Hepatitis B Vaccination and Control of Hepatitis B???Related Liver Disease

Hepatitis B virus (HBV) infection can cause acute liver diseases, such as acute hepatitis and fulminant hepatitis, and chronic liver diseases, such as chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. These HBV-related liver diseases may develop in both children and adults. In hyperendemic areas, primary HBV infection occurs mainly during infancy or early childhood. Approximately two billion people in the world have been infected by HBV, and 350 million of them have become chronic hepatitis B surface antigen (HBsAg) carriers. Although most of the complications of chronic HBV infection develop in adulthood, it is not uncommon to see children who have acute or fulminant hepatitis B, acute exacerbation of chronic hepatitis B, and, occasionally, hepatitis B–related liver cirrhosis or hepatocellular carcinoma in hyperendemic areas (1). Chronic HBV infection can occur in children of any age, as early as the perinatal period. After HBV immunoprophylaxis became available, the epidemiology of HBV infection and its related diseases changed. Immunoprophylaxis is crucial for the global control of HBV infection and related liver diseases. The goal of this review is to provide an overview of the epidemiology and complications of HBV infection and the effect of hepatitis B immunoprophylaxis on infection control and current problems of availability. EPIDEMIOLOGY OF HEPATITIS B VIRUS INFECTION BEFORE VACCINATION The status of the endemicity for HBV infection has been classified into high, intermediate, and low, according to the prevalence rate for HBV infection in each area (Table 1). In areas where HBV infection is prevalent, such as Asia, Africa, southern Europe, and Latin America, primary HBV infection occurs mainly during infancy and childhood. In rural Senegal, by the age of 2 years, 25% of children are infected, and at age 15, the infection rate, reflected by the seropositive rate of the antibody to hepatitis B core antigen (anti-HBc), increases to 80%(1). In Taiwan, most chronic HBsAg carriers are infected before 2 years of age (2). The HBsAg seropositive rate is 5% in infants and increases to 10% at 2 years of age. The HBsAg carrier rate remains stationary thereafter, whereas the infection rate reaches 50% by the age of 15 years.TABLE 1: Classification of the prevalent status of chronic HBV infection in the world population before HBV vaccination progams, according to the prevalence of HBsAgPerinatal transmission from HBsAg carrier mothers to their infants is a very important route of transmission leading to chronicity. It accounts for the transmission route of 40% to 50% of HBsAg carriers in many hyperendemic areas. Approximately 90% of infants of hepatitis B e antigen (HBeAg)–seropositive carrier mothers become HBsAg carriers (3). Horizontal transmission through intrafamilial spread or the parenteral route is another means of HBV transmission. The two most important routes of horizontal transmission are highly infectious family members, such as elder siblings, and improperly sterilized syringes (4). Other sources of infection include institutionalized children and multiple or large blood transfusions. ACUTE OR FULMINANT HEPATITIS B Hepatitis B virus can infect people of any age. An incubation period of 2 to 6 months is observed in acute hepatitis B. Symptoms may occur as early as 2 months of age in infants of HBsAg carrier mothers. Acute or fulminant hepatitis B occurs mainly in infants of hepatitis B e antibody seropositive mothers in high-prevalence areas. Horizontal transmission, such as transfusion or injection through an unsterile needle or syringe, is another route of transmission for acute or fulminant hepatitis B. Case–control studies were undertaken in Moldova to identify risk factors for acute hepatitis B (5). Injections are a major source of HBV transmission and highlight the importance of proper infection control procedures in preventing transmission of blood-borne infections. Acute hepatitis B usually runs a self-limited course, and recovers with anti-HBs seroconversion. A very high mortality rate (67%) has been observed in children with fulminant hepatitis B. Those who survive usually recover without sequelae. In both acute and fulminant hepatitis B, HBV is cleared rapidly from the host. Preocore mutant was reported to be related to fulminant hepatitis B in adults (6) but this has not been confirmed by later studies (7). Studies in Taiwanese children have shown that 33% of the children with fulminant hepatitis B have hepatitis B precore stop codon mutant. The prevalence rate is similar to that (30%) in children with acute hepatitis B (8). These results suggest that the precore stop codon mutant cannot explain the severe clinical course of fulminant hepatitis B. LIVER DISEASES ASSOCIATED WITH CHRONIC HEPATITIS B VIRUS INFECTION Chronic HBV infection is defined as the persistence of HBV infection, which manifests as seropositive HBsAg for more than 6 months. Mild histologic changes in the liver may begin early (9), but children with chronic HBV infection are usually asymptomatic. Even with acute exacerbation of liver function and active inflammation of the liver tissue, jaundice or growth failure is very rare. General malaise may appear but is usually subjective. Liver histology may show progression to severe liver damage in later life during the process of acute exacerbation and HBeAg seroconversion. HBeAg