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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 2019 Jul 18];3:54-75. Available from: http://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.

 
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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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