doi:10.1136/gut.2005.077891
2008;57;105-124; originally published online 14 May 2007; Gut

G Dusheiko and N Antonakopoulos


Current treatment of hepatitis B
/>Updated information and services can be found at:
These include:
References


/>This article cites 174 articles, 46 of which can be accessed free at:
service
Email alerting
the top right corner of the article
Receive free email alerts when new articles cite this article - sign up in the box at
Correction
/>available online at:
been appended to the original article in this reprint. The correction is also
have
correctionA correction has been published for this article. The contents of the
Notes

/>To order reprints of this article go to:
/> go to: GutTo subscribe to
on 11 August 2008 gut.bmj.comDownloaded from
Current treatment of hepatitis B
G Dusheiko, N Antonakopoulos
UCL Centre for Hepatology and
Royal Free Hospital, London, UK

Correspondence to:
Professor Geoff Dusheiko,
University Department of
Medicine, Royal Free Hospital,
Pond Street, London HA5 1DE,
UK;
uk
Hepatitis B has a complex natural history and
causes a wide spectrum of disease. There is a large
reservoir of carriers of hepatitis B virus (HBV) in
the human population. Low (less than 2% of the
population), intermediate (2–8%), and high pre-
valence regions (more than 8%) are recognised.
Population movements and immigration are chan-
ging the prevalence of the disease in several non-
endemic countries in Europe and elsewhere.
Treatment is indicated for chronic, progressive
disease, although there is a role for rapidly acting
nucleoside analogues in fulminant acute hepatitis
or subacute hepatic necrosis. Substantial health
care resources will be required for the worldwide
burden of disease. In endemic areas the direct costs
can total 3.2% of the national health care
expenditure.
12
Several difficulties remain in formulating treat-
ments for HBV infection and thus areas of
disagreement on the management of chronic
hepatitis B exist. Choices of treatment depend on
a number of factors predictive of treatment

response, clinical circumstances and stage of
disease, potency of different agents, the likelihood
and consequences of resistance to treatment, as
well as the personal choice of the patient and
physician.
3
Current guidelines are not always
constant or agreed and will require rapid adjust-
ment as new treatments become available.
4–6
Thus
this review summarises an overall view of treat-
ment and points to areas of controversy.
REPLICATION OF HBV AND HOST IMMUNE
RESPONSE
Key steps in the replication of HBV have been
defined. After entry into the cell, the virus is
uncoated, and translocated to the nucleus. Relaxed
circular HBV DNA is converted into supercoiled, or
covalently closed (cccDNA) from which a prege-
nomic RNA is transcribed. HBV replicates through
transcription of HBV RNA to DNA. The crucial
steps include encapsidation, minus strand (2)
DNA strand synthesis, plus strand (+) DNA
synthesis, and maturation and release of viral
particles. cccDNA is shuttled back to the nucleus.
Importantly, the stability and replenishment of
cccDNA accounts for the difficulty in eradicating
hepatitis B, and acts as an archive of antiviral
resistant DNA. HBV also integrates within the

host genome. HBV is not generally cytopathic but
HBV DNA levels correlate with long term progres-
sion.
Acute hepatitis B is self limited in the majority
of immunologically normal adults.
17
After acute
hepatitis low levels of virus persist for decades after
acute resolution of disease. Recovery from
hepatitis B is associated with long term persistence
of cytotoxic T lymphocytes (CTL) that actively
maintain CTL responses for life.
8–10
An inadequate innate and adaptive host immune
response accounts for persistent infection, and
immunological tolerance is evident in HBeAg
positive patients with high viral loads.
Conversely, HBV clearance is associated with a
degree of liver damage. The host immune responses
that characterise the chronic phase of active disease
are not sufficient to control active viral replication
(for reasons that are uncertain). High antigen
expression in the liver may impair T cell effector
functions,
11
and in many patients the immune
paresis is irreversible despite a reduction in viral
load. HBV specific T cell responses are weak,
narrowly focused, or totally undetectable in the
peripheral blood of patients with long lasting

chronic hepatitis B.
12–14
However, T cell responsive-
ness can be partially restored. Treatment with
both lamivudine and adefovir has been shown to
restore or enhance transiently the HBV specific
HLA class II response to HBV antigens. A complex
pattern of genomic variability and selection of pre-
core mutants and core promoter mutants occurs
during prolonged chronic infection, accounting for
different serological patterns of disease.
CHRONIC HEPATITIS B
Chronic hepatitis B is defined as persistence of
hepatitis B surface antigen (HBsAg) in the circula-
tion for more than six months. The disease may
cause liver damage varying from mild chronic
hepatitis to severe, active hepatitis, cirrhosis, and
primary liver cancer. Chronic hepatitis B is more
likely to follow infections acquired in childhood
than those acquired in adult life, and is more likely
to occur in patients with natural or acquired
immune deficiencies, including HIV infection.
DIAGNOSIS AND PATHOLOGY
Hepatitis B is usually diagnosed by the detection of
HBsAg in serum. Detection of viral DNA is the
optimal method of establishing hepatitis B virae-
mia and standardised quantitative assays are
valuable for monitoring virus loads during antiviral
therapy.
15 16

Quantitative assays for HBV DNA
were previously limited by a lack of standardisa-
tion but more recently a World Health
Organisation (WHO) standard has been devel-
oped.
17 18
HBeAg is a marker of viraemia but
detection anti-HBe does not indicate clearance of
virus replication. Typically the levels of serum
aminotransferases are raised in patients with
HBeAg, HBV DNA positive active chronic hepati-
tis, but patients may have normal or near normal
values. Many patients go on to develop moderate
to severe HBeAg positive chronic hepatitis with
RECENT ADVANCES IN CLINICAL PRACTICE
Gut 2008;57:105–124. doi:10.1136/gut.2005.077891 105
on 11 August 2008 gut.bmj.comDownloaded from
raised serum alanine aminotransferase (ALT) after
several decades of infection, which can ultimately
progress to cirrhosis. The levels of aminotrans-
ferases may fluctuate with time. Usually, the levels
of ALT are higher than those of aspartate
aminotransferase (AST). However, with progres-
sion of the disease to cirrhosis, the AST/ALT ratio
may be reversed. An increase in these enzymes may
be the only abnormality to be found in individuals
with asymptomatic and anicteric infections. A
progressive decline in serum albumin concentra-
tions and prolongation of the prothrombin time
are characteristically observed after decompensated

cirrhosis has developed.
Single measures of ALT (and HBV DNA) are
not useful in a disease as dynamic as hepatitis B,
and there is controversy over the level below
which HBV DNA concentrations are indicative
of ‘‘inactive’’ disease, or indicate a threshold for
initiating treatment. Thus longitudinal mea-
fosures, over at least a few months or longer, are
required. HBV genotypes have been reported to
correlate with spontaneous and interferon
induced HBeAg seroconversion, activity of liver
disease, and progression to cirrhosis and hepato-
cellular carcinoma. In China and Japan, where
genotypes B and C predominate, there is evidence
for increased pathogenicity of genotype C over B,
with the likelihood of developing hepatocellular
carcinoma.
19–22
In chronic hepatitis B with mild activity, only
rare piecemeal necrosis is seen. Characteristic
hepatocytes with eosinophilic ‘‘ground glass’’ cells
are relatively common in anti-HBe positive
patients with low levels of virus replication.
Lobular hepatitis is more common in patients with
active virus replication and raised serum ALT.
HBsAg and HBcAg can be detected by immuno-
peroxidase staining in routinely fixed liver biopsy
sections. Patients with high levels of viraemia may
have minimal hepatitis.
23

