Long-term Effects of Hepatitis B Immunization of Infants in Preventing Liver Cancer Mei-Hwei Chang, 1,2 San-Lin You, 3 Chien-Jen Chen, 4 Chun-Jen Liu, 2 Ming-Wei Lai, 5 Tzee-Chung Wu, 6 Shu-Fen Wu, 7 Chuan-Mo Lee, 8 Sheng-Shun Yang, 9 Heng-Cheng Chu, 10 Tsang-Eng Wang, 11 Bor-Wen Chen, 12 Wan-Long Chuang, 13 Maw-Soan Soon, 14 Ching-Yih Lin, 15 Shu-Ti Chiou, 16 Hsu-Sung Kuo, 17 Ding-Shinn Chen, 2,4 and the Taiwan Hepatoma Study Group 1 Department of Pediatrics; 2 Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan; 3 Department of Public Health, College of Medicine, Bigdata Research Center, Fu-Jen Catholic University, New Taipei, Taiwan; 4 Academia Sinica, Taipei, Taiwan; 5 Division of Hepatogastroenterology, Department of Pediatrics, Chang Gung University and Hospital, Linkou, Taiwan; 6 Department of Pediatrics, Taipei Veterans General Hospital, and School of Medicine, National Yang Ming University, Taipei, Taiwan; 7 Department of Pediatrics, Division of Gastroenterology, China Medical University Hospital, Taichung, Taiwan; 8 Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 9 Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Faculty of Medicine, National Yang-Ming University, Taichung, Taiwan; 10 Department of Internal Medicine, Tri-Service General Hospital, Taipei, Taiwan; 11 Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan; 12 Department of Pediatrics, Koo Foundation Sun Yat-Sen Cancer Center, Taipei, Taiwan; 13 Department of Internal Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 14 Division of Gastroenterology and Hepatology, Department of Internal Medicine, Changhua Christian Hospital, Chang-Hua, Taiwan; 15 Division of Gastroenterology, Department of Internal Medicine, Chi-Mei Medical Center, Tainan, Taiwan; 16 Institute of Public Health, National Yang-Ming University, and Ministry of Health and Welfare, Health Promotion Administration, Taipei, Taiwan; and 17 Ministry of Health and Welfare, Centers for Disease Control, Taipei, Taiwan See Covering the Cover synopsis on page 379; see editorial on page 390. BACKGROUND & AIMS: The incidence of hepatocellular car- cinoma (HCC) increases with age, but protective antibody re- sponses decrease with time after infants are immunized against hepatitis B virus (HBV). We investigated whether immunization of infants against HBV prevents their developing HCC as adults. We also searched for strategies to maximize the cancer- preventive effects. METHODS: We collected data from 2 Taiwan HCC registry systems on 1509 patients (6–26 years old) diagnosed with HCC from 1983 through 2011. Data on history of HBV immunization and prenatal maternal levels of HBV an- tigens of all HCC patients born after July 1984 were retrieved from the HBV immunization data bank of the Taiwan Center for Disease Control. We collected data on birth cohort-specific populations (6–26 years old) of Taiwan using the National Household Registry System. Rates of HCC incidence per 10 5 person-years were derived by dividing the number of patients with HCC by the person-years of the general population. Rela- tive risks (RR) for HCC were estimated by Poisson regression analysis in vaccinated vs unvaccinated birth cohorts. We stratified patients by age group to evaluate the association of birth cohorts and HCC risks. RESULTS: Of the 1509 patients with HCC, 1343 were born before, and 166 were born after, the HBV vaccination program began. HCC incidence per 10 5 person-years was 0.92 in the unvaccinated cohort and 0.23 in the vaccinated birth cohorts. The RRs for HCC in patients 6–9 years old, 10–14 years old, 15–19 years old, and 20–26 years old who were vaccinated vs unvaccinated were 0.26 (95% confidence interval [CI], 0.17–0.40), 0.34 (95% CI, 0.25–0.48), 0.37 (95% CI, 0.25–0.51), and 0.42 (95% CI, 0.32–0.56), respectively. The RR for HCC in 6- to 26-year-olds was lower in the later vs the earlier cohorts (born in 1992–2005 vs 1986–1992; P < .001 and 1986–1992 vs 1984–1986; P < .002). Transmission of HBV from highly infectious mothers and incomplete immunization were associated with develop- ment of HCC. CONCLUSIONS: Based on an analysis of 1509 patients with HCC in Taiwan, immunization of infants against HBV reduces their risk of developing HCC as children and young adults. Improving HBV vaccination strategies and over- coming risk factors could reduce the incidence of liver cancer. Keywords: Cancer Prevention; Population Study; Viral Hepatitis; Liver Carcinogenesis. L iver cancer is the second leading cancer death in humans. 1 Hepatitis B virus (HBV) infection is one of the main etiologic factors of hepatocellular carcinoma (HCC), 2 particularly in areas with high incidence of HCC. Taiwan is endemic for chronic HBV infection and HCC. Previously, we provided the first evidence in humans that universal hepatitis B immunization in infancy can effectively reduce the incidence of liver cancer in children and Abbreviations used in this paper: CI, confidence interval; HBeAg, hepatitis B e antigen; HBIG, hepatitis B immunoglobulin; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; RR, relative risk. Most current article © 2016 by the AGA Institute 0016-5085/$36.00 http://dx.doi.org/10.1053/j.gastro.2016.05.048 Gastroenterology 2016;151:472–480 CLINICAL LIVER