Feature

CVD Prevention, Treatment Challenging as Patients With HCV, HIV Live Longer

Due to successful treatment options, people with hepatitis C virus and HIV 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.

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.

There are few data from epidemiological studies in this population except related to death and myocardial infarction. “The idea of treating and reducing CV risks in this population is a relatively new concept. Patients hadn’t lived long enough to worry about it in the past, and there has always been a concern about drug interactions,” 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, told HCV Next.

Recent research established that many patients with HCV and HIV are at elevated risk for myocardial infarction, heart failure, metabolic syndrome and other cardiac conditions. The next phase of research might provide clues on how to mitigate these risks.

Increased Susceptibility

Several factors could possibly explain why HCV and HIV 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, said in an interview.

Chris Longenecker

Chris T. Longenecker

Abnormal lipid levels also are common in patients with HCV and HIV, according to Longenecker. “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 that as much as 75% of all excess CVD in this population might be related to nontraditional risk factors, Steven 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, told HCV Next.

“HIV-infected patients have a number of metabolic abnormalities, body composition abnormalities and abnormalities in lipids and inflammatory pathways, which all contribute to CVD,” he 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,” Grinspoon said.

Inflammation and immune activation may play key roles, Judith Currier, MD, professor of medicine and chief of the division of infectious diseases at David Geffen School of Medicine at UCLA, told HCV Next.

Judith Currier

Judith Currier

“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.”

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.

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.”

Ischemic heart disease, coronary artery disease and myocardial infarction 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 heart failure 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 heart failure and cardiomyopathy in people with HCV, he said.

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 from a cardiology perspective.

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

What is missing, however, is a validated risk calculator applicable to this population, she said.

“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 [or HCV] 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.

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 Douglas. “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.”

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.

Attention on Statins

As attention to statin use in patients with both HIV and HCV grows, studies are showing that statin use may be beneficial in these patient groups.

Statin use in patients with HCV and compensated cirrhosis seems to offer a protective effect against death and decompensation, according to a study presented at the 2015 International Liver Congress.

“In compensated HCV cirrhosis, statin users have a significantly lower incidence of decompensation and better overall survival compared to statin non-users,” Arpan Mohanty, MBBS, from Yale School of Medicine, New Haven, Conn., said during her presentation. “Risk of decompensation and death was reduced by over 40%.”

In this retrospective cohort study, Mohanty and colleagues used the U.S. Department of Veterans HCV Clinical Case Registry, and by doing so, she said all patients had an equal opportunity to receive statins.

To mimic a randomized controlled trial, propensity score matching was used to take the 43,350 patients who were monoinfected with HCV and had cirrhosis down to down to 2,062 non-users and 685 users matched by their likelihood of receiving statins. Up to five statin non-users were matched to one statin user. The matched cohorts were similar at baseline in age, race, sex, lab results and comorbidities.

“The probability of decompensation and death were significantly lower in the statin users,” Mohanty said (P < .001 for both). Unadjusted hazard ratios for decompensation and death were significantly lower in the statin group with an HR of 0.55 for decompensation (0.39-0.77) and 0.56 for death (0.46-0.69).

“When adjusted for common predictors of decompensation and death in compensated cirrhosis, like age, BMI, albumin, FIB 4 score and MELD score, the risk of decompensation in statin use was reduced by 45% and that, too, of death,” Mohanty said.

Sensitivity analyses considering an alternate definition of decompensation, excluding patients without HCV-RNA confirmation and excluding patients who received HCV antiviral therapy also yielded similar hazards ratios.

“Statin use is low in patients with cirrhosis, even in those with a high cardiovascular risk,” Mohanty said. “Until randomized controlled trials confirm these results, statins cannot be widely recommended in this setting. However, in patients who otherwise require statins, their use should not be avoided.”

More to be Learned

As helpful as these findings should be, more research in many related areas is necessary in the near future, experts said.

“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,” he said.

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.”

Another area that could bear fruit is “alternative approaches to reduce chronic inflammation,” Hsue said. Studies are underway 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.” – by Erik Swain

Disclosures: Currier reports being an investigator for the REPRIEVE trial.  Douglas and Grinspoon are co-principal investigators for the REPRIEVE trial, which is being funded in part by Kowa Pharmaceuticals. Hsue reports receiving honoraria from Amgen, Bristol-Myers Squibb and Gilead. Longenecker reports receiving salary support through a grant from Medtronic Philanthropy and receiving prior research funding from Bristol-Myers Squibb.