is a marker of active HBV replication (10). By mechanisms that remain unclear, serum HBeAg is gradually cleared, and HBV replication is reduced as the child ages. This process of HBeAg clearance is usually preceded by an acute exacerbation of liver function and histologic changes in the liver associated with elevation of aminotransferases and active inflammation of the liver. The peak level of aminotransferase elevation may be mild and transient. An elevation of alanine aminotransferase (ALT) levels to more than 300 IU/L is not unusual. An ALT level of more than 1000 IU/L is rare in young children but is more frequently seen in adolescents. Those with such high ALT levels often also have bridging hepatic necrosis—that is, a broad extent of hepatic necrosis with portal-to-portal and/or portal-to-central necrosis. The process of HBe seroconversion takes place insidiously in most individuals for a period of 2 to 7 years (11). After the detection of an elevation of aminotransferase levels, approximately 40% of children clear HBeAg within 1 year. The annual HBeAg seroconversion rate is less than 2% in children less than 3 years of age and approximately 5% in children more than 3 years of age. After HBeAg clearance, aminotransferase levels gradually return to normal range, and anti-HBe develops spontaneously. By a conventional dot blot hybridization method, HBV DNA was detected in approximately only 1% of the anti-HBe sera (12). However, polymerase chain reaction (PCR) has shown that HBV DNA persists for the long term in the serum of children with chronic hepatitis B after HBe seroconversion. Bortolotti et al. (13) studied 39 children after HBe seroconversion. They found 87% of children had HBV DNA detectable by PCR within 5 years of follow-up and in 58% of cases 10 years after seroconversion. The ALT levels were persistently normal in 92% but slightly elevated in 8%. Acute exacerbation with reactivation of HBV replication and re-elevation of aminotransferases is unusual in children once anti-HBe appears (11,14). Permanent liver damage occurs, and integration of the genome of HBV occurs insidiously and gradually, despite the disappearance of HBeAg. Development of liver cirrhosis or hepatocellular carcinoma is occasionally observed but is rare during childhood (15). Approximately 80% of children with hepatocellular carcinoma were anti-HBe seropositive (16). The annual HBsAg clearance rate is very low (only 0.56%) (17), and it occurs only after clearance of HBeAg. After loss of HBsAg, its antibody (anti-HBs) remains low or undetectable in the majority (0 to <100 mIU/mL). Hsu et al. (17) reported that 10 of 420 HBsAg carrier children cleared HBsAg, but hepatocellular carcinoma developed later in one when the child was aged 11 years (unpublished personal data). As age increases, the cumulative rate of acute exacerbation of liver function and worsening liver histology becomes higher. The risk of liver cirrhosis and development of hepatocellular carcinoma also is increased. It is estimated that the relative risk of hepatocellular carcinoma in adult HBsAg carriers is approximately 94 times higher than in the noncarrier normal population (18). In addition to liver diseases, extrahepatic manifestations may occur that are often associated with immune complex diseases. Membranous nephropathy and, less frequently, membranoproliferative glomerulonephritis have been strongly associated with chronic HBV infection, particularly in children in areas hyperendemic for HBV infection. Hepatitis B virus antigens are regarded as the antigens involved in the deposited immune complex (19). Children with membranous nephropathy are usually horizontally infected rather than perinatally infected. The liver diseases in these children are mild. The course of the renal disease is mostly benign and self-limited. Yet renal failure occurs on rare occasion. Other manifestations, such as polyarteritis nodosa and essential mixed cryoglobulinemia, are very rare. RISK FACTORS FOR THE PROGRESSION TO CHRONIC HEPATITIS B Both host and viral factors affect the outcome of HBV infection. Host factors are mainly those relating to the immune response to HBV infection, such as young age at infection, immune-compromised status in the host, some known genetic factors such as HLA, and other yet unknown host genetic factors (20). Age is one important factor, as illustrated in the epidemiologic data. The younger the age at infection, the higher the risk of progression to chronic infection. According a study in Taiwan, perinatal transmission of HBV from HBeAg-seropositive carrier mothers led to 90% of chronicity in their infants. Approximately 25% of the preschool children infected became chronic carriers (21), whereas only approximately 3% of the infected university students became chronic carriers (22). Immune-compromised hosts tend to have persistent HBV infection with active replication of the virus. Some HLA loci were reported to be related to persistent HBV infection. Class II loci, such as DRB1*1302 are protective against persistent infection (23), whereas DR-7 is positively associated with chronic HBV infection (24). Further studies are needed to clarify the role of host genetics and the outcome of HBV infection. Viral factors include the viral load and strains at infection. High viral load at infection may cause persistent infection, which is supported by the correlation of high maternal HBV DNA or seropositive HBeAg and persistence