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Abstract

Fifteen years have passed since genotypes of hepatitis B virus (HBV) were proposed by a sequence divergence of the entire genome >8% and named by capital alphabet letters.1Okamoto H. Tsuda F. Sakugawa H. Sastrosoewignjo R.I. Imai M. Miyakawa Y. Mayumi M. Typing hepatitis B virus by homology in nucleotide sequence comparison of surface antigen subtypes.J Gen Virol. 1988; 69: 2575-2583Crossref PubMed Scopus (920) Google Scholar It is only during the last few years, however, while HBV genotypes have attracted attention due to their clinical relevance.2Chu C.J. Lok A.S. Clinical significance of hepatitis B virus genotypes.Hepatology. 2002; 35: 1274-1276Crossref PubMed Scopus (225) Google Scholar HBV strains of even the same genotype may differ. Should subtypes of an HBV genotype have influence on biology of HBV and manifestation of acute or chronic liver disease, they need to be distinguished in epidemiological and clinical settings.We have subtyped HBV genotype B by the recombination with genotype C over the precore region plus core gene, and designated them Ba (with the recombination) and Bj (without it), respectively.3Sugauchi F. Orito E. Ichida T. Kato H. Sakugawa H. Kakumu S. Ishida T. Chutaputti A. Lai C.L. Ueda R. Miyakawa Y. Mizokami M. Hepatitis B virus of genotype B with or without recombination with genotype C over the precore region plus the core gene.J Virol. 2002; 76: 5985-5992Crossref PubMed Scopus (260) Google Scholar So far, Bj is found restricted to Japan, while Ba is ubiquitous in Asian countries other than Japan. In view of growing lines of evidence for a higher disease-inducing capacity of HBV genotype C than B,2Chu C.J. Lok A.S. Clinical significance of hepatitis B virus genotypes.Hepatology. 2002; 35: 1274-1276Crossref PubMed Scopus (225) Google Scholar subtypes Ba and Bj may differ clinically as well. In actuality, subtype Ba has inherited some characteristics of genotype C, possibly due to the recombination, in that it is associated with higher frequency of the core-promoter mutation and higher prevalence of hepatitis B e antigen in hosts than subtype Bj.4Sugauchi F. Orito E. Ichida T. Kato H. Sakugawa H. Kakumu S. Ishida T. Chutaputti A. Lai C.L. Gish R.G. Ueda R. Miyakawa Y. Mizokami M. Epidemiologic and virologic characteristics of hepatitis B virus genotype B having the recombination with genotype C.Gastroenterology. 2003; 124: 925-932Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar Furthermore, during lamivudine treatment, YMDD motif mutants develop more frequently in the patients infected with subtype Ba than Bj, leading to a higher rate of breakthrough hepatitis.5Akuta N. Suzuki F. Kobayashi M. Tsubota A. Suzuki Y. Hosaka T. Someya T. Saitoh S. Arase Y. Ikeda K. Kumada H. The influence of hepatitis B virus genotype on the development of lamivudine resistance during long-term treatment.J Hepatol. 2003; 38: 315-321Abstract Full Text Full Text PDF PubMed Scopus (116) Google ScholarOn the basis of virological and clinical differences between Ba and Bj, taken along with their distinct geographical distribution in Asia, we have expected that subtype Ba would be responsible for the development of hepatocellular carcinoma (HCC) in patients younger than 50 years in Taiwan who are infected with HBV genotype B,6Kao J.H. Chen P.J. Lai M.Y. Chen D.S. Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B.Gastroenterology. 2000; 118: 554-559Abstract Full Text Full Text PDF PubMed Scopus (847) Google Scholar which is rarely, if ever, seen in Japan.7Fujie H. Moriya K. Shintani Y. Yotsuyanagi H. Iino S. Koike K. Hepatitis B virus genotypes and hepatocellular carcinoma in Japan.Gastroenterology. 2001; 120: 1564-1565Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar, 8Orito 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: 590-594Crossref PubMed Scopus (383) Google Scholar, 9Sakugawa H. Nakasone H. Nakayoshi T. Orito E. Mizokami M. Yamashiro T. Maeshiro T. Kinjo F. Saito A. Miyagi Y. Preponderance of hepatitis B virus genotype B contributes to a better prognosis of chronic HBV infection in Okinawa, Japan.J Med Virol. 2002; 67: 484-489Crossref PubMed Scopus (46) Google Scholar We are delighted that Drs. Kao and Chen took interest in our speculation and compared HBV isolates of genotype B from young and old patients with HCC in Taiwan. They found all genotype B isolates belong to subtype Ba, and on that basis, doubt a role of subtypes of genotype B in hepatocarcinogenesis in young patients.It would be difficult, however, to evaluate the influence, if any, of subtypes of HBV genotype B on the development of HCC in countries where only one of them prevails. A case-control study in each Asian country for comparison of subtype Ba or Bj against genotype C, serving as an internal standard, would be required to settle whether or not these subtypes of genotype B differ in the capacity to induce HCC in young patients. Fifteen years have passed since genotypes of hepatitis B virus (HBV) were proposed by a sequence divergence of the entire genome >8% and named by capital alphabet letters.1Okamoto H. Tsuda F. Sakugawa H. Sastrosoewignjo R.I. Imai M. Miyakawa Y. Mayumi M. Typing hepatitis B virus by homology in nucleotide sequence comparison of surface antigen subtypes.J Gen Virol. 1988; 69: 2575-2583Crossref PubMed Scopus (920) Google Scholar It is only during the last few years, however, while HBV genotypes have attracted attention due to their clinical relevance.2Chu C.J. Lok A.S. Clinical significance of hepatitis B virus genotypes.Hepatology. 2002; 35: 1274-1276Crossref PubMed Scopus (225) Google Scholar HBV strains of even the same genotype may differ. Should subtypes of an HBV genotype have influence on biology of HBV and manifestation of acute or chronic liver disease, they need to be distinguished in epidemiological and clinical settings. We have subtyped HBV genotype B by the recombination with genotype C over the precore region plus core gene, and designated them Ba (with the recombination) and Bj (without it), respectively.3Sugauchi F. Orito E. Ichida T. Kato H. Sakugawa H. Kakumu S. Ishida T. Chutaputti A. Lai C.L. Ueda R. Miyakawa Y. Mizokami M. Hepatitis B virus of genotype B with or without recombination with genotype C over the precore region plus the core gene.J Virol. 2002; 76: 5985-5992Crossref PubMed Scopus (260) Google Scholar So far, Bj is found restricted to Japan, while Ba is ubiquitous in Asian countries other than Japan. In view of growing lines of evidence for a higher disease-inducing capacity of HBV genotype C than B,2Chu C.J. Lok A.S. Clinical significance of hepatitis B virus genotypes.Hepatology. 2002; 35: 1274-1276Crossref PubMed Scopus (225) Google Scholar subtypes Ba and Bj may differ clinically as well. In actuality, subtype Ba has inherited some characteristics of genotype C, possibly due to the recombination, in that it is associated with higher frequency of the core-promoter mutation and higher prevalence of hepatitis B e antigen in hosts than subtype Bj.4Sugauchi F. Orito E. Ichida T. Kato H. Sakugawa H. Kakumu S. Ishida T. Chutaputti A. Lai C.L. Gish R.G. Ueda R. Miyakawa Y. Mizokami M. Epidemiologic and virologic characteristics of hepatitis B virus genotype B having the recombination with genotype C.Gastroenterology. 2003; 124: 925-932Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar Furthermore, during lamivudine treatment, YMDD motif mutants develop more frequently in the patients infected with subtype Ba than Bj, leading to a higher rate of breakthrough hepatitis.5Akuta N. Suzuki F. Kobayashi M. Tsubota A. Suzuki Y. Hosaka T. Someya T. Saitoh S. Arase Y. Ikeda K. Kumada H. The influence of hepatitis B virus genotype on the development of lamivudine resistance during long-term treatment.J Hepatol. 2003; 38: 315-321Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar On the basis of virological and clinical differences between Ba and Bj, taken along with their distinct geographical distribution in Asia, we have expected that subtype Ba would be responsible for the development of hepatocellular carcinoma (HCC) in patients younger than 50 years in Taiwan who are infected with HBV genotype B,6Kao J.H. Chen P.J. Lai M.Y. Chen D.S. Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B.Gastroenterology. 2000; 118: 554-559Abstract Full Text Full Text PDF PubMed Scopus (847) Google Scholar which is rarely, if ever, seen in Japan.7Fujie H. Moriya K. Shintani Y. Yotsuyanagi H. Iino S. Koike K. Hepatitis B virus genotypes and hepatocellular carcinoma in Japan.Gastroenterology. 2001; 120: 1564-1565Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar, 8Orito 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: 590-594Crossref PubMed Scopus (383) Google Scholar, 9Sakugawa H. Nakasone H. Nakayoshi T. Orito E. Mizokami M. Yamashiro T. Maeshiro T. Kinjo F. Saito A. Miyagi Y. Preponderance of hepatitis B virus genotype B contributes to a better prognosis of chronic HBV infection in Okinawa, Japan.J Med Virol. 2002; 67: 484-489Crossref PubMed Scopus (46) Google Scholar We are delighted that Drs. Kao and Chen took interest in our speculation and compared HBV isolates of genotype B from young and old patients with HCC in Taiwan. They found all genotype B isolates belong to subtype Ba, and on that basis, doubt a role of subtypes of genotype B in hepatocarcinogenesis in young patients. It would be difficult, however, to evaluate the influence, if any, of subtypes of HBV genotype B on the development of HCC in countries where only one of them prevails. A case-control study in each Asian country for comparison of subtype Ba or Bj against genotype C, serving as an internal standard, would be required to settle whether or not these subtypes of genotype B differ in the capacity to induce HCC in young patients.