Liver infections

Hepatitis B and D

genotype has been shown to influence outcome; DRB1:1302 is

more often associated with viral clearance than other genotypes.
The severity of the hepatitis in both transient and persistent infections is variable depending on the nature of the host response.
Acute HBV infection the incubation period is 36 months. In
the week before icterus appears, some patients develop a serum
sickness-like syndrome including arthralgia, fever and urticaria.
The clinical picture varies from asymptomatic anicteric infection
to protracted icterus and, in some patients (<1%), liver failure
(fulminant hepatitis). The severity of the hepatitis increases with
age. The acute infection is self-limiting and does not need antiviral therapy. Most patients recover within 12 months after
the onset of icterus. Patients who are symptomatic may require
bed-rest but this probably does not accelerate recovery. Sexual
contacts should be offered hyperimmune globulin and then
immunized with the vaccine.
Chronic HBV infection (Table 1) chronic hepatitis B is
defined as viraemia and hepatic inflammation continuing for
more than 6 months following HBV infection. Most patients
acquire the infection at birth or after a subclinical infection as an
adult, so are unaware that they have been infected by the virus.

Howard C Thomas

Abstract
Chronic hepatitis B affects 400 million people worldwide and up to 30%
will die either of decompensated cirrhosis or hepatocellular carcinoma.
During the HBe antigen positive and negative viraemic phases, when viral
levels are > 105 IU/ml, the patient may develop progressive hepatitis and
fibrosis. In these phases, when patients have chronic hepatitis with some
degree of hepatic fibrosis, a trial of up to 12 months pegylated interferon
is indicated. In those not undergoing sustained HBV DNA suppression
maintained after cessation of this therapy, long term treatment with nucleoside analogues is indicated until HBV DNA is no longer detectable by
sensitive polymerase chain reaction (PCR) assays and liver function tests
return to normal. Some patients with high pre-treatment levels of viraemia
or failure to achieve negative HBV DNA levels on monotherapy, may need
combination antiviral therapy. Patients with cirrhosis should not have a
trial of interferon but should start on nucleoside therapy. Patients with
chronic hepatitis B are at risk of developing hepatocellular carcinoma and
older patients should be screened at 6 monthly intervals by ultrasound.

Histology
The histological appearance may range from almost complete
normality to various inflammatory states (previously classified as
chronic active hepatitis, chronic persistent hepatitis and chronic
lobular hepatitis) and cirrhosis, which may or may not show
associated necro-inflammatory activity. These terms have been
superseded by the grading of necro-inflammatory activity (out of
18) and staging of fibrosis (out of 6).1
Liver biopsy reveals the severity of the disease, but the histological appearances are not specific for hepatitis B (except when viral
markers are detected in the tissues, using specific techniques).
When a biopsy is performed within 6 months of an episode of
acute hepatitis, chronic hepatitis cannot be distinguished histologically from resolving acute disease.

Keywords anti-viral therapy; hepatitis B e antigen; hepatitis B virus;

Hepatitis D virus; viraemia

Hepatitis B virus (HBV) infection is parenterally transmitted; it

occurs in babies born to HBV-infected mothers, after transfusion
of blood and blood products, intravenous drug use or sexual
contact. Hepatitis D virus (HDV) infection occurs only in HBV
infected individuals.
The outcome of HBV infection depends on age and on genetic
factors determining the efficiency of the host immune response.
Almost 100% of children infected at birth, but only 210% of
those infected in adult life, develop persistent infection. Persistence of infection following acquisition of the virus in adulthood is
most common in men and in patients with immuno-deficiencies.
In Africans and Europeans, the major histocompatibility class II

Course of chronic disease

Chronic HBV infection generally passes through a series of stages,
both virologically and clinically.