of HBV infection in the infants. Hsu et al. (25) suggested that transplacental HBeAg modulates the immune response of the fetus, which leads to the immune tolerance of T cells to HBV and thus to persistent infection with HBV. Recently, different HBV strains also were reported to be related to the outcome of the infection. IMMUNOPROPHYLAXIS AGAINST HEPATITIS B VIRUS INFECTION Prevention of HBV infection and related liver diseases can be achieved by passive and active immunization. Passive immunization using hepatitis B immunoglobulin (HBIg) provides temporary immunity. For protection from hepatitis B transmission from highly infectious mothers (HBeAg-positive mothers), a combination of passive and active immunization provides the highest efficacy. Hepatitis B immunoglobulin should be administered within 24 hours after birth (28). Administration of the first dose of hepatitis B vaccine is recommended within the first week after birth. The HBV vaccine contains only purified HBsAg proteins but not HBV nucleic acids (Krugman S. The newly licensed hepatitis B vaccine. JAMA 1982;247:2012–5). It is safe with no risk of transmitting HBV. It has been used for nearly 20 years in more than 100 countries. Hepatitis B virus vaccines in clinical use can be divided into plasma and recombinant vaccines. The plasma vaccine is derived from plasma of HBV carriers. Recombinant HBV vaccine, which appeared on the market in the early 1990s, can be produced from yeast or other cells expressing the hepatitis B surface gene. Before the era of HBV vaccination, passive immunization with three doses of HBIg beginning within 24 hours after birth was useful in preventing perinatal HBV infection in high-risk infants (of HBeAg-positive HBsAg carrier mothers) and reduced the HBsAg carrier rate from 90% to 23%, with an efficacy of approximately 75%(26). Active immunization with three or four doses of hepatitis B vaccine has proved to be immunogenic in more than 90% of neonates of noncarrier mothers or HBeAg-negative carrier mothers (27) and has shown approximately 75% to 78% efficacy in infants of highly infectious mothers. With combination of passive and active immunization (i.e., one dose of hepatitis B immunoglobulin within 24 hours after birth followed by three or four doses of hepatitis B vaccine) the carrier rate was reduced to 3% in pilot studies and to 14% in the general population. The efficacy was increased to 85% to 95% in high-risk infants (28). Current practice for HBV immunization differs in different countries. To prevent perinatal transmission, active immunization with three doses of HBV vaccine at 0, 1, and 6 months administered to all infants is similar in most countries. The practice for administration of HBIg varies. In the United States, HBIg is administered at birth to all neonates of HBsAg-seropositive mothers, regardless of maternal HBeAg status. In Taiwan, one dose of HBIg is administered at birth to neonates of both HBeAg-and HBsAg-seropositive mothers. In Japan, two doses of HBIg, 1 month apart, are administered to HBeAg-and HBsAg-seropositive mothers. In all those practices, maternal screening for HBsAg and/or HBeAg is needed. In the majority of countries with universal HBV vaccination programs, including those in the Asian, Pan-Pacific, European, African, and South American countries, HBIg is not administered routinely to neonates in addition to three doses of HBV vaccine. To prevent later acquisition of HBV infection, HBV vaccination is focused on adolescents in low-prevalence areas. Three doses of HBV vaccine are administered to adolescents who have not received HBV vaccine before. The immune response after vaccination can persist for more than 10 years, even after the level of anti-HBs becomes undetectable. This is supported by the rapid development of protectable levels of anti-HBs in 82% of vaccinees with “nonprotected” (<10 mIU/mL) levels of anti-HBs, after one booster dose of HBV vaccine (29). Studies in T-cell immune response further support the persistence of immune memories. Immunologic memory for HBV, most sensitively detected by interleukin (IL)-5 production by sensitized T cells, has been shown to remain intact in children in whom anti-HBs became undetectable 10 years after HBV vaccination (31). None of the vaccinees observed for the long term became new chronic carriers, although approximately 1% of the vaccinees were infected and underwent seroconversion to become anti-HBc positive (29). EFFECT OF UNIVERSAL HEPATITIS B IMMUNIZATION ON CONTROL OF LIVER DISEASES IN CHILDREN Universal hepatitis B vaccination has effectively reduced the rate of chronic HBV infection in populations worldwide. The first universal hepatitis B vaccination program in the world was launched in Taiwan in July 1984 (31). During the first 2 years of this program, only neonates of HBsAg-positive mothers were included. The program was extended to all neonates in the third year of the program. It was subsequently extended to preschool and school children and, gradually, to all adults. The seroprevalence rates of HBsAg in Taiwanese children before and 10 years after the implementation of the vaccination program are shown in Table 2(2,32). The HBsAg carrier rate decreased significantly from approximately 10% before to less than 1% after the vaccination program in children less than 10 years of age. This vaccination program has reduced both the perinatal and horizontal transmission of HBV (32).TABLE 2: Seroprevalence