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Vol. 49, No. 5, 2006
Issue release date: August 2006
Intervirology 2006;49:266–273
(DOI:10.1159/000093456)

Sequential Accumulation of the Basal Core Promoter and the Precore Mutations in the Progression of Hepatitis B Virus-Related Chronic Liver Disease

Song B.-C. · Cui X.J. · Kim H.U. · Cho Y.-K.
Department of Internal Medicine, Cheju National University College of Medicine, Cheju National University Hospital, Jeju, Korea
email Corresponding Author

Abstract

Objectives: Despite the pathogenic role of the basal core promoter (BCP) and the precore mutations in chronic hepatitis B virus (HBV) infection, their role in the progression of liver disease is still controversial. We analyzed whether the accumulation of these mutations might enhance the progression of HBV-related chronic liver disease. Methods: Forty consecutive patients at each clinical status were analyzed. Clinical statuses were as follows: HBeAg-positive asymptomatic carrier (HBeAg+ ASC) (defined as HBeAg+, anti-HBe, HBV-DNA+ by hybridization, normal ALT); inactive HBsAg carrier; chronic hepatitis B; liver cirrhosis. The genotype and the BCP/precore regions were determined by PCR using genotype specific primers and direct sequencing, respectively. Results: All patients except one were infected with genotype C. The A to T mutation at nucleotide 1762 and/or G to A mutation at nucleotide 1764 were found in 30% in HBeAg+ ASC, 65.7% in inactive HBsAg carrier, 95% in chronic hepatitis B, and 90% in liver cirrhosis (p < 0.001). The prevalence of the G to A mutation at nucleotide 1896 was 5% in HBeAg+ ASC, 22.5% in inactive HBsAg carrier, 32.5% in chronic hepatitis B, and 50% in liver cirrhosis, respectively (p < 0.001). The T to C/A mutation at nucleotide 1753 in the BCP and G to A mutation at nucleotide 1899 in the precore were more frequent in liver cirrhosis than in the other clinical statuses (p < 0.05). Conclusion: Sequential accumulation of mutations in the BCP/precore has an important role in the progression of HBV-related liver disease.


 goto top of outline Key Words

  • Hepatitis B virus
  • Basal core promoter mutation
  • Genotype
  • Precore mutation
  • Chronic hepatitis B

 goto top of outline Abstract

Objectives: Despite the pathogenic role of the basal core promoter (BCP) and the precore mutations in chronic hepatitis B virus (HBV) infection, their role in the progression of liver disease is still controversial. We analyzed whether the accumulation of these mutations might enhance the progression of HBV-related chronic liver disease. Methods: Forty consecutive patients at each clinical status were analyzed. Clinical statuses were as follows: HBeAg-positive asymptomatic carrier (HBeAg+ ASC) (defined as HBeAg+, anti-HBe, HBV-DNA+ by hybridization, normal ALT); inactive HBsAg carrier; chronic hepatitis B; liver cirrhosis. The genotype and the BCP/precore regions were determined by PCR using genotype specific primers and direct sequencing, respectively. Results: All patients except one were infected with genotype C. The A to T mutation at nucleotide 1762 and/or G to A mutation at nucleotide 1764 were found in 30% in HBeAg+ ASC, 65.7% in inactive HBsAg carrier, 95% in chronic hepatitis B, and 90% in liver cirrhosis (p < 0.001). The prevalence of the G to A mutation at nucleotide 1896 was 5% in HBeAg+ ASC, 22.5% in inactive HBsAg carrier, 32.5% in chronic hepatitis B, and 50% in liver cirrhosis, respectively (p < 0.001). The T to C/A mutation at nucleotide 1753 in the BCP and G to A mutation at nucleotide 1899 in the precore were more frequent in liver cirrhosis than in the other clinical statuses (p < 0.05). Conclusion: Sequential accumulation of mutations in the BCP/precore has an important role in the progression of HBV-related liver disease.

