Skip to main content


Log in

Hepatitis B virus infection in children of HBV-related chronic liver disease patients: a study of intra-familial HBV transmission

  • Original Article
  • Published:
Hepatology International Aims and scope Submit manuscript



HBV-infected patients are potential sources of intra-familial transmission. We studied HBV transmission and molecular characteristics within families of HBV-related chronic liver disease (CLD) patients.


Family members [index cases (ICs), spouses, and 1–18-year-old children] of HBV-related CLD patients were tested for HBsAg, anti-HBc, and anti-HBs. HBsAg-positive subjects were tested for HBeAg/anti-HBe. Anti-HBc-positive children together with their family members were further investigated for HBV DNA. Sequences of positive isolates were analyzed over surface, precore (PC) and basal core promoter (BCP) regions.


Among 94 children of 46 ICs, the prevalence of HBsAg, anti-HBc, and anti-HBs was 10 (10.6 %), 19 (20.2 %), and 46 (48.9 %), respectively. Thirty-eight (40.4 %) children were seronegative, indicating susceptibility to HBV infection. HBV DNA was identified in all ICs, 4 spouses, and 16 children. Having both parents with HBsAg positive and at least two HBV carriers in the households were significant risk factors of intra-familial transmission. HBV genotype/subtype distributions were comparable between children and ICs/spouses, with predominance of genotype B. The majority of HBV DNA sequences found in children were identical to their corresponding ICs—particularly mothers—including mutation patterns in the surface, PC, and BCP regions. Recognized mutations associated with HBsAg detection and/or vaccination failure, T140I, T143S/M, G145R, and Y161F, were identified in 20 subjects; while mutations linked to HBeAg-defective variants, PC G1896A and BCP A1762T/G1764A, were found in 7 and 11 subjects, respectively.


Children of HBV-related CLD patients were at increased risk of HBV infection through multi-modal transmission routes despite negative parental HBsAg and HBeAg status.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others


  1. World Health Organization. Hepatitis B fact sheet no. 204. 2016. Accessed 20 July 2016. (updated July 2016)

  2. Chen ST, Chang MH. Epidemiology and natural history of hepatitis B in children. In Jonas MM, ed. Viral hepatitis in children. New York: Humana Press, 2010. 13–28

  3. Custer B, Sullivan SD, Hazlet TK, Iloeje U, Veenstra DL, Kowdley KV. Global epidemiology of hepatitis B virus. J Clin Gastroenterol 2004;38:S158–S168

  4. Ministry of Health Republic of Indonesia. Report on the national basic health research (RISKESDAS) 2007 Jakarta: The National Institute of Health Research and Development (NIHRD), 2010

  5. Milas J, Ropac D, Mulic R, Milas V, Valek I, Zoric I, Kozul K. Hepatitis B in the family. Eur J Epidemiol 2000;16:203–208

  6. Thakur V, Kazim SN, Guptan RC, Malhotra V, Sarin SK. Molecular epidemiology and transmission of hepatitis B virus in close family contacts of HBV-related chronic liver disease patients. J Med Virol 2003;70:520–528

  7. Yao GB. Importance of perinatal versus horizontal transmission of hepatitis B virus infection in China. Gut 1996;38:S39–S42

  8. Takegoshi K, Zhang W. Hepatitis B virus infections in families in which the mothers are negative but the fathers are positive for HBsAg. Hepatol Res 2006;36:75–77

  9. Abdel-Hady M, Kelly D. Chronic hepatitis B in children and adolescents: epidemiology and management. Paediatr Drugs 2013;15:311–317

  10. Lin CL, Kao JH, Chen BF, Chen PJ, Lai MY, Chen DS. Application of hepatitis B virus genotyping and phylogenetic analysis in intrafamilial transmission of hepatitis B virus. Clin Infect Dis 2005;41:1576–1581

  11. Datta S, Banerjee A, Chandra PK, Chowdhury A, Chakravarty R. Genotype, phylogenetic analysis, and transmission pattern of occult hepatitis B virus (HBV) infection in families of asymptomatic HBsAg carriers. J Med Virol 2006;78:53–59

