The Clinical Significance of (HBV) Genotypes

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The Clinical Significance of Hepatitis B Virus (HBV) Genotypes

Hepatitis B virus (HBV) has traditionally been classified into four subtypes or serotypes: adr, adw, ayr, and ayw. There is scant data on the clinical significance of the HBV serotypes. HBV has been classified into 7 genotypes, A-G.


In HCV infection, genotyping is commonly used in clinical evaluation. In contrast, researchers are only just starting to look at HBV genotyping as a clinical management tool. Following are excerpts from an editorial published in Hepatology that looks at the potential role of HCV genotyping in the management of chronic hepatitis B.

Clinical Significance of Hepatitis B Virus Genotypes

By Chi-Jen Chu, MD, and Anna S.F. Lok, MD

Contrary to hepatitis C virus genotyping, HBV genotyping is a research tool that is only beginning to gain popularity among researchers in hepatitis B. Whether HBV genotyping will constitute part of the clinical evaluation of hepatitis B patients depends on the availability of simple and inexpensive tests and the relevance of the information gained.

Currently, restriction fragment length polymorphism is the most commonly used method for HBV genotyping. A line probe assay similar to that used for hepatitis C virus genotyping is also available. These assays can be easily applied in clinical diagnostic laboratories. The key issue is, does knowledge of the HBV genotype help in patient management?

The specific questions include, (1) Is there a correlation between HBV genotype and HBV replication, activity of liver disease, clinical outcome, and treatment response? (2) What is the predominant HBV genotype in each country? Is the geographical distribution of HBV genotypes related to the endemicity of HBV infection? (3) Is there a correlation between HBV genotype and risk of progression to chronic infection? (4) Does infection with one HBV genotype confer protection against infection with other HBV genotypes?

Answers to some of the questions raised are beginning to emerge but many of the answers are based on a few studies in selected patient populations. Current information on the geographical distribution of HBV genotypes is summarized in Table 1.

Table 1. Geographic Distribution of HBV Genotypes and Serotypes

Genotypes
Serotypes
Distribution

A
adw2, ayw1
NW Europe, N America, Central Africa

B
adw2, ayw1
SE Asia, China, Japan

C
ayr, adrq+, adrq? adw2
SE Asia, China, Japan

D
ayw2, ayw3
S Europe, Middle East, India

E
ayw4
Africa

F
adw4q?/span>
American natives, Polynesia, Central and South America

G
adw2
United States, France



However, existing information is incomplete. As an example, earlier studies suggested that HBV genotype A is predominant in the United States. A recent study indicated that HBV genotype G is also prevalent because it was present in 11 of 82 patients from the state of Georgia. 燞owever, in an ongoing study involving 17 liver centers across the United States, we found all 7 HBV genotypes: A (33%), B (21%), C (34%), D (9%), E (1%), F (1%), and G (1%) (personal observations).

HBV genotype A was more common among whites and African Americans, whereas genotypes B and C were predominantly found in Asian Americans.

The high prevalence of HBV genotypes B and C among Asians raise the possibility that HBV genotype may be related to the endemicity of HBV infection. To date, there has been no study on the relationship between HBV genotype and mode of transmission. One study in Switzerland found that genotype A was more common among patients with chronic hepatitis B, whereas genotype D was more prevalent among patients with resolving acute hepatitis B suggesting that HBV genotype A was associated with a higher rate of chronic HBV infection. 燞owever, this study involved a total of 65 patients only and confounding factors such as age at infection, gender, mode of transmission, and coinfection with other hepatitis virus or human immunodeficiency virus were not analyzed.

HBV genotypes may contribute to the wide range in prevalence of HBV infection in different parts of the world through differences in rates of replication and abilities to evade immune clearance, but studies comparing the replication capacity and immune response of the various HBV genotypes have not been performed. However, many studies have shown a strong relationship between HBV genotypes and mutations in the precore and core promoter regions that abolish or diminish the production of hepatitis B e antigen (HBeAg) 燭hus, the most common precore mutation, a G to A substitution at nucleotide 1896 (G1896A), which creates a premature stop codon (eW28X) is found in association with HBV genotypes B, C, and D but not genotype A.

