Hepatitis B

Review
by
Brent Whitworth, MD
Hepatitis B Virus
Hepatitis B virus (HBV) infection is a global public health
problem.

It is estimated that there are more than 350 million HBV
carriers in the world, of whom 1 million will die annually from
HBV-related liver disease.

Some references have placed the number of affected persons
as much as 5% of the total world population.

In the United States, there are an estimated 1.25 million
hepatitis B carriers, defined as persons positive for hepatitis B
surface antigen (HBsAg) for more than 6 months.

Hepatitis B Virus


The spectrum of clinical manifestations of HBV infection varies
in both acute and chronic disease.

During the acute phase, manifestations range from subclinical
hepatitis to fulminant hepatitis.

During the chronic phase, manifestations range from an
asymptomatic carrier state to cirrhosis, and hepatocellular
carcinoma.


Hepatitis B Virus
Hepatitis B virus belongs to the family of hepadnaviruses,
which include duck hepatitis virus, woodchuck hepatitis virus,
and ground squirrel hepatitis virus.

The genome of HBV is a relaxed circular, partially double
stranded DNA of approximately 3200 base pairs in length.

The complete virion or Dane particle is 42 nm in diameter.

HBV has traditionally been classified into seven genotypes (A
to G) the clinical significance of which is yet to be determined.

Integration of HBV DNA into the host genome is not necessary
for viral RNA synthesis, and HBV transcripts are synthesized
entirely from episomal DNA.

Hepatitis B Virus
In addition to intact virions, serum and HBV-infected
hepatocytes contain subviral particles, which are produced in
great excess.

These 20-nm spheres and long filamentous proteins.

These subviral particles are not infectious because they
contain no viral DNA but are stongly immunogenic and
stimulate the production of antibodies.

This property was exploited in the development of the first
HBV vaccines.

The function of these subviral particles in the life cycle of the
virus is unknown.

Panel A shows HBV
virions (Dane
particles) and
filaments.


Panel B shows 20-nm
HBsAg particles

Epidemiology
In the Far East, the Middle East, Africa, and parts of South
America, the prevalence of HBV is high, with HBsAg positivity
rates ranging from 8% to 15%.

Perinatal transmission is most common in high prevalence
areas such as southeast Asia and China.

It is well established that the risk of persistent infection is
much greater in infants than in adults.

Sexual contact and percutaneous transmission (eg,
intravenous drug use) are most common in the United States,
Canada, and western Europe.


Epidemiology

In the United States, the estimated incidence of acute HBV
infection has been falling from a peak in 1985 of 70 cases per
10,000 population to 40 cases per 100,000 in 1991 likely as a
result of safer sexual practices.

The only region in the United States of high prevalence is
Alaska, where the prevalence rate in the native population is
6.4%.

HBV infection is more common in men than in women, with
the peak prevalence in men occurring between the ages of 10
and 29.


Epidemiology
Sexual activity is probably the single most important mode of
HBV transmission in areas of the world like the US.

Heterosexual sex now accounts for the majority of cases of
HBV infection (26%) in the US.

Sexual partners of persons infected with HBV are at risk for
infection, even in the absence of high-risk behavior.

The risk of heterosexual transmission is greater when the
infected person is female.

Because many patients with chronic HBV infection are
unaware of their infection, sexual contact is likely to be an
important mode of transmission worldwide.

The use of condoms appears to reduce the risk of sexual
transmission.

Epidemiology
Children of HBsAg-positive mothers who are not infected at
birth remain at high risk of early childhood infection; 60%
become infected by the age of 5 years.

The mechanism of this later infection, which is neither
perinatal nor sexual, is unknown.

Even with active and passive immunization, 5% to 10% of
babies may acquire HBV infection at birth.

In the United States and Western Europe, injection drug use
remains a very important mode of HBV transmission (23% of
all cases).


Pathogenisis
The pathogenisis of HBV-related liver disease is generally
thought to be related to cytotoxic T cell-mediated lysis of
infected hepatocytes.

