Thursday, June 28, 2012

Viral Hepatitis in the Elderly

From The American Journal of Gastroenterology
Viral Hepatitis in the Elderly

Andres F Carrion MD; Paul Martin MD; FACG

Posted: 06/28/2012; The American Journal of Gastroenterology. 2012;107(5):691-697. © 2012 Nature Publishing Group

Abstract and Introduction

As life expectancy continues to rise, elderly adults represent a rapidly growing proportion of the population. The likelihood of complications of acute and chronic liver disease and overall mortality are higher in elderly populations. Several physiological changes associated with aging, greater prevalence of co-morbid conditions, and cumulative exposure to hepatotropic viruses and environmental hepatotoxins may contribute to worse outcomes of viral hepatitis in the elderly. Although pharmacotherapy for hepatitis B and C continues to evolve, the efficacy, tolerability, and side effects of these agents have not been studied extensively in elderly adults. Immunization against hepatitis A and B in naïve elderly adults is an important public health intervention that needs to be revised and broadened.

Viral hepatitis has some unique clinical characteristics in older individuals who comprise an increasingly large segment of the US population. According to data from the US Census Bureau 12.7% of the US population is older than 65 years of age. The "Baby Boom" generation refers to individuals born between 1946 and 1964 and is the largest birth cohort in the US history, reflecting a marked increase in births following World War II. As the first Baby Boomers started turning 65 in 2011, the US Census Bureau projects that the elderly population will increase twofold by 2030 (72 million people) and will comprise ~20% of the US population.[1–3] There are important differences in the epidemiology, clinical presentation, and management of viral hepatitis in the elderly compared with younger individuals. For example, acute hepatitis A is more clinically severe in older individuals and, although acute hepatitis B and C are most commonly recognized in young adults with high-risk behaviors, acute infection can also occur in the elderly. With the aging of the cohort of individuals chronically infected with hepatitis C, it is anticipated that there will be an increasing burden of decompensated cirrhosis and hepatocellular carcinoma (HCC) for the next two decades.[4] It is also well established that elderly individuals with viral hepatitis have higher mortality rates than younger patients, reflecting in part a higher prevalence of co-morbid conditions.[5] Furthermore, physiological changes associated with aging, such as diminished immune response ("immune senescence"), metabolic derangements, nutritional deficiencies, and greater cumulative exposure to environmental hepatotoxins may also contribute to worse outcomes of viral hepatitis in the elderly.[6] Among the multiple age-related changes of the liver, significant reductions of up to 30–40% in parenchymal volume, liver blood flow, and perfusion have been noted.[7] Although there are no age-specific alternations in serum bilirubin levels, aminotransferases, and fractionated alkaline phosphatase levels, the hepatic metabolism of multiple substances (i.e., hepatic nitrogen clearance and aminopyridine demethylation) may be significantly impaired (up to 50%) with advanced age.[8] The age-related decline of liver regeneration has been described in animal models in which the mitogenic capacity of hepatocytes is reduced with aging (up to 70% lower than in younger animals).[9] This finding has also been recently corroborated in humans with significant reductions in liver regeneration noted in individuals older than 50 years compared with younger adults undergoing living donor liver transplantation.[10]

