Reducing liver cancer risk beginning at birth: experiences of preventing chronic hepatitis B virus infection in China

Abstract

In China, the death numbers due to primary liver cancer every year account for more than half of this disease burden worldwide. Hepatocellular carcinoma (HCC) represents the major histological type of primary liver cancer. In the Chinese population, at least 85% HCC cases are due to chronic infection with hepatitis B virus (HBV), most of which were acquired in the perinatal period or in early life. As of January 1992, HBV immunization of newborns was introduced to the national Expended Program of Immunization of China. Prior to this program, the Qidong County in China conducted an hepatitis B intervention study, which was a population-based, cluster randomized, controlled trial of HBV vaccination in neonates. The study demonstrated that among young adults < 30 years old, neonatal HBV immunization decreased around 84% risk of HBV-related liver cancer, and 70% risk of mortality due to severe end-stage chronic liver diseases. More than 72% efficacy of neonatal vaccination against chronic HBV infection in adulthood was achieved; however, when catch-up HBV vaccination was given to children at age 10-14 years, the protection efficacy was only 21%. No difference in mortality of HBV-related liver diseases was observed among the young adults < 30 years who received and those who did not receive the catch-up HBV vaccination. These results highlight the crucial importance of HBV vaccination of neonates in reducing the liver cancer risk beginning at birth in highly HBV endemic regions. Due to large numbers of HBV-infected pregnant women with high viremia in China, clinical studies in which antiviral therapy with the nucleot(s)ide analogues was given to HBV-infected pregnant women have provided important evidence that such therapy can reduce the risk of mother-to-child HBV transmission. These clinical data based on cohort studies, randomized clinical trials, and clinical practices in the Chinese population provide important information on prevention of liver cancer, particularly HCC, by preventing chronic HBV infection starting from birth for other populations.

Keywords

Hepatocellular carcinoma / prevention / vaccination / antiviral therapy / adolescent vaccine boost

References

[1] Zhang Y,Shi JF,Wang YT,Zhang Y.International trends in primary liver cancer incidence from 1973 to 2007..BMC Cancer2015;15:94 PMCID:PMC4359785

[2] Poon D,Chen LT,Lau WY,Singh H,Ooi LL,Khin MW,Asian Oncology Summit..Management of hepatocellular carcinoma in Asia: consensus statement from the Asian Oncology Summit 2009..Lancet Oncol2009;10:1111-8

[3] de Martel C,Plummer M.World-wide relative contribution of hepatitis B and C viruses in hepatocellular carcinoma..Hepatology2015;62:1190-200 PMCID:PMC5019261

[4] Ralphs S.The role of the hepatitis viruses in cholangiocarcinoma..J Viral Hepat2013;20:297-305

[5] Makvandi M.Update on occult hepatitis B virus infection..World J Gastroenterol2016;22:8720-34 PMCID:PMC5075547

[6] Raimondo G,Romanò L.A 2010 update on occult hepatitis B infection..Pathol Biol (Paris).2010;58:254-7

[7] Chen CH,Lee CM,Hung CH,Wang JH,Lu SN.A study on sequence variations in pre-S/surface, X and enhancer II/core promoter/precore regions of occult hepatitis B virus in non-B, non-C hepatocellular carcinoma patients in Taiwan..Int J Cancer2009;125:621-9

[8] Wang M,Feng X,Wang Y,Qi J,Li N,Qu C.Contribution of hepatitis B, C virus to liver cancer in China North areas: experience from Chinese National Cancer Center..Int J Infect Dis2017;65:15-21

[9] Yin J,He Y,Liu S,Tan X,Lu W,Bi S,Liang X,Cao G.Distribution and hepatocellular carcinoma-related viral properties of hepatitis B virus genotypes in Mainland China: a community-based study..Cancer Epidemiol Biomarkers Prev2010;19:777-86

[10] Cui Y.Update on epidemiology of hepatitis B and C in China..J Gastroenterol Hepatol2013;28 Suppl 1:7-10

[11] Beath SV,Watson RM,Kelly DA.Fulminant hepatitis B in infants born to anti-HBe hepatitis B carrier mothers..BMJ1992;304:1169-70 PMCID:PMC1882113

[12] Chang MH.Hepatitis B virus infection..Semin Fetal Neonatal Med2007;12:160-7

[13] Edmunds WJ,Nokes DJ,Whittle HC.The influence of age on the development of the hepatitis B carrier state..Proc Biol Sci1993;253:197-201

