Dr. Sharma is from the University of Iowa – Des Moines Internal Medicine Residency Program; Dr. Habib is from the Center for Liver Disease, Iowa Health – Des Moines; and Dr. Agrawal is from the Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL.

Release Date: May 15, 2008
Expiration Date: May 15, 2009

TARGET AUDIENCE
Internists, family practitioners, geriatricians, cardiologists, and others who care for older patients.

MEDIUM USED & METHOD OF PARTICIPATION
Read the article, complete the evaluation and post-test, and return both to: NACCME via fax at (610) 560-0502. You will receive your certificate in 6-8 weeks. If you would like to print your certificate immediately, go to http://cme.naccme.com, register as a NACCME user and access the activity test and evaluation online.

SUCCESSFUL COMPLETION
Successful completion entails participants obtaining a score of at least 70% on the post-test. A certificate of completion will be mailed to the address listed on your post-test/evaluation form within 6-8 weeks of receipt of the documents.

ACCREDITATION
MD/DO:
This activity is sponsored by the North American Center for Continuing Medical Education (NACCME). NACCME is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. NACCME designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity. This activity has been planned and produced in accordance with the ACCME Essential Areas and Policies.

SPONSOR
This activity is sponsored by The North American Center for Continuing Medical Education.

DISCLOSURES
All those with control over the content of continuing education programs sponsored by NACCME are expected to disclose whether they do or do not have any real or apparent conflict(s) of interest or other relationships related to the content of their presentation(s). It is not assumed that these relationships will have an adverse impact on presentations; they are simply noted here to fully inform participants.

The authors, Drs. Sharma, Habib, and Agrawal, have disclosed that they have no significant financial relationship with any organization that could be perceived as a real or apparent conflict of interest in the context of the subject of their article.

Reviewer: Dr. Miller has disclosed no significant financial relationship with any organization that could be perceived as a real or apparent conflict of interest in the context of the subject of this article.

Editor: M. Edwards has disclosed no significant financial relationship.

All NACCME employees involved in the planning and editing of this educational activity have disclosed that they have no significant financial relationship with any organization that could be perceived as a real or apparent conflict of interest in the context of this educational activity.

CONFLICT OF INTEREST RESOLUTION-CONTENT VALIDATION
In compliance with ACCME Standards for Commercial Support and NACCME’s policy and procedure for resolving conflicts of interest, this continuing medical education activity was reviewed by a member of the Advisory Board in December, 2007 for clinical content validity, to ensure that the activity’s materials are fair, balanced, and free of bias toward the commercial supporters of the activity, and that activity materials represent a standard of practice within the profession in the U.S. and that any studies cited in the materials upon which recommendations are made are scientifically objective and conform to research principles generally accepted by the scientific community

LEARNING OBJECTIVES
Upon completion of this educational activity, participants should be able to:
1. Explain the epidemiology of chronic hepatitis C virus infection in the older adult.
2. Discuss the clinical course of chronic hepatitis C virus and its distinctive progression in older adults, including effects on the aging immune system.
3. Recognize the importance of screening techniques, early intervention, and disease monitoring for hepatitis C virus infection.
4. Understand current guidelines for treatment and management of chronic hepatitis C virus in light of comorbid conditions in the older adult.

Introduction
Hepatitis C virus (HCV) is a leading cause of chronic liver disease. Hepatitis C virus is a public health problem with great impact on individuals, the healthcare system, and healthcare resources. However, few studies have looked at aspects of pathogenesis and treatment of this disease in old age. The management of liver disease in the elderly may differ in some aspects from management in younger patients. The aim of this review is to highlight the data on the epidemiology and clinical manifestations of chronic HCV infection in older adults, and to discuss the problems and solutions in the clinical management of the infection in this population group.

Epidemiology
Hepatitis C virus infection is a leading cause of chronic liver disease in the United States. The Centers for Disease Control and Prevention estimates that the number of new cases of acute HCV infection in the United States has fallen from approximately 230,000 per year in the 1980s to its current level of approximately 20,000 cases per year.1 Chronic hepatitis C accounts for 8000 to 13,000 deaths each year, and the majority of liver transplants performed in the United States are due to chronic hepatitis C.