Hepatitis A
The age-specific incidence of hepatitis A virus (HAV) infection in children and adults in the United States declined rapidly following implementation of vaccination of children and individuals at risk.[11] Data from 2009 published by the Centers for Disease Control and Prevention demonstrate a low incidence of acute HAV infection of 0.6 per 100,000 people.[12] The seroprevalence of anti-HAV immunoglobulin (Ig) G, a marker of prior infection with HAV, increases proportionally with age reflecting a cumulative risk of HAV infection throughout life. Data from the third National Health and Nutrition Examination Survey (NHANES III) indicate that 31% of the overall US population had serological evidence of prior HAV infection (data collected before implementation of HAV vaccination): 9% of children aged 6–11 years, 19% of young adults aged 20–29 years, 33% of middle age adults aged 40–49 years, and 75% of those older than 70 years of age.[13]
Recovery from acute HAV infection is usually uneventful, especially in children and younger adults in whom the infection is often subclinical.[14] However, elderly individuals with acute HAV are likely to have more profound hepatocellular dysfunction with frequent jaundice and coagulopathy, as well as a higher incidence of complications such as prolonged cholestasis, pancreatitis, and ascites.[15,16] Multiple factors have been implicated in the greater severity of HAV infection in the elderly. Of these putative factors, an attenuated immune response due to age-related qualitative impairment of cell-mediated immune function has been postulated to be the most significant.[15] The more severe clinical course of HAV in the elderly is reflected in higher hospitalization rates and mortality. For example, during an outbreak of HAV infection in Memphis, TN, USA (1994–1995) 42% of individuals aged 70 years or older required hospitalization compared with 3–20% of adults aged 40–49 years.[17] Epidemiological data from the United Kingdom reveals mortality rates from HAV infection in individuals older than 75 years as high as 15%, which markedly contrasts with the very low mortality in adults aged 25–35 years (0.03–0.06%).[18] Case fatality rates due to HAV infection in the United States between 1983 and 1987 were lower than in the United Kingdom; however, age-related differences in outcomes were similar with 0.004% deaths in the 5–14 years of age group, and 2.7% in adults older than 49 years.[15,19] More recent data from the Centers for Disease Control and Prevention (2004–2007) show a downward trend in mortality from hepatitis A as the cause of death in all age groups. Importantly, the largest reduction in mortality associated with acute HAV infection (~50%) between 2004 and 2007 was observed in elderly adults aged ≥75 years. These data also confirm that mortality due to HAV increases with age with no fatalities reported in individuals younger than 34 years of age, 0.05 per 100,000 adults aged between 45–54 years, and 0.11 per 100,000 adults ≥75 years of age.[20] Higher mortality in elderly individuals was also noted during a HAV outbreak in Dallas County, TX, USA in 1999. Of the 232 reported cases of HAV, 25% occurred in individuals older than 60 years of age and the only two fatalities reported were in individuals older than 70 years.[15] Overall, the basis for worse outcomes in the elderly is thought to be multifactorial and influenced by higher prevalence of co-morbid conditions, decline in immune function, and reduced regenerative capacity of the liver with advanced age.[21] There are no specific data about age-related differences of the antibody-mediated response against HAV in the elderly; however, evidence suggests that older individuals have decreased antibody affinity against antigens in general.[22]

Although no formal recommendations from the Centers for Disease Control and Prevention for HAV vaccination in elderly adults have been issued, individuals without serological evidence of immunity to HAV should be considered candidates for immunization.[8] Data from the NHANES III indicate that the seroprevalence of anti-HAV IgG is >33% in adults older than 40 years of age in the United States; therefore, prevaccination screening for serological evidence of HAV immunity may be a cost-effective strategy.[13,23] In general, seroprotection from HAV vaccine is inversely related to age at the time of immunization. For example, 100% seroprotection has been reported in adults aged 18–45 years vs. 93% in adults older than 60 years of age based on the development of anti-HAV IgG antibodies following two doses of HAV vaccine.[21] In developed countries, HAV infection in adults has become less common; however, international travel, particularly to developing countries, remains a significant risk for acquisition. The median age of travelers from areas of low endemicity to areas of high endemicity is >40 years of age.[24] In addition, outbreaks of HAV infection continue to occur within the United States, most typically traced to an infected food handler or contaminated fruits or vegetables.[25,26] Thus, even in the absence of formal recommendations, there are cogent reasons to advise vaccination in HAV-naïve adults.