Copyright © 2006 S. Karger AG, Basel


 goto top of outline References
  1. Locarnini S, McMillan J, Bartholomeusz A: The hepatitis B virus and common mutants. Semin Liver Dis 2003;23:5–20.
  2. Brunetto MR, Stemler M, Schodel F, Will H, Ottobrelli A, Rizzetto M, Verme G, Bonino F: Identification of HBV variants which cannot produce precore derived HBeAg and may be responsible for severe hepatitis. Ital J Gastroenterol 1989;21:151–154.
  3. Carman WF, Jacyna MR, Hadziyannis S, Karayiannis P, McGarvey MJ, Makris A, Thomas HC: Mutation preventing formation of hepatitis B e antigen in patients with chronic hepatitis B infection. Lancet 1989;ii:588–591.
  4. Brunetto MR, Stemler M, Bonino F, Schodel F, Oliveri F, Rizzetto M, Verme G, Will H: A new hepatitis B virus strain in patients with severe anti-HBe positive chronic hepatitis B. J Hepatol 1990;10:258–261.
  5. Carman WF, Fagan EA, Hadziyannis S, Karayiannis P, Tassopoulos NC, Williams R, Thomas HC: Association of a precore genomic variant of hepatitis B virus with fulminant hepatitis. Hepatology 1991;14:219–222.
  6. Liang TJ, Hasegawa K, Rimon N, Wands JR, Ben-Porath E: A hepatitis B virus mutant associated with an epidemic of fulminant hepatitis. N Engl J Med 1991;324:1705–1709.
  7. Omata M, Ehata T, Yokosuka O, Hosoda K, Ohto M: Mutations in the precore region of hepatitis B virus DNA in patients with fulminant and severe hepatitis. N Engl J Med 1991;324:1699–1704.
  8. Okamoto H, Tsuda F, Akahane Y, Sugai Y, Yoshiba M, Moriyama K, Tanaka T, Miyakawa Y, Mayumi M: Hepatitis B virus with mutations in the core promoter for an e antigen-negative phenotype in carriers with antibody to e antigen. J Virol 1994;68:8102–8110.
  9. Takahashi K, Aoyama K, Ohno N, Iwata K, Akahane Y, Baba K, Yoshizawa H, Mishiro S: The precore/core promoter mutant (T1762A1764) of hepatitis B virus: clinical significance and an easy method for detection. J Gen Virol 1995;76:3159–3164.
  10. Yuh CH, Chang YL, Ting LP: Transcriptional regulation of precore and pregenomic RNAs of hepatitis B virus. J Virol 1992;66:4073–4084.
  11. Chen IH, Huang CJ, Ting LP: Overlapping initiator and TATA box functions in the basal core promoter of hepatitis B virus. J Virol 1995;69:3647–3657.
  12. Kramvis A, Kew MC: The core promoter of hepatitis B virus. J Viral Hepatol 1999;6:415–427.
  13. 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.
  14. Takahashi K, Akahane Y, Hino K, Ohta Y, Mishiro S: Hepatitis B virus genomic sequence in the circulation of hepatocellular carcinoma patients: Comparative analysis of 40 full-length isolates. Arch Virol 1998;143:2313–2326.
  15. Takahashi K, Ohta Y, Kanai K, Akahane Y, Iwasa Y, Hino K, Ohno N, Yoshizawa H, Mishiro S: Clinical implications of mutations C-to-T1653 and T-to-C/A/G1753 of hepatitis B virus genotype C genome in chronic liver disease. Arch Virol 1999;144:1299–1308.
  16. Tur-Kaspa R, Klein A, Aharonson S: Hepatitis B virus precore mutants are identical in carriers from various ethnic origins and are associated with a range of liver disease severity. Hepatology 1992;16:1338–1342.
  17. Rodriguez-Frias F, Buti M, Jardi R, Cotrina M, Viladomiu L, Esteban R, Guardia J: Hepatitis B virus infection: precore mutants and its relation to viral genotypes and core mutations. Hepatology 1995;22:1641–1647.
  18. Chan HL, Leung NW, Hussain M, Wong ML, Lok AS: Hepatitis B e antigen-negative chronic hepatitis B in Hong Kong. Hepatology 2000;31:763–768.
  19. Laskus T, Persing DH, Nowicki MJ, Mosley JW, Rakela J: Nucleotide sequence analysis of the precore region in patients with fulminant hepatitis B in the United States. Gastroenterology 1993;105:1173–1178.
  20. Liu CJ, Kao JH, Lai MY, Chen PJ, Chen DS: Precore/core promoter mutations and genotypes of hepatitis B virus in chronic hepatitis B patients with fulminant or subfulminant hepatitis. J Med Virol 2004;72:545–550.
  21. Akarca US, Greene S, Lok AS: Detection of precore hepatitis B virus mutants in asymptomatic HBsAg-positive family members. Hepatology 1994;19:1366–1370.
  22. Buckwold VE, Xu Z, Chen M, Yen TS, Ou JH: Effects of a naturally occurring mutation in the hepatitis B virus basal core promoter on precore gene expression and viral replication. J Virol 1996;70:5845–5851.
  23. Moriyama K, Okamoto H, Tsuda F, Mayumi M: Reduced precore transcription and enhanced core-pregenome transcription of hepatitis B virus DNA after replacement of the precore-core promoter with sequences associated with e antigen-seronegative persistent infections. Virology 1996;226:269–280.