The prevalence of antibodies to HCV (anti-HCV) in the United States is approximately 1.6% (equating to approximately 4.1 million anti-HCV–positive persons), according to the most recent National Health and Nutrition Examination Survey (NHANES).2 The prevalence of positive HCV RNA was approximately 1.3% (or approximately 3.2 million persons who are HCV RNA-positive). The prevalence of seropositivity in the general population (age > 6 yr) was found to be the lowest among persons younger than age 29 years (0.4%) in the 1999-2002 NHANES.3 The highest rate of infection was observed in the cohort age 45-49 years (7.1% among men and 2.3% among women).3 The NHANES also showed an anti-HCV prevalence of 0.9% in persons older than age 60 years, and a peak greater than 4.0% in age-specific prevalence, which shifted from persons between 30 and 39 years of age to persons between 40 and 49 years of age during the last decade.2
Chronic infection is more prevalent and may be more severe in the elderly population. Epidemiological studies indicate an increase in prevalence of anti-HCV with age. It is estimated that the number of people who have been infected with HCV for more than 20 years will increase fourfold between 1990 and 2015.4 Also, over the next two decades, HCV-related mortality rate will likely double or even triple.4

Two of the major routes of transmission for HCV infection globally are blood transfusion and unsafe therapeutic injections (unsterile needles and/or multiple injections with the same needle, especially in the developing world). Infection in the elderly was most probably acquired during the 1960s-1980s from exposure to blood or blood products.5 Infection in young people is mainly due to high-risk behavior and needle-sharing among intravenous drug users.
Hepatitis C virus comprises a heterogeneous group of RNA viruses.6 There are six major genetic groups and a number of subtypes that are more closely related. Various studies have looked at the HCV genotype distribution among different age groups. In a survey of patients with chronic hepatitis C in the United States, no difference in age was seen among patients infected with HCV types 1, 2, and 4, and patients infected with HCV type 3 were younger than patients infected with types 1 and 2.7 In Italy and France, Nousbaum et al8 reported that infection with genotype 1b constituted 30.8% of infections with HCV in patients younger than 40 years and increased to 82.3% of cases older than 60 years of age.

Simmonds and colleagues9 found that infection with genotype 3 was more common in the younger age group, whereas infection with types 1 and 2 increased with increasing age among patients with chronic hepatitis C from western European countries. In a study from Saudi Arabia, 62% of patients with chronic hepatitis were found to be of genotype 4. Other genotypes were 1 (24.1%), 2 (7.4%), 3 (5.9%), 5 (0.3%), and 10 (0.3%). There were no differences in distribution patterns between sexes and ages. Patients with diabetes and those with a history of blood transfusion had the same pattern as those with community-acquired HCV. Among the non-Saudi Arabians (mostly Egyptians), genotype 4 predominated (88%).10

In a study from Europe, HCV genotype distribution was studied among age groups in 501 referred patients with chronic hepatitis C.11 Ten patients had coinfection with several genotypes. Two hundred seventy of 491 singly infected individuals (55%) had 1b, 66 (13.4%) 3a, and 57 (11.6%) 1a. Hepatitis C virus subtype 1b was predominant, but its prevalence increased with age (76.5% of patients born in the 1920s, 39.3% in the 1970s) (P < 0.0001). The authors also concluded that the 1b genotype seemed to be the oldest subtype, while others were imported later through increased population movements and changing habits.11

There is also some evidence that in the United States, men and patients of Latino ethnicity have a slightly higher incidence of acute infection. When compared with Caucasians, the incidence of acute infection in African Americans is similar, but African Americans appear to be at higher risk of developing chronic infection (95% vs 85%).12 The burden of HCV infection is expected to increase as the patients with ongoing long-term infection age and become subject to complications of chronic liver disease.