Hepatitis B
The NHANES III indicated that the prevalence of chronic hepatitis B virus (HBV) infection, defined in that cohort as detectable total anti-hepatitis B-core antibody and hepatitis B surface antigen (HBsAg), is 0.42% in the United States. Adults older than 50 years of age have on average a 1.5 to twofold higher prevalence of this infection across different ethnic groups compared with younger individuals.[27] The NHANES (1999–2006) showed an overall seroprevalence of past/present HBV infection in the United States of 4.7% (defined as positive total anti-hepatitis B-core). These data also show marked variations of the seroprevalence of the disease among different age groups with adults aged ≥50 having a 1.7 and 12.8 times higher seroprevalence of past/present infection than individuals aged 20–49 and 6–19 years, respectively. When compared with the prior NHANES survey (1988–1994), there was a significant decrease in the seroprevalence of past/present HBV infection in younger individuals but elderly adults had a non-significant increase.[28] Furthermore, there was a non-significant decrease in the seroprevalence of chronic HBV infection in all age groups when data from both surveys were compared.[28] Importantly, these surveys exclude the incarcerated, homeless, institutionalized, and recent immigrants; therefore, the seroprevalence estimates of past/present and chronic HBV infection are likely to be underestimated.[29] As expected foreign-born individuals living in the United States have a 4.4 higher prevalence of HBV infection compared with US born individuals.[27]

Clinical manifestations of acute HBV infection in the elderly may be different than in younger adults. During an outbreak of acute HBV in elderly nursing home residents, most infected individuals were asymptomatic with only a few presenting with jaundice and non-specific symptoms such as anorexia, nausea, and vomiting. No fatalities or individuals requiring hospitalization were reported during the outbreak.[30]

The natural course of chronic HBV infection is determined by multiple variables including age.[31] The risk of progression to chronic hepatitis B is inversely related to age at the time of infection. For example, progression to chronic hepatitis B has been reported in >90% of infants, 25–50% of children aged 1–5 years, and <5% of older children and young adults following an episode of acute HBV infection.[30] However, the rate of progression to chronic hepatitis B is higher in elderly individuals than in younger adults. Data from an outbreak of acute HBV infection in a nursing home in Japan showed that 59% of patients older than 65 years of age developed chronic infection.[30] The rate of spontaneous HBsAg seroclearance is also different in younger and elderly adults with chronic HBV infection. Individuals older than 60 years of age have a greater than twofold and 1.75 higher rates of cumulative HBsAg seroclearance compared with adults aged 40–49 years and 50–59 years, respectively (adjusted for several variables such as sex, baseline HBV-DNA level, baseline alanine aminotransferase (ALT) level, ethnicity, and body mass index). Importantly, this difference is even more pronounced when elderly and younger adults with HBV-DNA levels >10,000 copies/ml are compared.[32] Elderly individuals with acute HBV infection have similar rates of hepatitis B e antigen (HBeAg) positivity as younger adults (~77% for both groups) but significantly lower rates of antibodies to hepatitis e antigen (5.5% vs. 18.6%, respectively).[33] Among individuals with chronic HBV infection, the prevalence of HBeAg is inversely related to the patient's age. For example, adults older than 60 years of age have a fourfold higher prevalence of HBeAg compared with younger individuals aged 30–39 years.[34] No correlation was found between patient age and HBV precore mutant/total HBV ratio in one study including individuals aged 18–52 years.[35] With respect to HBV-DNA levels in patients naïve to treatment, age older than 40 years was associated with a 2.5 higher odds of serum HBV-DNA levels >108 copies/ml in a multicenter cross-sectional study from the United States (mainly HBV genotypes A, B, C, and a small proportion of genotypes D, E, F, and G). Patients with wild-type and variant precore/core promoter sequences were comparable in age.[36] However, data from a large Asian cohort show that adults older than 60 years of age infected with HBV genotypes B and C have lower HBV-DNA levels compared with individuals aged 30–59 years (HBeAg positive and negative). This difference persisted when only HBeAg-negative younger and elderly individuals were compared.[31] Additional data from the same Asian cohort demonstrate that progression to cirrhosis is mainly correlated with HBV-DNA levels but older age and male sex are also important risk factors.[37]

