Neonatal Hepatitis B Vaccination in TaiwanLessons and Questions for the United States
ABSTRACT & COMMENTARY
Synopsis: A universal hepatitis B vaccination program of Taiwanese newborns and children was initiated in 1984, and in the subsequent 10 years, the national incidence of hepatocellular carcinoma in children 6-9 years old has declined.
Source: Chang M-H, et al. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. N Engl J Med 1997;336:1855-1859.
Hepatitis B virus (HBV) is hyperendemic in Taiwan. HBV has a propensity to persist after a child sustains infection in early life, acquired either vertically or horizontally from an infected mother. Persistent carriers of HBV are at risk for the development of chronic liver disease as well as hepatocellular carcinoma, both during childhood and adult life. When infection occurs in early life, the HBV DNA may become incorporated into the host’s genome, where it has a long-term effect on genes involved in hepatic cell growth and proliferation.
In 1984, a national program of neonatal HBV vaccination was launched in Taiwan. For the first two years, only infants born of mothers who were chronic HBV carriers were immunized, but in 1986, it was extended to all newborns as well as older children. The effectiveness of the program is indicated by an increase in newborn vaccination rates from 15% in 1986 to 84% in 1994. Children received a French, plasma-derived HBV vaccine at birth and at 1, 2, and 12 months. Children born of mothers who were HBV carriers additionally received a dose of hepatitis B immune globulin within 24 hours after birth.
The annual incidence of hepatocellular cancer in children 6-14 years old was assessed using data from the Taiwan National Cancer Registry as well as by direct contact with 17 major hospitals and 10 tertiary referral centers. (Liver cancers in children younger than 6 years old were excluded so that cases of hepatoblastoma would not be included.) It was estimated that these sources identified at least 84% of all cases of hepatocellular cancer. The incidence of brain tumors during the same period of time was assessed as a control variable.
From 1981 to 1986, the average annual incidence of hepatocellular cancer was 0.07% per l00,000 children. From 1986 to 1990, this declined to 0.57% per 100,000 children. From 1990 to 1994, it had further declined to 0.36% per 100,000 children. The difference in incidence between 1981-1986 and 1990-1994 is statistically significant (P = 0.01) In contrast, there were no changes in the incidence of brain tumors during the same period of time.
COMMENT BY ROBERT B. BALTIMORE, MD, FAAP
In the 1980s, the AAP Committee on Infectious Disease (CID) and the CDC Advisory Committee on Immunization Practices (ACIP) advocated targeted screening of pregnant women to identify HBV carriers so that their infants could be treated in the newborn period to prevent perinatal infection. This was to be coupled with selective immunization of "high-risk groups." These strategies proved to be ineffective in reducing the incidence of HBV infections. In 1992, the CID and ACIP revised their recommendations and advocated universal neonatal immunization for hepatitis B.1 The recommendation for universal neonatal HBV immunization received mixed responses from the pediatric practice community, primarily because in the United States, HBV infections are overwhelmingly diseases of adult life. The cost of the HBV vaccine and the need for three additional injections were also factors for pediatric concern. Despite these kinds of concern, a survey in 1991-1992 reported that nearly half of American hospital nurseries routinely offer HBV immunization, and 40% of 1-year-olds have completed the recommended three-dose series.2
The goals of neonatal immunization against HBV in areas with a relatively low prevalence of HBV such as the United States are not primarily to prevent perinatal infection or infection during early childhood. The objectives are part of an international effort to eradicate HBV infections from the United States and ultimately the world, as has been accomplished with smallpox. Of course, we should continue to prevent vertical transmission to the newborn by identifying HBV carrier pregnant women and treating their newborns with HBV immune globulin as well as HBV immunization.
Zuckerman, in an accompanying editorial that correlates to the Chang article, points out that one million Europeans are infected with HBV.3 Of these Europeans, 90,000 will become chronically infected, and about 22,000 will ultimately die of cirrhosis and/or liver cancer. He further states that HBV is second only to tobacco among the identified human carcinogens.2 However, cirrhosis and hepatocellular carcinoma in the United States are diseases of adult life. Even in Taiwan, the peak age of hepatocellular cancer is 60 years. In American children, HBV-associated liver diseases and cancer are unusual.
Will neonatal immunization confer immunity in later life and so prevent HBV infections in adolescence and adults?4 We do not really know whether the infants we are currently immunizing will, in fact, be immune as adults or whether regular boosters will be necessary. HBV immunization is now part of our standard pediatric practice, but we should be aware that there are a number of issues that are still unresolved.
1. Committee on Infectious Diseases, American Academy of Pediatrics. Universal hepatitis B immunization. Pediatrics 1992;89:795-800.
2. Woodruff BA, et al. Progress toward integrating hepatitis B vaccine into routine immunization schedules in the United States, 1991 through 1994. Pediatrics 1996;97:798-803.
3. Zuckerman AJ. Prevention of primary liver cancer by immunization. N Engl J Med 1997;336:1906-1907.
4. Zuckerman IN. Non-response to hepatitis B vaccines and the kinetics of anti-Hbs production. J Med Virol 1996;50:283-288.