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Introduction to Chronic Hepatitis B Infection, last part 6 of 6
  The American Journal of Gastroenterology
Volume 101 Page S1 - January 2006
Teresa L. Wright, M.D.
1University of California, San Francisco, California
Chronic hepatitis B virus (HBV) infection affects over 350 million people worldwide and over 1 million die annually of HBV-related chronic liver disease. Although many individuals eventually achieve a state of nonreplicative infection, the prolonged immunologic response to infection leads to the development of cirrhosis, liver failure, or hepatocellular carcinoma (HCC) in up to 40% of patients. In endemic areas, where carrier rates are >5%, most individuals are infected perinatally, by vertical transmission, or in early childhood. In the United States, where prevalence is low except in particular areas and populations (e.g., Alaskan natives, immigrants from highly endemic areas), transmission is generally horizontal, percutaneous, or via sexual contact in adulthood. A variety of host (age at infection, gender, immune status); viral (viral load, genotype, mutation); and external (concurrent viral infections, alcohol consumption, chemotherapy) factors influence disease progression. Several variables (age at infection, gender, ethnicity, immune status) also influence the risk of chronic infection. Perinatal transmission, the most common mode of infection worldwide, can be reduced by appropriate prophylaxis (vaccination of the infant at birth together with hepatitis B immune globulin); anti-viral therapy in late pregnancy may also be beneficial. Five drugs are now FDA-approved for the treatment of HBV (interferon, lamivudine, adefovir, entecavir, and peginterferon alfa-2a), and suppressive anti-viral therapy improves the natural history of HBV. Patients with decompensated cirrhosis or HCC are highly likely to die unless they successfully undergo liver transplantation. While novel anti-viral drugs have improved the management of cirrhosis, strategies to prevent and treat HCC remain inadequate.
Hepatitis B is one of the most common infectious diseases in the world. Of the 2 billion individuals infected by hepatitis B virus (HBV), over 350 million are chronically infected, (1) with chronic infection manifested by persistence of the virus and HBV surface antigen (HBsAg) in serum and production of viral antigens and HBV DNA in the liver. Over a million individuals die annually of HBV-related chronic liver disease (2). Cirrhosis, liver failure, or hepatocellular carcinoma (HCC) develop in 15-40% of individuals with chronic HBV infection (3).
The prevalence of chronic HBV infection varies widely in different parts of the world (Fig. 1) (2, 4). The majority of individuals in areas with a high prevalence of chronic HBV infection, where carrier rates are >5%, are infected at the time of birth or during early childhood (2). In areas of low prevalence such as Northern Europe, infection is typically acquired during adulthood via percutaneous or sexual transmission. In the United States, although prevalence of chronic HBV infection is low, around 1.2 million people are infected (5). Moreover, there are certain areas and populations in the United States, such as Alaskan natives, Pacific Islanders, and infants of first-generation immigrant mothers from highly endemic areas, where prevalence of HBV infection is high (6). Factors influencing incidence and prevalence in the United States in addition to ethnicity and immigration patterns include intravenous drug use and high risk sexual activity.
HBV is present in blood, saliva, semen, vaginal secretions, and menstrual blood of infected individuals. Because HBV is resistant to breakdown outside the body, it is easily transmitted through contact with infected bodily fluids (2). Perinatal vertical transmission is the most common mode of transmission worldwide. Presence of HBV e antigen (HBeAg) in the mother's serum is associated with greater infectivity: (6, 7) The risk of perinatal HBV infection among infants born to HBV-infected mothers ranges from 10-40% in HBeAg-negative mothers to 70-90% in HBeAg-positive mothers (8). Children of HBsAg-positive mothers who do not become infected perinatally remain at high risk of infection during early childhood (8). In households of a chronically infected individual, HBV infection can occur via person-to-person, nonsexual contact (8).
Immunization is the most effective means of preventing HBV infection; vaccination offers >95% protection against the development of chronic infection (2, 6). The failure of immunization programs targeted at individuals with risk factors has led to the recommendation that hepatitis B vaccination should be included in routine vaccination schedules for infants (1, 6). Universal infant vaccination was introduced in the United States in 1991; vaccination coverage among children aged 19-35 months increased from 16% in 1992 to 90% in 2000 (5). From 1990 to 2002, the incidence of acute hepatitis B decreased by 67% across all age groups, while in children under 20 yr, incidence decreased by 89% (5). In the United States, vaccination is also recommended for all adolescents not previously vaccinated and adults at increased risk of infection (e.g., immunocompromised individuals) (8). It is also recommended that pregnant women be screened for HBsAg so that appropriate prophylactic treatment can be given perinatally (8). Post-exposure prophylaxis of adults involves hepatitis B immune globulin and, depending on vaccination status, vaccination. In cases of chronic exposure, vaccination of sexual partners and household contacts is recommended (6). Other preventive measures include needle exchange programs, screening of blood products, and educational approaches. Anti-viral therapy to suppress HBV replication in late pregnancy may reduce vertical transmission (9).