MAJOR PATTERNS OF CHRONIC HEPATITIS
Three broad groups of chronic hepatitis B are
recognised.
HBeAg positive chronic hepatitis B
HBeAg positive disease is typically associated with
high levels of HBV replication for a prolonged
period of time. The disease is found in young
individuals with chronic hepatitis B, who have
high levels of HBV DNA (usually .10
7
copies/ml)
in serum. They may have normal ALT in the
‘‘immunotolerant phase’’ of the disease, or have
raised ALT in later active disease. Spontaneous
seroconversion rates are higher in patients with
raised ALT and genotype B (vs C) and genotype D
(vs A). Importantly, patients with normal serum
ALT and high circulating concentrations of HBV
DNA show profound peripheral immunological
tolerance. Finite treatment remains difficult, prob-
ably for this reason. These individuals are poor
responders to interferon treatment, and often poor
short term responders to nucleoside or nucleotide
antiviral drugs because of resistance. Spon-
taneous seroconversion rates remain relatively
low in this group at approximately 20% at one
year.
HBeAg negative disease
Anti-HBe positive chronic hepatitis B is charac-
terised by the absence of HBeAg in serum due to

genotypic changes preventing expression of
HBeAg. Viral replication is detectable, and patients
show an active disease course characterised typi-
cally by fluctuations in levels of HBV replication
and not infrequently, fluctuations in serum ALT.
These patients are HBsAg positive and anti-HBe
positive. HBV DNA concentrations are typically
.10
5
copies/ml, but fewer than 10
8
copies/ml. Liver
biopsy shows necroinflammation and varying
stages of fibrosis. Sustained antiviral responses
are difficult to achieve with this group after both
interferon and nucleoside analogue therapy, but
viraemia and necroinflammatory change are
improved on treatment.
24 25
Inactive carrier state
Patients with an inactive carrier state are char-
acterised by a spontaneous remission in disease
activity. These patients are HBeAg negative, anti-
HBe positive with lower HBV DNA levels (,10
5
or
10
4
copies/ml), and little or no necroinflammation
or fibrosis, depending on the timing of seroconver-

sion. The disease may need to be a retrospective-
prospective diagnosis as inactive carriers show
some propensity to reactivation. The distinction
between inactive carriers and anti-HBe positive
patients who have progressive disease can be
difficult without longitudinal follow up, particu-
larly in endemic areas. Seroconversion to anti-HBe,
occurring relatively late in patients who acquire
the disease early in life, is not necessarily a marker
of remission if accompanied by ongoing HBV
replication.
In HBeAg positive patients, progression to
cirrhosis occurs at an annual rate of 2–5.5%, with
a cumulative five year incidence of progression of 8
to 20%. Recurrent exacerbations and bridging
fibrosis with severe necroinflammatory change
characterise patients who are more likely to
progress. The reported yearly incidence of hepatic
decompensation is about 3%, with a five year
cumulative incidence of 16%. In a European
multicentre longitudinal study to assess the
survival of 366 cases of HBsAg positive compen-
sated cirrhosis, death occurred in 23% of patients,
mainly from liver failure or hepatocellular carci-
noma. The cumulative probability of survival in
this cohort was 84% and 68% at 5 and 10 years,
respectively. The worst survival was in HBeAg and
HBV DNA positive subjects.
26
In population based

Taiwanese studies, patients remaining HBeAg
positive, and with continued HBV replication were
more likely to develop cirrhosis and hepatocellular
carcinoma.
27–29
RECENT ADVANCES IN CLINICAL PRACTICE
106 Gut 2008;57:105–124. doi:10.1136/gut.2005.077891
on 11 August 2008 gut.bmj.comDownloaded from
ANTIVIRAL THERAPY FOR HEPATITIS B
Treatment of acute hepatitis B
Most icteric patients with acute hepatitis B resolve
their infection and do not require treatment.
Fulminant hepatitis B is a severe form of acute
infection complicated by encephalopathy, bleed-
ing, and liver failure. Subacute hepatic necrosis is
characterised by a more protracted acute course
and transition to chronic hepatitis with ongoing
HBV replication. Patients with fulminant hepatitis
(including acute and subacute forms) should be
considered for liver transplantation if appropriate.
Interferons are not used for the treatment of acute
or fulminant hepatitis. There are no controlled
trials of lamivudine, adefovir telbivudine, or
entecavir for patients with acute fulminant or
subacute fulminant hepatitis. However, uncon-
trolled reports suggest some efficacy of lamivudine
in these patients, and, in the absence of rando-
mised controlled clinical trials, lamivudine (the
most studied) or another rapidly acting antiviral
drug can be tried if there is evidence of ongoing

HBV replication.
30–33
THERAPY OF CHRONIC HEPATITIS B
The treatment of hepatitis B remains complex,
with somewhat unpredictable responses. Current
antiviral agents either inhibit hepatitis B replica-
tion, or invoke an immune response, which may be
necessary but not sufficient to effect viral control.
Indications
Patients with mild disease and normal ALT may
not require immediate treatment and should be
monitored carefully at appropriate intervals. Most
clinicians consider that treatment should be
considered only if there is evidence of moderate
to severe activity. HBeAg positive patients should
be followed for a few months to ascertain their
status, and antiviral therapy should be considered
if there is active HBV replication (HBV DNA above
1610
5
copies/ml, (20 000 iu/ml) and raised ALT
after observation, with a biopsy showing active
hepatitis—that is, inflammation, necrosis, or accu-
mulating fibrosis. HBeAg positive patients with
greater disease activity may be more likely to
seroconvert to anti-HBe within one year of
treatment.
HBeAg negative patients should be considered
for antiviral therapy when the serum ALT is raised
and there is active viral replication (HBV DNA

above 1610
4–5
copies/ml (2000–20 000 iu/ml) and
active hepatitis (inflammation, necrosis, or accu-
mulating fibrosis). The threshold for treatment
remains uncertain. Anti-HBe positive patients with
normal ALT and low levels of DNA (,10 000
copies/ml, ,2000 iu/ml) should be monitored. No
definite consensus criteria have been established
for initiating treatment in this group. Indeed both
HBeAg positive and HBeAg negative patients
require careful and regular monitoring to ascertain
a change in the pattern of disease.
Many clinicians would consider a liver biopsy
helpful for determining the degree of necroinflam-
mation and fibrosis (fig 3). In many centres a
Figure 1 Serological
markers in the natural
history of hepatitis B
infection.
Box 1 Hepatitis B
c Hepatitis B virus causes a wide spectrum of disease
c Treatment is indicated for fulminant and particularly chronic progressive
disease
c Treatment remains difficult to formulate for all patients
c Three major forms of disease are recognised:
– HBeAg positive chronic hepatitis
– Anti-HBe positive chronic hepatitis
– Anti-HBe positive inactive carrier state
c The distinction between an inactive carrier state and anti-HBe positive disease

requires longitudinal assessment.
c Liver biopsy may be helpful in ascertaining the degree of inflammation and
fibrosis
RECENT ADVANCES IN CLINICAL PRACTICE
Gut 2008;57:105–124. doi:10.1136/gut.2005.077891 107
on 11 August 2008 gut.bmj.comDownloaded from
biopsy would be considered to assess the stage and
grade of inflammation, as hepatic morphology can
assist the decision to treat. There are several
established methods of scoring histology, measur-
ing activity (necroinflammation) separately from
stage (fibrosis). There are, however, several limita-
tions of biopsy, including sampling error, subjec-
tivity and reproducibility, and of course costs,
risks, and discomfort to the patient. The activity of
hepatitis B can vary over time but ultimately
determines the prognosis and response to treat-
ment, particular HBeAg seroconversion.
Assessment of fibrosis measures how far the
disease has progressed. Progression of disease in
hepatitis B is not necessarily linear, but is influ-
enced by episodes of activity.
34
Progression of
disease is often punctuated by episodes of activity
which are injurious to the liver. There is growing
interest in the use of non-invasive methods,
including serum markers and transient elastogra-
phy, to assess hepatic fibrosis.
Goals of treatment