Clinical and immunological features favouring

persistent hepatitis B virus infection
Neonatal exposure
In adults male gender, hypogammaglobulinaemia and cellmediated immune deficiencies

Howard C Thomas BSc PhD FRCP FRCPath FMedSci is Professor of Medicine

and Head of Department of Hepatology and Gastroenterology at
Imperial College, London, UK and General Physician and Hepatologist
at the Liver and Anti-viral Centre, St Marys Hospital, London. His
research interests include the pathogenesis and treatment of virus
induced chronic liver disease and hepatocellular carcinoma. He is also
Chairman of the Department of Health advisory group on Hepatitis
and edits the journal Viral Hepatitis. Competing interests: has given
advice to GSK, Gilead, BMS, Roche and Schering on the design and
analysis of clinical trials evaluating medications used in the treatment
of hepatitis B.

MEDICINE 35:1

Possible pathogenic mechanisms

Production of subnormal quantities of interferon- by
peripheral blood cells
Poor hepatocyte activation by interferon
Failure of antibody production
Failure to develop HBV-specific cytotoxic T cells
Table 1

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2006 Published by Elsevier Ltd.

Liver infections

Virological classification
HBe-positive virus infection is the form most commonly
encountered in Northern Europe and North America where
genotypes A and B are most common. The virus replicates and
encodes infected liver cells to synthesize and secrete hepatitis
Be antigen (HBeAg). As a result, HBeAg can be detected in the
serum. Later, viral DNA can become integrated into the cellular
DNA. At this stage, production of hepatitis Bs antigen (HBsAg)
can occur without viral replication.
HBe-negative virus infection has recently been recognized
and is common with genotypes C and D. This is a variant form of
HBV which can lead to productive viral infection without secretion of HBeAg. HBe-negative virus is also known as the pre-core
mutant, reflecting the mutation identified in the viral genome
(Figure 1). This form of the virus can emerge late in the course of
infection in individuals initially infected with HBe-positive virus
or can occur ab initio (particularly in patients from Mediterranean countries and the Far East).
HDV infection HDV is an RNA virus which encodes a
nucleocapsid antigen (HDAg) but no envelope. The virus replicates in patients with acute or chronic HBV infection, using the
HBV envelope (HBsAg).

Simultaneous HBV and HDV infection (co-infection) leads

to acute self-limiting infection in 9095% of patients. When
chronic infection occurs, the course of hepatitis is often more
severe.
HDV infection can supervene in established chronic HBV infection (superinfection) and usually results in reduced HBV replication and an increase in the severity of the hepatitis.
Stages of infection: in patients infected with HBe-positive virus,
up to four stages of chronic infection (each of which may last for
many years) may be described (Figure 2).
First stage (immune tolerance phase) initially (particularly
in those infected in utero or at birth) there may be high levels of
viraemia without biochemical or histological evidence of hepatitis. During this phase, therapy with interferon or nucleoside
analogues is not indicated because therapy rarely induces HBe
antigen clearance.
Second stage (immune clearance phase) viraemia and
HBe antigenaemia continue and there is increasing inflammatory necrosis of hepatocytes. HBV DNA is detectable at levels
between 103 and 109 genomes per ml. As this phase continues,
the inflammatory process (hepatitis) may become sufficiently
intense to permit lysis of infected hepatocytes, clearance of
HBeAg and the development of anti-HBe. If the inflammation
is sufficiently intense and prolonged, patients may develop
cirrhosis. The phenomenon of loss of HBeAg and conversion
to anti-HBe positivity is referred to as HBe antigen/antibody
seroconversion. When this occurs, there is a reduction of
inflammation accompanied by histological change from active
to inactive chronic hepatitis, or active cirrhosis to inactive cirrhosis in patients in whom seroconversion has been prolonged.
The spontaneous seroconversion rate is 510% per year,
though this varies between populations: HBe antigen clearance
is commonest in genotypes A and B. Treatment during this
phase with interferon and then, in those that do not undergo
HBe antigen/antibody seroconversion, maintenance viral suppressive therapy with nucleoside analogues, is indicated (see
below).
Third stage (immune control or latent phase) follows
seroconversion. Patients continue to produce HBsAg because
of integrated sequences of viral DNA within host cell DNA but
HBV replication is controlled by the cellular immune response at
levels <103 genomes per ml. The liver may show mild persistent
hepatitis, normal histology or cirrhosis which is inactive, and the
blood biochemistry may be normal. Despite the lack of HBeAg
and HBV-DNA being present at only very low levels by the polymerase chain reaction, the patients body fluids should still be
considered infectious.
Fourth stage (HBe negative viraemia/hepatitis phase)
further viraemia and hepatitis in the absence of HBe antigenaemia
may follow, reflecting emergence of the HBe-negative (pre-core
or core promoter mutant) strain of the virus. During this stage,
transaminases become elevated and HBV DNA is detectable by
PCR at concentrations of >103 genomes per ml, but HBeAg is
not present in the serum. Continuing hepatitis in this phase may
lead to cirrhosis. Treatment during this phase with interferon and
then, in those who do not show sustained control of viraemia and
resolution of hepatitis, maintenance viral suppressive therapy
with nucleoside analogues, is indicated (see later).

