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Cost-effectiveness analysis of hepatitis B vaccine booster in children born to HBsAg-positive mothers in rural China

  • Author Footnotes
    1 Yuting Wang and Ju-Fang Shi contributed equally to this work.
    Yuting Wang
    Footnotes
    1 Yuting Wang and Ju-Fang Shi contributed equally to this work.
    Affiliations
    Immunology Department, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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  • Author Footnotes
    1 Yuting Wang and Ju-Fang Shi contributed equally to this work.
    Ju-Fang Shi
    Footnotes
    1 Yuting Wang and Ju-Fang Shi contributed equally to this work.
    Affiliations
    Office of Cancer Screening, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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  • Le Wang
    Affiliations
    Office of Cancer Screening, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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  • Yongfeng Yan
    Affiliations
    Qidong Liver Cancer Institute and Qidong People’s Hospital, Qidong, Jiangsu, China
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  • Hongyu Yao
    Affiliations
    Qidong Liver Cancer Institute and Qidong People’s Hospital, Qidong, Jiangsu, China
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  • Min Dai
    Affiliations
    Office of Cancer Screening, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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  • Taoyang Chen
    Affiliations
    Qidong Liver Cancer Institute and Qidong People’s Hospital, Qidong, Jiangsu, China
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  • Chunfeng Qu
    Correspondence
    Corresponding author at: State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 17 Panjiayuan Nanli, Beijing 100021, China.
    Affiliations
    Immunology Department, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

    State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
    Search for articles by this author
  • Author Footnotes
    1 Yuting Wang and Ju-Fang Shi contributed equally to this work.
Open AccessPublished:November 19, 2018DOI:https://doi.org/10.1016/j.ijid.2018.08.024

      Highlights

      • Hepatitis B booster vaccination for high-risk children would be cost-effective.
      • Uncertainty of all variables could not change the conclusion that booster vaccination was cost-saving.
      • In a ‘worst case’ scenario, the cost-effectiveness ratio was still less than the GDP per capita in China in 2016.

      Abstract

      Objective

      In rural areas of China with highly endemic for hepatitis B virus (HBV) infection, protective efficacy was observed in adulthood when a one-dose HBV vaccine booster was administered to high-risk children born to mothers who were positive for hepatitis B surface antigen (HBsAg). The aim of this study was to estimate the cost-effectiveness of an HBV vaccine booster in this specific group of children when given at 10 years of age.

      Methods

      Two potential strategies were considered: strategy 1 was a one-dose booster given if the child was negative on HBsAg screening; strategy 2 was a one-dose booster given if the child was negative on both HBsAg plus anti-HBs screening. A decision tree combined with a Markov model was developed to simulate the booster intervention process and to simulate the natural history of HBV infection in a cohort of 10-year-old children who were born to HBsAg-positive mothers. The model was calibrated based on multiple selected outcomes. Costs and quality-adjusted life years (QALYs) were measured from a societal perspective. Cost-effectiveness ratios (CERs) of the different strategies were compared in both base-case and one-way sensitivity analyses.

      Results

      Compared to the current practice of ‘no screening and no booster’, both strategy 1 and strategy 2 were cost-saving, with CERs estimated at US$ −6961 and US$ −6872 per QALY gained, respectively. In the one-way sensitivity analysis for strategy 1, all the CERs were found to be less than US$ −5000 per QALY gained after considering the uncertainty of all the variables, including vaccination protective efficacy, natural history, behavior, and 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$ 3263 per QALY gained, which was still less than the GDP per capita of China in 2016 (US$ 8126).

      Conclusions

      A hepatitis B vaccine booster given to children born to HBsAg-positive mothers in rural China would be cost-effective and could be considered in HBV endemic areas.