The major goals of treatment for hepatitis B are to
prevent progression of the disease to cirrhosis, end
stage liver disease, or hepatocellular carcinoma. If
HBV replication can be suppressed, the accompa-
nying reduction in histological chronic active
hepatitis lessens the risk of cirrhosis and hepato-
cellular carcinoma.
35
Patients may request treat-
ment to reduce infectivity. Extrahepatic
manifestations of hepatitis B such as glomerulone-
phritis or polyarteritis nodosa require treatment.
The immediate objectives depend upon the stage
of disease. If the disease has not progressed to
cirrhosis then prevention of progression to
advanced fibrosis or cirrhosis is desirable. If
cirrhosis has developed then preventing decom-
pensation or hepatocellular carcinoma or death is
important. It may be somewhat more difficult to
eliminate the risk of hepatocellular carcinoma in
the short term.
If decompensated disease is already present, it is
important to attempt to rapidly reduce viral loads
and to stabilise the disease. Suppression of HBV
replication will improve synthetic function and a
decrease the Child–Pugh score in patients who
present with early decompensation. In some
patients this may perhaps obviate the need for
liver transplant. Lower viral loads enable liver
transplantation, with a reduced risk of recurrence.

End points
The end points of treatment are not clearly
defined, and differ in HBeAg positive versus
negative disease (fig 2). It is reasonable to infer
improvement in disease outcome if HBV replica-
tion is suppressed to fewer than 1610
4
copies/ml
(2000 iu/ml), with an accompanying improvement
in serum ALT and hepatic necroinflammatory
disease. Newer potent agents are capable of
suppressing most patients to fewer than 1610
3
copies/ml (200 iu/ml), or even to levels undetect-
able by current polymerase chain reaction (PCR)
assays—that is, ,200 copies/ml (50 iu/ml), which
may become the important benchmark.
HBeAg positive disease
In our current state of knowledge, antiviral
treatment for HBeAg positive disease is directed
to attaining loss of HBeAg and ideally, durable
seroconversion to anti-HBe. In HBeAg positive
disease reduction in HBV replication leads to an
accompanying reduction in ALT. A reduction of
HBV DNA concentrations to fewer than 10
4
copies/ml (2000 iu/ml) or preferably levels unde-
tectable by sensitive PCR to levels of around 200
copies/ml (or 50 iu/ml) or lower within six months
may enhance the rate of loss of HBeAg and reduce

the rate of resistance.
36 37
Loss of HBeAg and
associated suppression of viral leads to biochemical
remission, histological improvement, and in a small
percentage, loss of HBsAg. Histological improve-
ment follows suppression of necroinflammatory
disease.
Figure 2 End points of antiviral response in HBeAg positive and negative patients.
Figure 3 Active hepatitis B and cirrhosis.
RECENT ADVANCES IN CLINICAL PRACTICE
108 Gut 2008;57:105–124. doi:10.1136/gut.2005.077891
on 11 August 2008 gut.bmj.comDownloaded from
Loss of HBeAg and seroconversion to anti-HBe is
a potential stopping point in HBeAg positive
patients, although treatment with nucleoside
analogues should be prolonged for at least six
months after loss of HBeAg. Unfortunately a
variable T cell response and antiviral resistance
suggests that finite courses with such circum-
scribed responses occur in only a minority of
HBeAg positive patients, and the majority of
patients still require long term maintenance
suppressive treatment. Categorical analysis has
not clarified what relative or absolute reduction
in ALT and DNA predicts histological improve-
ment and HBeAg seroconversion, and will alter the
natural history of the disease, although there are
some pointers. It not clear whether profound
reductions in DNA (for example, 6–7 log

10
) are
critical for long term treatment. However, the
rapidity and efficacy of HBV DNA reduction to
fewer than 10
3
copies/ml or undetectable by
sensitive PCR (,200 to 300 copies/ml) clearly has
implications for the development of resistance and
loss of HBeAg.
HBeAg negative disease
In anti-HBe positive disease (as such patients are
already HBeAg negative), reduction in ALT and
HBV DNA, and the accompanying reduction in
cccDNA and histological improvement, are the end
points. Stopping points and finite courses of
treatment are less commonly achieved, because of
higher rates of relapse in these patients, but
progression can be halted if HBV DNA remains
suppressed and resistance or relapse does not occur.
Successful treatment with a nucleoside or nucleo-
tide is characterised by a decline in HBV DNA to
fewer than less than 10
4
copies/ml (,2000 iu/ml)
or preferably to levels undetectable by sensitive
PCR. Maintaining the response is the objective,
defined by a low viral load during treatment. As for
HBeAg positive disease, rapid lowering of viral load
lessens the risk of developing viral drug resistance.

ANTIVIRAL TREATMENT
Two major groups of antiviral treatment are
currently used. These include interferon alpha
(IFNa, or PEG-IFNa) and nucleoside or nucleotide
analogues.
Approaches to treatment of hepatitis B
Treatment can theoretically involve a finite course,
continuous long term therapy (or indefinite sup-
pressive therapy), or for many patients, a treat-
ment course that is undefined at the start and will
be dependent upon the initial response. There are
major uncertainties in predicting whether mono-
therapy will suffice, or whether de novo or add-on
combination therapies are necessary or more bene-
ficial. Thus there are several treatment options for
individual patients, making rational choices for first
line and second line treatment somewhat difficult.
38
Several guidelines have been published, but these will
require regular and frequent reassessment.
39–41
There
are various major areas of dissent which have not
been resolved (box 5).
LICENSED AGENTS
Interferons
IFNa binds to cellular receptors and activates
secondary messengers to initiate the production
of multiple proteins which are pivotal for the
defence of the cell against viruses. Their mechan-

ism of action is complex. The antiviral effects of
IFN include degradation of viral mRNA, inhibition
of viral protein synthesis, and prevention of the
viral infection of cells. The immunomodulating
effects of IFN include enhancement of antigen
presentation by HLA I and II to the immune
system, activation of natural killer (NK) cells and
other immune cells, and increased cytokine pro-
duction.
The main advantages of IFNa with nucleoside
analogues are the absence of resistance and the
possibility of immune mediated clearance of
hepatitis B.
42–44
A meta-analysis of 15 randomised
controlled trials in HBeAg positive patients showed
a 33% HBeAg seroconversion rate after 16 weeks of
IFNa treatment, compared with 12% in untreated
control patients.
45
The incidence of HBsAg loss was
7.8% and 1.8%, respectively. The recommended
regimen for HBeAg positive adult patients is 5 MU
daily or 10 MU thrice weekly for four to six
months.
46
Pretreatment factors predictive of
response to IFNa are low viral load, high serum
ALT, increased activity scores on liver biopsy, and
shorter duration of infection. The HBeAg serocon-