[14] Hyams KC.Risks of chronicity following acute hepatitis B virus infection: a review..Clin Infect Dis1995;20:992-1000

[15] Xia GL,Cao HL,Zhan MY,Nan JH.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..Int Hepatol Commun1996;5:12

[16] Hajarizadeh B,Dore GJ.Epidemiology and natural history of HCV infection..Nat Rev Gastroenterol Hepatol2013;10:553-62

[17] Beasley RP,Lin CC.Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22 707 men in Taiwan..Lancet1981;2:1129-33

[18] Sun Z,Zhu X.Prevention and control of hepatitis B in China..J Med Virol2002;67:447-50

[19] Liang X,Hadler S,Luo H,Kane M,Yang W.Origins, design and implementation of the China GAVI project..Vaccine2013;31 Suppl 9:J8-14

[20] Szmuness W,Harley EJ,Oleszko WR,Sadovsky R,Kellner A.Hepatitis B vaccine: demonstration of efficacy in a controlled clinical trial in a high-risk population in the United States..N Engl J Med1980;303:833-41

[21] Maupas P,Barin F,Goudeau A,Denis F.Efficacy of hepatitis B vaccine in prevention of early HBsAg carrier state in children. Controlled trial in an endemic area (Senegal)..Lancet1981;1:289-92

[22] Szmuness W,Zang EA,Kellner A.A controlled clinical trial of the efficacy of the hepatitis B vaccine (Heptavax B): a final report..Hepatology1981;1:377-85

[23] Chen DS.Hepatitis B vaccination: the key towards elimination and eradication of hepatitis B..J Hepatol2009;50:805-16

[24] W.H.O. Scientific Group.Prevention of primary liver cancer. Report on a meeting of a W.H.O. Scientific Group..Lancet1983;1:463-5

[25] Zanetti AR,Shouval D.The global impact of vaccination against hepatitis B: a historical overview..Vaccine2008;26:6266-73

[26] Zhu X,Wang L.National EPI vaccination and hepatitis B vaccine coverage rate and the related factors: results from the 1999 nationwide survey..Chin J Vac Immunization2000;6:193-7(in Chinese)

[27] Liang X,Yang W,Cui G,Zhang Y,Gong X,Wang F,Wang F,Jia Z,Wang H,Li L,Hadler SC.Epidemiological serosurvey of hepatitis B in China--declining HBV prevalence due to hepatitis B vaccination..Vaccine2009;27:6550-7

[28] Wang FZ,Shen LP,Wang F,Yuan QL,Bi SL,Wang HQ.Comparative analyze on hepatitis B seroepidemiological surveys among population aged 1-29 years in different epidemic regions of China in 1992 and 2014..Zhonghua Yu Fang Yi Xue Za Zhi2017;51:462-8(in Chinese)

[29] Finelli L, Bell BP. Chapter 4: Hepatitis B. Avaliable from: https://www.cdc.gov/vaccines/pubs/surv-manual/chpt04-hepb.pdf. [Last accessed on 19 Oct 2017]

[30] Chang MH,Chen DS,Lai MY.Fulminant hepatitis in children in Taiwan: the important role of hepatitis B virus..J Pediatr1987;111:34-9

[31] Huang LM,Hong JY,Chen DS.Changing aetiologic patterns of acute viral hepatitis in Taiwanese children..J Gastroenterol Hepatol1989;4:339-44

[32] Chiang CJ,You SL,Chen CJ.Thirty-year outcomes of the national hepatitis B immunization program in Taiwan..JAMA2013;310:974-6

[33] Qu C,Fan C,Wang Y,Lu LL,Huang F,Zhu J,Zhu Y,Liu G,Zang M,Dai M,Zhang Y.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..PLoS Med2014;11:e1001774 PMCID:PMC4280122

[34] Chen HL,Kong MS,Lee HC,Liu CC,Wu TC,Ni YH,Chen DS.Pediatric fulminant hepatic failure in endemic areas of hepatitis B infection: 15 years after universal hepatitis B vaccination..Hepatology2004;39:58-63

[35] Chang MH,Chen CJ,Lee CM,Chu HC,Yang SS,Chen DS.Decreased incidence of hepatocellular carcinoma in hepatitis B vaccinees: a 20-year follow-up study..J Natl Cancer Inst2009;101:1348-55