      Keywords

      Introduction

      In China, chronic infection with hepatitis B virus (HBV) is estimated to be associated with 60% of cirrhosis and 80% of liver cancer (
      • Wang F.-S.
      • Fan J.-G.
      • Zhang Z.
      • Gao B.
      • Wang H.-Y.
      The global burden of liver disease: the major impact of China.
      ). Due to the heavy disease burden, the Chinese government recommended HBV vaccination in 1992. In 2002, the vaccine was added to the National Immunization Program schedule for all neonates/infants, with the cost being fully paid for by the government. The latest nationwide study found that the prevalence of hepatitis B surface antigen (HBsAg) had reduced to 0.32% in the age group 1–4 years and to 0.94% in the age group 5–14 years in 2014, from 9.67% and 10.74%, respectively, in 1992 (
      • Wang F.
      • Zhang G.
      • Shen L.
      • Zheng H.
      • Wang F.
      • Miao N.
      • et al.
      Comparative analyze on hepatitis B seroepidemiological surveys among population aged 1-29 years in different epidemic regions of Chinain 1992 and 2014.
      ,
      • Xia G.-L.
      • Liu C.-B.
      • Cao H.-L.
      • Bi S.-L.
      • Zhan M.-Y.
      • Su C.-A.
      • et al.
      Prevalence of hepatitis B and C virus infections in the general Chinese population. Results from a nationwide cross-sectional seroepidemiologic study of hepatitis A, B, C, D, and E virus infections in China, 1992.
      ). Consistent with reports from other areas and countries (
      • Trépo C.
      • Chan H.L.
      • Lok A.
      Hepatitis B virus infection.
      ), the immunization program for infants in China has proven very successful in decreasing HBV infection in children and in preventing mother-to-children transmission.
      It has long been observed that neutralizing antibodies (anti-HBs) conferred by HBV vaccination wane in many individuals after 10–15 years (
      • Ni Y.H.
      • Huang L.M.
      • Chang M.H.
      • Yen C.J.
      • Lu C.Y.
      • You S.L.
      • et al.
      Two decades of universal hepatitis B vaccination in taiwan: impact and implication for future strategies.
      ). In recent years, breakthrough HBV infections in adults who were vaccinated during infancy have been documented in different areas, especially among individuals who were born to HBsAg-positive mothers (
      • Wu T.W.
      • Lin H.H.
      • Wang L.Y.
      Chronic hepatitis B infection in adolescents who received primary infantile vaccination.
      ,
      • Xu L.
      • Wei Y.
      • Chen T.
      • Lu J.
      • Zhu C.L.
      • Ni Z.
      • et al.
      Occult HBV infection in anti-HBs-positive young adults after neonatal HB vaccination.
      ,
      • Shahmoradi S.
      • Yahyapour Y.
      • Mahmoodi M.
      • Alavian S.M.
      • Fazeli Z.
      • Jazayeri S.M.
      High prevalence of occult hepatitis B virus infection in children born to HBsAg positive mothers despite prophylaxis with hepatitis B vaccination and HBIG.
      ). The use of a vaccine booster test in children/young adults to measure HBsAg anamnestic immune responses has led to controversial conclusions regarding the necessity of an adolescent booster, due to the different or unknown maternal HBsAg status of the populations enrolled (
      • But D.Y.-K.
      • Lai C.-L.
      • Lim W.-L.
      • Fung J.
      • Wong D.K.-H.
      • Yuen M.-F.
      Twenty-two years follow-up of a prospective randomized trial of hepatitis B vaccines without booster dose in children: final report.
      ,
      • Jan C.F.
      • Huang K.C.
      • Chien Y.C.
      • Greydanus D.E.
      • Davies H.D.
      • Chiu T.Y.
      • et al.
      Determination of immune memory to hepatitis B vaccination through early booster response in college students.
      ,
      • Wu T.W.
      • Lin H.H.
      • Wang L.Y.
      Chronic hepatitis B infection in adolescents who received primary infantile vaccination.
      ,
      • Zanetti A.R.
      • Mariano A.
      • Romanò L.
      • D’Amelio R.
      • Chironna M.
      • Coppola R.C.
      • et al.
      Long-term immunogenicity of hepatitis B vaccination and policy for booster: an Italian multicentre study.
      ).
      A recent study involving 9793 individuals found that HBV breakthrough infection did occur and that chronicity developed in around 0.51% of adults who had been protected in childhood by the neonatal vaccination series. The children born to HBsAg-positive mothers, mainly those who had lost anti-HBs, were at high risk of becoming HBsAg-positive (4.32%, 4/370). However, for the individuals who were born to HBsAg-negative mothers, HBV breakthrough infection only occurred and developed chronicity in about 0.25% (22/8850) of adults, and no vaccine booster protective efficacy was found among them, even for those who had become negative for anti-HBs (
      • Wang Y.
      • Chen T.
      • Lu L.-l.
      • Wang M.
      • Wang D.
      • Yao H.
      • et al.
      Adolescent booster with hepatitis B virus vaccines decreases HBV infection in high-risk adults.
      ). Notably, a one-dose vaccine booster given at 10–14 years of age to the children who were born to HBsAg-positive mothers was found to be beneficial (
      • Wang Y.
      • Chen T.
      • Lu L.-l.
      • Wang M.
      • Wang D.
      • Yao H.
      • et al.
      Adolescent booster with hepatitis B virus vaccines decreases HBV infection in high-risk adults.
      ).
      Currently, approximately 6% of women of child-bearing age in rural China have a chronic HBV infection, and in recent years, an estimated 1 000 000 infants have been born to HBsAg-positive mothers every year (
      • Zheng H.
      • Cui F.
      • Gong X.
      • Wang F.
      • Chen Y.
      • Wu Z.
      • et al.
      Status of the hepatitis B virus surface antigen and e antigen prevalence among reproductive women in China.
      ). The latest nationwide study showed that HBsAg seroprevalence was still as high as 4.38% in the age group 15–29 years (
      • Wang F.
      • Zhang G.
      • Shen L.
      • Zheng H.
      • Wang F.
      • Miao N.
      • et al.
      Comparative analyze on hepatitis B seroepidemiological surveys among population aged 1-29 years in different epidemic regions of Chinain 1992 and 2014.
      ), indicating the high risk of HBV infection via sexual transmission among peers, parenteral transmission, or horizontal (household) HBV exposure. It is imperative to protect those who are susceptible from horizontal transmission to consolidate the protective efficacy of vaccination. Although the cost-effectiveness is unknown, some medical doctors still recommend adolescent boosters, especially for high-risk individuals (
      • Lu C.Y.
      • Chiang B.L.
      • Chi W.K.
      • Chang M.H.
      • Ni Y.H.
      • Hsu H.M.
      • et al.
      Waning immunity to plasma-derived hepatitis B vaccine and the need for boosters 15 years after neonatal vaccination.
      ,
      • Lu C.Y.
      • Ni Y.H.
      • Chiang B.L.
      • Chen P.J.
      • Chang M.H.
      • Chang L.Y.
      • et al.
      Humoral and cellular immune responses to a hepatitis B vaccine booster 15–18 years after neonatal immunization.
      ,
      • Chinchai T.
      • Chirathaworn C.
      • Praianantathavorn K.
      • Theamboonlers A.
      • Hutagalung Y.
      • Hans L.B.P.
      • et al.
      Long-term humoral and cellular immune response to hepatitis B vaccine in high-risk children 18–20 years after neonatal immunization.
      ,
      • Wu T.W.
      • Lin H.H.
      • Wang L.Y.
      Chronic hepatitis B infection in adolescents who received primary infantile vaccination.
      ,
      • Qu C.
      • Chen T.
      • Fan C.
      • Zhan Q.
      • Wang Y.
      • Lu J.
      • et al.
      Efficacy of neonatal HBV vaccination on liver cancer and other liver diseases over 30-year follow-up of the Qidong hepatitis B intervention study: a cluster randomized controlled trial.
      ).
      Several previous studies have analyzed the cost-effectiveness of different strategies for primary HBV vaccination and have concluded that primary HBV vaccination of populations at certain ages in China are all cost-saving (
      • Hutton D.W.
      • So S.K.
      • Brandeau M.L.
      Cost-effectiveness of nationwide hepatitis B catch-up vaccination among children and adolescents in China.
      ,
      • Yin J.
      • Ji Z.
      • Liang P.
      • Wu Q.
      • Cui F.
      • Wang F.
      • et al.
      The doses of 10 μg should replace the doses of 5 μg in newborn hepatitis B vaccination in China: a cost-effectiveness analysis.
      ,
      • Zheng H.
      • Wang F.
      • Zhang G.
      • Cui F.
      • Wu Z.
      • Miao N.
      • et al.
      An economic analysis of adult hepatitis B vaccination in China.
      ). This study was performed to analyze the cost-effectiveness of the potential booster vaccination of the specific group of children born to HBsAg-positive mothers.

      Methods

      Decision tree–Markov model

      A cohort of children born to HBsAg-positive mothers in 2006, who were 10 years old in 2016, was assumed for enrollment. In China, HBV vaccines have been fully paid for by the government for all neonates/infants since 2002 (
      • Sun Z.
      • Ming L.
      • Zhu X.
      • Lu J.
      Prevention and control of hepatitis B in China.
      ), and no vaccine booster protection was found among children who were born to HBsAg-negative mothers (
      • Wang Y.
      • Chen T.
      • Lu L.-l.
      • Wang M.
      • Wang D.
      • Yao H.
      • et al.
      Adolescent booster with hepatitis B virus vaccines decreases HBV infection in high-risk adults.
      ). A screening process before booster vaccination was assumed for this specific group of children who were born to HBsAg-positive mothers. This would allow individuals with an existing infection to be identified and to be informed of their infection status so that appropriate therapy could be given. Some individuals in the real world would like to know their anti-HBs status in order to relieve anxiety.
      Two booster vaccination strategies were considered: strategy 1 was a one-dose booster given if the child was negative on HBsAg screening; strategy 2 was a one-dose booster given if the child was negative on both HBsAg plus anti-HBs screening (Figure 1A). The current practice of ‘no screening and no booster’ was set as the comparison group. A decision tree–Markov model was constructed using TreeAgePro 2014 (TreeAge Software, Inc., Williamstown, MA, USA). The decision tree model was used to simulate compliance with and the protective efficacy of the booster, and to compare cost-effectiveness among the different strategies. The Markov model (Figure 1B) was used to simulate the disease progression and calculate the health and economic outcomes.
      Figure 1
      Figure 1(A) Decision tree for the intervention comparison, and (B) Markov model for the natural history of hepatitis B virus infection. (Abbreviations: HBsAg, hepatitis B surface antigen; anti-HBs, antibodies against hepatitis B surface antigen; HBeAg, hepatitis B e antigen; HCC, hepatocellular carcinoma).
      Eleven health states were set based on the updated guidelines of the Chinese Society of Hepatology, Chinese Medical Association (
      • Chinese Society of Hepatology
      • Chinese Medical Association
      • Chinese Society of Infectious Diseases
      • Chinese Medical Association
      The guideline of prevention and treatment for chronic hepatitis B: a 2015 update.
      ), European Association for the Study of the Liver (EASL) (
      • European Association for the Study of the Liver
      EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection.
      ), and available parameters from HBV natural history studies published in the literature (Figure 1B). These were (1) susceptible, (2) immune, (3) immune tolerant, (4) inactive HBsAg carriage, (5) hepatitis B e antigen (HBeAg)-positive chronic hepatitis B, (6) HBeAg-negative chronic hepatitis B, (7) HBsAg seroclearance, (8) compensated cirrhosis, (9) decompensated cirrhosis, (10) hepatocellular carcinoma (HCC), and (11) death.
      The Markov model was set with a cycle length of 1 year from 10 years to 76 years (the average life expectancy in China in 2015; http://www.stats.gov.cn/tjsj/ndsj/2016/indexch.htm). The model was built with the following assumptions: (1) the National Health and Family Planning Commission of the People’s Republic of China recommends screening-based HBV booster vaccination for high-risk children; the costs would be paid by the parents; (2) serum anti-HBs-positive status indicates protection from HBV infection; (3) there is no vaccine-induced herd-immunity; and (4) adverse events following booster are rare and negligible.