  24. Buckwold VE, Xu Z, Yen TS, Ou JH: Effects of a frequent double-nucleotide basal core promoter mutation and its putative single-nucleotide precursor mutations on hepatitis B virus gene expression and replication. J Gen Virol 1997;78:2055–2065.
  25. Sato S, Suzuki K, Akahane Y, Akamatsu K, Akiyama K, Yunomura K, Tsuda F, Tanaka T, Okamoto H, Miyakawa Y, et al: Hepatitis B virus strains with mutations in the core promoter in patients with fulminant hepatitis. Ann Intern Med 1995;122:241–248.
  26. Friedt M, Gerner P, Lausch E, Trubel H, Zabel B, Wirth S: Mutations in the basic core promotor and the precore region of hepatitis B virus and their selection in children with fulminant and chronic hepatitis B. Hepatology 1999;29:1252–1258.
  27. Lindh M, Hannoun C, Dhillon AP, Norkrans G, Horal P: Core promoter mutations and genotypes in relation to viral replication and liver damage in East Asian hepatitis B virus carriers. J Infect Dis 1999;179:775–782.
  28. Laskus T, Rakela J, Nowicki MJ, Persing DH: Hepatitis B virus core promoter sequence analysis in fulminant and chronic hepatitis B. Gastroenterology 1995;109:1618–1623.
  29. Sterneck M, Gunther S, Santantonio T, Fischer L, Broelsch CE, Greten H, Will H: Hepatitis B virus genomes of patients with fulminant hepatitis do not share a specific mutation. Hepatology 1996;24:300–306.
  30. Chun YK, Kim JY, Woo HJ, Oh SM, Kang I, Ha J, Kim SS: No significant correlation exists between core promoter mutations, viral replication, and liver damage in chronic hepatitis B infection. Hepatology 2000;32:1154–1162.
  31. Lindh M, Andersson AS, Gusdal A: Genotypes, nt 1858 variants, and geographic origin of hepatitis B virus: large-scale analysis using a new genotyping method. J Infect Dis 1997;175:1285–1293.
  32. Orito E, Ichida T, Sakugawa H, Sata M, Horiike N, Hino K, Okita K, Okanoue T, Iino S, Tanaka E, Suzuki K, Watanabe H, Hige S, Mizokami M: Geographic distribution of hepatitis B virus (HBV) genotype in patients with chronic HBV infection in Japan. Hepatology 2001;34:590–594.
  33. Miyakawa Y, Mizokami M: Classifying hepatitis B virus genotypes. Intervirology 2003;46:329–338.
  34. Song BC, Cui XJ, Kim H: Hepatitis B virus genotypes in Korea: An endemic area of hepatitis B virus infection. Intervirology 2005;48:133–137.
  35. Kao JH, Chen PJ, Lai MY, Chen DS: Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B. Gastroenterology 2000;118:554–559.
  36. Chu CJ, Hussain M, Lok AS: Hepatitis B virus genotype B is associated with earlier HBeAg seroconversion compared with hepatitis B virus genotype C. Gastroenterology 2002;122:1756–1762.
  37. Sanchez-Tapias JM, Costa J, Mas A, Bruguera M, Rodes J: Influence of hepatitis B virus genotype on the long-term outcome of chronic hepatitis B in western patients. Gastroenterology 2002;123:1848–1856.
  38. Sugauchi F, Chutaputti A, Orito E, Kato H, Suzuki S, Ueda R, Mizokami M: Hepatitis B virus genotypes and clinical manifestation among hepatitis B carriers in Thailand. J Gastroenterol Hepatol 2002;17:671–676.
  39. Chan HL, Wong ML, Hui AY, Hung LC, Chan FK, Sung JJ: Hepatitis B virus genotype C takes a more aggressive disease course than hepatitis B virus genotype B in hepatitis B e antigen-positive patients. J Clin Microbiol 2003;41:1277–1279.
  40. Nakayoshi T, Maeshiro T, Nakasone H, Sakugawa H, Kinjo F, Orito E, Mizokami M: Difference in prognosis between patients infected with hepatitis B virus with genotype B and those with genotype C in the Okinawa Islands: a prospective study. J Med Virol 2003;70:350–354.
  41. Sumi H, Yokosuka O, Seki N, Arai M, Imazeki F, Kurihara T, Kanda T, Fukai K, Kato M, Saisho H: Influence of hepatitis B virus genotypes on the progression of chronic type B liver disease. Hepatology 2003;37:19–26.
  42. Chan HL, Hui AY, Wong ML, Tse AM, Hung LC, Wong VW, Sung JJ: Genotype C hepatitis B virus infection is associated with an increased risk of hepatocellular carcinoma. Gut 2004;53:1494–1498.
  43. Chan HL, Hussain M, Lok AS: Different hepatitis B virus genotypes are associated with different mutations in the core promoter and precore regions during hepatitis B e antigen seroconversion. Hepatology 1999;29:976–984.
  44. Orito E, Mizokami M, Sakugawa H, Michitaka K, Ishikawa K, Ichida T, Okanoue T, Yotsuyanagi H, Iino S: A case-control study for clinical and molecular biological differences between hepatitis B viruses of genotypes B and C. Japan HBV Genotype Research Group. Hepatology 2001;33:218–223.
  45. Fattovich G: Natural history of hepatitis B. J Hepatol 2003;39(suppl 1):S50–58.