Individuals diagnosed with chronic HBV should be counseled regarding non-pharmalogical management strategies, such as diet, rest, maintaining fluid balance, and avoidance of alcohol and other hepatotoxins. They should be advised to notify their sexual partner(s), who should be immunized, and to use condoms and avoid needle sharing.
A National Institutes of Health (NIH) workshop defined three stages in the natural history of chronic hepatitis B infection (10). The first stage is characterized by a period of immune tolerance, lasting 2-4 wk in healthy adults but often several decades in those infected neonatally or in early childhood (11). During this phase there is active viral replication, evidenced by secretion of HBeAg and high levels of serum HBV DNA, but no symptoms and no significant increase in serum alanine aminotransferase (ALT). An immunologic response may then develop during which HBeAg is still secreted, but serum HBV DNA levels decline as the number of infected cells decreases. This stage lasts a few weeks in patients with acute, symptomatic infection, but may persist for 10 or more years in those with chronic disease, potentially leading to cirrhosis and its complications. This immunoactive phase is characterized by intermittent flares of hepatitis evidenced by increases in serum ALT, with more frequent flares being associated with greater likelihood of progressive disease (12). In the third phase, the host immune response halts active viral replication; patients become HBeAg-negative and anti-HBeAg antibodies become detectable (seroconversion). This phase is usually preceded by a marked reduction in serum HBV DNA to levels undetectable by hybridization techniques, followed by normalization of serum ALT and resolution of liver necroinflammation (13). Around 50% of patients clear HBeAg within 5 yr of diagnosis, 70% within 10 yr (13).
The outcome after HBeAg seroconversion depends on the degree of pre-existing liver damage; patients without liver damage may suffer only slight fibrosis or mild chronic hepatitis, whereas those with pre-existing cirrhosis may experience further complications (14). Patients remain HBsAg-positive with integration of viral DNA into the host's hepatocyte genome (11), and with detectable HBV DNA in serum measured by sensitive polymerase chain reaction (PCR)-based assays (13). This inactive carrier state can last for the rest of the individual's life, but in some patients spontaneous or immunosuppression-induced reactivation of HBV replication occurs, putting patients at further risk of cirrhosis and HCC.
A minority of patients become HBsAg-negative and anti-HBs/anti-HBcore-positive. Reinfection or reactivation is unlikely unless patients are immunosuppressed (11); unfortunately, spontaneous loss of HBsAg is uncommon in patients with established chronic HBV infection (13).
The disease may progress in a significant proportion of patients after HBeAg seroconversion (15). This form of chronic HBV (HBeAg-negative CHB) is more common in areas where infection occurs at birth or during early childhood (15). HBeAg-negative patients harbor HBV variants with a mutation in the core promoter or the precore region of the HBV genome, affecting production of HBeAg but not replication (16). The most frequent variant creates a stop codon in the precore region, completely abolishing production of HBeAg (17). This mutation is prevalent in the Mediterranean, where 30-80% of patients with chronic HBV are HBeAg-negative (16, 18). The proportion of HBeAg-negative patients is also rising in other parts of the world, including the United States. Patients with HBeAg-negative chronic HBV are typically older than HBeAg-positive patients, and have more active, more advanced, and more progressive liver disease; severe necroinflammation is seen in more than 50% of patients with HBeAg-negative chronic HBV at diagnosis (13). Chronic HBeAg-negative hepatitis is usually a late phase in the natural history of chronic HBV infection, rather than a result of de novo infection with a mutated variant (13). HBeAg-negative chronic HBV responds to anti-viral therapy, with response rates similar to those in HBeAg-positive patients, but most patients relapse after discontinuation of treatment (2, 15, 18).
In patients with chronic HBV disease, reported 5-yr cumulative incidence of progression to cirrhosis is 8-20% (13). Without treatment, compensated cirrhosis typically progresses to decompensated cirrhosis, characterized by clinical complications such as ascites, jaundice, internal bleeding, and hepatic encephalopathy. The development of HCC arises most commonly (but not exclusively) in patients with cirrhosis (11). In areas of the world with a high prevalence of chronic HBV infection, such as Korea, China, India, and Turkey, HBV infection is the predominant cause of HCC (2). Patients with advanced liver disease, particularly those with HCC, are highly likely to die if they do not undergo liver transplantation.
The rate of progression to cirrhosis and/or HCC depends on the age of the patient at infection, and on several additional host, viral, and external factors (11).
Age at Infection
As previously discussed, the age at acquisition of hepatitis B infection influences the risk of chronicity, with rates of persistent infection being substantially higher in individuals infected perinatally or during infancy than in those infected as adults (19). Furthermore, the age at infection has an impact on the natural history of the disease.
Spontaneous HBeAg seroconversion rates are low in children and those infected early in life (20, 21). A large cohort study of Alaskan natives with chronic HBV infection demonstrated that loss of HBeAg was significantly more likely to occur in older carriers than younger individuals (p< 0.001). The observed probability of HBeAg loss within 5 yr of diagnosis was 0.39, 0.56, and 0.45 in carriers aged 0-18, 19-30, and 31-78 yr, respectively (22).