Due to successful treatment options, people with hepatitis C virus and HIV 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.

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.

There are few data from epidemiological studies in this population except related to death and myocardial infarction. “The idea of treating and reducing CV risks in this population is a relatively new concept. Patients hadn’t lived long enough to worry about it in the past, and there has always been a concern about drug interactions,” 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, told HCV Next.

Recent research established that many patients with HCV and HIV are at elevated risk for myocardial infarction, heart failure, metabolic syndrome and other cardiac conditions. The next phase of research might provide clues on how to mitigate these risks.

Increased Susceptibility

Several factors could possibly explain why HCV and HIV 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, said in an interview.

Chris Longenecker

Chris T. Longenecker

Abnormal lipid levels also are common in patients with HCV and HIV, according to Longenecker. “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 that as much as 75% of all excess CVD in this population might be related to nontraditional risk factors, Steven 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, told HCV Next.

“HIV-infected patients have a number of metabolic abnormalities, body composition abnormalities and abnormalities in lipids and inflammatory pathways, which all contribute to CVD,” he 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,” Grinspoon said.

Inflammation and immune activation may play key roles, Judith Currier, MD, professor of medicine and chief of the division of infectious diseases at David Geffen School of Medicine at UCLA, told HCV Next.

Judith Currier

Judith Currier

“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.”

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.

PAGE BREAK

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.”

Ischemic heart disease, coronary artery disease and myocardial infarction 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 heart failure 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 heart failure and cardiomyopathy in people with HCV, he said.

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 from a cardiology perspective.

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

What is missing, however, is a validated risk calculator applicable to this population, she said.

“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 [or HCV] 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.

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 Douglas. “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.”

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.

PAGE BREAK

Attention on Statins

As attention to statin use in patients with both HIV and HCV grows, studies are showing that statin use may be beneficial in these patient groups.

Statin use in patients with HCV and compensated cirrhosis seems to offer a protective effect against death and decompensation, according to a study presented at the 2015 International Liver Congress.

“In compensated HCV cirrhosis, statin users have a significantly lower incidence of decompensation and better overall survival compared to statin non-users,” Arpan Mohanty, MBBS, from Yale School of Medicine, New Haven, Conn., said during her presentation. “Risk of decompensation and death was reduced by over 40%.”

In this retrospective cohort study, Mohanty and colleagues used the U.S. Department of Veterans HCV Clinical Case Registry, and by doing so, she said all patients had an equal opportunity to receive statins.

To mimic a randomized controlled trial, propensity score matching was used to take the 43,350 patients who were monoinfected with HCV and had cirrhosis down to down to 2,062 non-users and 685 users matched by their likelihood of receiving statins. Up to five statin non-users were matched to one statin user. The matched cohorts were similar at baseline in age, race, sex, lab results and comorbidities.

“The probability of decompensation and death were significantly lower in the statin users,” Mohanty said (P < .001 for both). Unadjusted hazard ratios for decompensation and death were significantly lower in the statin group with an HR of 0.55 for decompensation (0.39-0.77) and 0.56 for death (0.46-0.69).

“When adjusted for common predictors of decompensation and death in compensated cirrhosis, like age, BMI, albumin, FIB 4 score and MELD score, the risk of decompensation in statin use was reduced by 45% and that, too, of death,” Mohanty said.

Sensitivity analyses considering an alternate definition of decompensation, excluding patients without HCV-RNA confirmation and excluding patients who received HCV antiviral therapy also yielded similar hazards ratios.

“Statin use is low in patients with cirrhosis, even in those with a high cardiovascular risk,” Mohanty said. “Until randomized controlled trials confirm these results, statins cannot be widely recommended in this setting. However, in patients who otherwise require statins, their use should not be avoided.”

More to be Learned

As helpful as these findings should be, more research in many related areas is necessary in the near future, experts said.

“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,” he said.

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.”

Another area that could bear fruit is “alternative approaches to reduce chronic inflammation,” Hsue said. Studies are underway 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.” – by Erik Swain

Disclosures: Currier reports being an investigator for the REPRIEVE trial.  Douglas and Grinspoon are co-principal investigators for the REPRIEVE trial, which is being funded in part by Kowa Pharmaceuticals. Hsue reports receiving honoraria from Amgen, Bristol-Myers Squibb and Gilead. Longenecker reports receiving salary support through a grant from Medtronic Philanthropy and receiving prior research funding from Bristol-Myers Squibb.