of hepatitis B surface antigen before and after universal vaccination against hepatitis B virusIn Thailand, Gambia, and Italy, the hepatitis B carrier rate has been reduced from 5% to 10% to less than 1%(33–35). Universal vaccination has greater efficacy in HBV infection control than selective immunization (35). Immunization targeted to high-risk groups in the United States and Italy have had minimal effect on the change of the seroprevalence rate. This suggests that HBV immunization should be conducted universally. DECREASE OF HEPATOCELLULAR CARCINOMA IN CHILDREN AFTER UNIVERSAL HEPATITIS B VIRUS IMMUNIZATION After initiation, the HBV universal vaccination program in July 1984 in Taiwan, we successfully demonstrated a decline in the incidence of hepatocellular carcinoma in children. The annual incidence of hepatocellular carcinoma in children was reduced from 0.52 per 100,00 children born before July 1984 to 0.13 per 100,000 children born afterward (36). We speculate that further decline of the incidence of hepatocellular carcinoma in adults will be seen in future long-term studies. PROBLEMS IN THE CONTROL OF HEPATITIS B VIRUS–RELATED LIVER DISEASES There are several problems that must be overcome to achieve the goal of eradication of HBV infection and related diseases. The first is vaccine failure or nonresponse (Table 3). Intrauterine infection is a difficult problem as well. Its rate is estimated to be less than 5% in infants of high-risk (HBeAg seropositive) mothers. In our 10-year follow-up study, 2.4% of infants of high-risk mothers had been persistently HBsAg seropositive since the first day of life, in spite of the combined use of HBIg and HBV vaccine (37). Immune-compromised hosts, either congenital or acquired, such as those receiving immunosuppression therapy or hemodialysis, have lower the response rate to HBV vaccination. The influence of hepatitis B surface mutants on the efficacy of vaccination needs constant epidemiologic survey (38). In Taiwanese HBsAg carrier children, the rate of hepatitis B surface mutant at the a determinant site, which is the target of the HBV neutralization antibody, increased from 7.8% before universal HBV vaccination to 28.1% 10 years after the universal vaccination program (39). Because of its low prevalence (<0.28% in the general population of children born after the vaccination program), the mutant is not currently a major problem for HBV immunoprophylaxis. But it may cause problems in the future, if the cumulative rate of occurrence of HBsAg mutants increases.TABLE 3: Possible causes of immunoprophylaxis failureThe second problem is anxiety concerning the safety of HBV vaccination. Because there is no solid basis for the correlation between HBV vaccination and demyelinating diseases, some people have an antivaccination opinion. Without sufficient evidence to support a causal association, reports of multiple sclerosis or other demyelination diseases occurring in adults who had recently received hepatitis B vaccination have raised concerns about the safety of HBV vaccine (40). French the hepatitis B vaccine in the universal immunization program. The Viral Hepatitis Prevention are into the for the of a the from several countries and reported that these not a causal between hepatitis B immunization and demyelinating diseases. The of a in HBV vaccine and some other has The of in HBV vaccine is in the safe range, but it be if it were The American of that infants of HBsAg-positive mothers should be after birth. For mothers, before HBV vaccine is available, administration of HBV vaccine can be at 6 months of age. The HBV vaccination have not in other countries. An HBV vaccine that not is to be in the The third problem is the of the and for booster This is a with an or vaccine, such as HBV vaccine. The by HBV vaccine has been shown to be protective for more than 10 years in hyperendemic areas. It is very that HBV vaccine can be for protection in the general population. with sources of immune to the population of infected people after implementation of the universal immunization program, the problem of a future booster Other such as from other vaccines and the high of HBV vaccine, are also to be The high of HBV vaccine for people in hyperendemic areas with should be as early as In the of of the importance of HBV vaccine in preventing the infection the goal of global control of HBV infection. A new HBV vaccine that not is although the current of was regarded as safe for vaccine with higher is also needed for immune-compromised of HBV vaccines with other vaccines such as or other hepatitis vaccines will the and The vaccination should be and in future studies. Because of the high and from other new vaccines has the of HBV vaccination in some countries. in the of HBV vaccine and support from global may to this Universal immunization for HBV should be into the program of immunization in children of all countries. This is particularly in areas in which HBV infection and hepatocellular carcinoma are The recommended that universal hepatitis B immunization be in all countries by the of Approximately countries have followed this The to the incidence of new HBV carriers children by 80% by and to the more than a million that occur from liver cirrhosis and hepatocellular carcinoma. With the integration of the hepatitis B vaccination program into of Immunization in most countries of the chronic HBV infection and its complications can be further reduced or in the