Background A nationwide hepatitis B vaccination program wasimplemented in Taiwan in July 1984. To assess the effect ofthe program on the development of hepatocellular carcinoma,we studied the incidence of this cancer in children in Taiwanfrom 1981 to 1994.
Methods We collected data on liver cancer in children from Taiwan'sNational Cancer Registry, which receives reports from each ofthe country's 142 hospitals with more than 50 beds. Data onchildhood liver cancer were also obtained from Taiwan's 17 majormedical centers. To prevent the inclusion of cases of hepatoblastoma,the primary analysis was confined to liver cancers in childrensix years of age or older. Data were also obtained on mortalityfrom liver cancer among children.
Results The average annual incidence of hepatocellular carcinomain children 6 to 14 years of age declined from 0.70 per 100,000children between 1981 and 1986 to 0.57 between 1986 and 1990,and to 0.36 between 1990 and 1994 (P<0.01). The correspondingrates of mortality from hepatocellular carcinoma also decreased.The incidence of hepatocellular carcinoma in children 6 to 9years of age declined from 0.52 for those born between 1974and 1984 to 0.13 for those born between 1984 and 1986 (P<0.001).
Conclusions Since the institution of Taiwan's program of universalhepatitis B vaccination, the incidence of hepatocellular carcinomain children has declined.
Hepatocellular carcinoma is closely associated with hepatitisvirus infections, particularly infection with hepatitis B virus(HBV).1,2,3,4,5,6 However, the cause-and-effect relation ofHBV to hepatocellular carcinoma is as yet unproved. In Taiwanthe association between hepatocellular carcinoma and HBV isstronger in children than in adults. The rate of seropositivityfor hepatitis B surface antigen (HBsAg) approaches 100 percentin children with hepatocellular carcinoma,7,8 as compared with70 to 80 percent in adults with the disease. Integration ofthe HBV genome into the host genome of hepatocellular carcinomahas been reported in children.9
To control hepatitis B, Taiwan launched a nationwide vaccinationprogram in 1984.10,11 In 10 years, this program reduced theHBsAg carrier rate in children from 10 percent to less than1 percent.12 However, it remains unclear whether the ultimategoal of reducing HBV-induced mortality, particularly that fromhepatocellular carcinoma, can be achieved. Since the incidenceof hepatocellular carcinoma in Taiwan peaks in the sixth decadeof life,6 it may take 40 years or longer to see an overall decreasein the rate of hepatocellular carcinoma as a result of the vaccinationprogram. The rate of hepatocellular carcinoma in children canbe considered as an early indicator of the effectiveness ofvaccination in reducing the rate of hepatocellular carcinoma.A decrease in the rate in children after universal vaccinationagainst hepatitis B would provide further evidence that HBVis a cause of hepatocellular carcinoma.
Methods
Population Data
In Taiwan, which has a population of 21 million, the healthcare system changed little from 1981 to 1994. All births, deaths,marriages, and divorces must be registered with the government'shousehold-registration offices. Information on education, employment,and migration is also recorded. These records are double-checkedannually by registration officers, who conduct home visits.Demographic data obtained from household-registration officesare complete and accurate. The year-end population statisticsfor children used in this study were obtained from the annualreports on demographic statistics published by the Ministryof Interior.
Nationwide Hepatitis B Vaccination Program
Taiwan's mass-vaccination program against hepatitis B was launchedin July 1984.10,11 For the first two years, the program coveredonly neonates born to mothers who were HBsAg carriers, but itwas extended to all neonates in July 1986, to preschool childrenin July 1987, to primary-school children in 1988, to middle-schoolchildren in 1989, and to adults in 1990. Infants were given5-µg doses of a plasma-derived HBV vaccine (Hevac B, InstitutPasteur, Marnes-la-Coquette, France) at birth and at 1, 2, and12 months of age. In addition, 0.5 ml (145 IU) of hepatitisB immune globulin (Abbott Laboratories, Cutter, or Green Cross,Taiwan) was given within 24 hours after birth to infants whosemothers had hepatitis B e antigen (HBeAg) or reciprocal serumtiters of HBsAg higher than 2560. Since November 1992, recombinantHBV vaccines have replaced plasma-derived vaccines and havebeen given at birth and at one and six months of age. The governmenthas covered all the costs of the program. Those who miss thescheduled vaccination are encouraged to receive hepatitis Bvaccines on a fee-for-service basis. In addition, HBV vaccinepaid for by parents was given to preschool children from 1987to 1994. The estimated vaccine coverage from 1981 to 1994 ininfancy and at six years of age is shown in Table 1.