      Model parameters

      Values for the model parameters were chosen from the cost-effectiveness analyses of primary HBV vaccination conducted in the Chinese population, or from original studies published in English or in Chinese before August 2017.

      Parameters of behavior and protective efficacy of booster vaccination

      No publication was found about the rate of awareness of HBsAg-positive status among women of reproductive age in rural China in 2006. The rate of HBsAg screening before delivery among pregnant women from 1992 to 2005 was 94.6% in developed Beijing (
      • Wang F.
      • Gong X.
      • Liu L.
      • Han L.
      • Zhang H.
      • Zhang H.
      • et al.
      Analysis on infection of hepatitis B virus among pregnant women in Beijing.
      ) and was 79.36% in 2007 in Shandong Province, where rural areas were more developed compared to the other areas of China (
      • Song L.
      • Zhang L.
      • Yan B.
      • Xu A.
      • Ji F.
      Analysis on HBsAg screening among puerperants and first dose hepatitis B vaccination of their newborn in Shandong Province in 2007.
      ). In the current study, it was assumed that 70% of HBsAg-positive mothers were aware of their infection status. Information from the school-based vaccination system was used in a previous economic analysis on catch-up vaccination (
      • Hutton D.W.
      • So S.K.
      • Brandeau M.L.
      Cost-effectiveness of nationwide hepatitis B catch-up vaccination among children and adolescents in China.
      ). However, it was considered that this would not be appropriate or efficacious for the current situation, because maternal HBsAg status is considered confidential information in China. Thus, a school-based health education and information program was considered more appropriate. Parents would be informed of the booster vaccination by the teachers so that the parents of the target children would be prompted to take them to the nearest clinic for screening and to receive the booster.
      No publication was found on the willingness of those in this specific high-risk population to receive the booster. Experts in the National Immunization Programs, Chinese Center for Disease Control and Prevention (CDC) were consulted. These experts stated that compliance with screening should be more than 70% in rural China. Based on the compliance reported in the economic analysis of catch-up vaccination (
      • Hutton D.W.
      • So S.K.
      • Brandeau M.L.
      Cost-effectiveness of nationwide hepatitis B catch-up vaccination among children and adolescents in China.
      ) and adult HBV vaccination (
      • Zheng H.
      • Wang F.
      • Zhang G.
      • Cui F.
      • Wu Z.
      • Miao N.
      • et al.
      An economic analysis of adult hepatitis B vaccination in China.
      ), the following was assumed for strategy 1: that 70% of individuals would participate in HBsAg screening and that 80% would receive the one-dose booster if negative. For strategy 2, it was assumed that 65% of individuals would participate in the HBsAg plus anti-HBs-screening and that 80% would receive the one-dose booster if both were negative. The protective efficacy of the one-dose booster was calculated as 57% using the formula (7.21 − 3.09%)/7.21%, based on a previous study that showed that the booster reduced the HBsAg-positive rate from 7.21% to 3.09% in adulthood in this specific population (
      • Wang Y.
      • Chen T.
      • Lu L.-l.
      • Wang M.
      • Wang D.
      • Yao H.
      • et al.
      Adolescent booster with hepatitis B virus vaccines decreases HBV infection in high-risk adults.
      ). The use of a two- or three-dose booster was not considered in the base-case analysis, because no report of protective efficacy was available.
      In the sensitivity analysis, the cost-effectiveness of two- or three-dose booster was considered. Booster test studies among children/young adults with unknown maternal HBsAg status have reported 95% anti-HBs-positive seroconversion after the two-dose booster and 98% after the three-dose booster (
      • Chen Y.
      • Liang X.
      • Yao J.
      • Cui F.
      • Li Q.
      • Jiang Z.
      • et al.
      Evaluation on the efficacy of recombinant hepatitis B vaccine booster immunization in 2789 children aged over 10 years.
      ,
      • Jan C.F.
      • Huang K.C.
      • Chien Y.C.
      • Greydanus D.E.
      • Davies H.D.
      • Chiu T.Y.
      • et al.
      Determination of immune memory to hepatitis B vaccination through early booster response in college students.
      ). In the present study, a conservative assumption was made by deducting 5% from the anti-HBs-positive seroconversion rates as the protective efficacy, thus 90% for the two-dose booster and 93% for the three-dose booster. Considering 80% compliance for the one-dose booster, compliance of 78% was assumed for the two-dose booster and 76% for the three-dose booster if negative on HBsAg screening (Table 1).
      Table 1Model parameters for intervention, behavior, natural history, and others.
      ParameterBase-case valueRange for sensitivity analysisNotes and references
      Compliance to screening and booster vaccination
       HBsAg screening0.700.20–0.90Assumed based on
      • Hutton D.W.
      • So S.K.
      • Brandeau M.L.
      Cost-effectiveness of nationwide hepatitis B catch-up vaccination among children and adolescents in China.
      and
      • Zheng H.
      • Wang F.
      • Zhang G.
      • Cui F.
      • Wu Z.
      • Miao N.
      • et al.
      An economic analysis of adult hepatitis B vaccination in China.
       HBsAg screening plus anti-HBs screening0.650.20–0.85
       One-dose booster vaccination0.800.55–0.95
      Efficacy of booster vaccinationBased on a previous study in Qidong, China (
      • Wang Y.
      • Chen T.
      • Lu L.-l.
      • Wang M.
      • Wang D.
      • Yao H.
      • et al.
      Adolescent booster with hepatitis B virus vaccines decreases HBV infection in high-risk adults.
      )