[36] McMahon BJ,Singleton RJ,Snowball M,Parkinson AJ.Elimination of hepatocellular carcinoma and acute hepatitis B in children 25 years after a hepatitis B newborn and catch-up immunization program..Hepatology2011;54:801-7

[37] Gwack J,Lee EH,Choi Y.Hepatitis B vaccination and liver cancer mortality reduction in Korean children and adolescents..Asian Pac J Cancer Prev2011;12:2205-8

[38] Tajiri H,Brooks S.Reduction of hepatocellular carcinoma in childhood after introduction of selective vaccination against hepatitis B virus for infants born to HBV carrier mothers..Cancer Causes Control2011;22:523-7

[39] Gao J,Chen WQ,Wu QJ,Yang WS,Xiang YB.Rural-urban, sex variations, and time trend of primary liver cancer incidence in China, 1988-2005..Eur J Cancer Prev2013;22:448-54

[40] Zuo T,Zeng H,Chen W.Analysis of liver cancer incidence and trend in China..Zhonghua Zhong Liu Za Zhi2015;37:691-6(in Chinese)

[41] Kurahashi N,Iwasaki M,Mizokami M.Vegetable, fruit and antioxidant nutrient consumption and subsequent risk of hepatocellular carcinoma: a prospective cohort study in Japan..Br J Cancer2009;100:181-4 PMCID:PMC2634663

[42] Zhang W,Li H,Cai H,Gao J,Zheng W.Vitamin intake and liver cancer risk: a report from two cohort studies in China..J Natl Cancer Inst2012;104:1173-81 PMCID:PMC3611811

[43] Liu Y,Marsh GM.Population attributable risk of aflatoxin-related liver cancer: systematic review and meta-analysis..Eur J Cancer2012;48:2125-36 PMCID:PMC3374897

[44] Sun Z,Thorgeirsson SS,Chen J,Lu P,Wang N,Lu L,Zhu Y,Ni Z,Wu Y,Wu Z,Gail MH.Dramatic reduction of liver cancer incidence in young adults: 28 year follow-up of etiological interventions in an endemic area of China..Carcinogenesis2013;34:1800-5 PMCID:PMC3731800

[45] Zhang W,Li HL,Cai H,Gao YT,Shu XO.Vegetable-based dietary pattern and liver cancer risk: results from the Shanghai women's and men's health studies..Cancer Sci2013;104:1353-61 PMCID:PMC3879410

[46] Chen JG.Changing rates for liver and lung cancers in Qidong, China..Chem Res Toxicol2014;27:3-6 PMCID:PMC3946948

[47] Pol S.Hepatitis: HBV vaccine--the first vaccine to prevent cancer..Nat Rev Gastroenterol Hepatol2015;12:190-1

[48] Karnik R.To "B" or not to "B": efficacy of a neonatal hepatitis B vaccination program to prevent primary liver cancer and end-stage liver disease..Gastroenterology2015;148:1073-5

[49] Chen JG,Parkin DM,Lu JH,Chen TY.Trends in the incidence of cancer in Qidong, China, 1978-2002..Int J Cancer2006;119:1447-54

[50] Xia QJ.Liver cell cancer in the young and adolescent and its relation to hepatitis B virus (HBV)..Zhonghua Zhong Liu Za Zhi1984;6:413-6(in Chinese)

[51] Sun Z,Gail MH,Zhang Q,Wang J,Liu G,Zhu Y.Increased risk of hepatocellular carcinoma in male hepatitis B surface antigen carriers with chronic hepatitis who have detectable urinary aflatoxin metabolite M1..Hepatology1999;30:379-83

[52] Ming L,Gail MH,Harris CC,Shao Y,Liu G,Sun Z.Dominant role of hepatitis B virus and cofactor role of aflatoxin in hepatocarcinogenesis in Qidong, China..Hepatology2002;36:1214-20

[53] Sun Z,Stjernsward J,Collins R,Hsia CC,Huang F.Design and compliance of HBV vaccination trial on newborns to prevent hepatocellular carcinoma and 5-year results of its pilot study..Cancer Detect Prev1991;15:313-8

[54] Wang Y,Lu LL,Wang D,Fan C,Zhang Y.Adolescent booster with hepatitis B virus vaccines decreases HBV infection in high-risk adults..Vaccine2017;35:1064-70