Table 1. Estimated Hepatitis B Vaccine and Hepatitis B Immune Globulin (HBIG) Coverage Rates in Infants and Hepatitis B Vaccine Coverage Rate and HBsAg Seroprevalence in Six-Year-Olds.
Inclusion Criteria for Cases of Childhood Hepatocellular Carcinoma
All cases of liver cancer among children 6 to 14 years of agein Taiwan between 1981 and 1994 were included in our study exceptthose that were a type other than hepatocellular carcinoma.Children younger than six years old were also excluded to preventthe inclusion of cases of hepatoblastoma.13,14
Trends in the Annual Incidence of Childhood Hepatocellular Carcinoma
To look for trends in the incidence of childhood hepatocellularcarcinoma after the program was implemented, we used three systemsto study the incidence of this disease from July 1981 to June1994. July 1 was used as a starting point for each year becausethe vaccination program was launched on July 1, 1984.
System 1: National Cancer Registry
We analyzed information, obtained from the data bank of theTaiwan National Cancer Registry of the Department of Health,on cases that occurred between July 1981 and June 1994 in childrenunder 14 years of age. This registry was established in 1979.Cases of cancer at each of Taiwan's 142 hospitals with morethan 50 beds were reported. We used data from 1981 onward toavoid possible gaps in reporting of data at the beginning ofthis system. The items registered included the patient's name,national identification number, date of birth, sex, date ofdiagnosis, location of tumor, and histologic data.
System 2: Multicenter Childhood Hepatocellular Carcinoma Registration Study
To ensure the accuracy of the data from the National CancerRegistry, we simultaneously conducted a multicenter collaborativestudy of the registry of childhood hepatocellular carcinoma.Pediatric gastroenterologists or oncologists from 17 major hospitals,including all 10 tertiary referral centers in Taiwan, participatedin this study. In addition to the data in the National CancerRegistry, this study included information on serum concentrationsof HBsAg, alpha-fetoprotein levels, and history of vaccinationagainst hepatitis B.
The data collected from these two systems were then merged,and the cases that did not overlap were added together aftereach was confirmed by the reporting hospital. According to thecapture–recapture method,15 the total number of childrenwith hepatocellular carcinoma during the study period is estimatedto be 294 (95 percent confidence interval, 272 to 316). Thecases identified by systems 1 and 2 are estimated to be 84 percentof all cases of childhood hepatocellular carcinoma. The ratewas not affected by age.
System 3: National Mortality Registry
Data on deaths in Taiwan between 1969 and 1993 among childrenunder 15 years of age were also analyzed for trends in mortalityresulting from childhood hepatocellular carcinoma during thestudy period.
Death certificates, which must be registered with the household-registrationoffices, are routinely reviewed and submitted to the nationaldeath-certification system by local health centers. By law,a certificate must be registered within one month of a death.All certificates are reviewed and coded by medical registrarsaccording to the Manual of the International Statistical Classificationof Diseases, Injuries, and Causes of Death16 in the centraloffice of the national death-certification system. The diagnosisand classification of underlying causes of death in Taiwan varyfrom area to area according to the level of medical services.In some cases, primary liver cancer may not be listed as theunderlying cause for children who in fact died from the disease,since other diagnostic terms may sometimes be used to describethe immediate cause of death. On the other hand, some metastaticliver tumors may be misclassified as primary liver cancer. Therefore,the mortality data were not merged with the more reliable incidencedata.
Incidence of Brain Tumors as a Control Variable
The incidence of brain tumors, common malignant tumors in children6 to 14 years of age, was used as a control variable. The diagnosisis usually not difficult, and there was no reason to expectany change in incidence during the study period.