version rate correlates with baseline ALT values
and reaches 30–40% for baseline ALT greater than
five times the upper limit of normal.
47
An increase
of ALT during the second or third month of
treatment can be observed.
HBV DNA suppression is the end point sought
in HBeAg negative patients, who relapse fre-
quently after IFNa treatment. Sustained response
rates of 6–24% at 12–18 months after end of
treatment have been reported.
48 49
For this reason
the recommended duration of treatment is one
year for this group of patients.
Pegylated a2a interferon
Pegylated forms of IFNa (PEG-IFNa) with
improved pharmacokinetic profiles and more con-
venient once weekly administration are licensed for
the treatment of hepatitis C, and PEG-IFNa2a is
licensed for the treatment of hepatitis B. The
efficacy of PEG-IFNa2a in HBeAg positive and
negative chronic hepatitis B has been established in
two large pivotal trials; PEG-IFNa2b has also
recently been shown to be active against HBeAg
positive chronic hepatitis.
50 51
HBeAg positive patients
A study in HBeAg positive patients compared

treatment for 48 weeks with PEG-IFNa2a, PEG-
IFNa2a plus lamivudine in combination, and
lamivudine monotherapy.
50
At the end of 24 weeks
RECENT ADVANCES IN CLINICAL PRACTICE
Gut 2008;57:105–124. doi:10.1136/gut.2005.077891 109
on 11 August 2008 gut.bmj.comDownloaded from
of follow up, HBeAg seroconversion rates were
32%, 27%, and 19%, respectively. ALT normal-
isation occurred in 41%, 39%, and 28% of the
same groups. HBeAg values higher than 100 iu/ml
at weeks 12 and 24 were highly predictive of
failure to achieve seroconversion. Conversely,
low HBeAg values at baseline, week 12, and week
24 correlated with improved rates of seroconver-
sion.
The addition of lamivudine to PEG-IFNa2a has
not improved seroconversion rates compared with
PEG-IFNa2a alone. However, in HBeAg positive
patients, a 27.2 log additive suppression of HBV
DNA at the end of 48 weeks in patients with
lamivudine plus PEG-IFNa2a was found, compared
to a 24.5 log suppression of HBV DNA in patients
treated with PEG-IFNa2a. Resistance to lamivu-
dine was reduced.
PEG-IFNa2b has also been shown to be active in
HBeAg positive patients, with similar seroconver-
sion rates.
51

There may be an effect of genotype
and other baseline factors on response to PEG-
IFNa2a in HBeAg positive chronic hepatitis B:
patients with genotype A and B tend to respond
better than patients with genotype C and D.
HBeAg negative patients
In a similar study of HBeAg negative patients, at
the end of 48 weeks of follow up, HBV DNA fewer
than 400 copies/ml was maintained in 17% of an
observational subset of PEG-IFNa2a treated
patients followed for three years post-treatment.
52
Baseline ALT and HBV DNA, patient age, sex, and
infecting HBV genotype significantly influenced
response at 24 weeks post-treatment.
53
HBsAg loss
occurred in 8% of a longer term cohort after three
years.
Somewhat higher HBeAg (and HBsAg) serocon-
version rates in HBeAg positive patients enhance
the possibility of a finite course of treatment.
Perhaps combination therapy with prolongation of
treatment with an oral agent might consolidate the
on-treatment response?
54
It will be interesting to observe patient choices
for first line therapy, given the pros and cons of
treatment with PEG-IFN vs nucleosides. Relapse
rates remain relatively high after stopping 48

weeks of PEG-IFNa2a treatment in anti-HBe
positive patients.
Frequent side effects and the need to monitor
patients closely are the main disadvantages of PEG-
IFN treatment. There is no role for alpha interferon
in the treatment of acute or fulminant hepatitis B.
The role of interferon in patients with decom-
pensated hepatitis B is more problematic, given
their effect on platelets and neutrophils and their
pro-inflammatory effects. Interferon should be
used with caution and with regular monitoring in
patients with compensated cirrhosis, as there is a
risk of hepatic decompensation with prolonged
treatment.
55
Moreover, the occurrence of serious
bacterial infections has been reported in this group
of patients.
56
NUCLEOSIDE ANALOGUES
Nucleoside analogues have similar structures to the
natural nucleotides and compete at the HBV
polymerase catalytic site during the synthesis of
viral DNA. They lack a hydroxyl group, preventing
the formation of a covalent bond with the
adjoining nucleotide, causing chain termination
of the elongation of DNA. Although all nucleotide
analogues act on HBV polymerase, their mechan-
ism differs; thus adefovir inhibits the priming of
reverse transcription, while lamivudine and emtri-

citabine inhibit the synthesis of the viral (2) strand
DNA.
57
Entecavir inhibits three major stages of
HBV replication.
58–61
Clevudine inhibits the elonga-
tion of the + strand DNA and has a weaker effect
on priming, and may have additional effects of
cccDNA. Nucleic acids in general are less effective
against cccDNA formation after viral entry in the
hepatocyte, and thus residual viraemia persists
during antiviral treatment.
62–64
There are various new nucleosides and nucleo-
tides in the pipeline. Thus the array of nucleosides
may shortly include the licensed drugs (lamivu-
dine, adefovir, entecavir, telbivudine), tenofovir,
emtricitabine (licensed for HIV), as well as
clevudine, elvucitabine, valtorcitabine, amdoxovir,
racivir, MIV 210, b-L-FddC, alamifovir, and
hepavir B.
The patterns of response observed with nucleo-
sides are broadly similar, although these agents
have different structures and inhibit different
phases of hepatitis B replication, including priming
of reverse transcription, elongation of (2) strand
DNA, DNA dependent DNA polymerase activity,
and (+) strand synthesis. Nucleosides and nucleo-
tides have variable mechanisms of action, and their

pharmacokinetics, inhibitory capacity, onset of
action, resistance patterns, and rates of HBeAg
seroconversion vary during the first year of
treatment.
LAMIVUDINE
Lamivudine (29,39-dideoxy-39-thiacytidine or 3TC)
is a cytidine analogue. It competes with cytosine in
the synthesis of the viral DNA. It is a (2)
enantiomer, and a phosphorylation step is required
for the transformation to active drug. The drug has
a strong track and safety record, and reliably
reduces HBV DNA concentrations in serum by 2–
4 log
10
. Raised serum ALT levels have likewise been
shown to predict a higher likelihood of HBeAg loss
in patients with chronic hepatitis B treated with
lamivudine. Lamivudine is a relatively inexpensive
drug, and the lack of side effects in patients with
advanced disease is attractive. As a result it has
become a widely used first line drug for the
treatment of HBeAg and anti-HBe positive disease.
The major disadvantage of lamivudine treatment is
the high rate of resistance observed in both HBeAg
and anti-HBe positive patients. Lamivudine resis-
tance has been mapped to mutations in the
tyrosine-methionine-aspartate-aspartate (YMDD)
motif of the reverse transcriptase (rt) domain of
HBV DNA polymerase. Lowering viral load may be
RECENT ADVANCES IN CLINICAL PRACTICE