Patients with chronic hepatitis B who clear HBeAg have more
vigorous CTL responses to HBV antigens than those who
remained HBeAg positive.

In one study HBV-specific cytotoxic T cells from patients
studied up to 23 years after clinical and serologic recovery
expressed activation markers indicating recent contact with
HBV antigens.

This observation suggests that complete eradication of HBV
rarely occurs after recovery from acute hepatitis and that
traces of virus can maintain the T cell response for decades
following clinical recovery, which in turn keeps the virus under
control.


Pathogenisis
Maximal reduction in HBV-DNA levels occurred prior to peak
increase in serum ALT levels, suggesting that viral control is
mediated through noncytolytic as well as cytolytic
mechanisms.

HBV is generally not a cytopathic virus, however direct
cytopathic liver injury can occur if the viral load is very high in
certain patients.

In most patients with chronic hepatitis B, for example, there is
no direct correlation between viral load and the severity of
liver disease.



Acute HBV Infection
In primary infection, HBsAg becomes detectable in the blood

after an incubation period of 4 to 10 weeks, followed shortly

by antibodies against the HBV core antigen.

A serum sickness-like syndrome may develop during the
prodromal period, followed by constitutional symptoms,
anorexia, nausea, jaundice and right upper quadrant
discomfort.

Viremia

is well established by the time HBsAg is detected, and
titers

of virus in acute infection are very high frequently

10
9

to 10
10
virions per milliliter.

When liver injury does occur in primary infection, ALT

levels
do not increase until after viral infection is well established,

reflecting the time required to generate the T-cellmediated

immune response that triggers liver injury.



Acute HBV Infection
Values up to 1000 to 2000 IU/L are typically seen during the
acute phase with ALT being higher than AST.

With clearance of the infection, the viral

antigens HBsAg and
HBeAg disappear from the circulation, and

free anti-HBs
antibodies become detectable.

In patients who recover, normalization of serum
aminotransferases usually occurs within one to four months.

Approximately 70 percent of patients with acute hepatitis B
have subclinical or anicteric hepatitis, while 30 percent
develop icteric hepatitis.




Acute HBV Infection

The disease may be more severe in patients coinfected with
other hepatitis viruses or with underlying liver disease.

Persistent elevation of serum ALT for more than six months
indicates progression to chronic hepatitis.

The rate of progression from acute to chronic hepatitis B is
primarily determined by the age at infection.



Fulminat Hepatitis

The most feared complication of acute HBV infection is
fulminant hepatic failure, defined as the onset of hepatic
encephalopathy within 8 weeks of the onset of symptoms.

The prognosis is poor once encephalopathy has developed.

Fulminant hepatic failure is unusual, occurring in
approximately 0.1 to 0.5 percent of patients.

Fulminant hepatitis B is believed to be due to massive
immune-mediated lysis of infected hepatocytes. This explains
why many patients with fulminant hepatitis B have no
evidence of HBV replication at presentation.

The reasons that HBV has a fulminant course in some patients
are not well-understood.



Chronic Hepatitis
Chronic HBV infection is usually defined as detectable
hepatitis B surface antigenemia for a period of six months or
more.


One feature of chronic HBV infection that is not widely
appreciated

is its dynamic natural history.

The natural course of chronic hepatitis B virus infection is
determined by the interplay between virus replication and the
host immune response.

The risk of chronic infection is related to two major factors:
the age at which infection is acquired and the immune state of
the host.

A history of acute hepatitis is elicited in only a small
percentage of patients with chronic HBV infection.


Chronic Hepatitis
The risk of developing chronic HBV infection after acute
exposure ranges from 90 percent in newborns of HBeAg-
positive mothers to 25 to 30 percent in infants and children
under 5 and less than 10 percent in adults.

Many patients with chronic hepatitis B are asymptomatic while
others have nonspecific symptoms such as fatigue.