Clinical Course of Chronic Hepatitis C in the Elderly
Chronic hepatitis progresses by the development of regenerative nodules and hepatic fibrosis. Patients with high-grade necroinflammatory scores or high stage of fibrosis have a higher risk of developing cirrhosis than patients without these histological features.13 Several studies have provided estimates of the proportion of patients with chronic infection who develop cirrhosis.14 Chronic hepatitis C develops in 55-85% of individuals infected with HCV. Rates of persistence of HCV infection vary between studies. Among persons infected during childhood or young adulthood, the rate of HCV clearance is probably higher than that rate among persons infected at an older age.15 A study in France comparing chronic HCV infection in patients older than age 65 years with infection in younger patients demonstrated that the older group had a significantly longer duration of infection (26 yr vs 20 yr), a higher age at infection (50 yr vs 24 yr), higher rates of genotype 1 infection (78% vs 57%), and increased likelihood of a history of transfusion (51% vs 29%).16 In the same study, the fibrosis stage among those who underwent liver biopsy was higher for those older than age 65 years, regardless of the duration of infection. The initial manifestation of infection was also more complicated (ascites, bleeding, jaundice, and hepatocellular carcinoma [HCC]) in persons older than age 65 years than in those younger than age 65 years (14% vs 4%).16

Most elderly people have coexisting diabetes, dyslipidemia, and other metabolic conditions that are correlated to chronic liver disease. Insulin resistance and type 2 diabetes mellitus play a role in the alteration of the natural course of HCV infection, leading to enhanced steatosis, steatohepatitis, and liver fibrosis.17 There have been several case-control studies depicting the correlation between HCV infection and type 2 diabetes mellitus. There is no specific difference between HCV genotypes 1 and 2 in the association with type 2 diabetes mellitus. The biological mechanism underlying insulin resistance or type 2 diabetes mellitus in HCV infection remains unclear. A high level of tumor necrosis factor-alpha is considered one of the reasons for insulin resistance, which acts by disturbing tyrosine phosphorylation of insulin receptor substrate-1, a central molecule of the insulin-signaling cascade. These findings provide direct experimental evidence for the contribution of HCV in the development of insulin resistance and in the pathogenesis of type 2 diabetes mellitus.18

Among HCV-infected individuals, not only does cirrhosis become more prevalent with age, but the median time for development of cirrhosis also decreases as the age of infection onset increases.19 In a study by Minola et al,19 the median time to development of cirrhosis was decreased from 33 years for persons age 21-30 years at the time of infection to 16 years for persons older than age 40 years. The interval between infection and diagnosis of HCC may be shorter when the infection is acquired at an older age.20 In another study by Tong and colleagues21 involving patients with post-transfusion hepatitis C, the mean time from transfusion to development of HCC was 14.7 years among persons older than age 50 years at the time of the transfusion (mean age, 58.5 yr), as compared with 31.5 years among those infected at younger than age 50 years (mean age, 29.2 yr).21 In patients with chronic hepatitis C, there are differences also in the rate of progression of fibrosis according to age at the time of infection.

Tong et al21 also studied other clinical outcomes after transfusion-associated hepatitis C, and found that among patients who were 50 years of age or older at the time of the transfusion (average age, 58.5 yr), the average time from the transfusion to the development of chronic hepatitis, chronic active hepatitis, and cirrhosis was 6.3, 10.7, and 9.8 years, respectively. Among patients who received the transfusion before the age of 50 (average age, 29.2 yr), the average time to the development of these diseases was 15.9, 20.4, and 23.6 years, respectively. In a study by Poynard and colleagues,22 fibrosis progression was rapid for those older than age 50 years, as compared to those who were younger than age 20 years at the time of infection who were found to have a slow progression during the subsequent 10 years.
A National Heart, Lung, and Blood Institute study looked at the mortality rates in two groups of patients: one with post-transfusion hepatitis C (mean age at transfusion, 49 yr) and the other without hepatitis C who had undergone transfusion.23 All-cause mortality was similar in the two groups (67% vs 65%, respectively), although there was a difference in liver-related mortality (4.1% vs 1.3%, respectively).

Age has also been shown to be associated with psychological symptoms that accompany chronic HCV infection.24 Cognitive impairment has been associated with chronic HCV infection in patients age 28-69 years with mild liver disease.25 There are no defined data on the prevalence of cognitive impairment among older patients, who may have a higher likelihood of this complication. These symptoms may appear even in the absence of clinically significant liver disease. Because of the increased prevalence of these psychological symptoms like depression, fatigue, and cognitive impairment among the elderly population, it is possible that they may be overlooked in those with HCV infection or may not be attributed to the disease.

Possible Reasons for Differences in Progression of Liver Disease in Older Adults
The mechanisms underlying the relatively rapid progression of liver disease in older adults are not properly understood. These differences may be due to the reason that the duration of the infection in older people is much longer, and so the liver cirrhosis and other complications may have already developed by that time. In addition, older patients with mild hepatic disease are not referred for evaluation because they often are asymptomatic. Possible mechanisms for the role of aging in fibrosis progression include higher vulnerability to environmental factors (especially oxidative stress), reduction in the rate of hepatic blood flow, and reduced mitochondrial capacity.22 The risk of HCC increases significantly with age, probably due to age-related changes in the ability to repair DNA.26 A significantly higher viremic load seen in older patients may be explained by the higher prevalence of genotype 1 among elderly persons,27 as well as impaired immunity.28 Several other studies have also shown that there is a decline in liver volume and a reduction in hepatic blood flow with age. Hepatic concentration of smooth endoplasmic reticulum, yield of liver microsomes, and the activity of several microsomal enzymes also decrease with age.29 The number of mitochondria in liver cells also decreases with age.30 Many pharmacokinetic studies have documented a decline in the hepatic clearance of many drugs metabolized by the liver as one ages.31 For patients who have undergone liver transplantation for hepatitis C, donor age rather than recipient age has a major influence on rate of liver fibrosis after transplantation.32 This also supports the reasoning that age-related changes in liver response might be a key factor that determines the increased susceptibility of the older liver to fibrosis.

Alterations in the cytokine profile that occur during aging may affect the course of chronic liver disease in elderly persons.33 Regenerative capacity of the liver also undergoes age-related changes. The decreased ability of the liver to recover after a severe viral or toxic injury in the elderly may be explained by a significant decrease in the regenerative capacity of the liver with increasing age.34 Preexisting chronic diseases may contribute to the increased side effects associated with aging in HCV-infected patients who are treated with antiviral medications.

Modulation of the Immune System by Chronic Hepatitis C
Hepatitis C virus infection in the older population is associated with a reduction in specific immunologic response. In addition, it may be accompanied by the emergence of new viral variants.35 The changes in the immune system that take place with the aging process may also have an impact on the persistence of infection and chronic disease in elderly persons. There is a general decline in T cell function in response to a viral infection with aging with a shift from a Th1 to a Th2 cytokine response.36 Repeated antigenic challenges to CD8+ T cells may lead to anergy, rather than effective memory.37 Several reports describe a gradual decline in the ability of the immune system to protect the host from pathogens and tumors. The age-related immune dysfunction may result from a decrease in the number and function of naïve T cells, resulting mainly in a reduced capacity to produce interleukin-2. Aging also produces a defect in T cell receptor signal transduction and activation. Elevated interleukin-6 levels that occur with aging may also affect the severity of liver inflammation.38

Screening
Old age has been shown to be associated with more severe histological damage at the onset of infection. Age at presentation and fibrosis stage have been shown to be predictors of HCC. Acquisition at a young age appears to result in a slower pace of progression to cirrhosis, while acquisition at an older age with a faster progression. On the other hand, longer duration of infection would also increase the risk of HCC in older patients who had acquired HCV at a young age, regardless of time of diagnosis or referral.39 Early intervention including disease monitoring should be initiated in patients with chronic HCV in order to slow progression to cirrhosis and reduce development of HCC. Routine screening for HCV antibody should be directed toward any group with a prevalence rate that is greater than that of the general population. However, all patients with a history of transfusion of clotting factor before 1987, patients who received blood products or an organ transplant before 1992, patients with a history of injection drug use, chronic dialysis recipients, infants born to mothers with HCV, and any patient with clinical evidence of liver disease should be screened (Table I).15 Also, all patients with HIV disease should be tested.40

Alanine aminotransferase (ALT) is a marker of liver inflammation, and the usefulness of the test remains controversial. There is no correlation between degree of ALT elevation and natural history of HCV. Patients with persistently normal ALT (defined as normal on more than 1 visit separated by 6 months), however, represent 30% of patients who present with chronic HCV. In general, these patients have a more benign disease course. In a study among patients older than age 65 years, the prevalence of elevated ALT levels was found to be similar to that in younger patients despite the higher rate of fibrosis and necrosis.16 Serum ALT levels in patients older than age 50 years with liver biopsy confirmed severe chronic hepatitis C were lower than those in younger patients with the same degree of liver inflammation, according to liver biopsy.41 This should be considered when using serum ALT levels to evaluate the degree of liver inflammation in older adults.