      Assumed based on the anti-HBs seroprotective rates after HBV vaccination booster studies of
      • Jan C.F.
      • Huang K.C.
      • Chien Y.C.
      • Greydanus D.E.
      • Davies H.D.
      • Chiu T.Y.
      • et al.
      Determination of immune memory to hepatitis B vaccination through early booster response in college students.
      and
      • Chen Y.
      • Liang X.
      • Yao J.
      • Cui F.
      • Li Q.
      • Jiang Z.
      • et al.
      Evaluation on the efficacy of recombinant hepatitis B vaccine booster immunization in 2789 children aged over 10 years.
       10 μg for one dose0.570.45–0.75
       10 μg for two doses0.900.57–0.95
       10 μg for three doses0.930.57–0.98
      Awareness rate of HBsAg status among HBsAg-positive mothers0.700.50–0.80
      • Wang F.
      • Gong X.
      • Liu L.
      • Han L.
      • Zhang H.
      • Zhang H.
      • et al.
      Analysis on infection of hepatitis B virus among pregnant women in Beijing.
      ,
      • Song L.
      • Zhang L.
      • Yan B.
      • Xu A.
      • Ji F.
      Analysis on HBsAg screening among puerperants and first dose hepatitis B vaccination of their newborn in Shandong Province in 2007.
      Initial probabilitiesResults of maternal HBsAg-positive children aged 1–14 years in a hepatitis B national serosurvey in 2014 (
      • Wang F.
      • Zheng H.
      • Zhang G.
      • Miao N.
      • Sun X.
      • Cui F.
      Sero-epidemiological analysis on hepatitis B among children aged 1-14 years old born to HBsAg positive mother in China, 2014.
      )
       Already infected (HBsAg screening positive rate)0.05710.02–0.07
       Immune (anti-HBs screening positive rate)0.56400.48–0.65
      Acute infection
       Outcome probabilities of acute infection
        Symptomatic0.300.15–0.45
      • Jia Y.
      • Li L.
      • Cui F.
      • Zhang D.
      • Zhang G.
      • Wang F.
      • et al.
      Cost-effectiveness analysis of a hepatitis B vaccination catch-up program among children in Shandong Province, China.
      ,
      • Kim S.-Y.
      • Billah K.
      • Lieu T.A.
      • Weinstein M.C.
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      ,
      • Liaw Y.-F.
      • Chu C.-M.
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      • Lu S.Q.
      • McGhee S.M.
      • Xie X.
      • Cheng J.
      • Fielding R.
      Economic evaluation of universal newborn hepatitis B vaccination in China.
      ,
      • Trépo C.
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      • Yin J.
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      • Liang P.
      • Wu Q.
      • Cui F.
      • Wang F.
      • et al.
      The doses of 10 μg should replace the doses of 5 μg in newborn hepatitis B vaccination in China: a cost-effectiveness analysis.
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      • Zheng H.
      • Wang F.
      • Zhang G.
      • Cui F.
      • Wu Z.
      • Miao N.
      • et al.
      An economic analysis of adult hepatitis B vaccination in China.
        Symptomatic infection requiring hospitalization0.120.01–0.50
      • Hutton D.W.
      • So S.K.
      • Brandeau M.L.
      Cost-effectiveness of nationwide hepatitis B catch-up vaccination among children and adolescents in China.
      ,
      • Trépo C.
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      Hepatitis B virus infection.
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      • Wu Q.
      • Cui F.
      • Wang F.
      • et al.
      The doses of 10 μg should replace the doses of 5 μg in newborn hepatitis B vaccination in China: a cost-effectiveness analysis.
        Hospitalized cases with fulminant hepatitis0.040.01–0.10
      • Hutton D.W.
      • So S.K.
      • Brandeau M.L.
      Cost-effectiveness of nationwide hepatitis B catch-up vaccination among children and adolescents in China.
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      • Trépo C.
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      • Cui F.
      • Wang F.
      • et al.
      The doses of 10 μg should replace the doses of 5 μg in newborn hepatitis B vaccination in China: a cost-effectiveness analysis.
        Fulminant cases resulting in death0.700.40–0.80
      • Choi H.J.
      • Ko S.Y.
      • Choe W.H.
      • Seo Y.S.
      • Kim J.H.
      • Byun K.S.
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      ,
      • Hutton D.W.
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      • Brandeau M.L.
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      ,
      • Liaw Y.-F.
      • Chu C.-M.
      Hepatitis B virus infection.
      ,
      • Trépo C.
      • Chan H.L.
      • Lok A.
      Hepatitis B virus infection.
      ,
      • Yin J.
      • Ji Z.
      • Liang P.
      • Wu Q.
      • Cui F.
      • Wang F.
      • et al.
      The doses of 10 μg should replace the doses of 5 μg in newborn hepatitis B vaccination in China: a cost-effectiveness analysis.
      ,
      • Zheng H.
      • Wang F.
      • Zhang G.
      • Cui F.
      • Wu Z.
      • Miao N.
      • et al.
      An economic analysis of adult hepatitis B vaccination in China.
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      An economic analysis of adult hepatitis B vaccination in China.
        Asymptomatic acute infection becoming chronicexp(−0.65 × age0.46)
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      Economic evaluation of universal newborn hepatitis B vaccination in China.
      Disease progression parameters of chronic HBV infection (annual transition probabilities)
       Immune tolerant
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        To HBeAg-positive chronic hepatitis B10∼: 0.0119; 13∼: 0.0535; 19∼: 0.1423±50%
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      Development of Markov models for economics evaluation of strategies on hepatitis B vaccination and population-based antiviral treatment in China.
       HBeAg-positive chronic hepatitis B
        To inactive HBsAg carriage0.0780.063–0.093
      • Yang P.
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      Development of Markov models for economics evaluation of strategies on hepatitis B vaccination and population-based antiviral treatment in China.
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        To HBsAg seroclearance0.00430.0007–0.0093
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      Efficacy of neonatal HBV vaccination on liver cancer and other liver diseases over 30-year follow-up of the Qidong hepatitis B intervention study: a cluster randomized controlled trial.
        To compensated cirrhosis10∼: 0.01; 20∼: 0.02; 40∼: 0.027±50%
      • Lu S.Q.
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      Economic evaluation of universal newborn hepatitis B vaccination in China.
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      • Yin J.
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      The doses of 10 μg should replace the doses of 5 μg in newborn hepatitis B vaccination in China: a cost-effectiveness analysis.
        To HCC10∼: 0.0000288; 30∼: 0.001175; 40∼: 0.0064±50%
      • Wen W.-H.
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      • Ni Y.-H.
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      The development of hepatocellular carcinoma among prospectively followed children with chronic hepatitis B virus infection.
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      • Yang P.
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      Development of Markov models for economics evaluation of strategies on hepatitis B vaccination and population-based antiviral treatment in China.
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      • Yin J.
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      • Wu Q.
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      The doses of 10 μg should replace the doses of 5 μg in newborn hepatitis B vaccination in China: a cost-effectiveness analysis.
       Inactive HBsAg carriage
        To HBeAg-positive chronic hepatitis B0.0060–0.011
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      • Yeh C.-T.
      • Sheen I.S.
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      • Yang P.
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      • Zou Y.
      Development of Markov models for economics evaluation of strategies on hepatitis B vaccination and population-based antiviral treatment in China.
        To HBeAg-negative chronic hepatitis B0.04270.02–0.05
      • Chu C.M.
      • Liaw Y.F.
      Predictive factors for reactivation of hepatitis B following hepatitis B e antigen seroconversion in chronic hepatitis B.
      ,
      • Yang P.
      • Zhang S.
      • Sun P.
      • Cai Y.
      • Lin Y.
      • Zou Y.
      Development of Markov models for economics evaluation of strategies on hepatitis B vaccination and population-based antiviral treatment in China.
        To HBsAg seroclearance0.01140.0057–0.0171
      • Qu C.
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      • Fan C.
      • Zhan Q.
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      Efficacy of neonatal HBV vaccination on liver cancer and other liver diseases over 30-year follow-up of the Qidong hepatitis B intervention study: a cluster randomized controlled trial.
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      Hepatitis B virus infection.
        To compensated cirrhosis0.00102±50%
      • Hung H.-F.
      • Chen T.H.-H.
      Probabilistic cost-effectiveness analysis of the long-term effect of universal hepatitis B vaccination: an experience from Taiwan with high hepatitis B virus infection and Hepatitis B e Antigen positive prevalence.
      ,
      • McMahon B.J.
      • Alberts S.R.
      • Wainwright R.B.
      • Bulkow L.
      • Lanier A.P.
      Hepatitis B-related sequelae. Prospective study in 1400 hepatitis B surface antigen-positive Alaska native carriers.
      ,
      • Yu M.-W.
      • Hsu F.-C.
      • Sheen I.S.
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      • et al.
      Prospective study of hepatocellular carcinoma and liver cirrhosis in asymptomatic chronic hepatitis B virus carriers.
        To HCC10∼: 0.0000288; 30∼: 0.0006; 40∼: 0.0061±50%
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      • et al.
      Carriers of inactive hepatitis B virus are still at risk for hepatocellular carcinoma and liver-related death.
      ,
      • Wen W.-H.
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      The development of hepatocellular carcinoma among prospectively followed children with chronic hepatitis B virus infection.
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      The doses of 10 μg should replace the doses of 5 μg in newborn hepatitis B vaccination in China: a cost-effectiveness analysis.
       HBeAg-negative chronic hepatitis B
        To HBsAg seroclearance0.00670.0017–0.0087
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      Predictors of HBsAg seroclearance in HBeAg-negative chronic hepatitis B patients.
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      Efficacy of neonatal HBV vaccination on liver cancer and other liver diseases over 30-year follow-up of the Qidong hepatitis B intervention study: a cluster randomized controlled trial.
        To compensated cirrhosis10∼: 0.01; 20∼: 0.02; 40∼: 0.027±50%
      • Lu S.Q.
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      Economic evaluation of universal newborn hepatitis B vaccination in China.
      ,
      • Wu G.
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      The doses of 10 μg should replace the doses of 5 μg in newborn hepatitis B vaccination in China: a cost-effectiveness analysis.
        To HCC10∼: 0.0000288; 30∼: 0.000286; 40∼: 0.0064±50%
      • Wen W.-H.
      • Chang M.-H.
      • Hsu H.-Y.
      • Ni Y.-H.
      • Chen H.-L.
      The development of hepatocellular carcinoma among prospectively followed children with chronic hepatitis B virus infection.
      ,
      • Yang P.
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      Development of Markov models for economics evaluation of strategies on hepatitis B vaccination and population-based antiviral treatment in China.
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      The doses of 10 μg should replace the doses of 5 μg in newborn hepatitis B vaccination in China: a cost-effectiveness analysis.
       Compensated cirrhosis
        To decompensated cirrhosis0.0360.025–0.050
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      Cost-effectiveness analysis of a hepatitis B vaccination catch-up program among children in Shandong Province, China.
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      Large variations in risk of hepatocellular carcinoma and mortality in treatment naïve hepatitis B patients: systematic review with meta-analyses.
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      Development of Markov models for economics evaluation of strategies on hepatitis B vaccination and population-based antiviral treatment in China.
       Decompensated cirrhosis
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      Cost-effectiveness of nucleoside analog therapy for hepatitis B in China: a Markov analysis.
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      The doses of 10 μg should replace the doses of 5 μg in newborn hepatitis B vaccination in China: a cost-effectiveness analysis.
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      Development of Markov models for economics evaluation of strategies on hepatitis B vaccination and population-based antiviral treatment in China.
      ,
      • Yin J.
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      The doses of 10 μg should replace the doses of 5 μg in newborn hepatitis B vaccination in China: a cost-effectiveness analysis.
       HCC to death (disease-specific)0.340.30–0.70
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      • Gluud L.L.
      • Fialla A.D.
      • Dahl E.K.
      • Krag A.
      Large variations in risk of hepatocellular carcinoma and mortality in treatment naïve hepatitis B patients: systematic review with meta-analyses.
      ,
      • Yang P.
      • Zhang S.
      • Sun P.
      • Cai Y.
      • Lin Y.
      • Zou Y.
      Development of Markov models for economics evaluation of strategies on hepatitis B vaccination and population-based antiviral treatment in China.
      HBsAg, hepatitis B surface antigen; anti-HBs, antibodies against hepatitis B surface antigen; HBV, hepatitis B virus; HBeAg, hepatitis B e antigen; HCC, hepatocellular carcinoma.