People with subclinical persistent infection,

normal serum
aminotransferase levels, and normal or nearly normal

findings
on liver biopsy are termed asymptomatic chronic HBV

carriers.

Those with abnormal liver function and histologic

features are
classified as having chronic hepatitis B.

Chronic Hepatitis
Some patients experience exacerbations of the infection which
may be asymptomatic, mimic acute hepatitis, or manifest as
hepatic failure.

During exacerbations, the serum ALT concentration may be as
high as 50 times the upper limit of normal .

Most exacerbations are asymptomatic and are discovered
during routine follow-up.

Exacerbations are more commonly observed in men than
women.

In a small percentage of patients, exacerbations result in
hepatic decompensation and rarely death from hepatic failure.


Chronic Hepatitis
Chronic HBV infection generally consists of two phases: an
early replicative phase with active liver disease; and a late or
nonreplicative phase with remission of liver disease.

In patients with perinatally acquired HBV infection, there is an
additional immune tolerance phase in which virus replication
is not accompanied by active liver disease

In perinatally acquired HBV, the initial phase is characterized
by high levels of HBV replication but no evidence of active
liver disease as manifested by lack of symptoms, normal
serum ALT concentrations and minimal changes on liver
biopsy.

The exact mechanisms by which this occurs are unknown but
is thought to be from tranplacental transfer of HbeAg affecting
the responsiveness of T cells. This is referred to immune
tolerance.

Chronic Hepatitis HBeAg
High titers of HBV in the blood are often indicated

by the
continued presence of HBeAg.

With the passage of time, there is also

a tendency for HBeAg
to disappear from the blood, along with

seroconversion to
positivity for anti-HBe antibodies

a progression that occurs
at a rate of 5 to 10 percent per year

in persistently infected
people.

In light of the cross-immunoreactivity between HBcAg and
HBeAg, a possible function of HBeAg is to divert the immune
response of the host away from virally infected hepatocytes
that express HBcAg on their surfaces.

The absence of HBeAg production would be associated with a
vigorous and, for the virus, potentially lethal immune
response against the hepatocyte. This is not proven.




Chronic Hepatitis HBeAg
HBeAg-negative carriers are a heterogeneous group.

Most such

carriers have low levels of viral DNA, relatively
normal levels

of alanine aminotransferase, and a good
prognosis.

Patients in the low replicating phase are HBeAg negative and
anti-HBe positive.

In some patients, virus replication has ceased although they
remain HBsAg (hepatitis B surface antigen) positive.

These patients with HBeAg-negative chronic hepatitis may
have residual wild type virus or HBV variants that cannot
produce HBeAg due to precore or core promoter variants.



Chronic Hepatitis
The cumulative rate of spontaneous HBeAg clearance is
estimated to be approximately 2 percent during the first three
years and only 15 percent after 20 years of infection.

Some patients with chronic HBV infection become HBsAg
negative.

The annual rate of delayed clearance of HBsAg has been
estimated to be 0.5 to 2 percent in Western patients and
much lower (0.1 to 0.8 percent) in Asian countries.

In most reports, noncirrhotic patients who cleared HBsAg
appeared to have a good prognosis.

The ability of hepatitis B virus to cause complications despite
clearance of HBsAg probably results from its integration into
the genome.



Chronic Hepatitis
These patients may have low level HBV replication, but liver
disease is usually inactive.

The natural history of HBV persistence suggests

that there is
an ongoing immune attack on infected cells in

the liver an
attack that is usually inadequate to eradicate

infection
altogether, but that does reduce the number of infected

cells
and thereby lowers the circulating viral load.

Other factors that may play a role in the progression of HBV-
related liver disease include gender, alcohol consumption, and
concomitant infection with other hepatitis virus(es).

The outcome of chronic HBV infection depends upon the
severity of liver disease at the time HBV replication is
arrested.

Cirrhosis develops in about 20 percent of people

with chronic
hepatitis


Solid lines
indicate a
smooth
transition from
replicative to
nonreplicative
or minimally
replicative
infection and
remission of
liver disease.