    External Resources

  46. Lok AS, McMahon BJ: Chronic hepatitis B. Hepatology 2001;34:1225–1241.
  47. Bruix J, Castells A, Bosch J, Feu F, Fuster J, Garcia-Pagan JC, Visa J, Bru C, Rodes J: Surgical resection of hepatocellular carcinoma in cirrhotic patients: Prognostic value of preoperative portal pressure. Gastroenterology 1996;111:1018–1022.
  48. Di Lelio A, Cestari C, Lomazzi A, Beretta L: Cirrhosis: diagnosis with sonographic study of the liver surface. Radiology 1989;172:389–392.
  49. Naito H, Hayashi S, Abe K: Rapid and specific genotyping system for hepatitis B virus corresponding to six major genotypes by PCR using type-specific primers. J Clin Microbiol 2001;39:362–364.

 goto top of outline Author Contacts

Byung-Cheol Song, MD
Department of Internal Medicine, Cheju National University College of Medicine
Cheju National University Hospital, 154 Samdo 2-dong
Jeju 690–716 (Republic of Korea)
Tel. +82 64 750 1253, Fax +82 64 750 1553, E-Mail drsong@cheju.ac.kr


 goto top of outline Article Information

Received: June 13, 2005
Accepted: August 8, 2005
Published online: May 22, 2006
Number of Print Pages : 8
Number of Figures : 0, Number of Tables : 5, Number of References : 49


 goto top of outline Publication Details

Intervirology (International Journal of Basic and Medical Virology)

Vol. 49, No. 5, Year 2006 (Cover Date: August 2006)

Journal Editor: Liebert, U.G. (Leipzig)
ISSN: 0300–5526 (print), 1423–0100 (Online)

