The Big Picture

HCV: A Systemic Disease with Extrahepatic Features

Hepatitis C virus infection is known to be associated with chronic hepatitis, cirrhosis and hepatocellular carcinoma. However, HCV can have serious consequences for other organ systems as well. Extrahepatic HCV-associated disorders include cardiovascular, central nervous system, dermatological, endocrine, renal and rheumatologic diseases.

 

Thinking of HCV as a systemic disease reinforces the concept that there should be access to HCV therapy and care for all patients with this infection because it is more than a matter of the amount of liver fibrosis or scarring.

Ira M Jacobson MD

Ira M. Jacobson

Clinicians should be aware of the potential extrahepatic manifestations and how they can impact and/or alter the treatment of patients. Once we accept these associations, it is difficult to conceive of the denial of currently anticipated, highly effective, new therapies to patients with HCV.

Links Established

The association between HCV and diabetes gets the most attention. A seminal paper published in Annals of Internal Medicine in 2000 reported a relationship between type 2 diabetes and HCV infection. The research team studied about 10,000 adults aged 20 years and older who participated in the Third National Health and Nutrition Examination Survey (1988-1994). Of 9,841 participants with a complete evaluation for HCV and diabetes, 1,242 had type 2 diabetes and 230 had HCV. The likelihood of developing type 2 diabetes was more than three times greater for participants with HCV. However, the same association was not observed with type 1 diabetes. This association was confirmed in subsequent studies.

Other research has focused on the association between HCV and increased prevalence of insulin resistance. Studies such as the HALT-C trial have demonstrated that insulin resistance is ameliorated in patients who have a sustained virologic response after treatment for HCV. Moreover, patients who have had SVR to interferon-based therapy for HCV have a lower incidence of diabetes in the ensuing years compared with their nonresponder counterparts. In a European study conducted by Romero-Gómez and colleagues, the incidence of type 2 diabetes and impaired fasting glucose was reduced by half in patients with chronic HCV who had SVR. In another study by Arase and colleagues, the risk for type 2 diabetes was reduced by two-thirds in patients with SVR emerging from a Japanese cohort of 2,842 patients with chronic HCV infection who were followed for a mean of about 6 years.

Still other recent studies have suggested that patients cured of HCV are less likely to develop complications of diabetes. Hsu and colleagues reported in Hepatology that HCV antiviral therapy was associated with improved renal and cardiovascular outcomes in patients with HCV and diabetes. The population-based cohort study included more than 2.2 million adults in Taiwan who had diabetes and were followed for a median of 8 years (n=1,411 treated with pegylated interferon/ribavirin matched with 1,411 untreated controls). From 2003 to 2011, the cumulative incidence of end-stage renal disease was 1.1% in the treated group, 9.3% in the untreated group and 3.3% in a matched group of diabetic patients without HCV. The cumulative incidence of ischemic stroke during follow-up was 3.1% in the treated group, 5.3% in the untreated group and 6.1% in the uninfected group. The cumulative incidence of acute coronary syndromes was 4.1% in the treated group, 6.6% in the untreated group and 7.4% in the uninfected group. Compared with untreated patients, antiviral therapy was associated with a multivariate-adjusted HR of 0.16 for end-stage renal disease, 0.53 for ischemic stroke and 0.64 for acute coronary syndromes.

There is also incontrovertible evidence linking HCV with cryoglobulinemia with vasculitis and some non-Hodgkin B-cell lymphomas. Cryoglobulins are common in patients with HCV, although a smaller percentage develop clinically overt cryoglobulinemia. Complications of cryoglobulinemia may include purpura, arthralgias or arthritis, neuropathy, glomerulonephritis and intestinal involvement. The latter two syndromes can be life-threatening. Although patients with major visceral involvement may require plasmapheresis and/or immunosuppressive therapy, including rituximab, the clinical features of cryoglobulinemia commonly resolve with successful antiviral therapy.

