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Research Letter |

Thirty-Year Outcomes of the National Hepatitis B Immunization Program in Taiwan FREE

Chun-Ju Chiang, PhD1; Ya-Wen Yang, MSc2; San-Lin You, PhD3; Mei-Shu Lai, MD, PhD1; Chien-Jen Chen, ScD3
[+] Author Affiliations
1Graduate Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan
2Taiwan Cancer Registry, Taipei, Taiwan
3Genomics Research Center, Academia Sinica, Taipei, Taiwan
JAMA. 2013;310(9):974-976. doi:10.1001/jama.2013.276701.
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Published online

Hepatitis B virus (HBV) infection causes infant fulminant hepatitis (IFH), and chronic HBV infection may progress to chronic liver disease (CLD) and hepatocellular carcinoma (HCC). Taiwan launched a nationwide HBV immunization program for newborns in July 1984,1 which has successfully lowered the prevalence of chronic HBV carriers, incidence of HCC, and mortality of IFH in vaccinated birth cohorts.24 The mortality of CLD before and after HBV immunization has never been examined. We assessed the 30-year outcomes of the immunization program.

From July 1984 to June 1986, the immunization program covered only newborns with high-risk mothers who were seropositive for HBV surface antigen. Coverage was extended to all newborns in July 1986, preschool children in July 1987, and primary school children in 1988-1990. Recombinant HBV vaccines replaced plasma-derived vaccines in 1992. The immunization coverage rates for birth cohorts from 1984 to 2010 was 88.8% to 96.9%.2,5

The mortality of IFH, CLD, and HCC and the incidence of HCC were compared among birth cohorts born before and after the launch of the program. The National Death Certificates Database (1977-2011) was used to derive the mortality rates of IFH (International Classification of Diseases, Ninth Revision [ICD-9] code 570), CLD (ICD-9 code 571), and HCC (ICD-9 codes 1550 and 1552); the National Cancer Registry Database (1977-2009) was used to derive the incidence rates of HCC (International Classification of Diseases for Oncology code C220).6 Infant fulminant hepatitis was analyzed in birth cohorts to 2009-2011, whereas other outcomes were analyzed in birth cohorts to 2001-2004 (age range: 5-29 years in 2009). To control sex and duration of HBV infection, sex-adjusted or age- and sex-adjusted incidence and mortality rate ratios were calculated using Poisson regression models (SAS version 9.2; SAS Institute Inc). Two-sided P< .05 was considered statistically significant. This study was approved by the data release review board of the Bureau of Health Promotion, which waived the requirement for informed consent.

Infant fulminant hepatitis mortality rates and sex-adjusted rate ratios declined significantly for infants born from 1977-1980 to 2009-2011 (Table). The decline was greatest from 1981-1984 to 1985-1988 and from 1989-1992 to 1993-1996, coincident with the launch of the national immunization program in 1984 and the change to recombinant vaccines in 1992. Compared with 1977-1980, the sex-adjusted rate ratio declined to 0.88 (95% CI, 0.65-1.21) in 1981-1984, 0.46 (95% CI, 0.31-0.69) in 1985-1988, and 0.03 (95% CI, 0.01-0.24) in 2009-2011.

Table Graphic Jump LocationTable.  Mortality Rates of Infant Fulminant Hepatitis, Chronic Liver Diseases, and Hepatocellular Carcinoma and Incidence Rates of Hepatocellular Carcinoma of Birth Cohorts Born Before and After the Launch of Hepatitis B Immunization Program in 1984 in Taiwan

There was a continuous decline in age- and sex-adjusted rate ratios of CLD and HCC mortality and HCC incidence for birth cohorts born after implementation of the program. The birth cohort born in 1981-1984, which received HBV vaccines at preschool ages instead of early infancy, had significantly lower CLD and HCC mortality and HCC incidence than those born in 1977-1980. The age- and sex-adjusted rate ratio in 2001-2004 was 0.11 (95% CI, 0.02-0.80) for CLD mortality, 0.08 (95% CI, 0.02-0.34) for HCC mortality, and 0.20 (95% CI, 0.06-0.65) for HCC incidence.

Males had significantly higher CLD and HCC mortality and HCC incidence than females in most age groups (Figure). The 1985-2006 birth cohorts had significantly lower CLD and HCC mortality and HCC incidence rates than those born in 1977-1984 for both sexes.

Place holder to copy figure label and caption
Figure.
Age- and Sex-Specific Mortality and Incidence Rates of Chronic Liver Disease and Hepatocellular Carcinoma for Birth Cohorts Born Before and After the Launch of the Hepatitis B Immunization Program in 1984 in Taiwan
Graphic Jump Location

The mortality of IFH in vaccinated birth cohorts decreased by more than 90% from 1977-1980 to 2009-2011, which was greater than the previously reported reduction (approximately 70%) from 1975-1984 to 1985-1998.4 This long-term, high-coverage immunization program was associated with lower IFH mortality through increasing individual and herd immunity of vaccinated cohorts. From 1977-1980 to 2001-2004, the age- and sex-adjusted rate ratios for individuals aged 5 to 29 years decreased by more than 90% for CLD and HCC mortality and by more than 80% for HCC incidence, which were higher than the previously reported reduction (70%) in HCC incidence for youth aged 6 to 19 years.3

The national HBV therapy program launched in November 2003 may also be contributing to the reduction in risk of IFH, CLD, and HCC; however, this contribution is likely minimal because few members of the study cohorts were eligible for therapy. Hepatitis B virus immunization in infancy has been associated with a reduction in the risk of IFH, CLD, and HCC in Taiwan.