For additional information: http://www.karger.com/INT


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Objectives: Despite the pathogenic role of the basal core promoter (BCP) and the precore mutations in chronic hepatitis B virus (HBV) infection, their role in the progression of liver disease is still controversial. We analyzed whether the accumulation of these mutations might enhance the progression of HBV-related chronic liver disease. Methods: Forty consecutive patients at each clinical status were analyzed. Clinical statuses were as follows: HBeAg-positive asymptomatic carrier (HBeAg+ ASC) (defined as HBeAg+, anti-HBe, HBV-DNA+ by hybridization, normal ALT); inactive HBsAg carrier; chronic hepatitis B; liver cirrhosis. The genotype and the BCP/precore regions were determined by PCR using genotype specific primers and direct sequencing, respectively. Results: All patients except one were infected with genotype C. The A to T mutation at nucleotide 1762 and/or G to A mutation at nucleotide 1764 were found in 30% in HBeAg+ ASC, 65.7% in inactive HBsAg carrier, 95% in chronic hepatitis B, and 90% in liver cirrhosis (p < 0.001). The prevalence of the G to A mutation at nucleotide 1896 was 5% in HBeAg+ ASC, 22.5% in inactive HBsAg carrier, 32.5% in chronic hepatitis B, and 50% in liver cirrhosis, respectively (p < 0.001). The T to C/A mutation at nucleotide 1753 in the BCP and G to A mutation at nucleotide 1899 in the precore were more frequent in liver cirrhosis than in the other clinical statuses (p < 0.05). Conclusion: Sequential accumulation of mutations in the BCP/precore has an important role in the progression of HBV-related liver disease.



 goto top of outline Author Contacts

Byung-Cheol Song, MD
Department of Internal Medicine, Cheju National University College of Medicine
Cheju National University Hospital, 154 Samdo 2-dong
Jeju 690–716 (Republic of Korea)
Tel. +82 64 750 1253, Fax +82 64 750 1553, E-Mail drsong@cheju.ac.kr


 goto top of outline Article Information

Received: June 13, 2005
Accepted: August 8, 2005
Published online: May 22, 2006
Number of Print Pages : 8
Number of Figures : 0, Number of Tables : 5, Number of References : 49


 goto top of outline Publication Details

Intervirology (International Journal of Basic and Medical Virology)

Vol. 49, No. 5, Year 2006 (Cover Date: August 2006)

Journal Editor: Liebert, U.G. (Leipzig)
ISSN: 0300–5526 (print), 1423–0100 (Online)

