Patient ProfilePublication Exclusive

Treating the Elderly with HCV: Unique Complications, Considerations

The definition of “elderly” has been a subject of debate scientifically and in the popular press. Some regard age older than 60 years as elderly whereas conventionally those older than age 65 years merit this description.

Paul Martin

Paul Martin

With an increasing number of aging baby boomers meriting this description and living longer, and given the high prevalence of HCV in this population, we can anticipate an increasing number of HCV-infected elderly patients presenting for care.

HCV infection in the elderly has some unique features, including more rapid fibrosis progression and more likely presentation with complications. They show less elevation of ALT levels and typically have had more contraindications to interferon-based therapy. They also have competing morbidities, which may also limit access to therapy. However, with well tolerated highly efficacious regimens, more elderly patients will become candidates for therapy.

Demographics

Data published in Gastroenterology in 2010 suggested that the total number of individuals chronically infected with HCV peaked in 2001, reflecting acquisition of HCV infection in the preceding decades. Given the slowly progressive nature of HCV, it is projected that the incidence of cirrhosis will increase through 2030. Using the 1999-2002 NHANES data, Armstrong and colleagues demonstrated that 65.6% of patients with HCV were born between 1945 to 1964, with peak prevalence in the group aged 40 to 49 years. This group, is now advancing into their 50s and 60s. They comprised 4.3% of the all patients with HCV, 6.2% of men and 9.4% of black patients.

In looking at the 2003-2010 NHANES data, researchers found that people who were older than age 60 years and HCV-RNA positive were much more likely to have had a blood transfusion prior to 1992 (AOR=8.5; 95% CI, 4.5-16.3).

In the REVEAL study, it became clear that chronic HCV infection greatly increased the odds of mortality from hepatic and extrahepatic diseases, with hepatic diseases as a whole having a hazard ratio of 12.48 in patients with chronic HCV.

Natural History

As the population ages, we are getting a better idea of the natural history of HCV, with data such as the REVEAL study giving us a strong mortality endpoint. But, the impact of age does not begin only when our patients are elderly. The age they were at infection can greatly impact the progression of their disease paths.

A 2002 study showed that 33 years was the median time to cirrhosis if infected with HCV between the ages of 21 to 30 years. Yet, if a person was infected after the age of 40 years, the median time to cirrhosis was just 16 years. Another study showed that patients older than age 50 years only needed a duration of infection of 10 years to progress to cirrhosis. Men have an additional push to their fibrosis, as compared to their female counterparts with a significantly higher percentage of men progressing to cirrhosis at 40 years of infection duration.

Anti HCV

Source: Adapted from Armstrong GL. Ann Intern Med. 2006;144:705-714 

These factors have implications in the consequences of HCV in our older patients.

A 2006 study proposed that HCV in the elderly population — aged older than 65 years — is both a severe and neglected, yet curable disease.

In more than 2,000 liver biopsies, extensive fibrosis was related to age at biopsy, age of infection, higher body-mass index, diabetes and alcohol use. The data showed that 36% of patients older than age 80 years had normal ALT, as compared to 26% of patients younger than 65 years (P<.001).

Yet 14% of patients older than age 65 years presented with complications of HCV infection, while only 4% of younger patients had complications. Among those complications were hepatocellular carcinoma and hepatocellular failure, both of which were more frequent in older patients. HIV coinfection, male sex and consumption of more than 50 g of alcohol per day were also factors associated with increased complications.

Severity of HCV also increases with age, though elderly patients are understudied, according to a 2012 study.

In this study, “early elderly” patients aged 65 years to 74 years (n=1,134) and “late elderly” aged 75 years and older, 30% of patients had advanced liver disease, a factor that increased with increasing age. Approximately 40% of patients had normal transaminase levels. Excluding those with past infection, 51% did not receive any antiviral treatment and only 25% were treated after age 65 years. Late elderly patients, women and those with advanced liver disease were less likely to be treated.

In a Japanese study that spanned 3 decades, researchers found that 76.3% of patients older than 60 years were left untreated.