  12. Bozkaya H, Akarca US, Ayola B, Lok AS. High degree of conservation in the hepatitis B virus core gene during the immune tolerant phase in perinatally acquired chronic hepatitis B virus infection. J Hepatol 1997;26:508–516

  13. Martinson FE, Weigle KA, Royce RA, Weber DJ, Suchindran CM, Lemon SM. Risk factors for horizontal transmission of hepatitis B virus in a rural district in Ghana. Am J Epidemiol 1998;147:478–487

  14. Okamoto H, Nishizawa T. Non-B non C non-G hepatitis virus gene, polynucleotide, polypeptide, virion, method for separating virion, and method for detecting virus. 1992.

  15. Turyadi, Thedja MD, Ie SI, Harahap AR, El-Khobar KE, Roni M, Muljono DH. HBsAg, HBeAg and HBV DNA level changes and precore/basal core promoter mutations in the natural history of chronic hepatitis B in Indonesian patients. Hepatol Int 2013;7:969–980

  16. Iizuka H, Ohmura K, Ishijima A, Satoh K, Tanaka T, Tsuda F, Okamoto H, et al. Correlation between anti-HBc titers and HBV DNA in blood units without detectable HBsAg. Vox Sang 1992;63:107–111

  17. Norder H, Courouce AM, Magnius LO. Molecular basis of hepatitis B virus serotype variations within the four major subtypes. J Gen Virol 1992;73:3141–3145

  18. Okamoto H, Imai M, Tsuda F, Tanaka T, Miyakawa Y, Mayumi M. Point mutation in the S gene of hepatitis B virus for a d/y or w/r subtypic change in two blood donors carrying a surface antigen of compound subtype adyr or adwr. J Virol 1987;61:3030–3034

  19. Thedja MD, Muljono DH, Nurainy N, Sukowati CH, Verhoef J, Marzuki S. Ethnogeographical structure of hepatitis B virus genotype distribution in Indonesia and discovery of a new subgenotype, B9. Arch Virol 2011;156:855–868

  20. Herbert A. SPSS Notes (SPSS version 15.0) 2008. In Salford Royal Hospitals NHS Trust. 2008. Accessed 1 July 2016

  21. Darmawan E, Turyadi, El-Khobar KE, Nursanty NK, Thedja MD, Muljono DH. Seroepidemiology and occult hepatitis B virus infection in young adults in Banjarmasin, Indonesia. J Med Virol 2015;87:199–207

  22. Ragheb M, Elkady A, Tanaka Y, Murakami S, Attia FM, Hassan AA, Hassan MF, et al. Multiple intra-familial transmission patterns of hepatitis B virus genotype D in north-eastern Egypt. J Med Virol 2012;84:587–595

  23. van der Sande MA, Waight P, Mendy M, Rayco-Solon P, Hutt P, Fulford T, Doherty C, et al. Long-term protection against carriage of hepatitis B virus after infant vaccination. J Infect Dis 2006;193:1528–1535

  24. Amiri SS, Amiri MJS, Roushan MRH. Possible sources for transmission of hepatitis B virus infection in 80 children in Babol, North of Iran. Casp J Intern Med 2010:50–52

  25. Livingston SE, Simonetti JP, Bulkow LR, Homan CE, Snowball MM, Cagle HH, Negus SE, et al. Clearance of hepatitis B e antigen in patients with chronic hepatitis B and genotypes A, B, C, D, and F. Gastroenterology 2007;133:1452–1457

  26. Inui A, Komatsu H, Sogo T, Nagai T, Abe K, Fujisawa T. Hepatitis B virus genotypes in children and adolescents in Japan: before and after immunization for the prevention of mother to infant transmission of hepatitis B virus. J Med Virol 2007;79:670–675

  27. Wen WH, Chen HL, Ni YH, Hsu HY, Kao JH, Hu FC, Chang MH. Secular trend of the viral genotype distribution in children with chronic hepatitis B virus infection after universal infant immunization. Hepatology 2011;53:429–436