The association of HCV with lymphoma has been thoroughly reviewed, and recently by Peveling-Oberhag and colleagues in the Journal of Hepatology. Epidemiological evidence has established an association between chronic HCV infection and B-cell non-Hodgkin’s lymphoma. The lymphoma types most commonly linked with HCV include marginal zone lymphoma and diffuse large B-cell lymphoma. Remission and even resolution of indolent lymphomas with successful antiviral therapy has been reported.

Another systemic complication of HCV infection may be premature arteriosclerosis, as suggested in several studies evaluating carotid arterial atherosclerosis. Some, but not all, studies evaluating the issue have suggested an excess of cardiac and cerebrovascular disease. However, further studies on this association are needed.

In the R.E.V.E.A.L-HCV study, investigators collected blood in 1991 from tens of thousands of people with hepatitis B virus in seven cities in Taiwan and followed them for 13 years. In this natural history study, HBV viral levels linked closely with downstream risks for liver cancer and cirrhosis. Then, the researchers went back to those blood samples and looked for HCV antibodies and HCV RNA, and identified about 1,000 people with chronic HCV; the data showed that they all had increased all-cause mortality related to renal disease, cardiovascular disease and certain cancers. Cancers of the prostate and esophagus were five times more common among people with HCV than those without HCV. This issue is crying out for more research.

In addition, HCV has been linked to the development of Sjögren syndrome, neuropathies, thyroid disease, polyarthritis and the presence of autoantibodies in the serum, among others. HCV infection may have a negative effect on quality of life, and may be associated with fatigue, depression and cognitive impairment.

Reduced Mortality After Cure

Studies have demonstrated that all-cause mortality, not just liver-related mortality, is reduced in patients who are cured of their HCV infection. This applies to both patients with and without cirrhosis.

In one study, van der Meer and colleagues assessed the relationship between SVR and mortality in 530 patients with chronic HCV infection and advanced hepatic fibrosis who had started interferon-based therapy between 1990 and 2003. During a median follow-up of 8.4 years, 36% achieved SVR. Thirteen patients with SVR died (10-year cumulative all-cause mortality rate, 8.9%) compared with 100 patients without SVR (10-year cumulative all-cause mortality rate, 26%). SVR was associated with reduced risk for all-cause mortality (HR=0.26) and reduced risk for liver-related mortality or transplantation (HR=0.06).

Results from a large Veterans Affairs database study by Backus and colleagues revealed a similar reduction in all-cause mortality in patients with HCV who had an SVR.

A Call for Attention

The associations discussed in this editorial represent another set of reasons why primary care physicians should be attuned and well-versed on HCV and its effect on other organs.

PCPs are involved in the prevention of common diseases and disorders in the general population, such as diabetes, cardiovascular disease and obesity. These links play to themes that are much more general than those that might otherwise be considered in the province of hepatologists and gastroenterologists and infectious disease specialists. This plays to the theme of disease prevention in primary care.

The experts I speak with bring this up regularly. Recently, at various venues, my colleagues have expressed increasing concern over the potential constraints in being able to access the new HCV therapies for our patients with mild disease. It begs the question of how we can accept such limitations in access if patients have a systemic disease that causes other problems.

Consideration of HCV as a Systemic Disease

A major emerging issue is whether each patient with HCV is a treatment candidate and should be offered and have access to these new regimens, as expensive as they are. I feel passionately that they should.

Our methods for distinguishing patients with mild fibrosis from advanced fibrosis have some limitations. Liver biopsy or FibroScan can underestimate the amount of scarring in the liver. If we have a uniform policy of withholding therapy from patients with mild fibrosis, there is a chance that the patient actually has more fibrosis than believed. More importantly, despite the fact that we have a general idea of the proportion of patients with significant progression of fibrosis over a number of years, there are individual outliers. We can never completely ensure that an individual with mild fibrosis will not progress significantly in the short term. This is all the more so in patients with HCV genotype 3.

In addition, there is a tremendous psychosocial burden of having HCV. It causes chronic worry and is associated with depression. Some speculate that with regard to neuropsychiatric effects, there is a biologic effect of the virus induced by inflammatory mediators like cytokines, but it is very difficult to dissociate that from the psychological effects of knowing you have a chronic viral infection that could be harmful one day or that could be transmitted to others. On the other hand, cognitive dysfunction has also been linked to HCV.