HBe-negative (pre-core variant) virus

Hepatitis B pre-core mutant virus is found most commonly in
patients from Mediterranean countries and the Far East.
It causes an anti-HBe-positive HBV DNA-positive form of chronic
hepatitis. The virus has a novel translation stop codon in the
pre-core gene, and should not be confused with other
Mediterranean envelope mutants that cause clinical disease,
despite apparent adequate vaccination, because of changes in
the surface gene. The pre-core gene product is unnecessary for
the formation of viral particles, but essential for the production of
HBeAg. In certain hosts, this variant and the HB core promoter
variant may result in fulminant hepatitis.
Novel stop codon in the pre-core gene leading to the
pre-core mutant virus
HBeAg
HBcAg
AUG
1814
5

AUG
1901
Precore

UAG
2450
Core
3

1896
UGG
UAG
AUG initiation codon, at which translation of protein starts
UGG a codon at position 28 of the pre-core reading frame,
encoding tryptophan in wild-type virus
UAG a substitution of the nucleotide adenine for guanine at
codon 28 in the mutant virus, producing a termination codon in
the pre-core mutant
Figure 1

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Liver infections

Stages of infection in patients infected with HBe-positive virus

Viraemia

Phase 1
Immune tolerance

Phase 2
Immune clearance

HBeAg-positive viraemia
(HBV DNA-positive;
>105 IU/ml)
Alanine
aminotransferase

Phase 3
Immune control
or latent

Phase 4
Emergence of HBe-negative
variant

(HBV DNA < 105 IU/ml)

HBeAg-negative viraemia
(HBV DNA-positive;
>105 IU/ml)

50

Time (years)
Liver histology

Chronic hepatitis

Chronic lobular/
hepatitis

Minimal hepatitis

Cirrhosis

Inactive
cirrhosis

Chronic hepatitis
Active
cirrhosis

Hepatocellular
carcinoma

Figure 2

Prognosis, in terms of the potential to develop cirrhosis and

hepatocellular carcinoma, is greatest in those with the highest
viraemia levels.

acterial peritonitis, and a tendency towards hepatic decompenb

sation with encephalopathy and death.
Hepatocellular carcinoma is common in regions with a high
prevalence of hepatitis B infection. The risk of hepatocellular
carcinoma in an HBsAg-positive male in the Far East is almost
300 times greater than that in HBsAg-negative controls. In 80%
of patients, there is a background of cirrhosis with chronic HBs
antigenaemia. The risk in chronic HBsAg carrier with normal
liver histology is very low.

Clinical features
The clinical picture in individuals with chronic HBV infection
varies widely, and the histological picture cannot always be
predicted from the symptoms. Patients with chronic hepatitis
are often asymptomatic, though they may suffer from malaise,
and well-compensated cirrhosis can be asymptomatic. Compared with patients with autoimmune liver disease, patients with
chronic HBV-induced hepatitis are less likely to have florid liver
disease, particularly at the stage of active inflammation; they also
have lower globulin levels.