There has been an enormous interest in finding alternative tests or models that would yield the same information obtained from biopsy. Some physicians are reluctant to perform liver biopsy for elderly patients because of the presumed increased risk for complications. A study by Wai et al42 demonstrated that the use of a simple noninvasive index that measures the aspartate aminotransferase to platelet ratio index was able to predict significant fibrosis and cirrhosis with a high degree of accuracy. Cirrhosis was predicted accurately in 81% of patients.42 The results of this study are promising, but significant fibrosis (defined as Ishak score of 3 or more) was predicted in just more than half.42 FibroTest-ActiTest™43 combines the quantitative results of six serum markers—levels of alpha 2-macroglobulin, haptoglobin, gamma-glutamyl transpeptidase, total bilirubin, apolipoprotein A1, and ALT—together with age (the higher the age, the greater the score44) and sex to estimate fibrosis stage and necroinflammatory activity grade. It provides a quantitative estimate of liver fibrosis and inflammation that corresponds to other commonly used scoring systems of fibrosis staging and necroinflammatory activity grades (Table II).45 Another panel of serum markers, FIBROSpect II® (Prometheus),46 uses the combination of hyaluronic acid concentration, levels of tissue inhibitors of metalloproteinases, and alpha 2-macroglobulin level. In a study of patients with chronic hepatitis C, the prevalence of severe fibrosis estimated by FibroTest-ActiTest was 73% among patients older than age 65 years, as compared with 35% among younger patients.16 Another method for assessing fibrosis is transient elastography (FibroScan®), which measures liver stiffness through pulse-echo ultrasonography.44 In patients with chronic hepatitis C (mean age, 51 yr), results of a combination of FibroScan and FibroTest-ActiTest correlated very well with the results of liver biopsy.44 Studies examining the validity of the FibroTest-ActiTest versus that of liver biopsy for patients with chronic hepatitis C have generally not included elderly patients.47 Further evaluations of these methods in studies that include elderly patients are needed.

Treatment
According to current guidelines, the treatment of choice for chronic hepatitis is provided by a combination of pegylated interferon (pegIFN) alfa (-2a or -2b) plus ribavirin.48,49 Indications for therapy include elevated/normal ALT, necroinflammation and fibrosis on liver biopsy, HCV RNA-positive, extrahepatic manifestations (renal disease, cryoglobulinemia, porphyria cutanea tarda), and patient preference. Absolute contraindications to therapy include severe uncontrolled depression, unstable cardiac disease, uncontrolled concomitant disease, pregnancy, hemolytic diseases, renal disease or creatinine greater than 2 mg/dL, and seizure disorder. Relative contraindications to therapy include active drug and alcohol use, moderate depression/situational suicidal ideation, decompensated liver disease, and autoimmune diseases.50 Sustained virologic response (SVR) is reached in 54-63% of patients in several large, multicenter, randomized trials.51-53 Data from these meta-analyses and other large, randomized, clinical trials of this combination therapy show that different rates of response are associated with several different factors. Among these, age older than 40 years has been shown to be an independent predictor of reduced SVR.52-55 In a recent retrospective study aimed at evaluating the influence of antiviral therapy in long-term outcome of patients with chronic hepatitis C with bridging fibrosis and cirrhosis (METAVIR F3-F4), the cumulative incidence of hemorrhage, ascites, and HCC were compared between patients who did or did not develop SVR. The mean age in the study was 55 ± 10 years. Median follow-up period was 5 years after the first biopsy and 2 years after the last treatment. Sustained virologic response was not associated with age or body mass index. Also, the authors noted that in patients with bridging fibrosis (F3) and cirrhosis (F4), antiviral therapy is associated with significant regression of fibrosis and long-term improved outcome with lower rates of complications of cirrhosis and HCC.49
The American Association for the Study of Liver Diseases guideline does not stipulate an upper age limit for antiviral therapy.51 In practice, however, elderly patients are less referred and considered for treatment. In large, multicenter, randomized trials of therapy with pegIFN and ribavirin (cohorts with a mean age of 42-43 yr), older age has been shown to be associated with a poorer response to treatment. On multivariate analysis, age older than 40 years was an independent predictor of poor response (odds ratio [OR], 2.60, for SVR of those less than age 40 yr).53 In addition, it is generally agreed that adult patients who have failed to respond or have responded only temporarily to IFN alone should be offered a combination of IFN and ribavirin, unless they have major contraindication to such therapy. There are no conclusive data on re-treatment rates in the elderly because the numbers of older patients that have been involved in these studies have been too few. It is still not clear though whether the efficacy of pegIFN alfa and ribavirin in patients with chronic HCV who are older than 65 years is the same as or worse than for patients in the 40-65-year age group.56