      Incidence and transition probabilities of HBV infection

      Based on the report from a nationwide serological survey of hepatitis in China, 2014 (
      • Wang F.
      • Zheng H.
      • Zhang G.
      • Miao N.
      • Sun X.
      • Cui F.
      Sero-epidemiological analysis on hepatitis B among children aged 1-14 years old born to HBsAg positive mother in China, 2014.
      ), the initial probabilities were set at 0.0571 for the HBsAg-positive rate and 0.564 for the anti-HBs-positive rate (Table 1) for the cohort of children who were born to HBsAg-positive mothers and who were 10 years old in 2016. In order to estimate the age-specific annual incidence of HBV infection in susceptible individuals in the high-risk population who were born to HBsAg-positive mothers, the age-specific annual incidence in the general population was calculated using the non-linear least-squares method based on the nationwide HBV prevalence in China in 1992 (
      • Yang P.
      • Zhang S.
      • Sun P.
      • Cai Y.
      • Lin Y.
      • Zou Y.
      Development of Markov models for economics evaluation of strategies on hepatitis B vaccination and population-based antiviral treatment in China.
      ,
      • Yin J.
      • Ji Z.
      • Liang P.
      • Wu Q.
      • Cui F.
      • Wang F.
      • et al.
      The doses of 10 μg should replace the doses of 5 μg in newborn hepatitis B vaccination in China: a cost-effectiveness analysis.
      ). This would characterize natural HBV infections without vaccination, because the time was just before HBV vaccination was recommended for newborns (
      • Xia G.-L.
      • Liu C.-B.
      • Cao H.-L.
      • Bi S.-L.
      • Zhan M.-Y.
      • Su C.-A.
      • et al.
      Prevalence of hepatitis B and C virus infections in the general Chinese population. Results from a nationwide cross-sectional seroepidemiologic study of hepatitis A, B, C, D, and E virus infections in China, 1992.
      ). Based on the theoretical expression of the incidence (details showed in the Supplementary material) and the difference in HBsAg prevalence between 1992 and 2006 (
      • Liang X.
      • Bi S.
      • Yang W.
      • Wang L.
      • Cui G.
      • Cui F.
      • et al.
      Epidemiological serosurvey of hepatitis B in China—declining HBV prevalence due to hepatitis B vaccination.
      ,
      • Xia G.-L.
      • Liu C.-B.
      • Cao H.-L.
      • Bi S.-L.
      • Zhan M.-Y.
      • Su C.-A.
      • et al.
      Prevalence of hepatitis B and C virus infections in the general Chinese population. Results from a nationwide cross-sectional seroepidemiologic study of hepatitis A, B, C, D, and E virus infections in China, 1992.
      ), it was estimated that the average annual decline in incidence in the general population was 2.16%. The age-specific incidence of HBV infection in susceptible individuals in the high-risk population who were born to HBsAg-positive mothers in 2016 was based on the increased risk (odds ratio 7.38) of chronic HBV infection among the high-risk population and the annual decline in incidence in the general population. There are currently no available data on the occurrence of chronic HBV infection in susceptible individuals after 25 years of age; thus it was assumed that new HBV infection only occurred during the age range 10–25 years. A detailed description of the methodology is provided in the Supplementary material.
      The probabilities of progression or regression of HBV infection (Table 1) were obtained from economic analyses, meta-analyses, and observational epidemiological studies that were mainly conducted in Chinese populations. Age-specific probabilities were applied when necessary and feasible.

