The Role of HBV Genotypes in the Outcome...

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

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 ½ 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.

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