Dotted lines
indicate flares
of hepatitis
associated with
abortive
immune
clearance or
reactivation of
HBV.

Hepatocellular Carcinoma
The majority of patients with HBV remain asymptomatic with
a very low risk of cirrhosis or HCC.

Risk factors for HCC in patients with chronic HBV infection
include male gender, family history of HCC, older age,
presenceof HBeAg in an adult, history of reversions from anti-
HBe to HBeAg, presence of cirrhosis, and coinfection with
hepatitis C virus.

It is important to note that, although HCC is more common in
persons with cirrhosis, 30 to 50 percent of HCC associated
with HBV occurs in the absence of cirrhosis.

The prognosis is not so good in HBV-infected patients from
endemic areas and in patients with chronic hepatitis B.


Hepatocellular Carcinoma
The estimated five-year rates of progression are:

Chronic hepatitis to cirrhosis 12 to 20 percent

Compensated cirrhosis to hepatic decompensation
20 to 23 percent

Compensated cirrhosis to HCC 6 to 15 percent


Among Chinese patients with chronic HBV infection, the life-
time risk of a liver-related death has been estimated at 40 to
50 percent for men and 15 percent for women.

Hepatitis B - Prognosis
Patients with a prolonged replication phase have a worse
prognosis mostly due to the development of cirrhosis and
hepatocellular carcinoma

Recurrent episodes of hepatitis may, either directly or indirectly
through immune-mediated injury, increase the risk of fibrosis,
cirrhosis, and perhaps carcinogenesis

Clearance of HBeAg was associated with a 2.2-fold decrease in
death rate.

Other independent factors associated with poor survival were
older age, hypoalbuminemia, thrombocytopenia, splenomegaly,
and hyperbilirubinemia.

Even among patients with decompensated cirrhosis, suppression
of HBV replication and delayed HBsAg clearance can result in
improvement in liver disease.


Hepatitis C and HBV
Acute coinfection with HBV and HCV may shorten the duration of
HBs antigenemia and lower the peak serum aminotransferase
concentration compared with acute HBV infection alone.

However, acute coinfection of HCV and HBV, or acute HCV on
preexisting chronic HBV have also been reported to increase the
risk of severe hepatitis and fulminant hepatic failure.

Coexistent HCV infection has been estimated to be present in 10
to 15 percent of patients with HBV-associated chronic hepatitis,
cirrhosis, or HCC.

Most patients who have dual HCV and HBV infections have
detectable serum HCV RNA but undetectable or low HBV DNA
levels, indicating that HCV is the predominant cause of liver
disease in these patients.

Nevertheless, the liver disease is usually more severe than in
patients infected by HBV alone and are at greater risk for HCC


Hepatitis D and HBV
Although HDV can replicate autonomously, the simultaneous
presence of HBV is required for complete virion assembly and
secretion.

Patients with hepatitis D are always dually infected with HDV and
HBV.

Acute HBV and HDV coinfection tends to be more severe than
acute HBV infection alone and is more likely to result in fulminant
hepatitis.

HBV/HDV coinfection most commonly occurs in the Mediterranean
area and parts of South America.

The availability of HBV vaccines and public health education on
prevention of transmission of HBV infection has led to a
significant decline in the prevalence of HDV infection in the past
decade.

Hepatitis D and HBV
Coinfection of HBV and HDV usually results in a more severe
acute hepatitis with a higher mortality rate than is seen with
acute hepatitis B alone, but rarely results in chronic infection.

HDV superinfection can manifest as a severe "acute" hepatitis in
previously asymptomatic HBV carriers or exacerbations of
underlying chronic hepatitis B.

Unlike coinfection, HDV superinfection in HBV carriers almost
always results in chronic infection with both viruses.

Although persons with chronic HBV/HDV infection can exhibit a
wide spectrum of liver pathology, a higher proportion develops
cirrhosis, hepatic decompensation, and HCC compared with those
with chronic HBV infection alone.