[55] Romano' L,Van Damme P.The worldwide impact of vaccination on the control and protection of viral hepatitis B..Dig Liver Dis2011;43 Suppl 1:S2-7

[56] Trépo C,Lok A.Hepatitis B virus infection..Lancet2014;384:2053-63

[57] Locarnini S,Chen DS.Strategies to control hepatitis B: Public policy, epidemiology, vaccine and drugs..J Hepatol2015;62:S76-86

[58] Ni YH,Chang MH,Lu CY,Kao JH,Chen HL,Chen DS.Two decades of universal hepatitis B vaccination in taiwan: impact and implication for future strategies..Gastroenterology2007;132:1287-93

[59] Pan CQ,Bhamidimarri KR,Liang XF,Tong MJ.An algorithm for risk assessment and intervention of mother to child transmission of hepatitis B virus..Clin Gastroenterol Hepatol2012;10:452-9

[60] Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection. Avaliable from: http://apps.who.int/iris/bitstream/10665/154590/1/9789241549059_eng.pdf. [Last accessed on 19 Oct 2017]

[61] Ekra D,Konate S,Fretz C,Douai C,Gessner BD.A non-randomized vaccine effectiveness trial of accelerated infant hepatitis B immunization schedules with a first dose at birth or age 6 weeks in Côte d'Ivoire..Vaccine2008;26:2753-61

[62] Lau YL,Ng KW,Lam B,Yeung CY.Response of preterm infants to hepatitis B vaccine..J Pediatr1992;121:962-5

[63] Freitas da Motta MS,Jorge SM,Sandoval de Souza CB.Immunogenicity of hepatitis B vaccine in preterm and full term infants vaccinated within the first week of life..Vaccine2002;20:1557-62

[64] Lu LL,Wang J,Ji Y,Chen T,Petersen E,Qu C.Maternal transmission risk and antibody levels against hepatitis B virus e antigen in pregnant women..Int J Infect Dis2014;28:41-4

[65] Zou H,Duan Z,Pan C.Virologic factors associated with failure to passive-active immunoprophylaxis in infants born to HBsAg-positive mothers..J Viral Hepat2012;19:e18-25

[66] van Zonneveld M,Niesters HG,Schalm SW.Lamivudine treatment during pregnancy to prevent perinatal transmission of hepatitis B virus infection..J Viral Hepat2003;10:294-7

[67] Wiseman E,Holden S,Kidson BL,Maley MW,Locarnini SA.Perinatal transmission of hepatitis B virus: an Australian experience..Med J Aust2009;190:489-92

[68] Singh AE,Osiowy C,Kouadjo E,Lee B.Factors associated with vaccine failure and vertical transmission of hepatitis B among a cohort of Canadian mothers and infants..J Viral Hepat2011;18:468-73

[69] Jaffe A.A review of antiviral use for the treatment of chronic hepatitis B virus infection in pregnant women..Gastroenterol Hepatol (N Y).2017;13:154-63

[70] Brown RSJr,Lok AS,Ahmed AT,Wang Z,Murad MH.Antiviral therapy in chronic hepatitis B viral infection during pregnancy: a systematic review and meta-analysis..Hepatology2016;63:319-33

[71] Zhang H,Pang Q,Yan M.Telbivudine or lamivudine use in late pregnancy safely reduces perinatal transmission of hepatitis B virus in real-life practice..Hepatology2014;60:468-76 PMCID:PMC4282428

[72] Han GR,Zhao W,Wang CM,Yue X,Tang X.A prospective and open-label study for the efficacy and safety of telbivudine in pregnancy for the prevention of perinatal transmission of hepatitis B virus infection..J Hepatol2011;55:1215-21

[73] Chen HL,Chang CH,Shyu MK,Hu JJ,Zhao LL,Lai MW,Lin HM,Hsu JJ,Chan KA.Efficacy of maternal tenofovir disoproxil fumarate in interrupting mother-to-infant transmission of hepatitis B virus..Hepatology2015;62:375-86

[74] Pan CQ,Dai E,Han G,Zhang H,Zhu B,Jiang H.Tenofovir to prevent hepatitis B transmission in mothers with high viral load..N Engl J Med2016;374:2324-34

[75] Wainwright RB,Parkinson AJ,McMahon BJ.Protection provided by hepatitis B vaccine in a Yupik Eskimo population--results of a 10-year study..J Infect Dis1997;175:674-7