110 Gut 2008;57:105–124. doi:10.1136/gut.2005.077891
on 11 August 2008 gut.bmj.comDownloaded from
associated with some restoration of CTL reactiv-
ity.
65
Elimination of lamivudine occurs mainly by
renal elimination and dosages should be adapted to
creatinine clearance.
Lamivudine in acute hepatitis B
Although 95% of immune competent adults clear
HBsAg spontaneously, lamivudine may play a role
in acute HBV infection in preventing progression
to fulminant hepatic failure. In small uncontrolled
studies of patients with acute severe HBV, with an
INR .1.5, raised bilirubin, and raised ALT,
treatment with lamivudine 100 mg/day may have
prevented death from fulminant hepatic failure.
Lamivudine in chronic hepatitis B
Lamivudine has been used for a more than a decade
for the treatment of chronic hepatitis B with
proven efficacy. This agent ushered in a new era
of safe and effective oral agents active against
hepatitis B. Much information has been gleaned
from the early controlled trials of lamivudine and
by the use of lamivudine as the control arm in
trials of newer agents (tables 1 and 2). Longer term
studies have also been informative.
In HBeAg positive patients reductions in HBV
DNA concentration, HBeAg seroconversion, ALT
normalisation, and histological improvement

observed after one year of treatment reach 44%,
17%, 41%, and 52%, respectively.
66
Pretreatment
factors predictive of response are high baseline
serum ALT levels and a high degree of histological
necroinflammation.
67 68
Several factors, including
genotype and the presence of cirrhosis, may predict
the durability of response to lamivudine; higher
rates of resistance have been reported in serotype
adw (genotype A) than ayw (genotype D) (54% vs
(8%).
69
Early viral suppression, in particular HBV
DNA levels either below 200 copies/ml or under
than 3 log
10
after six months of treatment predict
a lower risk of resistance after one year of
treatment.
70 71
In HBeAg negative patients after one year of
treatment with lamivudine, HBV DNA became
‘‘undetectable’’ with a non-standardised assay in
70% of patients, serum ALT normalised in 75%,
and histological improvement was noticed in 60.
72
However, the overwhelming majority of patients

relapsed after treatment cessation.
Long term lamivudine treatment can prevent
complications of HBV related liver disease as long
as viral suppression is maintained.
73
Thus liver
disease progression can be prevented with a
prolonged viral response but this response is
attenuated in those with virological breakthrough
(that is, resistance). There is wide experience of
lamivudine in preventing chemotherapy associated
exacerbations of hepatitis B. Lamivudine is effec-
tive in preventing reactivation, although this can
be unpredictable. The argument for ‘‘deferred’’ or
‘‘pre-emptive therapy’’ is probably weighted in
favour of early treatment and prolonged treat-
ment.
Resistance to lamivudine
Lamivudine resistance is conferred through
acquired selection of HBV with mutations of the
YMDD motif of the HBV DNA polymerase gene.
74
Resistance to lamivudine emerges in higher rates in
HIV-HBV coinfection,
75
and more rapidly in
patients with HBV genotype A than genotype D
during the first year of infection.
76
Variants

emerging during lamivudine treatment show
mutations in the viral polymerase within the
catalytic domain (C domain), which includes the
YMDD motif (for example, M204V or M204I), and
within the B domain (such as L180M or V173L).
These mutants have a reduced replicative capacity
compared with the wild type virus. The common-
est mutation is the substitution of methionine to
isoleucine or valine (rtM204V/I) at the highly
conserved YMDD motif of the reverse transcrip-
tase. Four major patterns have been observed:
L18OM + M204V; M204I; L180M + M204I; V173L
+ L180M + M204V; and occasionally L180M +
M204V/I. The L18OM + M204V occurs most
often. Although viral ‘‘fitness’’ may be reduced as
lower levels of HBV DNA occur, recent studies
have suggested that the disease may progress.
77
The
incidence of lamivudine resistance is 15–20% per
year, with 70% of patients becoming resistant after
five years of treatment. Lamivudine resistance is
accompanied by a breakthrough of HBV DNA
levels and a subsequent rise of ALT, but this is
variable. In patients with decompensated cirrhosis
treated with lamivudine monotherapy, early detec-
tion of viral breakthrough is critical. A 1 log
10
rise
of previously undetectable HBV DNA levels is

taken as indicative of phenotypic resistance; adding
adefovir before waiting for an ALT rise would be
helpful for those patients (see below)
Box 2 Goals of treatment
c The major goal of treatment is to prevent progression to cirrhosis, end stage
liver disease, or hepatocellular carcinoma
c Extrahepatic complications require treatment
c If cirrhosis has developed, then prevention of decompensation or
hepatocellular carcinoma is important
c If decompensated disease is present then the goal is to stabilise the disease,
or lower viral loads before liver transplantation
Box 3 End points of treatment
c The end points of treatment differ between HBeAg positive and HBeAg
negative disease
c In HBeAg positive disease treatment is directed toward achieving HBeAg
seroconversion
– Treatment may be stopped at a point thereafter
– Raised ALT levels predict a higher likelihood of HBeAg loss
c In HBeAg negative disease, reduction in ALT, and HBV DNA and the
accompanying histological improvement are the end points.
c Stopping points and finite courses of treatment are difficult to achieve with
nucleoside analogues
RECENT ADVANCES IN CLINICAL PRACTICE
Gut 2008;57:105–124. doi:10.1136/gut.2005.077891 111
on 11 August 2008 gut.bmj.comDownloaded from
In summary, the two main clinical concerns
during lamivudine monotherapy are the emergence
of viral resistance and withdrawal hepatitis flares.
Patients who remain HBeAg positive are suscep-
tible to flare with the development of resistance.

After emerging of resistance, the clinical benefit of
continuing lamivudine is doubtful, and resistance
can be taken to imply treatment failure. Adefovir
and tenofovir (and to a degree, entecavir) are active
against lamivudine resistant hepatitis B, but it is
advisable to continue lamivudine and adefovir in
these patients, rather than replacing lamivudine
with adefovir. Nonetheless the clinical course after
the development of resistance is complex and
variable. Hepatitis is common, but is not always
severe. Most patients generally experience worsen-
ing of liver disease.
77
The efficacy of lamivudine monotherapy is
offset by the development of resistance, restricting
its use as first line monotherapy—although mono-
therapy will suffice for three to five years in about
one third of anti-HBe positive patients with low
levels of replication. The value of lamivudine
monotherapy is being questioned because of the
likelihood of subsequent resistance to a lineage of
drugs including entecavir, telbivudine, and possibly
adefovir. Telbivudine shares cross resistance with
lamivudine.
78 79
Clevudine and emtricitabine share
also cross resistance with lamivudine, with muta-
tions emerging at the C, B, and B domains,
respectively.
Lamivudine could form (as will other nucleosides

with even lower rates of resistance) the backbone
of maintenance combination therapies.
Lamivudine resistance has typically been managed
by sequential treatment with adefovir (or more
recently entecavir), but the advantage of this
strategy compared with de novo combination
therapy is questionable.
ADEFOVIR DIPIVOXIL
Adefovir dipivoxil is an orally bioavailable prodrug
of adefovir, a phosphonate acyclic nucleotide
analogue of adenosine monophosphate.
80
Adefovir
diphosphate acts by selectively inhibiting the
reverse transcriptase-DNA polymerase of HBV by
direct binding in competition with the endogenous
substrate deoxyadenosine triphosphate (dATP).
81
Adefovir lacks a 39 hydroxyl group and, after
incorporation into the nascent viral DNA, results
in premature termination of viral DNA synthesis.
Unlike other nucleoside analogues such as lamivu-
dine, adefovir is monophosphorylated and is not
dependent on initial phosphorylation by viral
nucleoside kinases to exert its antiviral effect.
Clearance of adefovir is by renal excretion.
Adefovir pharmacokinetics are substantially altered
in subjects with moderate and severe renal impair-
ment (creatinine clearance ,50 ml/min).
82 83