Extraheaptic Manifestations
The two major extrahepatic complications of chronic HBV are
polyarteritis nodosa and glomerular disease.

Extrahepatic manifestations, which are thought to be mediated
by circulating immune complexes, occur in 10 to 20 percent of
patients with chronic HBV infection.

HBV can induce both membranous nephropathy and, less often,
membranoproliferative glomerulonephritis.

Most cases of HBV-related glomerulonephropathy occur in
children.

Polyarteritis nodosa with a systemic vasculitis can occur with
either acute or chronic HBV infection.

This syndrome typically presents with abdominal pain resulting
from arteritis of the medium-sized arteries with ischemia to the
intestine or gallbladder.
Extraheaptic Manifestations



Other manifestations of HBV-associated vasculitis include
neuropathy, cutaneous vasculitis, arthritis, and Raynauds
phenomenon, membranoproliferative

Neurologic manifestations of HBV infection include Guillain-Barr
syndrome and a polyneuropathy (usually related to polyarteritis).

Rarely HBV is associated with pericarditis and pancreatitis.

Testing for HBV



The following groups should be tested for HBV infection by
testing for HbSAg and anti-HBs:

Persons born in hyperendemic area, men who have sex
with men, injecting drug users, dialysis patients, HIV-
infected individuals, pregnant women, and family
members, household members, and sexual contacts of
HBV-infected persons.


Testing for HBV
Testing should be performed for HBsAg and anti-HBs.

A positive result for antibody to hepatitis B core antigen does not
differentiate between recovered and chronic infection.

In addition, false-positive test results are not uncommon in
persons with isolated antibodies to hepatitis B core antigen.

The appropriate HBV DNA assay to use for initial evaluation of
patients with chronic HBV infection has not been determined.

An arbitrary value of >10(5) copies/mL was chosen as a
diagnostic criterion for chronic hepatitis B at a recent NIH
conference.

The problem is assays for HBV DNA are not well standardized,
HBV DNA levels fluctuate, and the theshold associated with
progressive disease is unkown.




Prevention of HBV
Three main strategies exist for the prevention of HBV infection: 1)
behavior modification to prevent disease transmission, 2) passive
immunoprophylaxis, and 3) active immunization.

Patients with chronic HBV infection should be counseled regarding
lifestyle modifications and prevention of transmission.

Carriers of HBV should be counseled as to the risk of transmission to
others.

Counseling should include precautions to prevent sexual
transmission, perinatal transmission, and risk of inadvertent
transmission via environmental contamination from a blood spill.

Household members are at increased risk of HBV infection and
therefore should be vaccinated if they test negative for HBV serologic
markers.

Carriers should be advised to cover open cuts and scratches and
clean up blood spills with bleach, because HBV can survive on
environmental surfaces for at least 1 week.




Prevention of HBV
Passive immunoprophylaxis is used in four situations:

1) neonates born to HBsAg-positive mothers;
2) after needlestick exposure
3) after sexual exposure
4) after liver transplantation in patients who are HBsAg positive
pretransplantation.

The mechanism by which hepatitis B immune globulin (HBIG)
prevents HBV infection is uncertain.

Effective vaccines have been available since the early to mid-
1980s.

In areas of the world with high endemism of HBV infection,
current recommendations are for universal vaccination.

HBV vaccine is highly effective. Anti-HBs develops in over 95% of
vaccine recipients



Treatment of HBV
The aims of treatment of chronic hepatitis B are to achieve sustained
suppression of HBV replication and remission of liver disease.

The end points used to assess treatment response include
normalization of serum ALT level, undetectable serum HBV DNA by
an unamplified assay, loss of HBeAg with or without detection of anti-
HBe, and improvement in liver histology.

In patients with HBeAg-positive chronic hepatitis, a response

to
treatment is usually defined by the reduction of serum HBV

DNA to
levels that cannot be detected with nonpolymerase-chain-reaction

assays and by the loss of HBeAg.