[76] Dentinger CM,Butler JC,Zanis CL,Bruden DL,Khristova ML,Parkinson AJ.Persistence of antibody to hepatitis B and protection from disease among Alaska natives immunized at birth..Pediatr Infect Dis J2005;24:786-92

[77] Beasley RP,Lin CC,Twu SJ.Incidence of hepatitis among students at a university in Taiwan..Am J Epidemiol1983;117:213-22

[78] Zanetti AR,Romanò L,Chironna M,Cuccia M,Marrone F,Parlato A,Zotti C,Mele A.Long-term immunogenicity of hepatitis B vaccination and policy for booster: an Italian multicentre study..Lancet2005;366:1379-84

[79] FitzSimons D,Vorsters A.Hepatitis B vaccination: a completed schedule enough to control HBV lifelong? Milan, Italy, 17-18 November 2011..Vaccine2013;31:584-90

[80] Lu CY,Chiang BL,Chang MH,Su IJ,Huang LM,Lee CY.Humoral and cellular immune responses to a hepatitis B vaccine booster 15-18 years after neonatal immunization..J Infect Dis2008;197:1419-26

[81] Jan CF,Chien YC,Davies HD,Huang LM,Chen DS.Determination of immune memory to hepatitis B vaccination through early booster response in college students..Hepatology2010;51:1547-54

[82] Chinchai T,Praianantathavorn K,Hutagalung Y,Thantiworasit P.Long-term humoral and cellular immune response to hepatitis B vaccine in high-risk children 18-20 years after neonatal immunization..Viral Immunol2009;22:125-30

[83] Zhu CL,Chen T,Lu LL,Lu J,Qu C.Presence of immune memory and immunity to hepatitis B virus in adults after neonatal hepatitis B vaccination..Vaccine2011;29:7835-41

[84] But DY,Lim WL,Wong DK.Twenty-two years follow-up of a prospective randomized trial of hepatitis B vaccines without booster dose in children: final report..Vaccine2008;26:6587-91

[85] McMahon BJ,Bruden D,Peters H,Bulkow L,Bell BP.Antibody levels and protection after hepatitis B vaccine: results of a 22-year follow-up study and response to a booster dose..J Infect Dis2009;200:1390-6

[86] Neaigus A,Zhao M,Friedman SR.Sexual and other noninjection risks for HBV and HCV seroconversions among noninjecting heroin users..J Infect Dis2007;195:1052-61

[87] Xu L,Chen T,Zhu CL,Huang F,Sun Z.Occult HBV infection in anti-HBs-positive young adults after neonatal HB vaccination..Vaccine2010;28:5986-92

[88] Wu TW,Wang LY.Chronic hepatitis B infection in adolescents who received primary infantile vaccination..Hepatology2013;57:37-45

[89] Hong M,Low D,Fieni S,Urbani S,Guccione E.Trained immunity in newborn infants of HBV-infected mothers..Nat Commun2015;6:6588 PMCID:PMC4389241

[90] Lee AK,Wong VC.Mechanisms of maternal-fetal transmission of hepatitis B virus..J Infect Dis1978;138:668-71

[91] Starr TK,Hogquist KA.Positive and negative selection of T cells..Annu Rev Immunol2003;21:139-76

[92] Crotty S.A brief history of T cell help to B cells..Nat Rev Immunol2015;15:185-9 PMCID:PMC4414089

[93] Fazilleau N,Rosen H.The function of follicular helper T cells is regulated by the strength of T cell antigen receptor binding..Nat Immunol2009;10:375-84 PMCID:PMC2712297

[94] Nurieva RI,Martinez GJ,Tanaka S,Wang YH.Bcl6 mediates the development of T follicular helper cells..Science2009;325:1001-5 PMCID:PMC2857334

[95] Romanò L,Tozzi AE,Zanetti AR.Chronic hepatitis B infection in adolescents vaccinated at birth: an alarm bell in favor of the need for a booster?.Hepatology2014;59:349

[96] Carmody E.Time to re-evaluate the effect of the adolescent booster of hepatitis B vaccine..Int J Infect Dis2017;60:88-90

[97] Liu J,Wang Q,Zhang M,Yan D.Seroepidemiology of hepatitis B virus infection in 2 million men aged 21-49 years in rural China: a population-based, cross-sectional study..Lancet Infect Dis2016;16:80-6