriate treatment of HIV-infected patients. One example is the idea that, because of the drug interactions with ART, you should give all HIV-infected patients pravastatin and shy away from stronger statins like rosuvastatin or atorvastatin,” Longenecker said. “That does a disservice to those who truly merit a stronger statin, such as those with prior atherosclerotic [CV] events or very high-risk cholesterol or risk profile.”

Not all ART interacts with statins. Further, patients with HIV who are taking ART that does have interactions can start on lower doses of atorvastatin that can be titrated up to submaximal doses while monitoring for LDL response and symptoms, he said. Longenecker also noted that evidence suggests a left ventricular assist device may be considered for patients with HIV and advanced HF.

PAGE BREAK

The same treatment approach can also be applied to patients with HCV, as a mechanism has not been found to disprove otherwise, experts said. In this patient population, physicians should monitor and treat, if necessary, patients’ cholesterol, BP and diabetes to minimize their traditional CV risk factors.

Specialized clinics for patients with HIV and CVD are at the forefront of a new model of care, Hsue and Longenecker said, noting that their institutions have them. Hsue said it is “a great model to provide better care,” and Longenecker said the program at his institution offers group exercise interventions and a community garden to promote a healthy lifestyle.

Further research

The NIH and NHLBI have placed a greater focus on trying to understand CVD in patients with HIV.

The research has informed clinicians that patients with HIV and HCV should be treated in the same way as the general population, using the primary care and preventive medicine guidelines, regardless of their diagnosis. Even with that information, the question persists whether more aggressive treatment should be done in each of these patient populations.

Hossein Bahrami, MD, PhD, MPH, FAHA
Hossein Bahrami

“We have been investigating [CV] diseases in HIV patients for a while, but in the last few years, we have a relatively better understanding of the problem,” Hossein Bahrami, MD, PhD, MPH, FAHA, assistant professor of medicine (cardiology), radiology and preventive medicine at the University of Southern California Keck School of Medicine, told Cardiology Today. “We are now at the stage that we have had enough studies to allow us to plan next steps, including prevention and early detection of CAD as well as screening methods and even incorporating specific guidelines for [CAD] prevention in HIV patients.”

Aberg said “we’re understanding more, and we believe this persistent immune activation and effects on the immune system are driving this increased risk for CAD, but we don’t understand how we can intervene to change that. We can manage the lipids with a statin and we can treat diabetes, but we haven’t figured out a way to actually decrease that inflammation.”

Chloe L. Thio, MD
Chloe L. Thio

Image: Johns Hopkins Medicine; reprinted with permission.

The same can be said about patients with HCV. Although it is known that higher hepatitis C RNA levels have a stronger link with subclinical outcomes, the cause of it is unknown. “Is it because hepatitis C, the virus itself, is playing a direct role, or is it because if there’s more virus around, there’s more inflammation?” Thio said.

Once the mechanism behind inflammation in patients with HCV is discovered, researchers can learn more about targeted treatment options that confront both the risk for CVD and HCV itself, she said.

Aside from inflammation, hypotheses for the cause of CVDs in patients with HIV include fibrosis in the myocardium and the initial infection of HIV.

Biomarkers aid in CVD risk prediction for patients with HIV
Click here to view a larger image.
PAGE BREAK

More patients are switching from older ART, which caused patients to develop lipid abnormalities and insulin resistance, to newer versions of the treatment with minimal adverse events. Although the benefits of newer ART are evident, Aberg asked, “Do you have regression then because you’ve switched [medications], or will you continue to have ongoing damage from the previous exposure of those medications?”

Whether HFrEF may be reversed after initiation of ART is another unanswered question, Longenecker said, noting that case reports and smaller case series are encouraging, but more rigorous observational studies have not been completed.

Now that patients with HIV are living longer due to ART, proper clinical outcomes trials are becoming more feasible.

“We’ll learn a lot more about interventions [and] the effectiveness of certain interventions in the future in the next 10 years or so,” Longenecker said.

Greater awareness

With the research that has been completed and the information that has been gleaned, one of the most important things that the clinical community has learned is how important it is to increase awareness in both their own community and the HIV and HCV patient communities.

“The clinical community needs to be aware and to treat individuals with HIV and [CHD] aggressively,” Aberg said. “Many of us believe that persons living with HIV have an increased risk for [CHD], so start screening at a younger age, and then using statins, for example, and referring to cardiology when necessary. Really hitting on the importance of healthy diet, exercise and lifestyle changes — especially getting patients to stop smoking — would have a tremendous impact in the reduction of [CHD].” – by Darlene Dobkowski

Disclosures: Aberg reports conducting multicenter trials for Bristol-Myers Squibb, Gilead and GlaxoSmithKline without direct support and serving on the scientific advisory board for Merck. Bahrami, Post and Thio report no relevant financial disclosures. Hsue reports receiving grant support from the NIH and Pfizer and honoraria from Gilead Sciences. Longenecker reports receiving honoraria from Gilead Sciences and a research grant from Medtronic Foundation.