These considerations cumulatively represent a compelling argument for universal treatment of HCV-infected patients. With the consideration of HCV being a systemic disease, a patient does not have to have cirrhosis or advanced fibrosis in order to be at risk for developing diabetes or premature arteriosclerosis from HCV. There is a more general concept that our culture is antithetical to the idea of withholding highly effective therapies for chronic, potentially dangerous, disease states on the basis of cost. I know there are people who would have a tremendous problem with that and will say that is how the health care system got into trouble in the first place. However, the question is: What potentially fatal disease do we not treat when it could be cured because it is too expensive to do so?

References:

Adinolfi LE. World J Gastroenterol. 2014;20:3410-3417.

Arase Y. Hepatology. 2009;49:739-744.

Backus LI. Clin Gastroenterol Hepatol. 2011;9:509-516.

Dammacco F. N Engl J Med. 2013;369:1035-1045.

Delgado-Borrego A. Clin Gastroenterol Hepatol. 2010;8:458-462.

Hsu YC. Hepatology. 2014;59:1293-1302.

Jacobson IM. Clin Gastroenterol Hepatol. 2010;8:1017-1029.

Mehta SH. Ann Intern Med. 2000;133:592-599.

Peveling-Oberhag J. J Hepatol. 2013;59:169-177.

Romero-Gómez M. J Hepatol. 2008;48:721-727.

Van der Meer AJ. JAMA. 2012;308:2584-2593.

For more information:

Ira M. Jacobson, MD, is chief of the division of gastroenterology and hepatology and Vincent Astor distinguished professor of medicine at the Joan Sanford I. Weill Medical College of Cornell University; attending physician at New York-Presbyterian Hospital Cornell Campus; and medical director of the Center for the Study of Hepatitis C. He is also a Co-Chief Medical Editor of HCV Next. Jacobson can be reached at HCV Next, 6900 Grove Road, Thorofare, NJ 08086; email: imj2001@med.cornell.edu.

Disclosure: Jacobson reports no relevant financial disclosures.

Hepatitis C virus infection is known to be associated with chronic hepatitis, cirrhosis and hepatocellular carcinoma. However, HCV can have serious consequences for other organ systems as well. Extrahepatic HCV-associated disorders include cardiovascular, central nervous system, dermatological, endocrine, renal and rheumatologic diseases.

 

Thinking of HCV as a systemic disease reinforces the concept that there should be access to HCV therapy and care for all patients with this infection because it is more than a matter of the amount of liver fibrosis or scarring.

Ira M Jacobson MD

Ira M. Jacobson

Clinicians should be aware of the potential extrahepatic manifestations and how they can impact and/or alter the treatment of patients. Once we accept these associations, it is difficult to conceive of the denial of currently anticipated, highly effective, new therapies to patients with HCV.

Links Established

The association between HCV and diabetes gets the most attention. A seminal paper published in Annals of Internal Medicine in 2000 reported a relationship between type 2 diabetes and HCV infection. The research team studied about 10,000 adults aged 20 years and older who participated in the Third National Health and Nutrition Examination Survey (1988-1994). Of 9,841 participants with a complete evaluation for HCV and diabetes, 1,242 had type 2 diabetes and 230 had HCV. The likelihood of developing type 2 diabetes was more than three times greater for participants with HCV. However, the same association was not observed with type 1 diabetes. This association was confirmed in subsequent studies.

Other research has focused on the association between HCV and increased prevalence of insulin resistance. Studies such as the HALT-C trial have demonstrated that insulin resistance is ameliorated in patients who have a sustained virologic response after treatment for HCV. Moreover, patients who have had SVR to interferon-based therapy for HCV have a lower incidence of diabetes in the ensuing years compared with their nonresponder counterparts. In a European study conducted by Romero-Gómez and colleagues, the incidence of type 2 diabetes and impaired fasting glucose was reduced by half in patients with chronic HCV who had SVR. In another study by Arase and colleagues, the risk for type 2 diabetes was reduced by two-thirds in patients with SVR emerging from a Japanese cohort of 2,842 patients with chronic HCV infection who were followed for a mean of about 6 years.