      Costs

      All costs were measured from the societal perspective. Costs of screening and booster vaccination were derived from a nationwide economic analysis of adult HBV vaccination conducted by the Chinese CDC in 2014, which covered the screening and vaccination delivery costs (
      • Zheng H.
      • Wang F.
      • Zhang G.
      • Cui F.
      • Wu Z.
      • Miao N.
      • et al.
      An economic analysis of adult hepatitis B vaccination in China.
      ). Considering the cost differences of screening and vaccination among different regions, and the waste of screening and vaccination resources due to over-screening and over-provision of booster among children born to HBsAg-negative mothers, four-fold the base-case value was set as the higher bound in the sensitivity analysis. It was assumed that a target child could walk to the nearest clinic escorted by one of their parents with no additional travel costs. The productivity loss due to the time spent by the parents was considered an indirect cost. It was assumed that each visit would take 1.5 h on average, at US$ 1.84/h (
      • Zheng H.
      • Wang F.
      • Zhang G.
      • Cui F.
      • Wu Z.
      • Miao N.
      • et al.
      An economic analysis of adult hepatitis B vaccination in China.
      ), and that the current multi-level immunization system in each province of China would be able to provide HBV screening and booster vaccination. Based on the economic analysis on catch-up vaccination (
      • Hutton D.W.
      • So S.K.
      • Brandeau M.L.
      Cost-effectiveness of nationwide hepatitis B catch-up vaccination among children and adolescents in China.
      ), a setup cost of US$ 0.40 per child was assumed in the base-case analysis. In the sensitivity analysis, the range of the setup cost was assumed to be US$ 0.20 to US$ 0.60 per child.
      The annual costs per patient of HBV-related diseases consisted of direct medical costs, direct non-medical costs, and the indirect costs of the escorted persons. These data were derived from a nationwide multicenter survey on the HBV-associated economic burden that was conducted in 27 general and specialized hospitals located in six provinces of China, with 4726 patients enrolled in 2010 (
      • Zhang S.
      • Ma Q.
      • Liang S.
      • Xiao H.
      • Zhuang G.
      • Zou Y.
      • et al.
      Annual economic burden of hepatitis B virus-related diseases among hospitalized patients in twelve cities in China.
      ). As no data were available from this survey on the costs of asymptomatic HBsAg carriers, eight hepatologists from Beijing You’an Hospital, Qidong People’s Hospital, and Qidong Hospital for Infectious Diseases were consulted (
      • Wang Y.
      • Huang H.
      • Qin H.
      • Yao H.
      • Chen S.
      • Yu D.
      • et al.
      Medical expenditure of hepatitis B virus infection and its impact factors analysis in Qidong, Jiangsu Province.
      ). In the sensitivity analysis, the costs of HBV-related diseases varied from 50% to 150% of the base-case values to cover the majority of reported data and variation across different regions of China. According to a community-based nationwide survey on health-seeking behaviors among HBsAg-positive adults, the Chinese CDC reported that 18% of asymptomatic HBsAg carriers underwent a medical examination at least once a year and 11% of chronic hepatitis B patients received various treatments (
      • Zheng H.
      • Wang F.
      • Zhang G.
      • Wu Z.
      • Miao N.
      • Sun X.
      • et al.
      Study on health-seeking behavior and influencing factors among Chinese hepatitis B surface antigen positive adults.
      ). All costs are presented in US$, with the exchange rate of 1 US$ = 6.6423 CNY in 2016 (Table 2).
      Table 2Model parameters for costs and utility weights.
      ParameterBase-case valueRange for sensitivity analysisNotes and references
      Costs associated with screening and vaccination, US$
       Direct costs
        HBsAg screening and delivery cost2.101.75–8.40
      • Zheng H.
      • Wang F.
      • Zhang G.
      • Cui F.
      • Wu Z.
      • Miao N.
      • et al.
      An economic analysis of adult hepatitis B vaccination in China.
      and
      • Lin Y.
      • Zhang S.
      • Yang P.
      • Cai Y.
      • Zou Y.
      Cost-effectiveness and affordability of strategy for preventing mother-to-child transmission of hepatitis B in China.
        HBsAg and anti-HBs screening and delivery cost3.332.98–8.40
        Per-dose vaccine and delivery cost2.672.14–10.68
       Indirect costsAssumed based on results from
      • Zheng H.
      • Wang F.
      • Zhang G.
      • Cui F.
      • Wu Z.
      • Miao N.
      • et al.
      An economic analysis of adult hepatitis B vaccination in China.
        Work loss for one-visit screening or vaccination (US$ per visit)2.761.84–7.36
      Annual cost per patient with different HBV-related disease, US$
       Direct costs
        Acute hepatitis B2555±50%Based on results from
      • Zhang S.
      • Ma Q.
      • Liang S.
      • Xiao H.
      • Zhuang G.
      • Zou Y.
      • et al.
      Annual economic burden of hepatitis B virus-related diseases among hospitalized patients in twelve cities in China.
      , a nationwide multicenter survey of the HBV-associated economic burden in China (N = 4726)
        Fulminant hepatitis8971±50%
        Chronic hepatitis B3436±50%
        Compensated cirrhosis5428±50%
        Decompensated cirrhosis6903±50%
        Hepatocellular carcinoma9070±50%
        Immune tolerant/inactive HBsAg carriage228±50%
       Indirect costs
        Acute hepatitis B377±50%
        Fulminant hepatitis2316±50%
        Chronic hepatitis B544±50%
        Compensated cirrhosis844±50%
        Decompensated cirrhosis1280±50%
        Hepatocellular carcinoma3913±50%
      Utility weights
      Health/asymptomatic infection0.820.80–0.84From
      • Lin Y.
      • Zhang S.
      • Yang P.
      • Cai Y.
      • Zou Y.
      Cost-effectiveness and affordability of strategy for preventing mother-to-child transmission of hepatitis B in China.
      , a cost-effectiveness analysis of the strategy for preventing mother-to-child transmission of hepatitis B in China; the utility weights of cirrhosis and hepatocellular carcinoma were obtained by meta-analysis
        Acute hepatitis B0.760.66–0.78
        Fulminant hepatitis0.260.15–0.35
        HBeAg-positive chronic hepatitis B0.760.66–0.78
        HBeAg-negative chronic hepatitis B0.750.72–0.78
        Immune tolerant/inactive HBsAg carriage0.7950.76–0.82
        Compensated cirrhosis0.720.66–0.75
        Decompensated cirrhosis0.570.47–0.61
        Hepatocellular carcinoma0.510.39–0.57
      Discount rate0.030.01–0.06
      HBsAg, hepatitis B surface antigen; anti-HBs, antibodies against hepatitis B surface antigen; HBV, hepatitis B virus; HBeAg, hepatitis B e antigen; HCC, hepatocellular carcinoma. All costs and QALYs were discounted to year 2016 at 3%.

      Utility weights

      There are currently no available data from the nationwide survey on the utility weights of HBV-related diseases. Data on QALY-related utility weights (Table 2) for HBV-related diseases from a cost-effectiveness analysis for preventing mother-to-child transmission of HBV in China in 2017 were used (
      • Lin Y.
      • Zhang S.
      • Yang P.
      • Cai Y.
      • Zou Y.
      Cost-effectiveness and affordability of strategy for preventing mother-to-child transmission of hepatitis B in China.
      ). In this study, the meta-analysis was conducted to pool the utility weights of cirrhosis and HCC.

      Cost-effectiveness analysis

      The cost-effectiveness ratio (CER) for each of the booster strategies compared with the current practice of no screening and no booster was used as the key indicator, by dividing the difference of the discounted cost by the difference of the discounted QALYs. All costs and QALYs were discounted at a 3% annual rate. One-way sensitivity analyses were performed to assess the uncertainty of the primary results with the range of variables listed in Table 1, Table 2. The CERs under a most pessimistic scenario (the ‘worst case’) were also calculated to make a most conservative estimation, that is, when all the parameters were simultaneously at the worst for the booster strategy.

      Results

      Model validation

      The model predicted outcomes were compared with the observed outcomes from previous reports (Table 3). Observational studies reported that about 10–25% of individuals chronically infected with HBV developed HCC (
      • Omata M.
      • Cheng A.-L.
      • Kokudo N.
      • Kudo M.
      • Lee J.M.
      • Jia J.
      • et al.
      Asia–Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update.
      ), that 70–90% of HCC cases were associated with cirrhosis (
      • Omata M.
      • Cheng A.-L.
      • Kokudo N.
      • Kudo M.
      • Lee J.M.
      • Jia J.
      • et al.
      Asia–Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update.
      ), and that 25–40% of HBV-infected individuals might die of cirrhosis and/or HCC (
      • Kao J.-H.
      • Chen D.-S.
      Global control of hepatitis B virus infection.
      ,
      • Trépo C.
      • Chan H.L.
      • Lok A.
      Hepatitis B virus infection.
      ). Our model predicted that the proportion of HCC in chronic HBV-infected individuals was 21.3%, the proportion of cirrhosis-associated HCC was 71.3%, and the proportion of death after chronic HBV infection was 30.5% (Table 3). The values predicted by the model were all within the observed ranges.
      Table 3Model validation: comparison between values predicted by the model and observed outcomes, prior to any intervention.
      Selected outcomesProportion predicted by the modelProportion observed in the literature
      Value rangeData sources
      HCC/chronic HBV infection21.3%10–25%Reported by Omata et al. in a guideline, 2017 (
      • Omata M.
      • Cheng A.-L.
      • Kokudo N.
      • Kudo M.
      • Lee J.M.
      • Jia J.
      • et al.
      Asia–Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update.
      ) and in a

      World Health Organization. Hepatitis B fact sheet, reviewed July 2017. http://www.who.int/mediacentre/factsheets/fs204/en/.