Nephrotoxicity is the major side effect of higher
doses of adefovir. Adefovir causes a proximal con-
voluted tubule lesion characterised biochemically by
Table 1 One year studies of PEG-IFN, entecavir, and telbivudine in HBeAg positive patients where lamivudine was the control arm
Lamivudine 100 mg PEG-IFN Lamivudine 100 mg Entecavir 0.5 mg Lamivudine 100 mg Telbivudine 600 mg
Number 272 214 355 354 463 458
Histological response* 38% 34% 62% 72% 56% 64%
HBV DNA decline (log
10
) 25.8 24.5 25.4 26.9 25.5 26.5
DNA negative (PCR){ 40% (5%){ 25% (14%){ 38% 69% 40% 60%
ALT normal 39% (41%){ 62% (28%){ 60% 68% 75% 72%
HBeAg seroconversion 20% (19%){ 27% (32%){ 18% 21% 22% 21%
Resistance1 27% 4% 18% 0–2% 10% 3%
Reference 48 83
The same definitions were used in the investigational drug and the lamivudine control arm.
*Histological response was measured by varying methods.
{PCR negatively was variously measured (typically ,200 to ,400 copies/ml).
{Values in brackets are at the end of follow up.
1Resistance defined variously; the PEG-IFN study may have received lamivudine previously.
ALT, alanine aminotransferase; HBeAg, hepatitis B ‘‘e’’ antigen; HBV, hepatitis B virus; PCR, polymerase chain reaction; PEG-IFN, pegylated interferon.
Table 2 One year studies of PEG-IFN, entecavir, and telbivudine in HBeAg negative patients where lamivudine was the control arm
Lamivudine 100 mg PEG-IFN Lamivudine 100 mg Entecavir 0.5 mg Lamivudine 100mg
Telbivudine
600 mg
Number 181 177 286 296 224 222
Histological response* 40% 48% 61% 70% 66% 66%
HBV DNA decline (log
10
) 24.1 24.2 24.5 25.0 24.0 25.2

DNA negative (PCR){ 73% (7%){ 63% (19%){ 72% 90% 71% 88%
ALT normal 38% (59%){ 73% (44%){ 71% 78% 79% 74%
Resistance1 18% 1% 2% 8% 9% 2%
Reference 50 83
The same definitions were used in the investigational drug and lamivudine control arm.
*Histological response was measured by varying methods.
{PCR negatively was variously measured (typically ,200–,400 copies/ml).
{Value in brackets is the end of follow up.
1Resistance defined variously; the PEG-IFN study may have received lamivudine previously.
ALT, alanine aminotransferase; HBeAg, hepatitis B ‘‘e’’ antigen; HBV, hepatitis B virus; PCR, polymerase chain reaction; PEG-IFN, pegylated interferon.
RECENT ADVANCES IN CLINICAL PRACTICE
112 Gut 2008;57:105–124. doi:10.1136/gut.2005.077891
on 11 August 2008 gut.bmj.comDownloaded from
a rise in urea and creatinine. However, in the two
largest hepatitis B phase 3 trials involving 695
patients, no renal toxicity was found at the 10 mg
dose.
Adefovir in HBeAg positive disease
The efficacy of adefovir has been assessed in
patients with HBeAg positive and negative disease
and other settings in the spectrum of chronic
hepatitis B infection. Adefovir 10 mg daily resulted
in significant improvement when compared with
placebo: improvement in liver histology (53% vs
25%), reductions in HBV DNA (3.52 vs 0.55 log
copies/ml), normalisation of ALT (48% vs 16%),
and HBeAg seroconversion (12% vs 6%). There
were no significant side effects and no resistance
was found. As a result, adefovir 10 mg daily is the
recommended and approved dose. A dose effect of

10 mg vs 30 mg in the pivotal phase III trial was
apparent: 10 mg resulted in 3.5 log suppression of
HBV DNA vs 4.5 log suppression by 30 mg at 48
weeks. The 10 mg dose was chosen because of the
more favourable risk–benefit ratio, but this dose is
not optimal for a proportion of patients.
An increment in HBeAg loss and ALT normal-
isation can occur over time: 40% HBeAg serocon-
version rates have been reported after three years of
treatment. These incremental responses imply that
continued treatment of HBeAg positive patients
with an antiviral drug with a low rate of resistance
leads to satisfactory HBeAg seroconversion rates
that improve with time. However, a high propor-
tion of patients in this analysis received a
misallocation of drug, with interrupted therapy
associated with flares in serum aminotransferases
after the first year of treatment, and the data are
based on Kaplan–Meier extrapolation of a subset of
HBeAg positive patients who continued long term
treatment.
A variable proportion of patients, particularly
HBeAg positive patients with a higher body mass
index (BMI) and a high viral load, have slower and
poor primary responses. In one analysis 25% of
patients had a smaller than 2.2 log
10
reduction; the
third quartile had a 2.2–3.5 log
10

reduction. These
effects may be seen in routine clinical practice
where worse compliance and a higher BMI may
affect susceptibility to adefovir, resulting in poor
primary responses.
Adefovir in HBeAg negative chronic hepatitis B
These patients require long term treatment to
suppress viraemia. In the pivotal anti-HBe positive
adefovir study
84
185 patients were randomised to
placebo or adefovir 10 mg daily for 48 weeks. At 48
weeks the adefovir treated group had significant
improvement when compared with placebo:
improvement in liver histology (64% vs 33%),
reduction in HBV DNA (3.91 vs 1.35 log copies
per ml), an undetectable HBV DNA (,400 copies/
ml) in 51% vs 0%), and normalisation of ALT (72%
vs 29%). No significant side effects compared with
placebo were reported, and no genotypic resistance
was found. Thus adefovir is an agent that has low
rates of resistance and good long term viral
suppression, which is of particular benefit in
HBeAg negative HBV infection.
Longer term results indicate that continued
treatment with adefovir resulted in suppression
of HBV DNA to levels of ,1000 copies/ml in 79%
of patients after 144 weeks of treatment.
Resistance mutations were noted in 5.9% of
patients after 144 weeks.

85
HBV DNA concentra-
tions were less than 1000 copies/ml in 67% of
patients after 240 weeks. The cumulative prob-
ability of HBV polymerase mutations was 29%.
Creatinine elevations were found in 3%.
86
It is important to identify patients with high
levels of replication, or host factors, for whom
adefovir monotherapy will not suffice. Many anti-
HBe positive patients could be treated with
adefovir monotherapy, as first line treatment is
effective in this group. Long term therapy is
required, and resistance has been reported but at
lower rates than with lamivudine therapy. In other
groups—such as HBeAg positive patients or anti-
HBe positive patients with decompensated cirrho-
sis or high viral loads—rapid suppression of HBV
DNA replication with a low risk of primary non-
response or resistance is important, and combina-
tion therapies could be advantageous.
Adefovir resistant mutations
There are various structural differences between
lamivudine and adefovir that predict lower rates of
resistance with adefovir.
87
First, adefovir dipho-
sphate more closely resembles its natural substrate
deoxyadenosine triphosphate (dATP) than lamivu-
dine, which contains an L-sugar ring.