Management
Antiviral therapy is indicated in patients with progressive liver
disease (histological evidence of active inflammation and evidence of developing fibrosis). This requires liver biopsy. These
patients are usually in the second or forth stages of the disease
with levels of viraemia >105 genomes per ml. Biochemical blood
tests (ALT elevation) will identify those with significant necroinflammatory activity but only liver biopsy will allow assessment
of hepatic fibrosis. Tests reflecting collagen synthesis such as
pro-collagen peptides reflect only part of the story in that they
do not reflect collagen breakdown. Imaging tests (ultrasound
or MRI) are measures of cumulative collagen deposition but are
insensitive.
Patients with continuing viral replication with serum HBVDNA concentrations greater than 105 genomes per ml and liver
biopsy evidence of fibrosis should be offered treatment.
There are currently two approaches to the management of
HBV infection.

Presenting features
Incidental presentation patients are most commonly asymptomatic and are recognized following blood donation, or blood or
other routine medical screening.
Following symptomatic HBV infection symptoms include
general malaise, fatigue, arthralgia and right hypochondrial discomfort. At later stages, patients may present with hepatic decompensation or during acute flares of hepatitis. After an episode of
acute HBV infection, patients should be followed up until HBsAg
disappears, anti-HBs appears and liver function tests become normal. If this does not occur within 6 months, the patient is chronically infected with HBV and specialist referral is required.
Negative IgM antibody to hepatitis B core antigen (HBcAg)
at presentation suggests a patient is not in an episode of acute
hepatitis, but already has chronic HBV infection.

Circumscribed therapy
This involves relatively short-term therapy with either interferons or nucleoside analogues, allowing recovery of the immune
response to an extent which then allows control of the infection in the absence of further antiviral drug administration.

Complications
Cirrhosis the complications of cirrhosis include portal
hypertension with variceal bleeding, ascites with spontaneous

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Liver infections

The immunostimulant properties of the interferons may offer

advantage over the nucleoside analogues, in this respect.

able to control re-emergence of HBV. This is the case in 60

70% of patients with HBe antigen positive disease and 80% of
HBe antigen negative viraemic subjects. In these patients, long
term suppression of HBV replication with either nucleoside or
nucleotideanalogues will be necessary until the infected cells
containing cccDNA have been eliminated. The half-life of these
cells may be 10 or more years and therefore therapy must be protracted.3 In such circumstances suppression of HBV levels to very
low levels is essential to stop or reduce the chance of emergence
of drug resistant variants and regenerating hepatocytes should
be protected from infection. In this approach it seems likely that
combination therapy will be necessary. Pegylated interferons are
not the preferred choice because they are parenterally administered and have more side effects than the nucleoside/nucleotide
analogues.

HBe antigen positive infection: recovery of the immune response

is marked by HBe antigen/antibody seroconversion and occurs
in up to a third of patients (33% in a recent metaanalysis by Lok
and McMahon)2 with active inflammatory liver disease when
treated with standard alpha interferon for 612 months usually
at dosages of 5 megaunits daily or 910 megaunits three times
a week. The results with pegylated alpha 2a and 2b when given
for 12 months are slightly (but not significantly) better (3637%)
than standard interferon (33%) and statistically better than lamivudine (18%), adefovir (12%) and entecavir (21%) at one year.
The current pricing of pegylated interferon and its convenience
of administration (once a week) has meant that most physicians
are using it rather than standard interferon. The patients undergoing HBe antigen/antibody conversion usually become inactive
(HBV-DNA <105 with a normal ALT and minimal hepatitis) usually need no further therapy. The 6070% who do not undergo
seroconversion need long term viral suppressive therapy with,
ideally, orally administered drugs of low toxicity and with low
rates of emergence of drug resistant virus. No ideal drug currently exists. The best approach usually entails treatment with
nucleoside or nucleotide analogues, such as lamivudine, adefovir
and entecavir. Because of cost, most physicians will use lamivudine first and then add adefovir if lamivudine-resistant virus
emerges, which is the case in over 80% of cases after 4 years
therapy. The resistance rate with entecavir is much lower and it
would be the drug of first choice for maintenance viral suppression were it not for the fact that it costs several times as much as
lamivudine. Entecavir is currently the most potent and the lower
rate of emergence of resistance variants will make it the drug of
choice assuming that it is affordable. Entecavir resistance can be
treated with adefovir should it occur. Results with telbivudine
and tenofovir are awaited.