Still other recent studies have suggested that patients cured of HCV are less likely to develop complications of diabetes. Hsu and colleagues reported in Hepatology that HCV antiviral therapy was associated with improved renal and cardiovascular outcomes in patients with HCV and diabetes. The population-based cohort study included more than 2.2 million adults in Taiwan who had diabetes and were followed for a median of 8 years (n=1,411 treated with pegylated interferon/ribavirin matched with 1,411 untreated controls). From 2003 to 2011, the cumulative incidence of end-stage renal disease was 1.1% in the treated group, 9.3% in the untreated group and 3.3% in a matched group of diabetic patients without HCV. The cumulative incidence of ischemic stroke during follow-up was 3.1% in the treated group, 5.3% in the untreated group and 6.1% in the uninfected group. The cumulative incidence of acute coronary syndromes was 4.1% in the treated group, 6.6% in the untreated group and 7.4% in the uninfected group. Compared with untreated patients, antiviral therapy was associated with a multivariate-adjusted HR of 0.16 for end-stage renal disease, 0.53 for ischemic stroke and 0.64 for acute coronary syndromes.

There is also incontrovertible evidence linking HCV with cryoglobulinemia with vasculitis and some non-Hodgkin B-cell lymphomas. Cryoglobulins are common in patients with HCV, although a smaller percentage develop clinically overt cryoglobulinemia. Complications of cryoglobulinemia may include purpura, arthralgias or arthritis, neuropathy, glomerulonephritis and intestinal involvement. The latter two syndromes can be life-threatening. Although patients with major visceral involvement may require plasmapheresis and/or immunosuppressive therapy, including rituximab, the clinical features of cryoglobulinemia commonly resolve with successful antiviral therapy.

The association of HCV with lymphoma has been thoroughly reviewed, and recently by Peveling-Oberhag and colleagues in the Journal of Hepatology. Epidemiological evidence has established an association between chronic HCV infection and B-cell non-Hodgkin’s lymphoma. The lymphoma types most commonly linked with HCV include marginal zone lymphoma and diffuse large B-cell lymphoma. Remission and even resolution of indolent lymphomas with successful antiviral therapy has been reported.

Another systemic complication of HCV infection may be premature arteriosclerosis, as suggested in several studies evaluating carotid arterial atherosclerosis. Some, but not all, studies evaluating the issue have suggested an excess of cardiac and cerebrovascular disease. However, further studies on this association are needed.

In the R.E.V.E.A.L-HCV study, investigators collected blood in 1991 from tens of thousands of people with hepatitis B virus in seven cities in Taiwan and followed them for 13 years. In this natural history study, HBV viral levels linked closely with downstream risks for liver cancer and cirrhosis. Then, the researchers went back to those blood samples and looked for HCV antibodies and HCV RNA, and identified about 1,000 people with chronic HCV; the data showed that they all had increased all-cause mortality related to renal disease, cardiovascular disease and certain cancers. Cancers of the prostate and esophagus were five times more common among people with HCV than those without HCV. This issue is crying out for more research.

In addition, HCV has been linked to the development of Sjögren syndrome, neuropathies, thyroid disease, polyarthritis and the presence of autoantibodies in the serum, among others. HCV infection may have a negative effect on quality of life, and may be associated with fatigue, depression and cognitive impairment.

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Reduced Mortality After Cure

Studies have demonstrated that all-cause mortality, not just liver-related mortality, is reduced in patients who are cured of their HCV infection. This applies to both patients with and without cirrhosis.

In one study, van der Meer and colleagues assessed the relationship between SVR and mortality in 530 patients with chronic HCV infection and advanced hepatic fibrosis who had started interferon-based therapy between 1990 and 2003. During a median follow-up of 8.4 years, 36% achieved SVR. Thirteen patients with SVR died (10-year cumulative all-cause mortality rate, 8.9%) compared with 100 patients without SVR (10-year cumulative all-cause mortality rate, 26%). SVR was associated with reduced risk for all-cause mortality (HR=0.26) and reduced risk for liver-related mortality or transplantation (HR=0.06).