For additional information: http://www.karger.com/INT


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Locarnini S, McMillan J, Bartholomeusz A: The hepatitis B virus and common mutants. Semin Liver Dis 2003;23:5–20.
  2. Brunetto MR, Stemler M, Schodel F, Will H, Ottobrelli A, Rizzetto M, Verme G, Bonino F: Identification of HBV variants which cannot produce precore derived HBeAg and may be responsible for severe hepatitis. Ital J Gastroenterol 1989;21:151–154.
  3. Carman WF, Jacyna MR, Hadziyannis S, Karayiannis P, McGarvey MJ, Makris A, Thomas HC: Mutation preventing formation of hepatitis B e antigen in patients with chronic hepatitis B infection. Lancet 1989;ii:588–591.
  4. Brunetto MR, Stemler M, Bonino F, Schodel F, Oliveri F, Rizzetto M, Verme G, Will H: A new hepatitis B virus strain in patients with severe anti-HBe positive chronic hepatitis B. J Hepatol 1990;10:258–261.
  5. Carman WF, Fagan EA, Hadziyannis S, Karayiannis P, Tassopoulos NC, Williams R, Thomas HC: Association of a precore genomic variant of hepatitis B virus with fulminant hepatitis. Hepatology 1991;14:219–222.
  6. Liang TJ, Hasegawa K, Rimon N, Wands JR, Ben-Porath E: A hepatitis B virus mutant associated with an epidemic of fulminant hepatitis. N Engl J Med 1991;324:1705–1709.
  7. Omata M, Ehata T, Yokosuka O, Hosoda K, Ohto M: Mutations in the precore region of hepatitis B virus DNA in patients with fulminant and severe hepatitis. N Engl J Med 1991;324:1699–1704.
  8. Okamoto H, Tsuda F, Akahane Y, Sugai Y, Yoshiba M, Moriyama K, Tanaka T, Miyakawa Y, Mayumi M: Hepatitis B virus with mutations in the core promoter for an e antigen-negative phenotype in carriers with antibody to e antigen. J Virol 1994;68:8102–8110.
  9. Takahashi K, Aoyama K, Ohno N, Iwata K, Akahane Y, Baba K, Yoshizawa H, Mishiro S: The precore/core promoter mutant (T1762A1764) of hepatitis B virus: clinical significance and an easy method for detection. J Gen Virol 1995;76:3159–3164.
  10. Yuh CH, Chang YL, Ting LP: Transcriptional regulation of precore and pregenomic RNAs of hepatitis B virus. J Virol 1992;66:4073–4084.
  11. Chen IH, Huang CJ, Ting LP: Overlapping initiator and TATA box functions in the basal core promoter of hepatitis B virus. J Virol 1995;69:3647–3657.
  12. Kramvis A, Kew MC: The core promoter of hepatitis B virus. J Viral Hepatol 1999;6:415–427.
  13. 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.
  14. Takahashi K, Akahane Y, Hino K, Ohta Y, Mishiro S: Hepatitis B virus genomic sequence in the circulation of hepatocellular carcinoma patients: Comparative analysis of 40 full-length isolates. Arch Virol 1998;143:2313–2326.
  15. Takahashi K, Ohta Y, Kanai K, Akahane Y, Iwasa Y, Hino K, Ohno N, Yoshizawa H, Mishiro S: Clinical implications of mutations C-to-T1653 and T-to-C/A/G1753 of hepatitis B virus genotype C genome in chronic liver disease. Arch Virol 1999;144:1299–1308.
  16. Tur-Kaspa R, Klein A, Aharonson S: Hepatitis B virus precore mutants are identical in carriers from various ethnic origins and are associated with a range of liver disease severity. Hepatology 1992;16:1338–1342.
  17. Rodriguez-Frias F, Buti M, Jardi R, Cotrina M, Viladomiu L, Esteban R, Guardia J: Hepatitis B virus infection: precore mutants and its relation to viral genotypes and core mutations. Hepatology 1995;22:1641–1647.
  18. Chan HL, Leung NW, Hussain M, Wong ML, Lok AS: Hepatitis B e antigen-negative chronic hepatitis B in Hong Kong. Hepatology 2000;31:763–768.
  19. Laskus T, Persing DH, Nowicki MJ, Mosley JW, Rakela J: Nucleotide sequence analysis of the precore region in patients with fulminant hepatitis B in the United States. Gastroenterology 1993;105:1173–1178.
  20. Liu CJ, Kao JH, Lai MY, Chen PJ, Chen DS: Precore/core promoter mutations and genotypes of hepatitis B virus in chronic hepatitis B patients with fulminant or subfulminant hepatitis. J Med Virol 2004;72:545–550.
  21. Akarca US, Greene S, Lok AS: Detection of precore hepatitis B virus mutants in asymptomatic HBsAg-positive family members. Hepatology 1994;19:1366–1370.
  22. Buckwold VE, Xu Z, Chen M, Yen TS, Ou JH: Effects of a naturally occurring mutation in the hepatitis B virus basal core promoter on precore gene expression and viral replication. J Virol 1996;70:5845–5851.