      Cirrhosis-associated HCC/HCC71.3%70–90%Reported by Omata et al. in a guideline, 2017 (
      • Omata M.
      • Cheng A.-L.
      • Kokudo N.
      • Kudo M.
      • Lee J.M.
      • Jia J.
      • et al.
      Asia–Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update.
      )
      HBV-related death
      Deaths due to decompensated cirrhosis or HCC.
      /chronic HBV infection
      30.5%25–40%Review by
      • Kao J.-H.
      • Chen D.-S.
      Global control of hepatitis B virus infection.
      ; review by
      • Trépo C.
      • Chan H.L.
      • Lok A.
      Hepatitis B virus infection.
      HCC, hepatocellular carcinoma; HBV, hepatitis B virus; WHO, World Health Organization.
      a Deaths due to decompensated cirrhosis or HCC.

      Base-case results

      Compared with the current no-screening and no-booster intervention, booster vaccination reduced the number of cases of HBV-related diseases. By taking strategy 1–one-dose booster if negative on HBsAg screening – among 100 000 high-risk children, 485 chronic HBV-infected cases and 153 HBV-related deaths could be avoided if 36 962 children received the booster. By taking strategy 2–one-dose booster if negative on both HBsAg plus anti-HBs screening – among 100 000 high-risk children, 365 chronic HBV-infected cases and 115 HBV-related deaths could be avoided if 13 792 children received the booster vaccination (Table 4).
      Table 4Predicted numbers of events or various diseases caused by HBV with different intervention strategies, per 100 000 10-year-old children born to HBsAg-positive mothers.
      Vaccination event or HBV-related diseasesNo screening and no booster

      (Comparison group)
      Strategy 1: one-dose booster if negative on HBsAg screening
      Numbers in parentheses are the numbers of cases prevented by the booster intervention.
      Strategy 2: one-dose booster if negative on both HBsAg plus anti-HBs screening
      Numbers in parentheses are the numbers of cases prevented by the booster intervention.
      Booster vaccinated036 96213 792
      Hospitalized acute symptomatic hepatitis B773581 (192)636 (137)
      Fulminant hepatitis3224 (8)26 (6)
      Chronic HBV infection19911506 (485)1626 (365)
      Compensated cirrhosis191144 (47)156 (35)
      Decompensated cirrhosis251190 (61)205 (46)
      Hepatocellular carcinoma423320 (103)345 (78)
      HBV-related death
      Deaths due to decompensated cirrhosis, hepatocellular carcinoma, or fulminant hepatitis.
      629476 (153)514 (115)
      HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen; anti-HBs, antibodies against hepatitis B surface antigen.
      a Numbers in parentheses are the numbers of cases prevented by the booster intervention.
      b Deaths due to decompensated cirrhosis, hepatocellular carcinoma, or fulminant hepatitis.
      During the simulated lifetime from age 10 years to 76 years, strategy 1 and strategy 2 were both cost-saving when compared to no screening and no booster, with US$ 78 (strategy 1) and US$ 59 (strategy 2) saved per person; the CERs were US$ −6961/QALY and US$ −6872/QALY, respectively. Both strategies led to greater effectiveness but lower costs (Table 5).
      Table 5Cost-effectiveness analysis of a one-dose adolescent booster vaccination, compared to no intervention.
      Different strategies taken in high-risk children at 10 years oldDiscounted cost, US$Discounted QALYsCost-effectiveness ratio, US$/QALY
      Comparison group

      No screening and no booster
      129023.2486
      Strategy 1

      One-dose booster if negative on HBsAg screening
      121223.2599−6961
      Strategy 2

      One-dose booster if negative on HBsAg plus anti-HBs screening
      123123.2572−6872
      HBsAg, hepatitis B surface antigen; QALY, quality-adjusted life year; anti-HBs, antibodies against hepatitis B surface antigen.

      Sensitivity analysis

      Strategy 1 appeared slightly more favorable than strategy 2 (Table 5). Therefore, a one-way sensitivity analysis for strategy 1 was conducted among more than 60 variables, including protective efficacy, natural history of HBV infection, behavior, and various costs and utility weights. All CERs were less than US$ −5000 per QALY gained. The following parameters showed a great impact on the CERs: the annual cost per patient due to compensated cirrhosis, utility of chronic hepatitis B, annual cost per patient due to chronic hepatitis, and utility of inactive HBsAg carriage (Figure 2).
      Figure 2
      Figure 2One-way sensitivity analysis for the one-dose adolescent booster vaccination, given if negative for HBsAg on screening, compared to the current practice of no screening and no booster.
      The CERs related to the parameters of screening and booster vaccination were found to be robust, such as work loss for one-visit screening or vaccination, HBsAg screening and delivery cost, per-dose vaccine and delivery cost, compliance with screening or one-dose booster, and protective efficacy of booster vaccination. When all the parameters were simultaneously set at the values most unfavorable to the booster strategy (the ‘worst case’ scenario), strategy 1 was not cost-saving anymore, with the CER increased to US$ 3263/QALY. However, it was still lower than the GDP per capita of China in 2016 (US$ 8126). The one-dose booster vaccination of high-risk children if negative on HBsAg screening was cost-effective.
      The cost-effectiveness of two-dose and three-dose booster vaccination was further analyzed based on strategy 1. The CER of two-dose booster vaccination was US$ −6966/QALY (range US$ −7037/QALY to US$ −6565/QALY) and the CER of three-dose booster vaccination was US$ −6910/QALY (range US$ −7000/QALY to US$ −6066/QALY), after considering the parameter values (Table 1), including compliance, per-dose vaccine cost, and work loss for one-visit vaccination. Both the two-dose and three-dose booster provided more benefits and saved more costs.