It was also found that those patients with higher platelet counts had better survival rates. At 10 and 15 years, respectively, cumulative survival rates in untreated elderly patients were 90.7% and 72.7% if platelets were 150,000/mm3 or higher. If platelets were lower than 100,000/mm3, survival was 53.5% and 25%, respectively.

Hepatocarcinogenesis rates also reflected platelet count. Untreated patients with low platelets showing a HCC rate of 19.5% and 43% at 10 and 15 years, respectively, while their high platelet counterparts showed rates of 5.1% and 14%, respectively.

Treatment with interferon increased survival in the low platelet subgroup (P=.0001), but did not have the same effect in the higher platelet group.

Need for Liver Transplant

As HCV-related liver disease progresses faster in older patients, the need for liver transplantation arises.

In a 2012 study, researchers identified all new adult liver transplant (LT) candidates registered with the Organ Procurement and Transplantation Network for LT between 1995 and 2010, then noted those with a primary diagnosis of HCV, with or without HCC.

Progression F4

Source: Adapted from Massard J. J Hepatol. 2006;44(1Suppl):S19-24.

When stratified by birth cohort, the data showed that the birth cohorts spanning from 1941 to 1960 accounted for 81% of all new registrants with HCV. Between 2000 and 2010, a four-fold increase was seen in new registrants with HCV and HCC.

The researchers concluded that 2015 will bring another increase in the proportion of new registrants with HCV and HCC who were born in or before 1955.

They attributed this increase in demand to the development of HCC in patients with HCV and suggested the transplant community may need to reconsider current treatment paradigms over the next 10 years.

Role of Antiviral Therapy

There are, of course, challenges to treating older patients who have HCV.

They often have more frequent comorbidities — 38% of those older than age 60 years have potential interferon contraindications, as compared with 18% of younger patients — and studies have shown lower sustained virological response achievement in older patients when using pegalyted interferon and ribavirin.

However, a 2010 study showed that while achieving SVR in older patients had a slightly less significant impact on cumulative incidence of HCC than in younger patients, eradication of the virus did have a preventive effect on HCC.

Registrants LT

Source: Adapted from Biggins SW. Liver Transpl. 2012 Dec;18(12):1471-8.

That study did conclude that aging was the strongest indicator for a nonresponse to interferon-based therapy.

In this new age of direct-acting antivirals and interferon-free treatments, more information is needed on the treatment of our elderly population. Though these regimens seem well tolerated, patients older than age 70 years are generally not included in registration trials and drug-drug interactions are a potential concern in this population.

One study suggested that older patients with less advanced liver fibrosis saw less benefit to achieving SVR and suggested these patients might await future regimens with even better tolerability.

As we consider the new treatments becoming available to our patients, we should consider how they might factor into the care of those who fall into the category of “elderly.”

References:
Armstrong GL. Ann Intern Med. 2006; 144:705-714.
Asahina Y. Hepatology. 2010 Aug;52(2):518-27.
Biggins SW. Liver Transpl. 2012 Dec;18(12):1471-8.
Carrion AF. Am J Gastroenterol. 2012 May;107(5):691-7.
Davis GL. Gastroenterology. 2010; 138(2): 513-521
Denniston, MM. Ann Intern Med. 2014; 160(5):293-300.
Gramenzi A. Dig Liver Dis. 2012; 44(8):674-80.
Ikeda K. Am J Med. 2009; 122(5):479-86.
Innes H. J Hepatol. 2014 Jun;60(6):1118-26.
Iwasaki Y. Hepatology. 2006 Jan;43(1):54-63.
Lee MH et al. J Infect Dis. 2012; 206:469-477.
Massard J. J Hepatol. 2006;44(1 Suppl):S19-24.
Minola E. Blood. 2002; 99(12):4588-91.
Poynard T. J Hepatol. 2001; 34(5):730-9.
Thabut D. Am J Gastroenterol. 2006; 101(6):1260-7.
For more information:
Paul Martin, MD, AGAF, is professor of medicine and chief of the Division of Hepatology at the University of Miami School of Medicine. He is also a member of the HCV Next Editorial Board. He can be reached at 1400 N.W. 12th Ave., Miami, FL 33136; email: pmartin2@med.miami.edu.
Disclosure: Martin reports financial relationships with Abbvie, Bristol-Myers Squibb, and Gilead Sciences, Inc.