Therapeutic options for HBV have greatly expanded since the mid-1990s with the introduction of oral therapies. Clinical trials showed equivalent therapeutic efficacy of standard and pegylated interferons in the elderly compared with younger adults.[38] Lamivudine was also equally effective in individuals younger and older than 60 years of age as evidenced by response to therapy, loss of HBV-DNA, and development of viral resistance.[39] Unfortunately, the use of lamivudine is limited by the high rate of development of resistant mutants. Anti-HBV therapy with newer nucleoside or nucleotide analogs (tenofovir, entecavir, and adefovir) is associated with high rates of recurrence after treatment is stopped; therefore, most individuals require long-term therapy with these drugs.[40] Interferon-based therapy may also be effective; however, virologic relapse is more frequent in the elderly (defined as reappearance of HBV-DNA and/or HBeAg).[41]

Vaccination against HBV is recommended in elderly individuals at risk for infection, including all nursing home residents because of the higher risk of transmission of HBV in these facilities.[42] Nursing home residence is associated with an increased risk for HBV infection due to breaches in standard precautions and cross-contamination with blood and other body fluids. Therefore, HBV immunization should also be recommended for care providers at these institutions.[42] The prevalence of HBsAg has been reported to be higher in nursing home residents compared with non-institutionalized populations in the same geographic area.[42] Normal aging is associated with a decline in immune function; therefore, elderly individuals have an attenuated immune response to HBV vaccination compared with younger adults (70% vs. 98%, respectively).[43] The major factor implicated is T-cell dysfunction in elderly adults. Supporting this hypothesis, in vitro studies have demonstrated that production of antibodies against HBsAg is normal when T cells from young individuals are added to serum from older adults.[43] Furthermore, aging is also associated with a decreased number of T cells. In an attempt to overcome this disadvantage, particularly the quantitative deficiency of T cells, growth factors (i.e., granulocyte-monocyte colony stimulating factor) have been used as an adjuvant to enhance vaccine-induced seroprotection in elderly individuals.[44] However, a pilot trial evaluating this intervention did not show a clinically significant effect on immune response in healthy elderly individuals following HBV immunization.[45]

HCC is a major complication of chronic HBV infection. Older age is a predictor for development of HCC in patients with chronic hepatitis B by increasing the risk of this neoplasm by a 2.7 increment with every decade of life.[46,47] Therefore, age is a factor in determining initiation of surveillance for HCC in patients with chronic HBV infection but current guidelines only provide age-specific recommendations for HCC surveillance in hepatitis B carriers of Asian ethnicity (men >40 years of age and women >50 years of age).[48] Spontaneous annual seroclearance rates of HBsAg are higher in older adults compared with younger individuals; however, HBsAg seroclearance (either spontaneous or as a result of antiviral therapy) does not eliminate the risk of HCC.[32,49] Furthermore, recent data suggest that HBsAg seroclearance after 45–50 years of age is associated with higher incidence of HCC compared with seroclearance at a younger age. The increased incidence of HCC in patients with "late" HBsAg seroclearance may reflect the oncogenic nature of HBV.[50]

Reactivation of HBV infection with elevated HBV-DNA and ALT levels may occur in up to 50% of HBV-infected individuals following immunosuppressive chemotherapy.[48] Although the majority of cases of HBV reactivation in this setting are asymptomatic, fatal hepatic decompensation is well recognized.[51] Reactivation of HBV in patients receiving antineoplastic chemotherapy typically results in interruption of treatment with reduced antineoplastic efficacy.[52] However, data from prospective studies suggest that older adults receiving antineoplastic chemotherapy are at lower risk for HBV reactivation compared with younger individuals.[51,53] Rituximab and systemic corticosteroids, two key agents in the treatment of lymphoid neoplasms, which occur more commonly in younger adults, have been associated with a higher risk of HBV reactivation.[54,55] Current recommendations for testing for HBsAg and anti-hepatitis B-core in individuals at risk for HBV infection before initiation of immunosuppressive chemotherapy are not different for younger and elderly adults.[48] Prophylactic use of antiviral agents in HBV carriers regardless of age is indicated if immunosuppressive therapy is to be initiated: lamivudine or telbivudine if the anticipated duration of treatment is ≤12 months, and tenofovir or entecavir if longer treatment is anticipated.[48]