It is still inconclusive whether the dose of pegIFN alfa-2a should be modified for elderly people. A study involving healthy subjects age 20-80 years revealed similar pharmacokinetics of pegIFN alfa-2b in all age groups.57 Another study found that absorption of pegIFN alfa-2a was delayed and its half-life prolonged in elderly persons.58 PegIFN alfa-2a is also a mild inhibitor of cytochrome P-450, which metabolizes drugs such as tricyclic antidepressants, theophylline, and risperidone, among others, that are frequently used in this population age group.59

A common adverse effect of ribavirin is reversible hemolytic anemia. Incidence of hemolytic anemia due to ribavirin increases with age; dose reduction or ribavirin discontinuation were reported to be more frequent in patients age 55 years or older.60 Dose reduction is recommended when the hemoglobin level is less than 10 g/dL, and therapy cessation is recommended when the hemoglobin concentration decreases to less than 8.5 g/dL. Kidneys excrete a large amount of the ribavirin, and so the risk of toxic reaction to this drug may be greater for patients with impaired renal function. Ribavirin should not be administrated to patients with a creatinine clearance of less than 50 mL/min/1.73m2, and should be used cautiously in elderly patients by monitoring their renal function with dosage adjustments made accordingly. Studies have shown that epoetin alfa at 40,000 U weekly can maintain ribavirin dose, improve hemoglobin by a mean of 2 g/dL, and improve quality of life in patients with IFN/ribavirin-induced anemia.61 In this population, the serum creatinine level might remain normal as the glomerular filtration rate decreases, and estimation of creatinine clearance should be done using equations that use age as a variable (Cockroft-Gault).62
Current guidelines suggest that regarding treatment, only patients who have liver involvement more severe than portal fibrosis, with at least moderate inflammation and necrosis and a significant risk of liver cirrhosis during their estimated life expectancy, should be considered candidates for therapy. Most of the current recommendations for treatment are based on large, multicenter, randomized, controlled studies that have excluded patients older than age 65 years.63 They have also excluded patients with dementia, depression, and anemia or decompensated liver disease and other renal, coronary, and cerebral vascular diseases, which are common in elderly persons. Therefore, the treatment of patients older than age 60 with chronic hepatitis C has not been well studied. Progression to cirrhosis and end-stage liver disease can possibly be avoided in many older patients if treated. Physicians are also hesitant to treat elderly patients with chronic hepatitis C because of the fear of complications that older individuals are unlikely to tolerate. Despite an initial biochemical response to IFN alfa alone in 50% of patients, only approximately 10% to 15% of treated patients achieve a SVR. Poynard et al64 performed a meta-analysis of randomized trials (17 trials vs controls and 16 trials comparing different IFN regimens). The mean age of subjects in most of those trials was younger than 50 years. Three reports have dealt specifically with IFN alfa treatment in elderly patients with chronic hepatitis C. All three reports used a serum biochemical response as the criterion for determining the efficacy of IFN alfa.27,65,66 Bresci and colleagues65 found similar rates of biochemical response and side effects in 22 patients age 65 years and older and 21 patients younger than age 65. Similar results were found by Van Thiel et al66 in small groups of patients with HCV. Any viremia was not investigated in these studies and rate of SVR is not reported. Responses were classified as full if the ALT level was normal, and partial if the ALT fell by greater than 50% but was still abnormal after 6 months of therapy. All other responses were defined as failures. In the Van Thiel et al66 study, response rates to IFN among 25 older (age > 65 yr) and 25 younger (mean age, 44 ± 1 yr) anti-HCV–positive chronic hepatitis patients were similar. Side effects of IFN were similar in the older and younger groups. A limitation of this study is that some young subjects with mild hepatic disease may have been excluded since the severity of liver disease in patients with chronic HCV infection increases with age.
Horiike and colleagues27 also did not find a significant difference in the percentage of SVR between the two groups they treated: one with 19 patients older than age 60 years (average age, 62.5 yr) with IFN, and the other with 52 younger adults (average age, 44.1 yr). All of the patients were followed for 24 weeks after IFN treatment. In this study, there was no difference in HCV genotype distribution between the older and the younger groups. However, the HCV RNA titer was significantly higher in the older group, and the incidence of severe fibrosis in liver biopsy was significantly higher in the older group. Complete response (continuous normalization of ALT for 24 wk after IFN therapy) was achieved in five of 19 in the older group (26%) in comparison with 17 of 52 (33%) in the young group. After standardization of background factors (HCV RNA titer, HCV genotype, and liver histology), there was no significant difference in the efficacy of IFN therapy between the older and younger groups. These observations suggest that elderly patients with chronic hepatitis C can be treated safely with IFN alfa, with efficacy rates similar to those achieved in younger individuals.