  28. Thedja MD, Roni M, Harahap AR, Siregar NC, Ie SI, Muljono DH. Occult hepatitis B in blood donors in Indonesia: altered antigenicity of the hepatitis B virus surface protein. Hepatol Int 2010;4:608–614

  29. Ghany MG, Ayola B, Villamil FG, Gish RG, Rojter S, Vierling JM, Lok AS. Hepatitis B virus S mutants in liver transplant recipients who were reinfected despite hepatitis B immune globulin prophylaxis. Hepatology 1998;27:213–222

  30. Huang X, Hollinger FB. Occult hepatitis B virus infection and hepatocellular carcinoma: a systematic review. J Viral Hepat 2014;21:153–162

  31. Sarin SK, Kumar M, Lau GK, Abbas Z, Chan HL, Chen CJ, Chen DS, et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int 2016;10:1–98

  32. Hunt CM, McGill JM, Allen MI, Condreay LD. Clinical relevance of hepatitis B viral mutations. Hepatology 2000;31:1037–1044

  33. Tong MJ, Blatt LM, Kao JH, Cheng JT, Corey WG. Precore/basal core promoter mutants and hepatitis B viral DNA levels as predictors for liver deaths and hepatocellular carcinoma. World J Gastroenterol 2006;12:6620–6626

  34. Schaefer S. Hepatitis B virus: significance of genotypes. J Viral Hepat 2005;12:111–124

  35. Datta S. An overview of molecular epidemiology of hepatitis B virus (HBV) in India. Virol J 2008;5:156

  36. Fujiko M, Chalid MT, Turyadi, Ie SI, Maghfira, Syafri, Wahyuni R, et al. Chronic hepatitis B in pregnant women: is hepatitis B surface antigen quantification useful for viral load prediction? Int J Infect Dis 2015;41:83–89

  37. Jammeh S, Tavner F, Watson R, Thomas HC, Karayiannis P. Effect of basal core promoter and pre-core mutations on hepatitis B virus replication. J Gen Virol 2008;89:901–909

  38. Kidd-Ljunggren K, Oberg M, Kidd AH. Hepatitis B virus X gene 1751 to 1764 mutations: implications for HBeAg status and disease. J Gen Virol 1997;78:1469–1478

  39. Yang HI, Yeh SH, Chen PJ, Iloeje UH, Jen CL, Su J, Wang LY, et al. Associations between hepatitis B virus genotype and mutants and the risk of hepatocellular carcinoma. J Natl Cancer Inst 2008;100:1134–1143

  40. Liu CJ, Kao JH. Global perspective on the natural history of chronic hepatitis B: role of hepatitis B virus genotypes A to J. Semin Liver Dis 2013;33:97–102

Download references


The authors would like to thank all children and parents who participated in this study. Special thanks are extended to the Division of Hepatology, Department of Internal Medicine, Faculty of Medicine, University of Indonesia/Cipto Mangunkusumo Hospital, Jakarta, Indonesia, for recruitment of patients. Sincere gratitude is expressed to the Eijkman Institute, Jakarta, for the molecular work support and to the academic staff of the Department of Pediatrics, Faculty of Medicine, University of Indonesia, for discussions and suggestions.

Author information

Authors and Affiliations


Corresponding author

Correspondence to David H. Muljono.

Ethics declarations


This study was partly supported by a research grant from the Ministry for Research and Higher Education, Republic of Indonesia.

Conflict of interest

All authors declare that he/she has no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This study was approved by The Committee of Medical Research Ethics of the Faculty of Medicine, University of Indonesia (no. 297/PT02.FK/ETIK/2009).

Informed consent

Informed consent was obtained from all individual participants included in the study.

Additional information

H. Gunardi and M. Y. Iskandar contributed equally.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gunardi, H., Iskandar, M.Y., Turyadi et al. Hepatitis B virus infection in children of HBV-related chronic liver disease patients: a study of intra-familial HBV transmission. Hepatol Int 11, 96–104 (2017).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: