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REVIEW ARTICLE Table of Contents   
Year : 2006  |  Volume : 3  |  Issue : 1  |  Page : 54-75
Hepatitis B virus genotypes: Epidemiology and therapeutic implications


1 Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
2 Division of Gastroenterology, Department of Internal Medicine; Graduate Institute of Clinical Medicine; Hepatitis Research Center and Department of Medical Research, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan

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   Abstract 

Hepatitis B virus (HBV) is a global health problem. Effective and individualized treatment of chronic hepatitis B to prevent progression to end-stage liver diseases and hepatocellular carcinoma is thus needed. HBV has been designated eight genotypes (A-H) based on genome sequence divergence. Each genotype has its distinct geographic and ethnic distribution. The epidemiology of HBV genotypes and their implications on the responses to antiviral therapy have become increasingly recognized. Recent studies suggested that sustained responses to standard interferon in patients with genotype A or B are better than those with genotype C or D. However, conflicting results exist regarding the response to peginterferon. Furthermore, therapeutic responses to nucleoside/nucleotide analogous are comparable among different HBV genotypes. In summary, clinical and pathogenic differences exist among HBV genotypes and future research should focus on molecular and virologic mechanisms underlying the clinical phenotypes of different HBV genotypes.

How to cite this article:
Liu CJ, Kao JH. Hepatitis B virus genotypes: Epidemiology and therapeutic implications. Hep B Annual 2006;3:54-75

How to cite this URL:
Liu CJ, Kao JH. Hepatitis B virus genotypes: Epidemiology and therapeutic implications. Hep B Annual [serial online] 2006 [cited 2024 Mar 29];3:54-75. Available from: https://www.hepatitisbannual.org/text.asp?2006/3/1/54/32773



   Introduction Top


Hepatitis B virus (HBV) infection has a wide spectrum of liver diseases.[1],[2] Worldwide, the number of individuals infected with this virus has been estimated as high as 350 million.[3],[4] Thus, effective treatment for chronic hepatitis B to prevent progression to end-stage liver diseases and hepatocellular carcinoma (HCC) is urgently needed. The responses to antiviral therapy are influenced by both host and viral factors. Recently, HBV genotypes have attracted increasing attention since they may affect the disease progression and outcomes of HBV-related chronic liver disease, as well as the response to antiviral therapies. [5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44],[45],[46],[47],[48],[49],[50],[51],[52],[53],[54],[55],[56],[57],[58],[59],[60],[61],[62] Thus, understanding of HBV genotype and its correlates with the response to antiviral therapy is important.


   Epidemiology Top


HBV is a DNA virus and its genome consists of four overlapping genes encoding the viral envelope, nucleocapsid, polymerase and X protein. Due to error rate of the viral reverse transcriptase, HBV genome evolves and the estimated rate of nucleotide substitution is around 1.4-3.2“10 -5 /site per year.[63],[64] Eight genotypes of hepatitis B virus (HBV) have been detected by the sequence divergence >8% in the entire HBV genome of about 3,200 nucleotides (nt) and designated by capital letters from A to H in the order of documentation. [65],[66],[67],[68],[69],[70],[71],[72],[73] They have distinct geographical distribution and influence the severity of liver disease as well as the response to antiviral therapies as shown in [Table - 1]. Furthermore, subgenotypes have been reported for genotypes A, B and C; and named Aa/A1 (Asian/African type) and Ae/A2 (European type), Bj/B1 (Japanese type) and Ba/B2 (Asian type) and Ce/C1 (East Asian type) and Cs/C2 (Southeast Asian type) [Table - 2], [74],[75],[76],[77],[78],[79],[80],[81],[82],[83] which also differed in their geographic distributions. This pattern of defined geographic distribution was less evident for D1-D4, where the subgenotypes are widely spread in Europe, Africa and Asia. For details please see reviews.[84],[85]


   Clinical manifestations Top


Viral, host or environmental factors have been reported to determine the clinical outcomes of patients with chronic HBV infection.[82],[83],[86],[87],[88],[89],[90],[91],[92],[93],[94],[95],[96],[97],[98],[99] Particularly, HBV genotype may affect clinical and treatment outcomes of HBV infection. Genotypes B and C prevailing in Asia-Pacific region have been studied most extensively. Differences between genotypes A and D prevailing in Western countries also become increasingly recognized.

Most studies indicate that the severity and outcomes of chronic hepatitis B are more serious in patients with genotype C compared to those with genotype B.[5],[6],[7],[8],[27],[32],[33],[91] A prospective 14-year study on 4841 Taiwanese male HBV carriers demonstrated that HBV genotype C was associated with an increased risk of hepatocellular carcinoma (HCC) compared with other HBV genotypes.[32] In addition, the risk of HCC increased in parallel with serum viral loads. The associations of HBV genotype and viral load with HCC risk were additive. In another cross-sectional, hospital-based study, we comprehensively compared viral factors between 160 chronic HBV carriers and 200 patients with HCC. In univariate analysis, we found that statistically significant odds ratios favoring the development of HCC were obtained for male sex, advanced age, HBV genotype C infection, the precore A1896 mutation and basal core promoter T1762/A1764 mutation [Figure - 1].[91] Recently, Yang et al. reported that the risk of HCC was associated with HBV genotypes and mutants in a community-based prospective cohort study.[99] Totally, 3,644 adults residents who were HBsAg-positive and anti-HCV-negative were enrolled from seven townships in Taiwan between 1991 and 1992. During 41,695 person-years of follow-up, 162 HCC cases were identified. The relative risk of HCC after adjustment of gender, age, HBV load and alcohol drinking was 2.6 (95% confidence interval: 1.9-3.6) for HBV genotype C compared with genotype B, 0.3 (95% confidence interval: 0.2-0.5) for precore 1896A mutant compared with 1896G wild strain and 3.2 (95% confidence interval: 2.0-5.1) for basal core promoter 1762T/1764A mutant compared with 1762A/1764G wild strain.[99] These findings implicate that determination of HBV DNA level as well as HBV genotype may help identify the patients at risk of HCC development. From another aspect, whether suppressing viral load by effective antiviral treatments could reduce the risk of cirrhosis-related complications including HCC awaits further studies.

Of particular note, we found genotype B was significantly more common in our patients with HCC aged <50 years compared with age-matched asymptomatic carriers (80 versus 52%; P =0.03). This predominance was more marked in younger patients with HCC, being 90% in those aged <35 years and most were non-cirrhotic. These data suggest that HBV genotype C may be associated with more severe liver disease whereas genotype B may be associated with the development of HCC in young non-cirrhotic patients.[5] Similar findings were reported in Taiwanese pediatric patients with chronic HBV infection.[46] Of 26 children with HBV-related HCC, genotype B was the major genotype (74%). Subsequent studies from Japan and China confirmed that HBV genotype C is associated with the development of HCC.[27],[34] Nevertheless, they found that genotype B is rarely associated with the development of HCC. The reasons for the discrepancy in genotype predominance among HCC patients in Taiwan, China and Japan, particularly at a younger age, remain to be elucidated. One possibility is that the genotype B strains in Taiwan might be somewhat different from those in Japan and China.[35]

In Europe, Mayerat et al. found that most patients with genotype A have chronic hepatitis, whereas most patients with genotype D have acute hepatitis.[13] Recently, Thakur et al. showed that HBV genotype D is associated with a more severe liver disease and may predict the occurrence of HCC in young Indian patients.[15] In addition, Sanchez-Tapias et al. found that sustained biochemical and virologic remission including clearance of HBsAg were more frequent in Spanish patients with genotype A than those with genotype D or F.[14]

These lines of evidence have lent strong support to clinical and pathogenic differences between HBV genotype B and C in Asians. Nevertheless, additional large longitudinal studies in Western populations are warranted to determine whether clinically significant differences between genotype A and D are apparent.


   Responses to antiviral therapy Top


Currently, no effective antiviral treatments can cure chronic HBV infection.[92],[100],[101],[102],[103],[104],[105],[106],[107],[108],[109],[110],[111],[112],[113] Five drugs have been approved for the treatment of chronic hepatitis B: standard interferon (IFN) a, lamivudine, adefovir dipivoxil, pegylated IFN-α 2a and entecavir.[100],[101],[102],[103],[104],[105],[106],[107],[108],[109],[110],[111],[112],[113] The influence of HBV genotype on current antiviral treatments is only partly clarified. Moreover, due to the unique distribution of HBV genotypes in Eastern and Western countries, the therapeutic implications of HBV genotype could only be compared between genotype B and C or genotype A and D. For further details please see reviews.[84],[85]

Standard IFN

We first showed that the response rate, defined as normalization of serum alanine aminotransferase (ALT) level, loss of HBeAg and HBV DNA 48 weeks post-treatment, was 41 and 15% in Taiwanese genotype B and C patients, respectively ( P =0.045).[17] In those with higher baseline serum ALT levels, the response rate was 50 and 17%, respectively ( P = 0.025). Younger age and genotype B infection could predict a better response to IFN-α. Our recent clinical trial consistently demonstrated that genotype B responded better to standard IFN therapy than genotype C.[92] A total of 119 patients received 5 MU of IFN α-2b daily for 4 weeks followed by 5 MU thrice weekly for 28 weeks. They were followed up for 24 weeks post-treatment. By intention-to-treat analysis, the rate of HBeAg sero conversion was 30 versus 18% between genotype B and C at the end of treatment ( P =0.14) and 44 versus 22% at the end of follow-up ( P =0.02). Wai et al. compared the response to IFN therapy between genotype B and C in Chinese patients.[18] They similarly found the response was better in patients with genotype B than genotype C [12/31 (39%) versus 7/42 (17%); P = 0.034]. These data suggest that HBV genotype C, compared with genotype B, is associated with a lower response rate to IFN-a therapy. A similar situation was observed between HBV genotype A and D patients.[31] Hou et al., studied the relationship between HBV genotypes and IFN treatment response in 103 HBeAg positive patients with chronic hepatitis B in Europe,[31] including 46 patients infected with genotype A and 35 patients infected with genotype D. Response to IFN-α occurred more often in genotype A than in genotype D (33 versus 11%; P = 0.03). Recently, Erhardt et al. reported that in 144 consecutive patients with chronic HBV genotype A or D infection, genotype is an important and independent predictor of IFN responsiveness.[114] Sustained response (six months after treatment) to standard IFN therapy was higher in HBV genotype A compared with HBV genotype D infected patients (49 versus 26%; P <0.005). HBeAg status had no negative impact on IFN response. Multivariate logistic regression identified HBV genotype A and high pretreatment ALT levels (>2 upper limit of normal) as independent positive predictive parameters of IFN response. Therefore, they suggested that HBV genotype adapted treatment regimens may further improve treatment efficacy in chronic hepatitis B.

Pegylated IFN α

Cooksley et al. firstly showed that the response rate of using pegylated IFN α-2a or standard IFN α-2a was higher in genotype B versus C (33 versus 21%; 25 versus 6%; respectively) in a phase 2 clinical trial.[112] In a subsequent phase 3 multi-center study, the overall response rate for pegylated IFN α-2b also differed according to HBV genotype (genotype A vs. B vs. C vs. D, 47% vs. 44% vs. 28% vs. 25%).[110] Furthermore, the rate of HBsAg was 7%. Subgroup analysis revealed that loss of HBsAg differed according to HBV genotype: genotype A vs. B vs. C vs. D, 14% vs. 9% vs. 3% vs. 2%.[98] Nevertheless, conflicting data were found in another large phase 3 clinical trial. Lau et al. demonstrated that there was no statistically significant difference in the treatment response (HBeAg seroconversion at end of 24-week post-treatment) to pegylated IFN a-2a among viral genotypes (genotype A vs. B vs. C vs. D, 52% vs. 30% vs. 31% vs. 22%).[111] However, consistently, a higher rate of treatment response in genotype A compared to the other three genotypes was also documented in a recent study in terms of HBsAg seroconversion, in both HBeAg-positive chronic hepatitis B (genotype A vs. B vs. C vs. D: 22% vs. 0% vs. 2% vs. 0%) and HBeAg-negative chronic hepatitis B (genotype A vs. B vs. C vs. D: 18% vs. 2% vs. 3% vs. 0%).[115] Taking these evidences together, the association between HBV genotypes with the response to pegylated IFN-based therapy remains controversial and awaits further studies.

Lamivudine

A lot of data are now available on whether HBV genotype affects the outcome of lamivudine therapy, the development of lamivudine-resistant tyrosine-methionine-aspartate-aspartate (YMDD) mutation and the occurrence of breakthrough hepatitis accompanying the emergence of drug-resistant YMDD mutants. [19],[20],[21],[22],[23],[26],[39],[50],[51],[58],[59],[116]

Treatment outcomes

Our previous data suggested that genotype B had a slightly better virologic response to lamivudine compared with C (23% vs. 11%, P =ns) (19). Two studies from Hong Kong indicated that HBV genotype had no impact on the response to lamivudine therapy.[26],[50] In Spain, Buti et al. suggested that the outcome after lamivudine treatment was comparable between genotype A and D.[58] These data imply that HBV genotype may have no substantial impact on the response to lamivudine treatment. However, Chien et al. reported that the sustained response rate to lamivudine was much higher in patients with genotype B than those with C [38/62 (61%) vs. 5/20 (20%), P =0.009]. Age < 36 years and an additional lamivudine treatment over 8 months correlated with a higher sustained response rate.[20]

Drug resistance

Zollner et al. initially described that HBV serotype adw (exclusively genotype A in Europe) is associated with a 20-fold risk of lamivudine resistance than ayw (mainly genotype D in Europe).[22],[23],[51] However, they later found that the risk of the emergence of YMDD mutation was only slightly higher in genotype A patients than that in genotype D and the difference was noted only during the first year of lamivudine treatment.[58] If therapy was extended to > 2 years, the proportion of YMDD mutation was not different between genotype A and D,[58] indicating that lamivudine resistance takes longer time to emerge in genotype D patients.[51],[58] Accordingly, HBV serotype does not correlate with the risk of lamivudine resistance. These findings were consistent with our data and others.[19],[21],[26],[59],[116]

Breakthrough hepatitis with lamivudine resistance

In a Japanese study, severe breakthrough hepatitis accompanying the emergence of YMDD mutants only occurred in four (2%) of the 185 patients with genotype C.[21] In a report from Hong Kong, the chances of YMDD mutations with virological and biochemical breakthroughs were similar in patients with genotypes B and C in 154 HBeAg-positive patients receiving long-term lamivudine therapy.[26]

Adefovir dipivoxil

Only one study has addressed the influence of genotype on the response to adefovir dipivoxil therapy.[24] Westland et al. analyzed the frequency and distribution of genotypes in patients from two multinational phase 3 studies of adefovir dipivoxil. They found that the reductions in serum HBV DNA level did not correlate with viral genotype; similarly, there was no statistical difference in HBeAg seroconversion rates among patients with different genotypes.

Entecavir

One recent study evaluated the association between HBV genotype and the response to entecavir therapy.[117] Again, the reduction of serum HBV DNA level and histologic improvement did not differ among HBV genotypes in both HBeAg-positive and negative patients.

In brief summary, HBV genotype correlates well with the response to standard IFN, but not nucleoside/nucleotide-based therapy [Table - 3],[Table - 4]. The association between HBV genotype and response to pegylated IFN remains controversial. Alternatively, future genotype-based stratification trial should be considered to clarify the impact of HBV genotype. Finally, further studies should focus on the contribution of viral factors other than genotype to the treatment outcome of antiviral agents.[32],[59],[116]


   Conclusions Top


Differences exist in the clinical and virologic characteristics among different HBV genotypes. Therefore, determining HBV genotype in patients with chronic HBV infection would help gain information for etiologic, clinical and virologic investigations. From the therapeutic point of view, if responses to a given antiviral agent can be predicted based on HBV genotypes, therapy can then be individualized to spare the cost and adverse effects of ineffective treatment. Finally, the molecular and virologic mechanisms accounting for the clinical phenotypes of HBV genotypes need further examinations.


   Acknowledgments Top


This study was supported by grants from the National Health Research Institute; Department of Health and the National Science Council, Executive Yuan, Taiwan.

 
   References Top

1.Kao JH, Chen DS. Global control of hepatitis B virus. Lancet Infect Dis 2002;2:395-403.  Back to cited text no. 1    
2.Chen DS. From hepatitis to hepatoma: Lessons from type B viral hepatitis. Science 1993;262:369-70.  Back to cited text no. 2    
3.Lee WM. Hepatitis B virus infection. N Engl J Med 1997;337:1733-45.  Back to cited text no. 3    
4.Hepatitis B. Fact sheet WHO/204. Revised October 2000.  Back to cited text no. 4    
5.Kao JH, Chen PJ, Lai MY, Chen DS. Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B. Gastroenterology 2000;118:554-9.  Back to cited text no. 5    
6.Orito E, Mizokami M, Sakugawa H, Michitaka K, Ishikawa K, Ichida T, et al . A case-control study for clinical and molecular biological differences between hepatitis B viruses of genotypes B and C. Hepatology 2001;33:218-23.  Back to cited text no. 6    
7.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;122:1756-62.  Back to cited text no. 7    
8.Nakayoshi T, Maeshiro T, Nakasone H, Nakasone H, Sakugawa H, Kinjo F, et al . 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;70:350-4.  Back to cited text no. 8    
9.Tsubota A, Arase Y, Ren F, Tanaka H, Ikeda K, Kumada H. Genotype may correlate with liver carcinogenesis and tumor characteristics in cirrhotic patients infected with hepatitis B virus subtype adw. J Med Virol 2001;65:257-65.  Back to cited text no. 9    
10.Fujie H, Moriya K, Shintani Y, Yotsuyanagi H, Iino S, Koike K. Hepatitis B virus genotypes and hepatocellular carcinoma in Japan. Gastroenterology 2001;120:1564-5.  Back to cited text no. 10    
11.Lee CM, Chen CH, Lu SN, Tung HD, Chou WJ, Wang JH, et al . Prevalence and clinical implications of hepatitis B virus genotypes in southern Taiwan. Scand J Gastroenterol 2003;38:95-101.  Back to cited text no. 11    
12.Duong TN, Horiike N, Michitaka K, Yan C, Mizokami M, Tanaka Y, et al . Comparison of genotypes C and D of the hepatitis B virus in Japan: A clinical and molecular biological study. J Med Virol 2004;72:551-7.  Back to cited text no. 12    
13.Mayerat C, Mantegani A, Frei PC. Does hepatitis B virus (HBV) genotype influence the clinical outcome of HBV infection? J Viral Hepat 1999;6:299-304.  Back to cited text no. 13    
14.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;123:1848-56.  Back to cited text no. 14    
15.Thakur V, Guptan RC, Kazim SN, Malhotra V, Sarin SK. Profile, spectrum and significance of HBV genotypes in chronic liver disease patients in the Indian subcontinent. J Gastroenterol Hepatol 2002;17:165-70.  Back to cited text no. 15    
16.Kobayashi M, Arase Y, Ikeda K, Tsubota A, Suzuki Y, Saitoh S. Viral genotypes and response to interferon in patients with acute prolonged hepatitis B virus infection of adulthood in Japan. J Med Virol 2002;68:522-8.  Back to cited text no. 16    
17.Kao JH, Wu NH, Chen PJ, Lai MY, Chen DS. Hepatitis B genotypes and the response to interferon therapy. J Hepatol 2000;33:998-1002.  Back to cited text no. 17    
18.Wai CT, Chu CJ, Hussain M, Lok AS. HBV genotype B is associated with better response to interferon therapy in HBeAg(+) chronic hepatitis than genotype C. Hepatology 2002;36:1425-30.  Back to cited text no. 18    
19.Kao JH, Liu CJ, Chen DS. Hepatitis B viral genotypes and lamivudine resistance. J Hepatol 2002;36:303-4.  Back to cited text no. 19    
20.Chien RN, Yeh CT, Tsai SL, Chu CM, Liaw YF. Determinants for sustained HBeAg response to lamivudine therapy. Hepatology 2003;38:1267-73.  Back to cited text no. 20    
21.Akuta N, Suzuki F, Kobayashi M, Tsubota A, Suzuki Y, Hosaka T, et al . The influence of hepatitis B virus genotype on the development of lamivudine resistance during long-term treatment. J Hepatol 2003;38:315-21.  Back to cited text no. 21    
22.Zollner B, Petersen J, Schroter M, Laufs R, Schoder V, Feucht HH. 20-fold increase in risk of lamivudine resistance in hepatitis B virus subtype adw. Lancet 2001;357:934-5.  Back to cited text no. 22    
23.Zollner B, Petersen J, Puchhammer-Stockl E, Kletzmayr J, Sterneck M, Fischer L, et al . Viral features of lamivudine resistant hepatitis B genotypes A and D. Hepatology 2004;39:42-50.  Back to cited text no. 23    
24.Westland C, Delaney W 4th, Yang H, Chen SS, Marcellin P, Hadziyannis S, et al . Hepatitis B virus genotypes and virologic response in 694 patients in phase III studies of adefovir dipivoxil. Gastroenterology 2003;125:107-16.  Back to cited text no. 24    
25.Sumi H, Yokosuka O, Seki N, Arai M, Imazeki F, Kurihara T, et al . Influence of hepatitis B virus genotypes on the progression of chronic type B liver disease. Hepatology 2003;37:19-26.  Back to cited text no. 25    
26.Yuen MF, Wong DK, Sablon E, Yuan HJ, Sum SM, Hui CK, et al . Hepatitis B virus genotypes B and C do not affect the antiviral response to lamivudine. Antivir Ther 2003;8:531-4.  Back to cited text no. 26    
27.Orito E, Ichida T, Sakugawa H, Michitaka K, Ishikawa K, Ichida T, et al . Geographic distribution of hepatitis B virus (HBV) genotype in patients with chronic HBV infection in Japan. Hepatology 2001;34:590-4.  Back to cited text no. 27    
28.Ishikawa K, Koyama T, Masuda T. Prevalence of HBV genotypes in asymptomatic carrier residents and their clinical characteristics during long-term follow-up: The relevance to changes in the HBeAg/anti-Hbe system. Hepatol Res 2002;24:1-7.  Back to cited text no. 28    
29.Kao JH, Chen PJ, Lai MY, Chen DS. Genotypes and clinical phenotypes of hepatitis B virus in patients with chronic hepatitis B virus infection. J Clin Microbiol 2002;40:1207-9.  Back to cited text no. 29    
30.Kao JH. Hepatitis B viral genotypes: Clinical relevance and molecular characteristics. J Gastroenterol Hepatol 2002;17:643-50.  Back to cited text no. 30    
31.Hou J, Schilling R, Janssen HL. Molecular characteristics of hepatitis B virus genotype A confer a higher response to interferon treatment. J Hepatol 2001;34:15.  Back to cited text no. 31    
32.Yu MW, Yeh SH, Chen PJ, Liaw YF, Lin CL, Liu CJ, et al . Genotype and DNA levels of hepatitis B virus and the risk of hepatocellular carcinoma. J Natl Cancer Inst 2005;97:265-72.  Back to cited text no. 32    
33.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;179:775-82.  Back to cited text no. 33    
34.Ding X, Mizokami M, Yao G, Xu B, Orito E, Ueda R, et al . Hepatitis B virus genotype distribution among chronic hepatitis B virus carriers in Shanghai, China. Intervirology 2001;44:43-7.  Back to cited text no. 34    
35.Kao JH, Chen DS. Hepatitis B virus genotypes and hepatocellular carcinoma in Japan: Reply. Gastroenterology 2001;120:1564-5.  Back to cited text no. 35    
36.Kao JH. Clinical relevance of hepatitis B viral genotypes: A case of dιją vu? J Gastroenterol Hepatol 2002;17:113-5.  Back to cited text no. 36    
37.Kao JH, Chen DS. Clinical relevance of hepatitis B virus genotypes Ba and Bj in Taiwan. Gastroenterology 2003;125:1916-8.  Back to cited text no. 37    
38.Magnius LO, Norder H. Subtypes, genotypes and molecular epidemiology of the hepatitis B virus as reflected by sequence variability of the S-gene. Intervirology 1995;38:24-34.  Back to cited text no. 38    
39.Liu CJ, Huang WL, Chen PJ, Lai MY, Kao JH, Chen DS. End-of-treatment virologic response does not predict relapse after lamivudine treatment for chronic hepatitis B. World J Gastroenterol 2004;10:3574-8.  Back to cited text no. 39    
40.Chu CJ, Keeffe EB, Han SH, Perrillo RP, Min AD, Soldevila-Pico C, et al . Hepatitis B virus genotypes in the United States: Results of a nationwide study. Gastroenterology 2003;125:444-51.  Back to cited text no. 40    
41.Akuta N, Kumada H. Influence of hepatitis B virus genotypes on the response to antiviral therapies. J Antimicrob Chemother 2005;55:139-42.  Back to cited text no. 41    
42.Furusyo N, Kubo N, Nakashima H, Kashiwagi K, Hayashi J. Relationship of genotype rather than race to hepatitis B virus pathogenicity: A study of Japanese and Solomon Islanders. Am J Trop Med Hyg 2004;70:571-5.  Back to cited text no. 42    
43.Tanaka Y, Hasegawa I, Kato T, Orito E, Hirashima N, Acharya SK, et al . A case-control study for differences among hepatitis B virus infections of genotypes A (subtypes Aa and Ae) and D. Hepatology 2004;40:747-55.  Back to cited text no. 43    
44.Devarbhavi HC, Cohen AJ, Patel R, Wiesner RH, Dickson RC, Ishitani MB. Preliminary results: Outcome of liver transplantation for hepatitis B virus varies by hepatitis B virus genotype. Liver Transpl 2002;8:550-5.  Back to cited text no. 44    
45.Kew MC, Kramvis A, Yu MC, Arakawa K, Hodkinson J. Increased hepatocarcinogenic potential of hepatitis B virus genotype A in Bantu-speaking sub-saharan Africans. J Med Virol 2005;75:513-21.  Back to cited text no. 45    
46.Ni YH, Chang MH, Wang KJ, Hsu HY, Chen HL, Kao JH, et al . Clinical relevance of hepatitis B virus genotype in children with chronic infection and hepatocellular carcinoma. Gastroenterology 2004;127:1733-8.  Back to cited text no. 46    
47.Yuen MF, Wong DK, Sablon E, Tse E, Ng IO, Yuan HJ, et al . HBsAg seroclearance in chronic hepatitis B in the Chinese: Virological, histological and clinical aspects. Hepatology 2004;39:1694-701.  Back to cited text no. 47    
48.Yuen MF, Tanaka Y, Mizokami M, Yuen JC, Wong DK, Yuan HJ, et al . Role of hepatitis B virus genotypes Ba and C, core promoter and precore mutations on hepatocellular carcinoma: A case control study. Carcinogenesis 2004;25:1593-8.  Back to cited text no. 48    
49.Chan HL, Hui AY, Wong ML, Tse AM, Hung LC, Wong VW, et al . Genotype C hepatitis B virus infection is associated with an increased risk of hepatocellular carcinoma. Gut 2004;53:1494-8.  Back to cited text no. 49    
50.Chan HL, Wong ML, Hui AY, Chim AM, Tse AM, Hung LC, et al . Hepatitis B virus genotype has no impact on hepatitis B e antigen seroconversion after lamivudine treatment. World J Gastroenterol 2003;9:2695-7.  Back to cited text no. 50    
51.Zollner B, Petersen J, Schafer P, Schroter M, Laufs R, Sterneck M, et al . Subtype-dependent response of hepatitis B virus during the early phase of lamivudine treatment. Clin Infect Dis 2002;34:1273-7.  Back to cited text no. 51    
52.Kao JH, Chen PJ, Lai MY, Chen DS. Clinical and virological aspects of blood donors infected with hepatitis B virus genotypes B and C. J Clin Microbiol 2002;40:22-5.  Back to cited text no. 52    
53.Lin CL, Liao LY, Liu CJ, Chen PJ, Lai MY, Kao JH, et al . Hepatitis B genotypes and precore/basal core promoter mutants in HBeAg-negative chronic hepatitis B. J Gastroenterol 2002;37:283-7.  Back to cited text no. 53    
54.Kao JH, Chen PJ, Lai MY, Chen DS. Basal core promoter mutations of hepatitis B virus increase the risk of hepatocellular carcinoma in hepatitis B carriers. Gastroenterology 2003;124:327-34.  Back to cited text no. 54    
55.Kao JH, Chen PJ, Lai MY, Chen DS. Hepatitis B virus genotypes and spontaneous hepatitis B e antigen seroconversion in Taiwanese hepatitis B carriers. J Med Virol 2004;72:363-9.  Back to cited text no. 55    
56.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;72:545-50.  Back to cited text no. 56    
57.Chen JD, Liu CJ, Lee PH, Chen PJ, Lai MY, Kao JH, et al . Hepatitis B genotypes correlate with tumor recurrence after curative resection of hepatocellular carcinoma. Clin Gastroenterol Hepatol 2004;2:64-71.  Back to cited text no. 57    
58.Buti M, Cotrina M, Valdes A, Jardi R, Rodriguez-Frias F, Esteban R. Is hepatitis B virus subtype testing useful in predicting virological response and resistance to lamivudine? J Hepatol 2002;36:445-6.  Back to cited text no. 58    
59.Kuwahara R, Kumashiro R, Murashima S, Ogata K, Tanaka K, Hisamochi A, et al . Genetic heterogeneity of the precore and the core promoter region of genotype C hepatitis B virus during lamivudine therapy. J Med Virol 2004;72:26-34.  Back to cited text no. 59    
60.Kao JH, Chen DS. HBV genotypes and outcome of HBV infection. Hepatology 2005;41:216.  Back to cited text no. 60    
61.Chen BF, Chen PJ, Jow GM, Sablon E, Liu CJ, Chen DS, et al . High prevalence of mixed genotype infections in hepatitis B virus infected intravenous drug users. J Med Virol 2004;74:536-42.  Back to cited text no. 61    
62.Chen BF, Kao JH, Liu CJ, Chen DS, Chen PJ. Genotypic dominance and novel recombinations in HBV genotype B and C co-infected intravenous drug users. J Med Virol 2004;73:13-22.  Back to cited text no. 62    
63.Okamoto H, Imai M, Kametani M, Nakamura T, Mayumi M. Genomic heterogeneity of hepatitis B virus in a 54 year old woman who contracted the infection through materno-fetal transmission. Jpn J Exp Med 1987;57:231-6.  Back to cited text no. 63    
64.Orito E, Mizokami M, Ina Y, Moriyama EN, Kameshima N, Yamamoto M, et al . Host-independent evolution and a genetic classification of the hepadnavirus family based on nucleotide sequences. Proc Natl Acad Sci USA 1989;86:7059-62.  Back to cited text no. 64    
65.Okamoto H, Tsuda F, Sakugawa H, Sastrosoewignjo RI, Imai M, Miyakawa Y, et al . Typing hepatitis B virus by homology in nucleotide sequence: Comparison of surface antigen subtypes. J Gen Virol 1988;69:2575-83.  Back to cited text no. 65    
66.Norder H, Courouce AM, Magnius LO. Complete genomes, phylogenetic relatedness and structural proteins of six strains of the hepatitis B virus, four of which represent two new genotypes. Virology 1994;198:489-503.  Back to cited text no. 66    
67.Arauz-Ruiz P, Norder H, Robertson BH, Magnius LO. Genotype H: A new Amerindian genotype of hepatitis B virus revealed in Central America. J Gen Virol 2002;83:2059-73.  Back to cited text no. 67    
68.Bartholomeusz A, Schaefer S. Hepatitis B virus genotypes: comparison of genotyping methods. Rev Med Virol 2004;14:3-16.  Back to cited text no. 68    
69.Miyakawa Y, Mizokami M. Classifying hepatitis B virus genotypes. Intervirology 2003;46:329-38.  Back to cited text no. 69    
70.Stuyver L, De Gendt S, Van Geyt C, Zoulim F, Fried M, Schinazi RF, et al . A new genotype of hepatitis B virus: Complete genome and phylogenetic relatedness. J Gen Virol 2000;81:67-74.  Back to cited text no. 70    
71.Campos RH, Mbayed VA, Pineiro Y, Leone FG. Molecular epidemiology of hepatitis B virus in latin America. J Clin Virol 2005;34:S8-13.  Back to cited text no. 71    
72.Bahri O, Cheikh I, Hajji N, Djebbi A, Maamouri N, Sadraoui A, et al . Hepatitis B genotypes, precore and core promoter mutants circulating in Tunisia. J Med Virol 2006;78:353-7.  Back to cited text no. 72    
73.Amini-Bavil-Olyaee S, Alavian SM, Adeli A, Sarrami-Forooshani R, Sabahi F, et al . Hepatitis B virus genotyping, core promoter and precore/core mutations among Afghan patients infected with hepatitis B: A preliminary report. J Med Virol 2006;78:358-64.  Back to cited text no. 73    
74.Sugauchi F, Orito E, Ichida T, Kato H, Sakugawa H, Kakumu S, et al . Hepatitis B virus of genotype B with or without recombination with genotype C over the precore region plus the core gene. J Virol 2002;76:5985-92.  Back to cited text no. 74    
75.Sugauchi F, Mizokami M, Orito E, Ohno T, Kato H, Suzuki S, et al . A novel variant genotype C of hepatitis B virus identified in isolates from Australian Aborigines: Complete genome sequence and phylogenetic relatedness. J Gen Virol 2001;82:883-92.  Back to cited text no. 75    
76.Kramvis A, Weitzmann L, Owiredu WK, Kew MC. Analysis of the complete genome of subgroup A' hepatitis B virus isolates from South Africa. J Gen Virol 2002;83:835-9.  Back to cited text no. 76    
77.Sugauchi F, Orito E, Ichida T, Kato H, Sakugawa H, Kakumu S, et al . Epidemiologic and virologic characteristics of hepatitis B virus genotype B having the recombination with genotype C. Gastroenterology 2003;124:925-32.  Back to cited text no. 77    
78.Norder H, Arauz-Ruiz P, Blitz L, Pujol FH, Echevarria JM, Magnius LO. The T (1858) variant predisposing to the precore stop mutation correlates with one of two major genotype F hepatitis B virus clades. J Gen Virol 2003;84:2083-7.  Back to cited text no. 78    
79.Norder H, Courouce AM, Coursaget P, Echevarria JM, Lee SD, Mushahwar IK, et al . Genetic diversity of hepatitis B virus strains derived worldwide: Genotypes, subgenotypes and HBsAg subtypes. Intervirology 2004;47:289-309.  Back to cited text no. 79    
80.Nagasaki F, Niitsuma H, Cervantes JG, Chiba M, Hong S, Ojima T, et al . Analysis of the entire nucleotide sequence of hepatitis B virus genotype B in the Philippines reveals a new subgenotype of genotype B. J Gen Virol 2006;87:1175-80.  Back to cited text no. 80    
81.Kato H, Fujiwara K, Gish RG, Sakugawa H, Yoshizawa H, Sugauchi F, et al . Classifying genotype F of hepatitis B virus into F1 and F2 subtypes. World J Gastroenterol 2005;11:6295-304.  Back to cited text no. 81    
82.Chan HL, Tsui SK, Tse CH, Ng EY, Au TC, Yuen L, et al . Epidemiological and virological characteristics of 2 subgroups of hepatitis B virus genotype C. J Infect Dis 2005;191:2022-32.  Back to cited text no. 82    
83.Liu CJ, Kao JH. Subgenotypes of hepatitis B virus genotype C in Taiwan. J Infect Dis 2005;192:1308-9.  Back to cited text no. 83    
84.Liu CJ, Kao JH, Chen DS. Therapeutic implications of hepatitis B virus genotypes. Liver Int 2005;25:1097-107.  Back to cited text no. 84    
85.Kao JH, Chen DS. HBV genotypes: Epidemiology and implications regarding natural history. Curr Hepatitis Rep 2006;5:5-13.  Back to cited text no. 85    
86.Perrillo RP. Acute flares in chronic hepatitis B: The natural and unnatural history of an immunologically mediated liver disease. Gastroenterology 2001;120:1009-22.  Back to cited text no. 86    
87.Gunther S, Fischer L, Pult I, Sterneck M, Will H. Naturally occurring variants of hepatitis B virus. Adv Virus Res 1999;52:25-37.  Back to cited text no. 87    
88.Hunt CM, McGill JM, Allen MI, Condreay LD. Clinical relevance of hepatitis B viral mutations. Hepatology 2000;31:1037-44.  Back to cited text no. 88    
89.Lin HH, Wu WY, Kao JH, Chen DS. Hepatitis B post-partum e antigen clearance in hepatitis B carrier mothers: Correlation with viral characteristics. J Gastroenterol Hepatol 2006;21:605-9.  Back to cited text no. 89    
90.Chen BF, Liu CJ, Jow GM, Chen PJ, Kao JH, Chen DS. High prevalence and mapping of pre-S deletion in hepatitis B virus carriers with progressive liver diseases. Gastroenterology 2006;130:1153-68.  Back to cited text no. 90    
91.Liu CJ, Chen BF, Chen PJ, Lai MY, Huang WL, Kao JH, et al . Role of hepatitis B viral load and basal core promoter mutation in hepatocellular carcinoma in hepatitis B carriers. J Infect Dis 2006;193:1258-65.  Back to cited text no. 91    
92.Liu CJ, Lai MY, Chao YC, Liao LY, Yang SS, Hsiao TJ, et al . Interferon alpha-2b with and without ribavirin in the treatment of hepatitis B e antigen-positive chronic hepatitis B: A randomized study. Hepatology 2006;43:742-9.  Back to cited text no. 92    
93.Chen BF, Liu CJ, Jow GM, Chen PJ, Kao JH, Chen DS. Evolution of Hepatitis B virus in an acute hepatitis B patient co-infected with genotypes B and C. J Gen Virol 2006;87:39-49.  Back to cited text no. 93    
94.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;41:1576-81.  Back to cited text no. 94    
95.Liu CJ, Kao JH. Subgenotypes of hepatitis B virus genotype C in Taiwan. J Infect Dis 2005;192:1308-9.  Back to cited text no. 95    
96.Lin CL, Liao LY, Wang CS, Chen PJ, Lai MY, Chen DS, et al . Basal core-promoter mutant of hepatitis B virus and progression of liver disease in hepatitis B e antigen-negative chronic hepatitis B. Liver Int 2005;25:564-70.  Back to cited text no. 96    
97.Liu CJ, Chen BF, Chen PJ, Lai MY, Huang WL, Kao JH, et al . Role of hepatitis B virus precore/core promoter mutations and serum viral load on noncirrhotic hepatocellular carcinoma: A case-control study. J Infect Dis 2006;194:594-9.  Back to cited text no. 97    
98.Flink HJ, van Zonneveld M, Hansen BE, de Man RA, Schalm SW, Janssen HL. Treatment with peg-interferon alfa-2b for HBeAg-positive chronic hepatitis B: HBsAg loss is associated with HBV genotype. Am J Gastroenterol 2006;101:297-303.  Back to cited text no. 98    
99.Yang HI, Chen PJ, Yeh SH, Jen CL, You SL, Chen DS, et al . Risk of hepatocellular carcinoma associated with genotypes and mutants of hepatitis B virus: A community-based prospective cohort study. J Hepatol 2006;44:27A.  Back to cited text no. 99    
100.Liaw YF, Leung N, Guan R, Lau GK, Merican I; Asian-Pacific Consensus Working Parties on Hepatitis B. Asian-Pacific consensus statement on the management of chronic hepatitis B: An update. J Gastroenterol Hepatol 2003;18:239-45.  Back to cited text no. 100    
101.Lok AS, McMahon BJ; Practice Guidelines Committee, American Association for the Study of Liver Diseases (AASLD). Chronic hepatitis B: update of recommendations. Hepatology 2004;39:857-61.  Back to cited text no. 101    
102.de Franchis R, Hadengue A, Lau G, Lavanchy D, Lok A, McIntyre N, et al . EASL International Consensus Conference on Hepatitis B. 13-14 September, 2002 Geneva, Switzerland. Consensus statement (long version). J Hepatol 2003;39:S3-25.  Back to cited text no. 102    
103.Dooley JS, Davis GL, Peters M, Waggoner JG, Goodman Z, Hoofnagle JH. Pilot study of recombinant human alpha-interferon for chronic type B hepatitis. Gastroenterology 1986;90:150-7.  Back to cited text no. 103    
104.Hoofnagle JH, Peters M, Mullen KD, Jones DB, Rustgi V, Di Bisceglie A, et al . Randomized, controlled trial of recombinant human alpha-interferon in patients with chronic hepatitis B. Gastroenterology 1988;95:1318-25.  Back to cited text no. 104    
105.Wong DK, Cheung AM, O'Rourke K, Naylor CD, Detsky AS, Heathcote J. Effect of alpha-interferon treatment in patients with hepatitis B e antigen-positive chronic hepatitis B. A meta-analysis. Ann Intern Med 1993;119:312-23.  Back to cited text no. 105    
106.Shaw T, Locarnini S. Entecavir for the treatment of chronic hepatitis B. Expert Rev Anti Infect Ther 2004;2:853-71.  Back to cited text no. 106    
107.Lai CL, Ching CK, Tung AK, Li E, Young J, Hill A, et al . Lamivudine is effective in suppressing hepatitis B virus DNA in Chinese hepatitis B surface antigen carriers: A placebo-controlled trial. Hepatology 1997;25:241-4.  Back to cited text no. 107    
108.Dienstag JL, Schiff ER, Wright TL, Perrillo RP, Hann HW, Goodman Z, et al . Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med 1999;341:1256-63.  Back to cited text no. 108    
109.Liaw YF, Leung NW, Chang TT, Guan R, Tai DI, Ng KY, et al . Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B. Gastroenterology 2000;119:172-80.  Back to cited text no. 109    
110.Janssen HL, van Zonneveld M, Senturk H, Zeuzem S, Akarca US, Cakaloglu Y, et al . Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: A randomized trial. Lancet 2005;365:123-9.  Back to cited text no. 110    
111.Cooksley G, Manns M, Lau GK, Liaw YF, Marcellin P, Chow WC, et al . Effect of genotype and other baseline factors on response to peginterferon alfa-2a (40KD) (Pegasys) in HBeAg-positive chronic hepatitis B: Results from a large, randomized study. J Hepatol 2005;42:30.  Back to cited text no. 111    
112.Cooksley WG, Piratvisuth T, Lee SD, Mahachai V, Chao YC, Tanwandee T, et al . Peginterferon alpha-2a (40 kDa): An advance in the treatment of hepatitis B e antigen-positive chronic hepatitis B. J Viral Hepat 2003;10:298-305.  Back to cited text no. 112    
113.Liaw YF, Leung N, Guan R, Lau GK, Merican I, McCaughan G, et al . Asian-Pacific consensus statement on the management of chronic hepatitis B: A 2005 update. Liver Int 2005;25:472-89.  Back to cited text no. 113    
114.Erhardt A, Blondin D, Hauck K, Sagir A, Kohnle T, Heintges T, et al . Response to interferon alfa is hepatitis B virus genotype dependent: Genotype A is more sensitive to interferon than genotype D. Gut 2005;54:1009-13.  Back to cited text no. 114    
115.Hadziyannis S, Lau GK, Marcellin P, Piratvisuth T, Cooksley G, Bonino F, et al . Sustained HBsAg seroconversion in patients with chronic hepatitis B treated with peginterferon alfa-2a (40KD) (Pegasys). J Hepatol 2005;42:178.  Back to cited text no. 115    
116.Suzuki F, Tsubota A, Arase Y, Suzuki Y, Akuta N, Hosaka T, et al . Efficacy of lamivudine therapy and factors associated with emergence of resistance in chronic hepatitis B virus infection in Japan. Intervirology 2003;46:182-9.  Back to cited text no. 116    
117.Lurie Y, Manns MP, Gish RG, Chang TT, Yurdaydin C, Lai CL, et al . The efficacy of entecavir is similar regardless of disease-related baseline subgroups in treatment of nucleoside-naive, HBeAg(+) and HBeAg(-) patients wth chronic hepatitis B. J Hepatol 2005;42:184.  Back to cited text no. 117    

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Correspondence Address:
Jia-Horng Kao
Director, Hepatitis Research Center, National Taiwan University Hospital, 1 Chang-Te St., Taipei 100
Taiwan
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Source of Support: None, Conflict of Interest: None


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