Hepatitis C
The incidence and prevalence of hepatitis C virus (HCV) infection continue to decline, particularly among younger individuals. In the United States, the prevalence of HCV infection in the general population is 1.6% but varies among different age groups with adults 40–49 years of age now having the highest seroprevalence (4.3%). Elderly individuals aged 60–69 and 70 years or older have lower prevalence rates (0.9% and 1%, respectively).[56,57] Data from a European study show that the proportion of individuals infected with HCV genotype 1 increases with age: 57% in adults aged <65 years, 72% in those 65–80 years of age, and 84% in adults older than 80 years of age.[58] Risk factors for HCV infection in older individuals include blood product transfusions before 1992, military service, injection drug use, tattoos, hemodialysis, and employment as a health care worker.[59] The true prevalence of HCV infection among elderly adults residing in nursing homes is largely unknown; however, data from a prospective cohort study including residents of three different nursing homes in St Louis, MO, USA demonstrated that the seroprevalence of anti-HCV antibodies is surprisingly high in this population (4.5%).[60] Importantly, adults older than 65 years of age more often present with complications of cirrhosis particularly hepatic failure and HCC as initial manifestations of HCV infection compared with younger individuals.[58] Older age at the time of initial infection is an important factor associated with more advanced fibrosis score, even after adjusting for sex, alcohol consumption, body mass index, HIV status, and diabetes.[58] Furthermore, progression to fibrosis may be more rapid when initial HCV infection occurs in older individuals, regardless of duration of infection.[58,61,62] For example, the median time to development of cirrhosis from infection was 33 years in individuals infected with HCV between 21 and 30 years of age compared with 16 years in individuals older than 40 years of age.[63] Elderly individuals with HCV-RNA viremia are also more likely to have normal ALT levels than younger adults (46% vs. 10.6%, respectively; Table 1).[64] Similarly, the prevalence of elevated ALT levels is comparable in individuals older and younger than 65 years of age despite an apparent greater prevalence of fibrosis in the former group as determined by serological markers of fibrosis (Fibrotest-Fibrosure and Actitest).[58] Although the use of serological markers of fibrosis in patients older than 80 years of age has not been validated, preliminary investigations suggest that the characteristics of these tests are not affected by older age. The use of these non-invasive serological tests for assessment of fibrosis may potentially be valuable in older populations particularly when ALT levels are normal, as up to one third of elderly adults may have significant fibrosis despite elevation of the ALT.[58]

The National Institute of Health consensus conference on hepatitis C identified elderly patients with chronic HCV infection as a difficult-to-treat group. Although current practice guidelines do not establish an upper age limit for antiviral therapy, elderly individuals with HCV infection are more likely to have contraindications to antiviral therapy than younger adults.[65] Typically, major clinical trials have excluded individuals older than 65 years of age and, in general, adults over the age of 60 have a higher prevalence of co-morbidities compared with younger individuals (38% vs. 18%, respectively), particularly cardiovascular, renal, pulmonary, and hematological diseases that often preclude anti-HCV therapy in this population.[66] This was demonstrated on a study of 208 Japanese patients naïve to antiviral therapy (predominantly genotype 1) who underwent treatment with interferon-α-2b and ribavirin for a total of 24 weeks. Patients were stratified by age (<50, 50–59, and >60 years). A significantly higher prevalence of systemic hypertension, impaired renal function, anemia, thrombocytopenia, and leukopenia was noted at baseline in the elderly group. Discontinuation of therapy or dose reductions were twice more common in the elderly (77%) than in younger adults (38%). Importantly, patient age and systemic hypertension were found to be independently associated with adherence to therapy.[66] However, elderly individuals are less likely to have other barriers to anti-HCV therapy such as substance abuse and psychiatric disorders.[67]