Section Editor: Jody W. Zylke, MD, Senior Editor.

Corresponding Author: Chien-Jen Chen, ScD, Genomics Research Center, Academia Sinica, 128 Academia Rd, Sec 2, Taipei 11529, Taiwan (chencj@gate.sinica.edu.tw).

Author Contributions: Drs Chiang and Chen had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Chiang, You, Chen.

Acquisition of data: Chiang, Yang, You, Lai, Chen.

Analysis and interpretation of data: Chiang, Yang, You, Chen.

Drafting of the manuscript: Chiang, You.

Critical revision of the manuscript for important intellectual content: Chiang, Yang, You, Lai, Chen.

Statistical analysis: Chiang, Yang, You.

Administrative, technical, or material support: Chiang, You.

Study supervision: Lai, Chen.

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Chen reported serving as a consultant to Bristol-Myers Squibb, Merck Sharp & Dohme, GlaxoSmithKline, and Roche; receiving grants from Bristol-Myers Squibb and Roche; and receiving payment for lectures from Bristol-Myers Squibb, Merck Sharp & Dohme, and Roche. No other disclosures were reported.

Funding/Support: This work was supported by grants from the Bureau of Health Promotion, Department of Health, Executive Yuan, Taiwan, and Academia Sinica.

Role of the Sponsor: The Bureau of Health Promotion, Department of Health, Executive Yuan, Taiwan, and Academia Sinica had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Chen  DS, Hsu  NH, Sung  JL,  et al.  A mass vaccination program in Taiwan against hepatitis B virus infection in infants of hepatitis B surface antigen-carrier mothers. JAMA. 1987;257(19):2597-2603.
PubMed   |  Link to Article
Chien  YC, Jan  CF, Kuo  HS, Chen  CJ.  Nationwide hepatitis B vaccination program in Taiwan: effectiveness in the 20 years after it was launched. Epidemiol Rev. 2006;28:126-135.
PubMed   |  Link to Article
Chang  MH, You  SL, Chen  CJ,  et al; Taiwan Hepatoma Study Group.  Decreased incidence of hepatocellular carcinoma in hepatitis B vaccinees: a 20-year follow-up study. J Natl Cancer Inst. 2009;101(19):1348-1355.
PubMed   |  Link to Article
Kao  JH, Hsu  HM, Shau  WY, Chang  MH, Chen  DS.  Universal hepatitis B vaccination and the decreased mortality from fulminant hepatitis in infants in Taiwan. J Pediatr. 2001;139(3):349-352.
PubMed   |  Link to Article
Centers for Disease Control, Department of Health, ROC (Taiwan). CDC: 2012 annual report Centers for Disease Control. http://www.cdc.gov.tw/uploads/files/201208/67addf76-0493-4d7b-aa72-cd51beff6654.pdf. Accessed February 17, 2013.
Chiang  CJ, Chen  YC, Chen  CJ, You  SL, Lai  MS; Taiwan Cancer Registry Task Force.  Cancer trends in Taiwan. Jpn J Clin Oncol. 2010;40(10):897-904.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure.
Age- and Sex-Specific Mortality and Incidence Rates of Chronic Liver Disease and Hepatocellular Carcinoma for Birth Cohorts Born Before and After the Launch of the Hepatitis B Immunization Program in 1984 in Taiwan
Graphic Jump Location

Tables

Table Graphic Jump LocationTable.  Mortality Rates of Infant Fulminant Hepatitis, Chronic Liver Diseases, and Hepatocellular Carcinoma and Incidence Rates of Hepatocellular Carcinoma of Birth Cohorts Born Before and After the Launch of Hepatitis B Immunization Program in 1984 in Taiwan

References

Chen  DS, Hsu  NH, Sung  JL,  et al.  A mass vaccination program in Taiwan against hepatitis B virus infection in infants of hepatitis B surface antigen-carrier mothers. JAMA. 1987;257(19):2597-2603.
PubMed   |  Link to Article
Chien  YC, Jan  CF, Kuo  HS, Chen  CJ.  Nationwide hepatitis B vaccination program in Taiwan: effectiveness in the 20 years after it was launched. Epidemiol Rev. 2006;28:126-135.
PubMed   |  Link to Article
Chang  MH, You  SL, Chen  CJ,  et al; Taiwan Hepatoma Study Group.  Decreased incidence of hepatocellular carcinoma in hepatitis B vaccinees: a 20-year follow-up study. J Natl Cancer Inst. 2009;101(19):1348-1355.
PubMed   |  Link to Article
Kao  JH, Hsu  HM, Shau  WY, Chang  MH, Chen  DS.  Universal hepatitis B vaccination and the decreased mortality from fulminant hepatitis in infants in Taiwan. J Pediatr. 2001;139(3):349-352.
PubMed   |  Link to Article
Centers for Disease Control, Department of Health, ROC (Taiwan). CDC: 2012 annual report Centers for Disease Control. http://www.cdc.gov.tw/uploads/files/201208/67addf76-0493-4d7b-aa72-cd51beff6654.pdf. Accessed February 17, 2013.
Chiang  CJ, Chen  YC, Chen  CJ, You  SL, Lai  MS; Taiwan Cancer Registry Task Force.  Cancer trends in Taiwan. Jpn J Clin Oncol. 2010;40(10):897-904.
PubMed   |  Link to Article
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