Results from a large Veterans Affairs database study by Backus and colleagues revealed a similar reduction in all-cause mortality in patients with HCV who had an SVR.

A Call for Attention

The associations discussed in this editorial represent another set of reasons why primary care physicians should be attuned and well-versed on HCV and its effect on other organs.

PCPs are involved in the prevention of common diseases and disorders in the general population, such as diabetes, cardiovascular disease and obesity. These links play to themes that are much more general than those that might otherwise be considered in the province of hepatologists and gastroenterologists and infectious disease specialists. This plays to the theme of disease prevention in primary care.

The experts I speak with bring this up regularly. Recently, at various venues, my colleagues have expressed increasing concern over the potential constraints in being able to access the new HCV therapies for our patients with mild disease. It begs the question of how we can accept such limitations in access if patients have a systemic disease that causes other problems.

Consideration of HCV as a Systemic Disease

A major emerging issue is whether each patient with HCV is a treatment candidate and should be offered and have access to these new regimens, as expensive as they are. I feel passionately that they should.

Our methods for distinguishing patients with mild fibrosis from advanced fibrosis have some limitations. Liver biopsy or FibroScan can underestimate the amount of scarring in the liver. If we have a uniform policy of withholding therapy from patients with mild fibrosis, there is a chance that the patient actually has more fibrosis than believed. More importantly, despite the fact that we have a general idea of the proportion of patients with significant progression of fibrosis over a number of years, there are individual outliers. We can never completely ensure that an individual with mild fibrosis will not progress significantly in the short term. This is all the more so in patients with HCV genotype 3.

In addition, there is a tremendous psychosocial burden of having HCV. It causes chronic worry and is associated with depression. Some speculate that with regard to neuropsychiatric effects, there is a biologic effect of the virus induced by inflammatory mediators like cytokines, but it is very difficult to dissociate that from the psychological effects of knowing you have a chronic viral infection that could be harmful one day or that could be transmitted to others. On the other hand, cognitive dysfunction has also been linked to HCV.

These considerations cumulatively represent a compelling argument for universal treatment of HCV-infected patients. With the consideration of HCV being a systemic disease, a patient does not have to have cirrhosis or advanced fibrosis in order to be at risk for developing diabetes or premature arteriosclerosis from HCV. There is a more general concept that our culture is antithetical to the idea of withholding highly effective therapies for chronic, potentially dangerous, disease states on the basis of cost. I know there are people who would have a tremendous problem with that and will say that is how the health care system got into trouble in the first place. However, the question is: What potentially fatal disease do we not treat when it could be cured because it is too expensive to do so?

References:

Adinolfi LE. World J Gastroenterol. 2014;20:3410-3417.

Arase Y. Hepatology. 2009;49:739-744.

Backus LI. Clin Gastroenterol Hepatol. 2011;9:509-516.

Dammacco F. N Engl J Med. 2013;369:1035-1045.

Delgado-Borrego A. Clin Gastroenterol Hepatol. 2010;8:458-462.

Hsu YC. Hepatology. 2014;59:1293-1302.

Jacobson IM. Clin Gastroenterol Hepatol. 2010;8:1017-1029.

Mehta SH. Ann Intern Med. 2000;133:592-599.

Peveling-Oberhag J. J Hepatol. 2013;59:169-177.

Romero-Gómez M. J Hepatol. 2008;48:721-727.

Van der Meer AJ. JAMA. 2012;308:2584-2593.

For more information:

Ira M. Jacobson, MD, is chief of the division of gastroenterology and hepatology and Vincent Astor distinguished professor of medicine at the Joan Sanford I. Weill Medical College of Cornell University; attending physician at New York-Presbyterian Hospital Cornell Campus; and medical director of the Center for the Study of Hepatitis C. He is also a Co-Chief Medical Editor of HCV Next. Jacobson can be reached at HCV Next, 6900 Grove Road, Thorofare, NJ 08086; email: imj2001@med.cornell.edu.

Disclosure: Jacobson reports no relevant financial disclosures.