  23. Moriyama K, Okamoto H, Tsuda F, Mayumi M: Reduced precore transcription and enhanced core-pregenome transcription of hepatitis B virus DNA after replacement of the precore-core promoter with sequences associated with e antigen-seronegative persistent infections. Virology 1996;226:269–280.
  24. Buckwold VE, Xu Z, Yen TS, Ou JH: Effects of a frequent double-nucleotide basal core promoter mutation and its putative single-nucleotide precursor mutations on hepatitis B virus gene expression and replication. J Gen Virol 1997;78:2055–2065.
  25. Sato S, Suzuki K, Akahane Y, Akamatsu K, Akiyama K, Yunomura K, Tsuda F, Tanaka T, Okamoto H, Miyakawa Y, et al: Hepatitis B virus strains with mutations in the core promoter in patients with fulminant hepatitis. Ann Intern Med 1995;122:241–248.
  26. Friedt M, Gerner P, Lausch E, Trubel H, Zabel B, Wirth S: Mutations in the basic core promotor and the precore region of hepatitis B virus and their selection in children with fulminant and chronic hepatitis B. Hepatology 1999;29:1252–1258.
  27. Lindh M, Hannoun C, Dhillon AP, Norkrans G, Horal P: Core promoter mutations and genotypes in relation to viral replication and liver damage in East Asian hepatitis B virus carriers. J Infect Dis 1999;179:775–782.
  28. Laskus T, Rakela J, Nowicki MJ, Persing DH: Hepatitis B virus core promoter sequence analysis in fulminant and chronic hepatitis B. Gastroenterology 1995;109:1618–1623.
  29. Sterneck M, Gunther S, Santantonio T, Fischer L, Broelsch CE, Greten H, Will H: Hepatitis B virus genomes of patients with fulminant hepatitis do not share a specific mutation. Hepatology 1996;24:300–306.
  30. Chun YK, Kim JY, Woo HJ, Oh SM, Kang I, Ha J, Kim SS: No significant correlation exists between core promoter mutations, viral replication, and liver damage in chronic hepatitis B infection. Hepatology 2000;32:1154–1162.
  31. Lindh M, Andersson AS, Gusdal A: Genotypes, nt 1858 variants, and geographic origin of hepatitis B virus: large-scale analysis using a new genotyping method. J Infect Dis 1997;175:1285–1293.
  32. Orito E, Ichida T, Sakugawa H, Sata M, Horiike N, Hino K, Okita K, Okanoue T, Iino S, Tanaka E, Suzuki K, Watanabe H, Hige S, Mizokami M: Geographic distribution of hepatitis B virus (HBV) genotype in patients with chronic HBV infection in Japan. Hepatology 2001;34:590–594.
  33. Miyakawa Y, Mizokami M: Classifying hepatitis B virus genotypes. Intervirology 2003;46:329–338.
  34. Song BC, Cui XJ, Kim H: Hepatitis B virus genotypes in Korea: An endemic area of hepatitis B virus infection. Intervirology 2005;48:133–137.
  35. Kao JH, Chen PJ, Lai MY, Chen DS: Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B. Gastroenterology 2000;118:554–559.
  36. Chu CJ, Hussain M, Lok AS: Hepatitis B virus genotype B is associated with earlier HBeAg seroconversion compared with hepatitis B virus genotype C. Gastroenterology 2002;122:1756–1762.
  37. Sanchez-Tapias JM, Costa J, Mas A, Bruguera M, Rodes J: Influence of hepatitis B virus genotype on the long-term outcome of chronic hepatitis B in western patients. Gastroenterology 2002;123:1848–1856.
  38. Sugauchi F, Chutaputti A, Orito E, Kato H, Suzuki S, Ueda R, Mizokami M: Hepatitis B virus genotypes and clinical manifestation among hepatitis B carriers in Thailand. J Gastroenterol Hepatol 2002;17:671–676.
  39. Chan HL, Wong ML, Hui AY, Hung LC, Chan FK, Sung JJ: Hepatitis B virus genotype C takes a more aggressive disease course than hepatitis B virus genotype B in hepatitis B e antigen-positive patients. J Clin Microbiol 2003;41:1277–1279.
  40. Nakayoshi T, Maeshiro T, Nakasone H, Sakugawa H, Kinjo F, Orito E, Mizokami M: Difference in prognosis between patients infected with hepatitis B virus with genotype B and those with genotype C in the Okinawa Islands: a prospective study. J Med Virol 2003;70:350–354.
  41. Sumi H, Yokosuka O, Seki N, Arai M, Imazeki F, Kurihara T, Kanda T, Fukai K, Kato M, Saisho H: Influence of hepatitis B virus genotypes on the progression of chronic type B liver disease. Hepatology 2003;37:19–26.
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