Treatment of HBV cirrhosis and hepatocellular cancer

by liver transplantation
This has achieved significant success, particularly when HBV
replication is controlled with lamivudine before transplantation
and hyperimmune globulin and lamivudine are continued indefinitely afterwards. Only patients with early-stage hepatocellular
carcinoma (one or two lesions <23 cm in diameter) are offered
transplantation; in these, 5-year survival is 5070%. Interferons
are contraindicated in decompensated cirrhosis and after liver
transplantation.

Current service provision

Service is provided in the developing national system of Managed Clinical Networks in Hepatology, which have been recommended as part of the Action Plan for Hepatitis C.

References
1 Ishak K G, Baptista A, Bianchi L et al. Histological grading and
staging of chronic hepatitis. J Hepatol 1995; 22: 6969.
2 Lok A S, McMahon B J. Practice Guidelines Committee, American
Association for the Study of Liver Diseases (AASLD). Chronic hepatitis
B: update of recommendations. Hepatology 2004; 39: 85761.
3 Nowak M A, Bonhoeffer S, Hill A M, Boehme R, Thomas H C, McDadeH.
Viral dynamics in hepatitis B virus infection. Proc Natl Acad Sci USA
1996; 93: 4398402.

HBe antigen negative infection: long term control of the infection after a limited period of antiviral therapy with pegylated
interferon may occur in around 18% of cases. In the vast majority of cases this does not occur and long term viral suppressive
therapy with orally administered drugs of low toxicity and with
low rates of emergence of drug resistant virus is then the preferred approach. This usually entails treatment with nucleoside
or nucleotide analogues, such as lamivudine or entecavir, with
adefovir being added if resistance occurs. Once again because
of cost most physicians will use lamivudine first and then add
adefovir only if lamivudine-resistant virus emerges. This occurs
less frequently than in HBe antigen positive infection probably
because of the lower levels of viraemia initially. Entecavir is more
potent than either lamivudine or adefovir and is probably the
drug of choice for maintenance therapy. We are currently awaiting cost effectiveness analyses and longer term evaluation of the
rates of development of drug resistance: after two years of treatment in nucleoside naive patients, drug resistance has not been
seen. Again, results with telbivudine and tenofovir are awaited.

Further reading
Berenguer M, Wright T L. Viral hepatitis. In: Thomas, Lemon,
Zuckerman, eds. Liver transplantation in the management of
chronic viral hepatitis. Oxford: Blackwell Publishing, 2005.
Carman W F, Jacyna M R, Hadziyannis S et al. Mutation preventing
formation of hepatitis B e antigen in patients with chronic hepatitis
B infection. Lancet 1989; 2: 58891.
Chu C M, Karayiannis P, Fowler M J, Monjardino J, Liaw Y F, Thomas H C.
Natural history of chronic hepatitis B virus infection in Taiwan: studies
of hepatitis B virus DNA in serum. Hepatology 1985; 5: 4314.
Fung S K, Lok A S. Hepatitis B virus genotypes: do they play a role in
the outcome of HBV infection? Hepatology 2004; 40: 7902.
Marcellin P, Asselah T, Boyer N. Treatment of chronic hepatitis B. J Viral
Hepat 2005; 12: 33345.

Long term viral suppressive therapy

The second approach recognizes that, in some patients, the
immune system is unable to recover to the extent of then being

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