Efficacy Of Neonatal HBV Vaccination On Liver Cancer And The Necessity Of Hepatitis B Vaccine Booster

Background&Aim:Hepatitis B virus(HBV)infection is the major cause of primary liver cancer(PLC)in China.Neonatal hepatitis B vaccination has been implemented worldwide to prevent HBV infections.Its long-term protective efficacy on PLC and other liver diseases has not been fully examined.The Qidong Hepatitis B Intervention Study(QHBIS),a population-based,cluster randomized,controlled trial between 1983 and 1990 in Qidong,China,included 41 182 newborns who were randomly assigned to the vaccination group in which 40 211 participants completed the HBV vaccination series and 41 730 newborns who were randomly assigned to the control group in which the participants received neither vaccine nor placebo.However,23 368 participants(58.1%)in the control group received catch-up vaccination at age 10～14 years,28 988 participants(72.1%)in the vaccination group received one-dose adolescent booster vaccination.Two cross-sectional surveys on HBsAg seroprevalence were conducted in 1996-2000 and 2008-2012.HBV vaccination is very efficacious in decreasing the seroprevalence HBsAg in children and in preventing the liver cancer in young adults.Neutralizing antibodies(anti-HBs)after immunization with HBV vaccines against HBsAg wane after 10～15 years.We analyzed the effect of an adolescent booster given to vaccination-protected children born to mothers with different HBsAg-carrying status against HBV infection in their mature adulthood.And we conducted cost-effectiveness analysis of the booster vaccination to this specific group of children.Methods:To determine the impact of hepatitis B virus(HBV)and/or hepatitis C virus(HCV)on primary liver cancer(PLC)in China north areas.A total of 2 172 histologically confirmed PLC patients attending the National Cancer Center/Cancer Hospital,Chinese Academy of Medical Sciences during the period January 1,2003 to December 31,2014 were enrolled.Details of HBsAg,antibodies against HBV core antigen(anti-HBc),and anti-HCV status were recorded.Sequencing of the HBV PreS-S gene and the C/E1 and NS5B fragments of HCV was performed and the genotypes were analyzed for some of the patients with hepatocellular carcinoma(HCC).In QHBIS,information on PLC incidence and severe endstage liver diseases mortality were collected through linkage of all remaining cohort members to a well-established population-based tumor registry until December 31,2016.A total of 9 793 individuals,who were HBsAg(-)at childhood(baseline)and donated blood samples,both during childhood and adulthood,from the vaccination group in QHBIS,were enrolled.Among them 7 414 received a one-dose,10μg-recombinant HBV vaccine booster at 10～14 years of age.At endpoint(23～28 years of age),we determined the HBV serological markers,quantified their serum HBV-DNA,amplified and sequenced the HBV PreS-S region of each chronic HBV-infected adults.In the cost-effectiveness analysis,two potential strategies were considered,strategy-1 was a one-dose booster if negative for HBsAg-screening,and strategy-2 was a one-dose booster if negative for HBsAg plus anti-HBs-screening.A decision tree combined with Markov model was developed to simulate the booster intervention process,and to simulate the natural history of hepatitis B virus infection in a cohort of 10-years-old children who were born to HBsAg-positive mothers.Based on multiple selected outcomes,the model was calibrated.Costs and quality-adjusted life years(QALYs)were measured from a societal perspective.Cost-effectiveness ratios(CERs)among different strategies were compared in both base-case and one-way sensitivity analyses.Results:Among the 2 172 histologically confirmed PLC cases,1 823(83.9%)had HCC and 238(11.0%)had intrahepatic cholangiocarcinoma(iCCA).Among HCC cases,HBV infection alone was found in 1 567(86.0%)cases;of these,18.2%(331/1 823)were HBsAg(-)&anti-HBc(+).Serum HBV-DNA was detectable in 70%of HBsAg(-)&anti-HBc(+)HCC cases.The dominant HBV genotype was HBV-C2(94.4%).HCV infection alone was found in 2.5%(46/1 823)of cases;HCV-lb(72.1%)was the dominant genotype.In QHBIS,by December 31,2016,4 cases of PLC in the vaccination group and 17 cases of PLC were identified in the vaccination and control group,respectively.The estimated efficacy on incidence rate of PLC at age below 33 years and severe endstage chronic liver diseases mortality was 79%(95%CI:36%-93%)and 68%(95%CI:25%-87%),respectively.During age 10 to 25,0.51%(50/9 793)individuals were identified as chronic HBV infection.The individuals who were born to HBsAg(+)mothers had significantly increased risk of developing chronic HBV infections in adulthood compared with those who were born to HBsAg(-)mothers;the adjusted OR was 12.56,95%CI:7.14-22.08.One dose of adolescent booster showed significant protection on high-risk adults from chronic HBV infection;P for trend was 0.015.No differences in HBV genotype distribution and and frequencies of amino acid variations in PreS-S genes were found among the participants who were boosted at adolescence and those who were not boosted.In the cost-effectiveness analysis,compared to the current no-screening and no-booster intervention,both strategy-1 and strategy-2 were cost-saving,with CERs estimated at US$-6 996 and US$-6 919 per QALY gained,respectively.In the one-way sensitivity analysis for strategy-1,all the CERs were found to be less than US$-5 000 per QALY gained after considering the uncertainty of all the variables,including vaccination protective efficacy,natural history,behavior,various costs and utility weights.In a "worst case" scenario(all parameter values simultaneously being at the worst)the CER of strategy-1 increased to US$1 896 per QALY gained,which was still less than the GDP per capita of China,2016(US$8 126).Conclusions:HBV remains the major contributor to PLC in China north areas.Individuals with occult HBV infection should not be ignored in liver cancer screening.Neonatal HBV vaccination was found to significantly decrease HBsAg seroprevalence in childhood through young adulthood and subsequently reduce the risk of PLC and other liver diseases in young adults in rural China.Maternal HBsAg(+)status was an independent risk factor for vaccination-protected children to develop HBV breakthrough infection in adulthood.Adolescent boosters might be appropriate for high-risk individuals who were born to HBsAg-positive mothers when their serum anti-HBs<10 mIU/ml.Hepatitis B booster vaccination would be cost-effective to the high risk children,which could be considered in HBV endemic areas.