Correlation between History of HBV Vaccination and Childhood Hepatocellular Carcinoma
The history of vaccination against hepatitis B, including thedate of administration of each dose of hepatitis B vaccine andhepatitis B immune globulin, has been registered at the nationallevel for each neonate in the program since July 1984, the beginningof the nationwide vaccination program.10 This record was retrievedand reviewed for each child with hepatocellular carcinoma bornafter July 1984.
Statistical Analysis
The annual incidence of childhood hepatocellular carcinoma wasdetermined by dividing the annual number of cases in children6 to 14 years of age by the year-end population of childrenof the same age. The statistical significance of the differencein the incidence of childhood hepatocellular carcinoma for thetwo periods under comparison was examined by using the Poissontest.17
In order to compare the incidence rates in annual cohorts bornbetween July 1975 and June 1988, the incidence among childrenin a given birth cohort was calculated by dividing the numberof cases of hepatocellular carcinoma by the total number ofperson-years observed when the subjects were 6 to 14 years old.The effect of the nationwide vaccination program on the incidenceof hepatocellular carcinoma was assessed by Poisson regressionanalysis, with control for year of birth (before or after July1984), age, and vaccination status.
Results
The average incidence of hepatocellular carcinoma in children6 to 14 years of age from 1981 to 1986 was 0.70 per 100,000children (range, 0.65 to 0.78). The average incidence declinedto 0.57 (range, 0.48 to 0.62) for the period from 1986 to 1990and to 0.36 for the period from 1990 to 1994 (range, 0.23 to0.48). The ratio of the average incidence in the period from1986 to 1990 to that in the period from 1982 to 1986 was 0.81.This decline may have been due to the herd immunity that resultedfrom the mass-vaccination program and the vaccination of preschool-agechildren. The ratio of the incidence in the 1990-to-1994 periodto that in the 1986-to-1990 period was 0.63. This faster declinewas attributed to the direct effect of mass vaccination. Theincidence from 1990 to 1994 was significantly lower than thatfrom 1981 to 1990 (P<0.01) (Table 2). The age-adjusted relativerisk of hepatocellular carcinoma after as compared with beforeJuly 1990 was 0.33 (P<0.001).
Table 2. Annual Incidence of Hepatocellular Carcinoma (HCC) and Brain Tumor in Children 6 to 14 Years of Age.
The mortality rate in children with hepatocellular carcinomashowed a parallel decline (Table 2). The age-adjusted relativerisk of death after as compared with before July 1990 was 0.51(P<0.001).
In contrast, the incidence of brain tumors in children 6 to14 years old did not show a similar decrease during the periodof observation, according to the same registration system (Table 2).The overall incidence of childhood cancer also did not showsuch a decrease during this period (data not shown). By contrast,the incidence of liver cancer in people over 14 years of ageincreased from 11.11 to 25.82 per 100,000 population from 1981to 1992 (Table 3). The incidence of liver cancer in childrenup to five years of age changed little during the same period(Table 3). The age-adjusted relative risk of liver cancer inchildren up to five years of age after as compared with beforeJuly 1984 was 0.97 (P = 0.91).
Table 3. Annual Incidence of Liver Cancer per 100,000 People over 14 or under 6 Years of Age.