Inconsistencies in the definition of response, lack of standardization
of HBV DNA assays, and heterogeneity in patient populations make it
difficult to compare response rates in clinical trials of treatment of
chronic hepatitis B.

Currently, three therapeutic agents have been approved by the FDA
for the treatment of chronic hepatitis B.



Who should be treated?
There are clear indications for therapy in HBeAg-positive

patients.

They have an increased risk of early progression to

chronic active
hepatitis and cirrhosis, and they have a risk

of hepatocellular
carcinoma that is substantially higher than

that for other carriers.

By contrast, asymptomatic HBeAg-negative

chronic carriers with
viral loads below 10
5
genomes per milliliter

and normal alanine
aminotransferase values tend to have a relatively

stable course,
with low rates of clinical or pathological progression.

At present, therapy is usually not offered to such persons.


Some HBeAg-negative patients have liver dysfunction

and
substantial viremia (>10
5
molecules per milliliter)


A recent trial suggest

that many of these patients would also
benefit from effective

antiviral therapy.


Who should be treated?

True cure of infection (loss of HBsAg and complete disappearance

of viremia, as measured by stringent PCR assays) is achieved

only infrequently (in 1 to 5 percent of patients) with current

regimens.

In the case of patients with HBeAg-negative chronic

hepatitis,
there is no information about which markers best

measure the
response to therapy.

Quantitation of viremia by

PCR assays would seem a logical
starting place, but there have

been no systematic studies to
guide the clinical interpretation

of results.



Interferon
Interferons (IFNs) have antiviral, antiproliferative, and
immunomodulatory effects.

Interferon alfa (IFN-alpha) has been shown to be effective in
suppressing HBV replication and in inducing remission of liver
disease.

A major problem with IFN-alpha treatment is relapse;
approximately half of the responders relapse when therapy is
discontinued, and relapses can occur up to 5 years post-therapy.

Overall, sustained response can be achieved in 15 to 30 percent
of patients and long-term follow-up showed that 15 to 50 percent
of sustained responders cleared HBsAg.

20 to 40 percent of patients with HBeAg-positive chronic hepatitis
B develop a flare in their ALT values during IFN-alpha treatment
which can be severe in patients with cirrhosis.



Interferon
IFN-alpha is administered as subcutaneous injections. 5 MU daily
or 10 MU 3x weekly for 16 to 24 weeks for HbeAg (+) chronic
and 12 months for HbeAg(-) chronic hepatitis.

Clinical trials of pegylated IFN-alpha singly and in combination
with other antivirals are ongoing.

IFN-alpha therapy is associated with many adverse effects.

Of these, flu-like symptoms, fatigue, leucopenia, and depression
are the most common.

Most patients develop tolerance to the flu-like symptoms after
the first week, but fatigue, anorexia, hair loss, and mood swings
including anxiety, irritability, and depression may persist
throughout the course of treatment and for a few weeks after
discontinuation of therapy.

IFN-alpha may also unmask or exacerbate underlying
autoimmune disorders.


Lamivudine (Epivir, 3TC)
Epivir works by incorporating (3TC-TP) into growing DNA chains
causing premature chain termination thereby inhibiting HBV DNA
synthesis.

Pretreatment ALT has been found to be the most important
predictor of response.

It has been shown to benefit patients with HBeAg-negative
chronic hepatitis B.

In one study, virologic and biochemical response was achieved in
63 percent patients who received 24 weeks of lamivudine therapy
versus 6 percent patients on placebo.

However, the vast majority (~90 percent) of patients relapsed
when treatment was stopped.

Unfortunately, extending the duration of treatment resulted in
progressively lower rate of response due to the selection of
lamivudine-resistant mutants.

Lamivudine (Epivir, 3TC)
Studies in patients with decompensated cirrhosis showed that lamivudine
treatment is well tolerated and results in clinical improvement in many
patients

Various adverse events including a mild (two- to threefold) increase in ALT
level have been reported in patients receiving lamivudine, but these events
occurred in the same frequency among the controls.

