感染HBV病毒后各种基因类型的角色

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The Role of HBV Genotypes in the Outcome of
Hepatitis B Virus Infection


Introduction

HBV Genotypes, HBeAg Seroconversion and Outcome of
  Chronic HBV Infection

HBV Genotypes and Treatment Response

         - Interferon
         - Lamivudine or Adefovir Dipivoxil
         - Cofactors in Liver Injury
         - Summary




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Introduction

Until very recently there have been scant data concerning the question of whether HBV genotype correlates with clinical outcomes of chronic HBV infection and response to treatment.

In an editorial published in the current issue of Hepatology (October 2004), Scott Fung and Anna Lok discuss this issue in depth and provide their thoughtful conclusions. Following is a summary of the editorial.

Hepatitis B virus (HBV) has been classified into 8 genotypes (A-H) based on an intergroup divergence of 8% or more in the complete nucleotide sequence.
There is enough information to describe the geographic distribution of HBV genotypes, but existing information is incomplete, as data in many parts of the world are not available. Interestingly, the distribution of HBV genotypes appears to vary with time and with population migration, as demonstrated in a recent study in the United States. Furthermore, subtypes have now been identified within some genotypes.
Genotypes A and C predominate in the US. However, genotypes B and D are also present in the US. Genotype F predominates in South America and in Alaska, while A, D and E predominate in Africa. Genotype D predominates in Russia and in all its prior dominions, while in Asia, genotypes B and C predominate.

In the past 2 ?years, there has been an explosion of knowledge in the literature on the epidemiology of HBV genotypes, according to Drs. Lok and Fung, and on their association with hepatitis B e antigen (HBeAg) seroconversion, activity of liver disease, and treatment response.

HBV Genotypes, HBeAg Seroconversion and Outcome of Chronic HBV Infection
Most of the information on the clinical significance of HBV genotypes has been based on studies of patients with chronic HBV infection in Asia. Because of the preponderance of genotypes B and C in Asian countries, the studies are restricted to comparisons of patients with these two genotypes.

Nevertheless, such comparisons provide very important information on the relation between HBV genotype B and C and the rate of progression of liver disease, since the age at the onset of infection is presumed to be the same (perinatal period) in the vast majority of patients.

These studies clearly showed that compared to genotype C, HBV genotype B is associated with spontaneous HBeAg seroconversion at a younger age, less active liver disease, and a slower rate of progression to cirrhosis.

Most studies, including those outside of Japan, reported that hepatocellular carcinoma (HCC) development is less frequent and occurs at an older age in patients with genotype B.

These data indicate that a shorter duration of high levels of HBV replication and less active necroinflammation may contribute to a more favorable outcome among patients with genotype B.

One study from Spain reported that HBeAg seroconversion rates were similar in patients with genotypes A and D, but sustained biochemical and virological remission was more common in patients with genotype A who had HBeAg seroconversion. Patients with genotype A also had a higher rate of HBsAg clearance.

To date there has been no published study comparing the rate of HBeAg seroconversion, activity of liver disease, and rate of progression to cirrhosis and HCC among patients with all known HBV genotypes.

The lack of such studies is related to the preponderance of 1 or 2 HBV genotypes in most geographical regions. The finding of HBV genotypes A to G in the United States permits studies that compare the clinical course of HBV infection among patients with a wider spectrum of HBV genotypes.

In one cross-sectional study of 694 patients in the United States, genotypes B and D were associated with a lower prevalence of HBeAg than genotype A, while genotype B was associated with a lower rate of hepatic decompensation compared to genotype A, C, or D.

However, other factors such as differences in ethnic/racial background, age at onset and duration of infection, and exposures to alcohol/environmental toxins rather than HBV genotypes may have contributed to the differences in clinical manifestations.

HBV Genotypes and Treatment Response

Interferon

HBV genotype has been reported to correlate with response to [standard] interferon treatment in several studies. Two studies from Asia found that patients with HBV genotype B had a higher rate of HBeAg seroconversion compared to those with genotype C.

One study from Germany reported that patients with genotype A had a higher rate of HBeAg seroconversion than those with genotype D. Although all 3 studies involved small numbers of patients, these findings were confirmed by a recent study of pegylated interferon (IFN), where HBeAg seroconversion occurred more often in patients with genotypes A (47%) and B (44%) than in those with genotypes C (28%) and D (25%).


Lamivudine or Adefovir Dipivoxil

Unlike IFN, a correlation between HBV genotype and response to lamivudine or adefovir dipivoxil therapy has not been demonstrated. Several studies in Asia, all involving small numbers of patients and varying duration of lamivudine treatment, showed that HBeAg seroconversion and breakthrough infection occurred in similar proportions of patients with genotypes B and C.

However, two studies, one in HBeAg-positive and one in HBeAg-negative patients found that patients with genotype B were more likely to sustain their response when treatment was discontinued.

Retrospective analysis of phase III clinical trials of adefovir dipivoxil found that all HBV genotypes resulted in a similar decrease in serum HBV DNA levels, but a correlation with HBeAg seroconversion could not be determined because of the small number of patients with HBeAg seroconversion.

There is very little information on the correlation between HBV genotypes and the outcome of acute [primary] HBV infection.


Cofactors in Liver Injury

The finding of more frequent and heavier exposure to alcohol, acetaminophen, and injected methamphetamine or cocaine prior to hospitalization and hepatitis C coinfection in all case patients suggests that cofactors that cause liver injury may be more important than viral factors in the fulminant course in the current study.

Similar observation was reported by the U.S. Acute Liver Failure Study Group. Among the patients with hepatitis A or B, those who had measurable acetaminophen levels had more pronounced aminotransferase elevations, suggesting that acetaminophen enhances hepatocellular injury in the setting of acute viral hepatitis.


Summary

In summary, there is increasing evidence that HBV genotype correlates with clinical outcomes of chronic HBV infection and response to treatment.

The evidence for a clinical difference is stronger between genotypes B and C, and in response to IFN but not nucleoside [NRTIs] or nucleotide [NtRTIs] treatment.

The exact reason(s) why HBV genotype may be related to clinical outcomes is not clear. It is possible that different genotypes may be associated with differences in replication fitness and expression of immune epitopes.

There is also a clear association between HBV genotypes and precore and core promoter mutations.

While the story of HBV genotypes continues to unfold at a rapid pace, genotyping should remain a research tool until the time when knowledge of the HBV genotype can be used to predict the risk of adverse outcomes (fulminant hepatitis, cirrhosis, or HCC) or to guide treatment decisions (choice or duration of therapy).

09/27/04

Reference
S K Fung and A S F Lok. Hepatitis B virus genotypes: Do they play a role in the outcome of HBV infection? Hepatology 40(4): 790-792. October 2004.