During the immune tolerant phase the host immune response to infection is negligible. Therefore, the majority of infected children (86-90%) will demonstrate minimal histologic changes on liver biopsy with evidence of mild inflammation only (23). However, although rare, children may develop serious sequelae during childhood, including severe hepatitis, cirrhosis, and HCC (24, 25). Universal vaccination programs with resulting decrease in incidence of hepatitis B infection in endemic areas have been shown to reduce the incidence of HCC in childhood. In Taiwan, an area endemic for hepatitis B infection, universal vaccination was introduced in July 1984. The average annual incidence of HCC in children aged 6-14 yr fell from 0.70 per 100,000 children in the period 1981-1986 to 0.57 in 1986-1990, and even further to 0.36 in 1990-1994 (26).
Individuals infected during childhood who develop chronic hepatitis B are more likely to develop serious sequelae in adulthood. This is presumed to be a result of the prolonged viremia that occurs with chronic infection. A male child infected at birth has a 25-40% lifelong risk of developing complications of liver disease, including HCC (27).
Infection acquired in adulthood does not involve the prolonged immunotolerance phase typical of early-life infection. After the period of active disease and HBeAg seroconversion, which occurs more rapidly in adults than in children, there may be histologic and biochemical regression of disease (28). However, liver disease may be progressive despite HBeAg seroconversion, with histologic progression associated with "flares" of serum ALT levels.
Host Factors
Host gender affects disease progression; the ratio of males to females with cirrhosis resulting from chronic HBV infection is approximately 2:1, and the incidence of HCC is three to six times higher in men than women (13).
Older age is another risk factor for HCC, though this may be a reflection of prolonged duration of HBV infection (13). The peak incidence for clinically evident cirrhosis or HCC is 50-60 yr of age (13).
The immune status of the patient also influences disease progression (see below), with more rapid progression in immunosuppressed patients than in those who are immune competent (11).
Viral Factors
Viral load is probably a significant factor in the natural history of hepatitis B (29), with patients with active replication being at greater risk of disease progression than those without detectable HBV DNA in serum. However, patients in the immune tolerant phase of disease may have a high level of replication in the absence of significant liver injury. Cirrhosis results from prolonged immune destruction of antigen-presenting hepatocytes, and prolonged viremia may influence disease progression. Risk of HCC is related in part to a direct effect of viral replication and genomic integration, and in part to the host immune response including necroinflammation and hepatic regeneration.
Recent studies have supported an association between the level of viral replication and the risk for the development of cirrhosis and HCC. A population-based prospective cohort study of 3,774 Taiwanese patients with CHB investigated the relationship between serum HBV DNA level and the risk for cirrhosis (30). A total of 560 individuals (15% of the study cohort) were HBeAg-positive at enrolment. Using individuals who were HBeAg-negative with undetectable HBV DNA as the reference, the relative risk for cirrhosis (adjusted for gender, age, anti-HCV, cigarette smoking, and alcohol consumption) in HBeAg-negative individuals rose from 1.9 to 4.9 in those with HBV DNA 104 and ≥105 copies/mL, respectively. In persons positive for HBeAg, the relative risk was 2.6 in those with HBV DNA ≦103 copies/mL, rising to 5.2 and 8.6 in individuals with HBV DNA 104 and ≥105 copies/mL, respectively.
A second study in Taiwan addressed the association between persistent elevation of HBV DNA and the risk for HCC (31). A total of 3,851 individuals with CHB were followed for 43,993 person-years, during which 176 patients were newly diagnosed with HCC (data obtained via the National Cancer Registry and the Death Certification System). A dose dependent relationship between HBV DNA level and HCC risk was reported. Relative risk was calculated in comparison to individuals with HBV DNA <104 copies/mL at study entry. In persons with HBV DNA levels ≥105 copies/mL at enrolment, the adjusted relative risk for development of HCC were 3.6, 6.9, and 9.1 for those with serum HBV DNA levels at follow-up examination of <104, 104-105, and ≥105 copies/mL, respectively. Although patients with high levels of viral replication carry the greatest risk, the results from this study suggest that those with lower rates of viral replication (104-105 copies/mL) are still at risk for the development of HCC.
HBV is classified into eight genotypes, A-H, on the basis of nucleotide divergence (32, 33). The various genotypes have differing geographic distribution (Fig. 1) and clinical impact.
Exogenous Factors
Coinfection with hepatotropic viruses (including hepatitis A, C, or D viruses) or HIV may influence the risk of disease progression in patients with chronic hepatitis B infection (34-39).
Immunosuppressive therapies also affect the natural history of chronic HBV. Immunosuppression after transplantation (liver, kidney, or heart) is associated with reactivation of disease and progression if HBV is not controlled (40). Similarly, reactivation of HBV as a result of cancer chemotherapy is a well-recognized phenomenon (41). Heavy alcohol consumption can increase the risk of progression to cirrhosis and HCC (42, 43).
Chronic HBV is a significant public health concern worldwide. The natural history and outcome of the infection depend on several viral, host, and external factors. Individuals with chronic HBV are at increased risk of developing cirrhosis or HCC; effective treatment interventions need to be considered and if possible implemented before the development of decompensated cirrhosis or HCC. Prevention via vaccination is a central strategy to reduce the future impact of the disease.
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