This accounts for the preponderance of HBeAg-negative chronic hepatitis B in Southern Europe and Asia.

In the last issue of HEPATOLOGY, Kato et al. explored the mechanism by which HBV genotype G, which has 2 stop codons in the precore region, maintains HBeAg production. 燭hey found that all 4 patients with HBV genotype G, who were HBeAg positive, were also coinfected with HBV genotype A. In one patient who seroconverted from HBeAg to hepatitis B e antibody, a shift from predominant HBV genotype A to predominant HBV genotype G was shown.

Based on partial sequencing of a few clones, the investigators suggested that there is evidence of recombination between the two genotypes, but more studies are needed to confirm these findings. It would also be important to determine if patients infected with one HBV genotype can be superinfected with other genotypes and if infection with multiple HBV genotypes results in more severe liver disease.

Several studies reported a correlation between HBV genotype and HBeAg clearance. These studies, all of Asian patients, found that the prevalence of HBeAg was higher in patients with genotype C compared to those with genotype B suggesting that HBeAg clearance occurred at higher rates among patients with genotype B. 燨ne study of 466 Japanese patients found that HBeAg was present in 53% of genotype C versus 16% of genotype B patients.

This difference was maintained after matching for gender, age, and liver disease in the two groups. In a recent study of 269 Chinese patients, we found that spontaneous HBeAg seroconversion occurred approximately one decade earlier among patients with HBV genotype B. 燱e also showed that patients with genotype B were more likely to have a sustained biochemical remission after spontaneous HBeAg seroconversion.

A correlation between HBV genotype and liver disease has also been found in several studies from Asia. One study in Japan found that liver dysfunction (defined as abnormal aminotransferase levels) was observed less frequently in hepatitis B carriers with adw serotype (mainly genotype B) compared to those with adr serotype (mainly genotype C).

Another study found that hepatitis B surface antigen carriers with genotype B had lower histologic activity scores. 燭wo other studies involving a total of 490 Chinese patients with chronic HBV infection found that genotype C was more prevalent in patients with cirrhosis.

It is possible that a longer duration of high levels of HBV replication may contribute to more active liver disease and, in turn, a higher rate of progression to cirrhosis among patients with HBV genotype C. The relationship between HBV genotypes and hepatocellular carcinoma is inconclusive.

One study found that HBV genotype B is associated with development of hepatocellular carcinoma at an earlier age, 燽ut this finding was not confirmed by other studies. 燭he relationship between HBV genotypes and liver disease in other ethnic populations has not been examined.

HBV genotype has also been related to response to interferon therapy. The correlation between HBV genotype and response to other antiviral therapy (such as lamivudine) remains to be determined. One study based on 26 patients reported that patients with adw serotype were more likely to develop resistance to lamivudine than those with ayw serotype but the correlation between serotype and response was not mentioned.

In summary, there is growing evidence that HBV genotypes may influence HBeAg seroconversion rates, mutational patterns in the precore and core promoter regions, and the severity of liver disease. In addition, different HBV genotypes predominate in various parts of the world. Thus, the heterogeneity in disease manifestations and response to antiviral treatment among patients with chronic hepatitis B in different parts of the world may, at least in part, be attributed to differences in HBV genotypes.

Further studies are needed to confirm these observations to determine if HBV genotyping should be included in the clinical evaluation of patients with chronic HBV infection and if treatment should be tailored accordingly.

References

02/10/03

References
- CJ Chu and A Lok. Clinical Significance of Hepatitis B Virus Genotypes (Editorial). Hepatology 35:5. May 2002.
- H Kato and others. Hepatitis B e antigen in sera from individuals infected with hepatitis B virus of genotype G. Hepatology 2002;35:922-929.