Clinical significance of hepatitis B virus genotypes

Traditionally, hepatitis B virus (HBV) is classified into 4 subtypes or serotypes (adr, adw, ayr, and ayw) based on antigenic determinants of the hepatitis B surface antigen.1 These subtypes can be further classified into 9 serotypes (ayw1, ayw2, ayw3, ayw4, ayr, adw2, adw4, adrq , and adrq ).2 Epidemiologic studies found that the prevalence of these serotypes varies in different parts of the world. In addition, antibody to the common determinant, “a,” confers protection against all serotypes. To date, there has been very little data on the clinical significance of HBV serotypes. Advances in molecular biology techniques revealed significant diversities in sequences of HBV isolates, accounting for the allelic differences among the 4 major HBV serotypes. Based on an intergroup divergence of 8% or more in the complete nucleotide sequence, HBV can be classified into 7 genotypes A-G.3-5 However, genotyping can be accomplished based on a partial sequence of the HBV genome such as the pre-S or S gene. Several methods have been used for HBV genotyping including direct sequencing, restriction fragment length polymorphism, line probe assay, and enzyme-linked immunoassay. 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. 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.5 However, 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.6 However, 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 Abbreviations: HBV, hepatitis B virus; HBeAg, hepatitis B e antigen. From the Division of Gastroenterology, University of Michigan Medical Center, Ann Arbor, MI. Received January 23, 2002; accepted February 21, 2002. Address reprint requests to: Anna S. F. Lok, M.D., Division of Gastroenterology, University of Michigan Medical Center, 3912 Taubman Center, Box 0362, Ann Arbor, MI 48109. E-mail: aslok@umich.edu; fax: 734-936-7392. Copyright © 2002 by the American Association for the Study of Liver Diseases. 0270-9139/02/3505-0032$35.00/0 doi:10.1053/jhep.2002.33161