An analysis of the incidence of liver cancer according to yearof birth showed that the incidence among children 6 to 14 yearsold declined from 0.64 per 100,000 person-years for the cohortborn between July 1975 and June 1976 to 0.1 per 100,000 person-yearsfor the cohort born between July 1985 and June 1986 (Figure 1).However, the incidence among children up to five years ofage did not decline for the cohorts born from 1974 to 1986 (Figure 1).There was a slow decline in the incidence of hepatocellularcarcinoma among children 6 to 14 years old who were born beforethe start of the vaccination program (between 1980 and 1984)and a faster decline among those born after the start of theprogram (between 1984 and 1988) (Figure 1). The Poisson regressionanalysis showed that the relative risk of liver cancer was 0.34in children 6 to 14 years old born after the implementationof the vaccination program, as compared with those born beforethe program, after adjustment for age and year of birth (P =0.03). From 1974 to 1984, hepatocellular carcinoma was diagnosedin a total of 82 children among Taiwan's approximately 15.7million children who were between the ages of six and nine yearsat any time during this period (0.52 per 100,000). From 1984to 1986, hepatocellular carcinoma was diagnosed in only threechildren between the ages of six and nine among a populationof about 2.3 million (0.13 per 100,000) (P<0.001) (Table 4).These three children, all boys born in 1985, received fourdoses each of hepatitis B vaccine. Two were born to HBsAg-carriermothers and received hepatitis B immune globulin at birth. Bothtested seropositive for HBsAg and hepatitis B e antibody whenhepatocellular carcinoma was diagnosed. The third child andhis mother consistently tested seronegative for HBsAg. Hepatocellularcarcinoma was confirmed in the child by histologic examination.Polymerase-chain-reaction assays detected HBV genome in boththe tumorous and nontumorous liver tissue of this child. Allthree children had markedly elevated serum alpha-fetoproteinlevels and space-occupying lesions in the liver. All three died.
Figure 1. Comparison of the Incidence of Liver Cancer in Children 6 to 14 and 0 to 5 Years of Age, According to Birth Cohort.
The incidence of liver cancer in children 6 to 14 years old declined, whereas the incidence in children 0 to 5 years old remained essentially unchanged. This may be explained by the reduction in the rates of both horizontal and perinatal transmission of HBV infection that resulted from the mass-vaccination program, which benefited the younger cohorts directly and the elder cohort indirectly by decreasing the reservoir of infection and reducing the risk of horizontal infection. The incidence of liver cancer in children between 6 and 14 years old declined to zero for children born in 1986 and 1987. The observed number of person-years for those born in 1986 was 613,837, and for those born in 1987 it was 313,311.
Table 4. Incidence of Liver Cancer per 100,000 Children in Birth Cohorts Determined According to the Date of Implementation of the Hepatitis B Vaccination Program.
Discussion
This study in Taiwan shows that 6 to 10 years after the initiationof the hepatitis B mass-vaccination program, the incidence ofchildhood hepatocellular carcinoma declined significantly. Thesedata are evidence that prevention of a viral infection in apopulation can reduce the incidence of a specific cancer.
Three lines of evidence support our finding of a decline inthe rate of childhood hepatocellular carcinoma after the initiationof the Taiwanese hepatitis B vaccination program. First, datafrom three different registration systems consistently showedsimilar trends toward decreases in childhood hepatocellularcarcinoma during the observation period from 1981 to 1994 (Table 2).Second, the annual incidence of another childhood cancer— namely, brain tumors in children of the same age —remained similar during the same period. The incidence of livercancer in children younger than six years also did not decrease.This suggests that the decrease in childhood hepatocellularcarcinoma is specific. Third, the incidence of hepatocellularcarcinoma decreased in children but gradually increased in peopleolder than 14 years between 1981 and 1993. The increase in incidencein adults is reasonable, since diagnostic accuracy has improvedand screening programs using ultrasonography and alpha-fetoproteinhave been launched for early detection of liver cancer in high-risksubjects.6 The increasing life span of the population and thegrowing role of hepatitis C virus18 may also contribute to theincrease of liver cancer in adults.
A decline in the incidence of liver cancer has been observedsince 1986 among children 6 to 14 years old who were born between1980 and 1984, before the start of the national vaccinationprogram. This decline is paralleled by a decrease in the rateof HBsAg carriage among children born before the program waslaunched (Table 1). The herd immunity resulting from the massvaccination of children in the highly infectious younger birthcohorts may have reduced the rate of horizontal HBV infectionamong unvaccinated older children. The reduction in the HBsAg-seropositivityrate among children in unvaccinated cohorts reflects a declineof a similar magnitude in the incidence of hepatocellular carcinoma.The decline in incidence among children born before the launchof the national vaccination program may be attributable to theherd immunity resulting from the program. The extension of thevaccination program to preschool children might also have contributedto the decline in the rate of HBsAg carriage and in the rateof hepatocellular carcinoma in children born before July 1984.