Older age is an independent factor associated with a lower likelihood of being considered for antiviral therapy. For example, treatment eligibility based on accepted guidelines is lower in elderly individuals compared with younger adults (16% vs. 26%, respectively).[66] Older adults are also less likely to accept antiviral treatment and discontinuation of therapy and dose reductions are more frequently required in this age group compared with younger adults.[67] For example, data from an observational study of 220 patients treated with interferon-α-2b and ribavirin demonstrated that discontinuation rates of ribavirin were significantly more frequent in the elderly compared with younger adults. Reasons for discontinuation of therapy were similar in both age groups and consisted mainly of anemia, constitutional symptoms (fatigue and anorexia), and depression.[67] In clinical practice, <15% of adults treated with interferon and ribavirin discontinue therapy; however, discontinuation rates have been reported to be as high as 30% and dose reductions are required in >70% of individuals aged 60 years or older within the first 12 weeks of therapy.[61,66] Despite these limitations, sustained virological response rates following combination therapy with standard interferon and ribavirin are similar in individuals older than 60 years of age and those younger than 60 years of age.[66,67] Results of treatment with pegylated interferon and ribavirin in elderly individuals are scarce. A pilot study of 33 patients naïve to treatment (mean age of 70.2 years) suggested lower sustained virological response rates with a pegylated interferon-based regimen in the elderly compared with younger adults (46% vs. 69.7%).[68] The proportion of patients developing side effects that led to discontinuation of therapy was twofold higher in elderly compared with younger adults (24.2% vs. 12.2%, respectively).[68]
Current practice guidelines recommend not withholding antiviral therapy based purely on advanced age but suggested that special attention should be paid to co-morbid conditions and tolerance for potential side effects.[69,70] Adverse effects typically resolve spontaneously within 2–3 weeks of discontinuing treatment; however, depression may take longer to resolve in the elderly compared with younger adults and often requires continuing pharmacotherapy.[71] Although the recently licensed direct acting antiviral agents (boceprevir and telaprevir) significantly increase sustained virological response, there are no data assessing the efficacy and/or toxicity of these drugs in elderly populations.[72,73,74]

Hepatitis E
Hepatitis E virus (HEV) infection is endemic and epidemic in Asia, Africa, and Mexico, whereas in the United States and Western Europe only sporadic cases have been reported. The NHANES III indicated, however, that the seroprevalence of anti-HEV IgG antibodies in the US population is 21%.[75] This data concurs with a previously reported seroprevalence of anti-HEV IgG in blood donors in the United States (18.3%) implying that subclinical HEV infection is frequent in non-endemic areas.[76] Although only limited data on acute HEV infection in the elderly are available, the seroprevalence of anti-HEV IgG antibodies in Indonesia has been reported to increase with age: 38% in children 5–9 years of age, and 70% in adults older than 60 years. The high seroprevalence of anti-HEV IgG reflects cumulative risk for infection throughout life in areas of the world where the infection is endemic.[77] Similarly, the seroprevalence of anti-HEV IgG was higher among elderly vs. younger immigrants from the former Soviet Union living in Germany (7.6% vs. 1–2%, respectively).[78] Differences in the seroprevalence of anti-HEV IgG in different age groups have also been reported in the United States. For example, 16% of blood donors younger than 60 years of age had positive anti-HEV IgG compared with 25.5% in those older than 60 years.[79] Importantly, a recent study demonstrated that a small but important proportion (3%) of patients with of acute liver injury in the United States suspected to be drug-induced were also seropositive for anti-HEV IgM. After reassessment and causality analysis, HEV was considered a probable etiology of acute liver injury in these cases. The majority of patients with serology consistent with acute HEV infection (78%) were older than 60 years of age.[80]
In conclusion, exposure to HEV also occurs frequently in Western industrialized countries and until the epidemiology of this virus is better understood, HEV should be considered a potential etiology of acute hepatitis in the elderly.

Elderly adults represent a rapidly growing population with distinct epidemiological, pathological, and therapeutic characteristics of multiple disease processes, including viral hepatitis A, B, C, and E (Table 2). This population has a greater risk of complications of acute and chronic liver disease as well as higher risk of mortality because of high prevalence of co-morbid conditions. Therapeutic regimens for chronic hepatitis B and C have not been studied exclusively in this age group and their true effectiveness and tolerance in elderly adults warrants further research. Indications for immunization against hepatitis A and B in elderly individuals need to be revised and broadened as many of them are at increased risk for infection and, even though elderly adults have an attenuated response to immunization, this remains an effective preventive measure.


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