      Discussion

      This study analyzed the cost-effectiveness of HBV booster vaccination in the assumed 10-year-old children born to HBsAg-positive mothers who had completed the vaccination series during infancy in China. A decision tree–Markov model was constructed and parameter values were selected from previous cost-effectiveness analysis and original studies published in English or in Chinese that were mainly conducted in Chinese populations. The natural history model was calibrated based on multiple selected outcomes. The values predicted by the model were all within the observed ranges documented in clinical practice. From the societal perspective, both strategy 1 and strategy 2 were cost-saving compared with the current no-screening and no-booster intervention, with CERs estimated at US$ −6961 and US$ −6872 per QALY gained, respectively. In the one-way sensitivity analysis for strategy 1, after considering the uncertainty of all the variables, including vaccination efficacy, natural history, behavior, and various costs and utility weights, all CERs were less than US$ −5000/QALY. In the ‘worst case’ scenario (all parameters simultaneously being at the worst), by taking strategy 1, the CER increased to US$ 3263/QALY, still less than the GDP per capita of China in 2016 (US$ 8126). The real cost-effectiveness of booster vaccination with more than one dose might be uncertain, as the compliance might be lower than our assumption and no report was available about the protective efficacy of more than one dose. Nevertheless, based on the current assumptions, the two- or three-dose booster would provide more benefits and cost less than the one-dose booster. Thus, it is suggested that at least one dose of booster vaccination in adolescence should be considered for high-risk children born to HBsAg-positive mothers when they have lost anti-HBs.
      Several studies have evaluated the cost-effectiveness of neonatal HBV vaccination, or catch-up vaccination for children or adults in China. All of them have come to the conclusion that primary HBV vaccination given to populations at certain ages is cost-saving, with the incremental cost-effectiveness ratio (ICER) ranging from US$ −13 238/QALY for universal HBV vaccination in Taiwan to US$ −1909/QALY for catch-up vaccination among children/adolescents in China (
      • Hung H.-F.
      • Chen T.H.-H.
      Probabilistic cost-effectiveness analysis of the long-term effect of universal hepatitis B vaccination: an experience from Taiwan with high hepatitis B virus infection and Hepatitis B e Antigen positive prevalence.
      ,
      • Hutton D.W.
      • So S.K.
      • Brandeau M.L.
      Cost-effectiveness of nationwide hepatitis B catch-up vaccination among children and adolescents in China.
      ,
      • Jia Y.
      • Li L.
      • Cui F.
      • Zhang D.
      • Zhang G.
      • Wang F.
      • et al.
      Cost-effectiveness analysis of a hepatitis B vaccination catch-up program among children in Shandong Province, China.
      ,
      • Lu S.Q.
      • McGhee S.M.
      • Xie X.
      • Cheng J.
      • Fielding R.
      Economic evaluation of universal newborn hepatitis B vaccination in China.
      ). The present study is the first to report a cost-effectiveness analysis of booster vaccination for a high-risk population. The one-dose booster given in the case of a negative HBsAg screening result was also cost-saving, with a CER estimated at US$ −6961/QALY, indicating this strategy to be favorable when compared with catch-up vaccination in general children/adolescents. The parameters that showed a great impact on CERs – costs of HBV-related diseases, annual transition probabilities, and incidence of HBV infection – were similar to the findings of other health economic evaluations conducted in the Chinese population (Supplementary material Table 1). Therefore, the parameter values and ranges in our model appear reasonable.
      Following the effective protection achieved by neonatal immunization, further benefit could be provided by booster vaccination to prevent horizontal transmission in this high-risk population when they participate in certain activities, such as unsafe sexual activities, dental treatments, razor sharing, tattoos, acupuncture, and body care and beauty treatments in public places. In December 2016, the National Health and Family Planning Commission recommended that vaccinated infants should be tested for the presence of HBsAg and the anti-HBs titer at 1–2 months after completion of the third dose of vaccine if they have been born to an HBsAg-positive mother. If the child is seronegative for HBsAg and has an anti-HBs of <10 mIU/ml, the fourth dose of vaccine should be given (
      • Qu C.
      • Duan Z.
      • Chen K.
      • Zou H.
      Reducing liver cancer risk beginning at birth: experiences of preventing chronic hepatitis B virus infection in China.
      ). As the fourth dose of HBV vaccine was only given starting in 2017, high-risk children should consider the vaccine booster when their anti-HBs has disappeared. In China, the provincial CDC immunization offices have branches to serve the immunization needs in various districts. The target population could go to the nearest clinic for screening and to receive the booster, if the Health and Family Planning Commission recommends the screening-based HBV booster. Therefore, HBsAg screening-based booster vaccination is not only cost-saving, but also feasible.
      It was assumed that chronic infection only occurred during the age range of 10 years to 25 years based on our previous study (
      • Wang Y.
      • Chen T.
      • Lu L.-l.
      • Wang M.
      • Wang D.
      • Yao H.
      • et al.
      Adolescent booster with hepatitis B virus vaccines decreases HBV infection in high-risk adults.
      ). This might have led to an underestimation of the superiority of booster vaccination. Considering the cost variation in different regions, four-fold the base-case value of costs associated with screening and vaccination was set as the higher bound in the sensitivity analysis and the costs of HBV-related diseases were assumed to vary from 50% to 150% of the base-case values to cover the majority of the reported data. Under these conservative assumptions, booster vaccination was still cost-saving. Even in the ‘worst case’ scenario, the CER was still less than the GDP per capita in China in 2016 (US$ 8126). The conclusion appears to be robust.
      This study has several limitations. The protective effect of adolescent booster was only observed in one high endemic rural area. Generalization of the study findings to HBV prevention in populations with a very low prevalence of HBsAg might be limited. It was noted that the HBsAg seroclearance rate was much lower in the neonatal vaccinated population (0.36% annually) than in the unvaccinated population (1.49% annually) (
      • Qu C.
      • Chen T.
      • Fan C.
      • Zhan Q.
      • Wang Y.
      • Lu J.
      • et al.
      Efficacy of neonatal HBV vaccination on liver cancer and other liver diseases over 30-year follow-up of the Qidong hepatitis B intervention study: a cluster randomized controlled trial.
      ). Hence, a lower HBsAg seroclearance rate was set in the current model. However, beyond that, most of the natural history parameters were derived from the unvaccinated population, due to the absence of data for the vaccinated population. There was no report from a national survey of the utility weights of HBV-related diseases; the utility weights pooled by meta-analysis were therefore used. The various survey instruments used in the original utility weights studies would have led to bias. Therefore, a wide range was given to the utility weights in the sensitivity analysis to cover the uncertainty. This study was based on the current incidence of HBV infection, treatment options, costs, and vaccination policy. The incidence of HBV infection will decrease with the wide use of HBV vaccination and the advent of antiviral therapy. Chronic HBV-infected patients may live with the disease for many years. Their costs and utility weights may change in the future with the development of new treatments. Since 2017, high-risk children negative for HBsAg at 1–2 months after completion of the third dose have been eligible for a fourth dose of the vaccine. Their risk of breakthrough infection later in life would be changed. All of the above changes would lead to uncertainty. Considering the disparate accessibility of antiviral therapy in different regions of China, booster vaccination should be preferred.
      Hepatitis B booster vaccination of children born to HBsAg-positive mothers in rural China would be cost-effective. We recommend that at least one dose of hepatitis B adolescent booster vaccination should be considered if anti-HBs has been lost, as these individuals are still at high risk of horizontal transmission in endemic areas after being protected by the neonatal HBV vaccination.

      Funding

      The project was funded by State Key Projects Specialized on Infectious Diseases (2017ZX10201201-006-003) to CQ, (2017ZX10201201-008-002) to JFS, and Key Research Projects for Precision Medicine (2017YFC0908103) to CQ. YW was supported by the Graduate Innovation Funding of Peking Union Medical College ( 2015-1001-09 ). The sponsors of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the manuscript.

      Conflict of interest

      The authors have no financial or other interests with regard to the submitted manuscript that might be construed as a conflict of interest.

      Author contributions

      Chunfeng Qu participated in the study design, revised and finalized the manuscript, and gave technical support. Yuting Wang participated in the study design, statistical analyses, and data collection and drafted the manuscript. Ju-Fang Shi participated in the study design, drafted the manuscript, and gave technical support. Le Wang participated in the statistical analyses and data collection. Yongfeng Yan, Hongyu Yao, and Taoyang Chen participated in data collection. Min Dai advised on data analysis.

      Appendix A. Supplementary data

      The following is Supplementary data to this article:

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      • A hepatitis B vaccine booster shot at age 10 could be cost-saving in China: But is it too soon to tell?
        International Journal of Infectious DiseasesVol. 78
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          Worldwide, over 240 million people are living with chronic hepatitis B virus (HBV) infection (Ott et al., 2012), and 786,000 individuals die from HBV related deaths, including cirrhosis and liver cancer, each year (MacLachlan et al., 2015; Lozano et al., 2012). The HBV vaccine has been shown to be highly effective, and over one billion doses have been delivered worldwide (World Health Organisation, 2018). The burden of hepatitis B in China is one of the highest in the world, with almost one-third of the world’s hepatitis B cases diagnosed in China.  
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