88
In contrast
to lamivudine, adefovir diphosphate has a minimal
acyclic linker in place of the L-sugar ring that
closely matches the D-sugar ring of dATP. This
similarity between adefovir diphosphate and dATP
means that a mutation in HBV DNA polymerase
not binding adefovir diphosphate would also
impair dATP binding. It also results in more
flexibility, allowing the adefovir to bind lamivu-
dine resistant HBV DNA polymerase without steric
hindrance.
12 13
Second, because adefovir is monopho-
sphorylated, it requires only two phosphorylation
steps compared with three for lamivudine.
Nevertheless, the development of resistant
mutations has been reported with adefovir mono-
therapy in both HBeAg positive and HBeAg
Box 4 Antiviral treatments for hepatitis B
c There are two major groups of drugs
– Interferon alpha (or pegylated interferon alpha)
– Nucleoside or nucleotide analogues
c Treatment can involve a finite course or indefinite maintenance suppressive
treatment
c In some with low levels of HBV replication, monotherapy may suffice, but for
most, combination treatments could become the norm
c Long term treatment with a single nucleoside analogue may lead to drug
resistance. In some circumstances newer agents cause relatively low ratesof
resistance

RECENT ADVANCES IN CLINICAL PRACTICE
Gut 2008;57:105–124. doi:10.1136/gut.2005.077891 113
on 11 August 2008 gut.bmj.comDownloaded from
negative patients. Sequencing of the RT domain of
the HBV polymerase has suggested that rtA181V/
T mutations (in the B domain) and rtN236T
mutations in the D domain confer resistance to
adefovir.
89
The reported mutations correlate with
HBV DNA rebounds of .1 log above nadir,
suggesting phenotypic resistance.
These studies have been based on careful
genotypic analysis of entire reverse transcriptase
region of the HBV genome.
90–92
Life table analysis
has suggested a cumulative incidence of 3.9% to
5.9% (in naive patients) after three years of
treatment. A figure of 18% at four years of
treatment has been reported. However, in clinical
practice higher rates are being reported.
93
Patients
with previous lamivudine resistance are at greater
risk of adefovir resistance.
94
HBV DNA levels at
week 48 predict the rate of resistance: suppression
to less than 3 log

10
was associated with a 4% rate
of adefovir resistance at week 144, but an HBV
DNA concentration of greater than 6 log
10
was
associated with 67% resistance at week 144.
Adefovir resistance is apparently uncommon in
treatment naive patients treated with adefovir and
emtricitabine (FTC) or adefovir and lamivudine in
combination.
Adefovir mutants remain sensitive to lamivu-
dine, emtricitabine, telbivudine, and entecavir.
91 92
The A181V mutation has a greater effect on
subsequent sensitivity to lamivudine than
N236T; this compares with observed in vitro
effects on fold sensitivity.
Adefovir in lamivudine resistant patients
Adefovir is an important drug for the treatment of
lamivudine resistant HBV infection. There is clear
evidence of the efficacy of adefovir in patients
failing lamivudine therapy. There a reports of
successful treatment of lamivudine resistant
patients with adefovir, particularly for pre- or
post-transplant recurrence of hepatitis B.
95–98
Adefovir improves outcomes for lamivudine resis-
tant patients awaiting transplantation. The wis-
dom of discontinuing lamivudine has been

challenged, given the rates of resistance or non-
response observed with adefovir monotherapy in
some centres.
99
Thus the early addition of adefovir
at the time of detection of a log rise in HBV DNA is
advocated. Resistance and clinical events are
reduced if adefovir is added at lower concentrations
of HBV DNA.
100 101
Liver transplant patients or waiting listed
patients with lamivudine resistant HBV have been
effectively treated with adefovir 10 mg.
102–104
ENTECAVIR
Entecavir, also known as BMS-200475, is a
cyclopentyl guanosine analogue. Early studies in
animals and humans indicate that it is a potent
inhibitor of viral replication. Recently activity
against HIV has been suggested.
105–108
Trials in the
woodchuck—an animal model of chronic
hepatitis B infection—indicated that cccDNA was
undetectable in liver samples for several months
post-treatment. Entecavir has been licensed for the
treatment of chronic hepatitis B.
Entecavir inhibits all three activities of the HBV
polymerase/reverse transcriptase: base priming,
reverse transcription of the negative strand from

the pregenomic messenger RNA, and synthesis of
the positive strand of HBV DNA. Phase III trails
have been completed.
HBeAg positive patients
Phase II trials indicated the efficacy of entecavir.
109
A randomised study of entecavir 0.5 mg daily vs
lamivudine 100 mg daily for 52 weeks in 715 naive
patients showed histological improvement in 72%
of entecavir treated and 62% of lamivudine treated
patients. HBV DNA was suppressed to ,300
copies/ml in 67% and 36% of entecavir and
lamivudine treated patients, respectively.
110
The
mean change from baseline was 26.9 log and 25.4
log, respectively. HBeAg seroconversion occurred in
21% and 18% of entecavir and lamivudine treated
HBeAg negative patients. A recently completed
phase III trial of 638 patients treated with
entecavir 0.5 mg daily or lamivudine 100 mg for
52 weeks showed that histological improvement
was achieved in 70% of entecavir treated and 61%
of lamivudine treated patients. HBV DNA suppres-
sion to fewer than 300 copies/ml occurred on
treatment in 90% of entecavir treated and 72% of
lamivudine treated patients. The mean change
from baseline of HBV DNA was 25.0 log and 24.5
log. ALT normalised in 78% and 71%, respectively.
Rebound to levels detectable by PCR occurs in the

majority of patients after cessation of treatment.
111
Entecavir for lamivudine resistant patients
Entecavir shows some efficacy against lamivudine
resistant HBV, but the effect is partial and higher
doses of entecavir (1.0 mg) are required. In a phase
III trial, 286 lamivudine resistant patients were
treated with 1.0 mg entecavir daily for 48 weeks.
HBV DNA was suppressed to fewer than 300
copies/ml in 19% of entecavir patients compared
with 1% of lamivudine patients. ALT normalised in
61% and 15%, respectively. HBeAg seroconversion
was observed in 8% vs 3%.
Entecavir resistance
After four years of follow up, a cumulative
resistance rate of approximately 1.2% of a subset
of naive treated and monitored patients has been
reported. Virological responders, however, have
not been evaluated in this protocol analysis.
Virological rebound and resistance has been
reported in 43% of lamivudine resistant patients
after four years of switching treatment to enteca-
vir. Lower rates of HBV suppression were reported
in this group, using 1.0 mg of entecavir. A com-
plex picture of entecavir resistance is emerging,
suggesting a requirement for new rt changes in
combination with those conferring lamivudine
resistance to reduce susceptibility to entecavir.
RECENT ADVANCES IN CLINICAL PRACTICE
114 Gut 2008;57:105–124. doi:10.1136/gut.2005.077891

on 11 August 2008 gut.bmj.comDownloaded from
Entecavir resistance requires M204V/I + L180M
mutations + T184, s202, or M250 mutations.
112
Entecavir is thus a potent inhibitor of HBV
replication. From initial studies, it seems to be safe
and well tolerated, with a frequency of adverse
events similar to lamivudine. As the drug is
excreted by the kidneys, dose adjustments are
required in cases of renal impairment, starting at
creatinine clearance below 50 ml/min. Although
entecavir is superior to lamivudine in terms of viral
suppression, one year HBeAg seroconversion rates
are not different between the two analogues (21%
and 18%, respectively), although these could
increase with time (but not at a linear rate,
apparently) given the lower rates of resistance to
entecavir. Careful observation will be required if
entecavir is used to treat lamivudine resistance as
resistance and breakthrough is ultimately likely in
many cases.
113–115
Entecavir (and lamivudine) resis-
tant HBV remains susceptible to adefovir.
Carcinogenicity after exposure to levels more than
35-fold greater than the dose administered in
humans has been reported in rodents. These lesions
include lung adenomas and carcinomas, and liver
adenomas and carcinomas. The cumulative human
risk will require post-marketing surveillance.