Perinatal mother-to-infant transmission of HBV is an importantfactor in the rate of HBsAg carriage. It accounts for 40 to50 percent of HBsAg carriers in Taiwan.19 These perinatallyinfected HBsAg carriers are at risk for hepatocellular carcinomaas adults20 or children.7,8 The HBsAg-positivity rate has beenshown to be as high as 94 percent among the mothers of childrenwith hepatocellular carcinoma in Taiwan.7 Similarly, perinataltransmission of woodchuck hepatitis virus has been reportedto cause liver cancer.5
The Taiwanese program of vaccination to reduce the perinataltransmission of HBV has been carried out successfully since1984. According to our previous observations in Taiwan,7,8,14the earliest time at which the effect of the hepatitis B vaccinationprogram on childhood hepatocellular carcinoma can be seen is1990, six years after the launch of the program. If the efficacyof the program were 100 percent, with a coverage of 100 percent,and childhood hepatocellular carcinoma were caused solely byHBV, there should be no hepatocellular carcinoma in childrenborn after July 1984. Children who missed the vaccination programor failed to respond to the vaccine could still have hepatocellularcarcinoma later on. In fact, hepatocellular carcinoma was foundin three children who were born after July 1984 and had receivedhepatitis B immunization through the national program. The effectof HBV vaccination on the declining incidence of childhood hepatocellularcarcinoma was most evident when different birth cohorts wereanalyzed (Table 4).
This HBV vaccination program has been integrated into the ExpandedProgramme on Immunization for Taiwanese infants since July 1986.We strongly recommend that hepatitis B vaccination be integratedinto the worldwide Expanded Programme on Immunization to interruptperinatal and early horizontal transmission of HBV and the subsequentdevelopment of chronic liver disease. Such measures are importantand urgent, particularly in areas with a high incidence of HBVinfection and hepatocellular carcinoma.
Since HBV-associated liver cancer peaks among people 50 to 60years of age in Taiwan,6 continued monitoring of the incidenceof hepatocellular carcinoma among children and adults is necessaryto further document the decrease in cases of hepatocellularcarcinoma in association with the initiation of the hepatitisB mass-vaccination program.
Supported by grants (DOH85-HR-518 and 86-HR-518) from the NationalHealth Research Institute, Taiwan.
* Other members of the Taiwan Childhood Hepatoma Study Group arelisted in the Appendix.
Source Information
From the Department of Pediatrics (M.-H.C.) and the Hepatitis Research Center (D.-S.C.), College of Medicine, and the Graduate Institute of Epidemiology, College of Public Health (C.-J.C., W.-Y.S.), National Taiwan University, Taipei; the Department of Health, Executive Yuan, Taipei (M.-S.L., H.-M.H.); the Department of Pediatrics, Veterans General Hospital, Taipei (T.-C.W.); the Department of Pediatrics, Chang-Gung Children's Hospital, Linkou, Taoyuan (M.-S.K.); and the Department of Pediatrics, Mackay Memorial Hospital, Taipei (D.-C.L.) — all in Taiwan.
Address reprint requests to Dr. Chang at the Department of Pediatrics, National Taiwan University Hospital, No. 7, Chung-Shan South Rd., Taipei, Taiwan.
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Appendix
The following additional institutions and investigators participatedin the Taiwan Childhood Hepatoma Study Group: C.-S. Chi, VeteransGeneral Hospital, Taichung; S.-N. Cheng, Tri-Service GeneralHospital; C.-J. Tsai, Kaoshiung Medical College; L.-H. Lin,Cathay General Hospital; M.-W. Lai, Taoyuan Provincial Hospital;M.-T. Cheng, Chang-hua Christian Hospital; A.-C. Chen, NationalCheng-Kung University Hospital; W.-C. Lee, Sa-lu Kong-Ten GeneralHospital; T.-C. Tsai, Hua-lien Tzu-Chi Buddhist Hospital; Y.-H.Tsai, Taiwan Provincial Taipei Hospital; C.-C. Wu, St. Mary'sHospital; S.-F. Wu, China Medical College Hospital; S.-C. Huang,Chang-Gung Children's Hospital, Kaohsiung; and U.-P. Ling, Chung-ShanMedical College Hospital.
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