The definition of “elderly” has been a subject of debate scientifically and in the popular press. Some regard age older than 60 years as elderly whereas conventionally those older than age 65 years merit this description.

Paul Martin

Paul Martin

With an increasing number of aging baby boomers meriting this description and living longer, and given the high prevalence of HCV in this population, we can anticipate an increasing number of HCV-infected elderly patients presenting for care.

HCV infection in the elderly has some unique features, including more rapid fibrosis progression and more likely presentation with complications. They show less elevation of ALT levels and typically have had more contraindications to interferon-based therapy. They also have competing morbidities, which may also limit access to therapy. However, with well tolerated highly efficacious regimens, more elderly patients will become candidates for therapy.

Demographics

Data published in Gastroenterology in 2010 suggested that the total number of individuals chronically infected with HCV peaked in 2001, reflecting acquisition of HCV infection in the preceding decades. Given the slowly progressive nature of HCV, it is projected that the incidence of cirrhosis will increase through 2030. Using the 1999-2002 NHANES data, Armstrong and colleagues demonstrated that 65.6% of patients with HCV were born between 1945 to 1964, with peak prevalence in the group aged 40 to 49 years. This group, is now advancing into their 50s and 60s. They comprised 4.3% of the all patients with HCV, 6.2% of men and 9.4% of black patients.

In looking at the 2003-2010 NHANES data, researchers found that people who were older than age 60 years and HCV-RNA positive were much more likely to have had a blood transfusion prior to 1992 (AOR=8.5; 95% CI, 4.5-16.3).

In the REVEAL study, it became clear that chronic HCV infection greatly increased the odds of mortality from hepatic and extrahepatic diseases, with hepatic diseases as a whole having a hazard ratio of 12.48 in patients with chronic HCV.

Natural History

As the population ages, we are getting a better idea of the natural history of HCV, with data such as the REVEAL study giving us a strong mortality endpoint. But, the impact of age does not begin only when our patients are elderly. The age they were at infection can greatly impact the progression of their disease paths.

A 2002 study showed that 33 years was the median time to cirrhosis if infected with HCV between the ages of 21 to 30 years. Yet, if a person was infected after the age of 40 years, the median time to cirrhosis was just 16 years. Another study showed that patients older than age 50 years only needed a duration of infection of 10 years to progress to cirrhosis. Men have an additional push to their fibrosis, as compared to their female counterparts with a significantly higher percentage of men progressing to cirrhosis at 40 years of infection duration.

Anti HCV

Source: Adapted from Armstrong GL. Ann Intern Med. 2006;144:705-714 

These factors have implications in the consequences of HCV in our older patients.

A 2006 study proposed that HCV in the elderly population — aged older than 65 years — is both a severe and neglected, yet curable disease.

In more than 2,000 liver biopsies, extensive fibrosis was related to age at biopsy, age of infection, higher body-mass index, diabetes and alcohol use. The data showed that 36% of patients older than age 80 years had normal ALT, as compared to 26% of patients younger than 65 years (P<.001).

Yet 14% of patients older than age 65 years presented with complications of HCV infection, while only 4% of younger patients had complications. Among those complications were hepatocellular carcinoma and hepatocellular failure, both of which were more frequent in older patients. HIV coinfection, male sex and consumption of more than 50 g of alcohol per day were also factors associated with increased complications.

PAGE BREAK

Severity of HCV also increases with age, though elderly patients are understudied, according to a 2012 study.

In this study, “early elderly” patients aged 65 years to 74 years (n=1,134) and “late elderly” aged 75 years and older, 30% of patients had advanced liver disease, a factor that increased with increasing age. Approximately 40% of patients had normal transaminase levels. Excluding those with past infection, 51% did not receive any antiviral treatment and only 25% were treated after age 65 years. Late elderly patients, women and those with advanced liver disease were less likely to be treated.

In a Japanese study that spanned 3 decades, researchers found that 76.3% of patients older than 60 years were left untreated.

It was also found that those patients with higher platelet counts had better survival rates. At 10 and 15 years, respectively, cumulative survival rates in untreated elderly patients were 90.7% and 72.7% if platelets were 150,000/mm3 or higher. If platelets were lower than 100,000/mm3, survival was 53.5% and 25%, respectively.