Recently, a retrospective study by Antonucci et al67 evaluated the effect of age on the treatment of chronic HCV hepatitis with pegIFN alfa plus ribavirin in a hospital-based cohort of adult patients with a consistent proportion of subjects older than age 65 years. An endpoint of the analysis was a SVR to antiviral treatment. After adjusting for potential confounders, the authors found that patients older than age 40 years had a significantly lower chance of achieving a SVR as compared with younger patients. Patients age 40-49, 50-64, and older than age 65 showed similar lower rates of SVR. This significant effect of age on SVR was maintained only in the subgroup of patients infected with HCV genotype 1 or 4. Among patients with HCV genotype 1 or 4, authors also observed greater adjusted odds of relapsing in those older than age 40 years. Side effects were more frequent in older patients, although only dermatitis reached statistical significance. The overall frequency of dose reduction or withdrawal was low, and it was similar among different age groups, and so a greater risk of side effects did not seem to have played any significant role in determining the lower efficacy of treatment in patients older than age 40 years. Interestingly (as in several recent clinical trials aimed at evaluating the efficacy of different schedules of combination therapy with pegIFN alfa in HCV patients with genotype 2 or 3), no association was found between age and SVR in this study. Some of the possible limitations of this study include its retrospective design and possible selection bias. Greater risk of adverse events combined with a low perceived benefit of therapy may explain the smaller proportion of older patients treated in comparison to younger patients. Older patients were more likely to be selected for therapy if physicians felt they would be relatively better candidates than younger patients.67

In another recent study by Ikeda and colleagues68 aimed at evaluating the IFN treatment in the elderly (= 60 yr), a large cohort of patients was analyzed with chronic hepatitis C from viewpoints of hepatocellular carcinogenesis and survival period. Four hundred fifty-nine elderly patients began IFN therapy before development of liver cancer. The elderly cohort was observed for a median period of 6.3 years. The results were as follows: cumulative survival rates in the untreated elderly population without overt cirrhosis were 94% at the end of the 10th year and 79% at the 15th year in the high platelet (= 150,000/mm3) group, 87% and 73% in the intermediate group (100,000-149,000/mm3) group, and 71% and 36% in the low platelet group (< 100,000/mm3), respectively. Fifth and 10th year hepatocarcinogenesis rates in the intermediate and low platelet groups (< 150,000/mm3) were 12% and 22% in the IFN group (n = 85) and 19% and 43% in untreated group (n = 474), respectively (P = 0.028). On multivariate analysis, IFN independently decreased carcinogenesis risk with a hazard ratio (HR) of 0.53 (P = 0.012) in these subgroups. Interferon treatment significantly increased cumulative survival rates in the subgroup of lower platelet group (P = 0.0028) but did not affect in the subgroups of higher platelet (P = 0.20). On multivariate analysis, it was also shown that IFN was significantly associated with a longer survival in the lower platelet subgroup (HR = 2.44; P = 0.011). This study showed that IFN for a subgroup of intermediate and low platelet count had significant advantages from the viewpoints of hepatocellular carcinogenesis and survival period. Also, initial platelet count is significantly associated with survival time in patients with chronic hepatitis C.68