A major concern with early treatment is the selection of resistant mutants

The optimal duration of lamivudine therapy in persons who have an initial
response is unknown.

Treatment may be discontinued in patients who have completed 1 year of
treatment and have persistent HBeAg seroconversion (HBeAg loss, anti-
HBe detection, and serum HBV DNA undetectable by non-PCR assays on
more than one occasion determined 2 to 3 months apart).

Durability of response after cessation of treatment is expected to be 60 to
80 percent.

Adefovir
Adefovir dipivoxil is a nucleotide analog of adenosine monophosphate.

It can inhibit both the reverse transcriptase and DNA polymerase activity
and is incorporated into HBV DNA causing chain termination.

In patients receiving adefovir, HBV DNA is reduced by 3.5 to 3.9 log10
from baseline.

Adefovir has been shown to be effective in suppressing not only wild-type
HBV but also lamivudine-resistant HBV mutants in both in vitro and in vivo
studies.

Adefovir when used in high doses has been reported to be associated with
renal tubular dysfunction resembling Fanconi syndrome as well as
deterioration in renal function.

Data on the durability of HBeAg seroconversion after adefovir is
discontinued have not been presented.

Preliminary data indicate that most patients with HBeAg negative chronic
hepatitis will relapse when adefovir is withdrawn after 1 year.

Other Treatments
Famciclovir

Clinical studies showed that famciclovir is well tolerated and effective
in suppressing HBV replication but its antiviral effect is less potent
than that of 3TC.

Resistance to famciclovir has been reported.

Entecavir

Entecavir, a carbocyclic analogue of 2'-deoxyguanosine, inhibits HBV
replication at three different steps.

In vitro studies showed that entecavir is more potent than lamivudine
and adefovir and is effective against lamivudine-resistant HBV mutants

Phase III clinical trials are ongoing.

Other Treatments
Tenofovir

Tenofovir disoproxil fumarate (TDF) is an acylic nucleotide reverse
transcriptase inhibitor, closely related to adefovir. It has been
approved for the treatment of HIV infection.

Tenofovir has been shown to have significant activity against HBV,
both wild-type virus and lamivudine-resistant HBV mutants.


Tenofovir has not been systematically evaluated in patients with HBV
infection alone.

The efficacy of tenofovir against HBV at the approved dose for HIV
infection makes it the treatment of choice for patients with HBV and
HIV coinfection who require anti-retroviral therapy, particularly those
with lamivudine-resistant infection.


What to Start?

Except for patients with contraindications or previous non-response to
specific therapy, either IFN-alpha, 3TC or adefovir may be used as
initial therapy for patients with compensated liver disease.

The advantages of IFN-alpha include a finite duration of treatment, a
more durable response and the lack of resistant mutants.

The disadvantages of IFN-alpha are the costs and side effects.

Lamivudine is more economical (if given for 1 year only) and well
tolerated but the durability of response appears to be lower, and long-
term therapy is associated with increasing risk of drug-resistant
mutants



What to Start?

The main advantages of adefovir include its activity against
lamivudine-resistant mutants and a very low rate of adefovir
resistance during initial therapy.

However, adefovir is significantly more costly than lamivudine, and the
durability of response, long-term safety and risk of drug resistance
remain to be determined.

Treatment may be initiated with IFN , 3TC, or adefovir as the 3
treatments have similar efficacy.



The Future
The past few years have seen the development of a

plethora of
new drugs for the treatment of HBV infection.

It

seems likely that combination therapy will become the wave of

the future in HBV therapy, but many questions remain to be
resolved

by clinical investigation.

Is combination therapy truly superior

to monotherapy, clinically
as well as virologically?

If, as

most expect, it proves to be superior, which combination of

drugs should be used for initial treatment?

Could more potent combination therapy reduce HBV levels to a

point where the remaining virus could be cleared by the host's

own immune system, either spontaneously or after therapeutic

vaccination with HBV antigens?