Hepatocarcinogenesis rates also reflected platelet count. Untreated patients with low platelets showing a HCC rate of 19.5% and 43% at 10 and 15 years, respectively, while their high platelet counterparts showed rates of 5.1% and 14%, respectively.

Treatment with interferon increased survival in the low platelet subgroup (P=.0001), but did not have the same effect in the higher platelet group.

Need for Liver Transplant

As HCV-related liver disease progresses faster in older patients, the need for liver transplantation arises.

In a 2012 study, researchers identified all new adult liver transplant (LT) candidates registered with the Organ Procurement and Transplantation Network for LT between 1995 and 2010, then noted those with a primary diagnosis of HCV, with or without HCC.

Progression F4

Source: Adapted from Massard J. J Hepatol. 2006;44(1Suppl):S19-24.

When stratified by birth cohort, the data showed that the birth cohorts spanning from 1941 to 1960 accounted for 81% of all new registrants with HCV. Between 2000 and 2010, a four-fold increase was seen in new registrants with HCV and HCC.

The researchers concluded that 2015 will bring another increase in the proportion of new registrants with HCV and HCC who were born in or before 1955.

They attributed this increase in demand to the development of HCC in patients with HCV and suggested the transplant community may need to reconsider current treatment paradigms over the next 10 years.

Role of Antiviral Therapy

There are, of course, challenges to treating older patients who have HCV.

They often have more frequent comorbidities — 38% of those older than age 60 years have potential interferon contraindications, as compared with 18% of younger patients — and studies have shown lower sustained virological response achievement in older patients when using pegalyted interferon and ribavirin.

However, a 2010 study showed that while achieving SVR in older patients had a slightly less significant impact on cumulative incidence of HCC than in younger patients, eradication of the virus did have a preventive effect on HCC.

Registrants LT

Source: Adapted from Biggins SW. Liver Transpl. 2012 Dec;18(12):1471-8.

That study did conclude that aging was the strongest indicator for a nonresponse to interferon-based therapy.

In this new age of direct-acting antivirals and interferon-free treatments, more information is needed on the treatment of our elderly population. Though these regimens seem well tolerated, patients older than age 70 years are generally not included in registration trials and drug-drug interactions are a potential concern in this population.

One study suggested that older patients with less advanced liver fibrosis saw less benefit to achieving SVR and suggested these patients might await future regimens with even better tolerability.

As we consider the new treatments becoming available to our patients, we should consider how they might factor into the care of those who fall into the category of “elderly.”

References:
Armstrong GL. Ann Intern Med. 2006; 144:705-714.
Asahina Y. Hepatology. 2010 Aug;52(2):518-27.
Biggins SW. Liver Transpl. 2012 Dec;18(12):1471-8.
Carrion AF. Am J Gastroenterol. 2012 May;107(5):691-7.
Davis GL. Gastroenterology. 2010; 138(2): 513-521
Denniston, MM. Ann Intern Med. 2014; 160(5):293-300.
Gramenzi A. Dig Liver Dis. 2012; 44(8):674-80.
Ikeda K. Am J Med. 2009; 122(5):479-86.
Innes H. J Hepatol. 2014 Jun;60(6):1118-26.
Iwasaki Y. Hepatology. 2006 Jan;43(1):54-63.
Lee MH et al. J Infect Dis. 2012; 206:469-477.
Massard J. J Hepatol. 2006;44(1 Suppl):S19-24.
Minola E. Blood. 2002; 99(12):4588-91.
Poynard T. J Hepatol. 2001; 34(5):730-9.
Thabut D. Am J Gastroenterol. 2006; 101(6):1260-7.
For more information:
Paul Martin, MD, AGAF, is professor of medicine and chief of the Division of Hepatology at the University of Miami School of Medicine. He is also a member of the HCV Next Editorial Board. He can be reached at 1400 N.W. 12th Ave., Miami, FL 33136; email: pmartin2@med.miami.edu.
Disclosure: Martin reports financial relationships with Abbvie, Bristol-Myers Squibb, and Gilead Sciences, Inc.