Future Directions
Taribavirin, a liver-targeting prodrug of ribavirin, may be safer than ribavirin.69 The combination of pegIFN and taribavirin therapy in a randomized, controlled study involving patients with a median age of 49 years (range, 23-68 yr) had the same efficacy as pegIFN and ribavirin therapy, but the incidence of anemia was 4% (5 of 135 patients) in the study group and 27% (12 of 45 patients) in the comparison group.70 Treatment with taribavirin may be an alternative to ribavirin therapy, especially for persons with anemia. Novel antiviral drugs, such as protease inhibitors,69 that may have fewer adverse effects may serve as potential alternatives. Further investigation is required to assess efficacy of these medications in older adults.

Importantly, despite the adverse effects of treatment with pegIFN and ribavirin, adherence to the therapy (defined as consumption of greater than 80% of the dose greater than 80% of the time) is crucial to achieve a virologic response.71 Adherence to the treatment regimen among patients older than age 56 years was less than that among younger patients.71 Based on murine model study there may be a possibility of an immunotherapeutic approach for treatment of HCV.72 There may be also be a possible clinical application of monoclonal antibodies for prevention of primary infection in transplanted livers.72 It may be worthwhile to investigate the possibility of treatment of HCV-infected elderly persons with decreased doses of drugs, thereby reducing the risk of adverse effects. Hepatitis C vaccine is not yet available. Vaccines designed to augment the immune response to HCV are in development. A pilot study of one candidate vaccine suggested a possible benefit on liver histology and improvement in serum aminotransferases.73 Hypervariable regions of the HCV genome, high rates of mutations, and an obscure humoral response are all challenges facing development of an effective HCV vaccine.

Conclusions
Despite the decrease in the incidence of acute hepatitis C, the prevalence of long-standing chronic hepatitis C infection is increasing among older adults. Ideally, the patient should get treatment for chronic HCV infection to decrease mortality risk and improve hepatic decompensation free survival; however, at present there are no clear guidelines regarding treatment for HCV infection in elderly patients. Efficacy and beneficial effects of treatment remain unknown in this population. Appropriate duration of treatment in elderly patients is also unknown. Decision for treating elderly patients with chronic hepatitis C should be made very cautiously, as treatment with pegIFN and ribavirin may impair quality of life and prove fatal. The degree of liver fibrosis should be assessed before consideration of therapy because of the higher risk of adverse effects from antiviral treatment in elderly persons. We suggest that optimal treatment with pegIFN alfa plus ribavirin can be safely extended to elderly patients with aggressive disease (stage 2 or above) without hepatic complications, who already have good quality of life, have a higher expected sustained viral response, and an absence of other comorbid problems such as poorly controlled diabetes mellitus, alcoholism, obesity, coronary heart disease, and significant psychiatric problems. Thorough screening for above-mentioned conditions is prudent to avoid complications. Alcohol abuse reduces the responsiveness to IFN, accelerates disease progression, and increases the risk of HCC. Patients with chronic hepatitis C should be counseled not to drink alcohol.

Further studies are needed to better assess the efficacy of a prolonged period of treatment in patients older than 40 years (specifically with genotype 1 or 4) to reduce their relapse rate. Screening for HCC by liver ultrasonography and alpha-fetoprotein determination every 6 months is recommended for all patients with chronic HCV infection and cirrhosis, unless they have a limited life expectancy or contraindications to HCC treatments. Surveillance for HCC in patients older than 70 years of age with chronic HCV infection and cirrhosis improves survival. There is a need for research on treatments with efficacy that at least matches that of pegIFN and ribavirin but with fewer adverse effects. Protease inhibitors, as well as immunotherapy, may be possible future treatment modalities. The efficacy and tolerability of combination therapy in patients with chronic hepatitis C older than age 65 should be evaluated in large-scale prospective studies. Until then, the treatment decisions should be individualized based on the severity of the liver disease, potential for serious adverse effects, likelihood of treatment response, and presence of comorbid conditions.

References
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