116
As
for all antiviral agents, resistance might be encoun-
tered in clinical practice in slow or incomplete
responders, albeit a relatively low rate.
117
Interestingly mycophenolic and ribavirin may
potentiate the effect of entecavir.
118
HBV SPECIFIC L-NUCLEOSIDES
Telbivudine is a thymidine analogue and belongs
to a new class of b-L-configuration nucleoside
analogues with specific activity against hepadna-
virus.
119–121
Preliminary studies have shown a
pronounced inhibition of HBV replication with a
safe profile and no effect on mitochondrial
metabolism. Pharmacokinetic studies indicate once
daily dosing.
122–132
Telbivudine is cleared by the
kidneys, and dosing adjustments are recom-
mended for patients with estimated creatinine
clearance of ,50 ml/min. Drug concentrations are
comparable in patients with varying degrees of
hepatic impairment. A phase II study in HBeAg
positive patients compared one year treatment
with two different doses of telbivudine (400 mg/
day and 600 mg/day), lamivudine 100 mg/day, and

their combination. A combination of telbivudine
and lamivudine was not superior to telbivudine
alone: the median decrease in HBV DNA levels
were 6.01, 4.57, and 5.99 log
10
copies/ml in the
telbivudine, lamivudine, and combination treat-
ments, respectively. HBV DNA was undetectable
in 61%, 32%, and 49% of the same groups of
patients, while HBeAg loss occurred in 33%, 28%,
and 17%.
70
Phase III studies of LdT vs lamivudine in HBeAg
and anti-HBe have been completed. The study
included 1367 HBeAg positive or negative patients
randomised to receive telbivudine 600 mg/day
(n = 680) or lamivudine 100 mg/day (n = 687).
37
HBeAg positive patients
A greater therapeutic response with telbivudine at
week 104 has been noted in HBeAg positive
patients (64% of those receiving telbivudine vs
48% of those on lamivudine) (table 1). The mean
log
10
decline was –5.7 log in recipients of telbivu-
dine vs –4.4 log in recipients of lamivudine. In
particular, HBV DNA was not detectable by PCR
in 56% of the HBeAg positive patients receiving
telbivudine vs 39% of those on lamivudine. HBeAg

seroconversion occurred in 30% at year 2; 70% had
normal ALT.
No differences by HBV genotype B or C among
HBeAg positive patients for those receiving either
telbivudine or lamivudine were noted. A clear
relation between viral load at week 24 and clinical
efficacy at week 104 in HBeAg positive patients
was shown.
36
For lamivudine and telbivudine
patients combined, histological responses, ALT
normalisation, and HBeAg loss were greatest for
patients whose week 24 HBV DNA was below the
quantitative level (46% in the combined lamivu-
dine/telbivudine groups) or between the quantita-
tive level and 3 log
10
compared with those whose
level of HBV DNA at 24 weeks was .4 log
10
(45%
of HBeAg positive patients and 80% of the HBeAg
negative patients treated with telbivudine had
undetectable HBV DNA by 24 weeks of treat-
ment). Limited follow up information suggests
that patients may discontinue treatment after
HBeAg seroconversion. Responses are durable in
approximately 80%.
37
Other studies have been

completed.
133
Anti-HBe negative patients
The mean log
10
decline was –5.0 and –4.2 in
telbivudine and lamivudine recipients, respectively
(table 2). At two years, HBV DNA was undetect-
able by PCR in 82% of HBeAg negative patients vs
52% of lamivudine recipients; 78% had normal
ALT.
Telbuvidine resistance
In this study viral breakthrough was defined per
protocol as HBV DNA .10
5
after being , 10
5
. Viral
resistance was defined as resistance mutations
documented in HBV DNA amplified from serum
from patients with viral breakthrough; 17.8% and
7.3% of the HBeAg positive and negative patients
overall showed resistance at two years, respec-
tively. Telbivudine associated resistant mutations
were all M204I or M204I + L180I/V. Lamivudine
associated resistant mutations were a mixture of
M204V, M204I, and + L180M double mutants. The
explanation for this lies in the pathways of
selection for tyrosine-methionine-aspartate-aspar-
tate mediated HBV resistance and the fact that

telbivudine is active against M204V, whereas
lamivudine has reduced activity against both
M204V and M204I mutants.
Response at week 24 also predicted resistance.
Resistance at two years was observed in 4% of
HBeAg positive patients and 2% of HBeAg negative
RECENT ADVANCES IN CLINICAL PRACTICE
Gut 2008;57:105–124. doi:10.1136/gut.2005.077891 115
on 11 August 2008 gut.bmj.comDownloaded from
patients who had undetectable HBV DNA at 24
weeks, but the rates of resistance increased
substantially in patients with higher levels of
viraemia at this time point.
Discontinuations up to week 52 were similar for
telbivudine compared with lamivudine treated
patients (8.1% and 12.8%, respectively).
Creatinine kinase elevations were observed in
13% at year 2. This side effect seems related to a
non-specific effect noted with some nucleosides.
Clinicians will, however, need to be required to
monitor creatinine kinase levels during treatment.
Adefovir can be added to patients with resistance
to telbivudine. Telbivudine cannot be used for the
treatment of lamivudine resistant patients. The
magnitude of early HBV suppression (24 weeks) is
linked to clinical efficacy and resistance at one
year.
Thus the optimal use of telbivudine is still being
sought. The combination of telbivudine with
lamivudine is unfavourable: telbivudine selects for

rtM204I and effectively shows cross resistance
with lamivudine.
78
Telbivudine is active against
N236T and A181V mutant HBV. Adefovir and
tenofovir should thus be tested in combination
with telbivudine.
NEW AGENTS IN DEVELOPMENT
Tenofovir
Tenofovir and adefovir are related molecules with a
similar mechanism of action. Tenofovir disoproxil
fumarate is the prodrug of tenofovir (PMPA).
Tenofovir diphosphate inhibits the activity of
HIV-1 rt by competing with the natural substrate
deoxyadenosine 59 triphosphate, and after incor-
poration into DNA by DNA chain termination.
The drug is approved at a dose of 300 mg for the
treatment of HIV. There is emerging clinical
evidence of the efficacy of tenofovir in chronic
hepatitis B, with less nephrotoxicity. The drug is
active against wild type and pre-core mutant
hepatitis B, as well as lamivudine resistant HBV
in vitro.
134–140
It is possible that tenofovir’s greater
efficacy is a result of the higher active dose. A large
scale randomised phase III controlled trial compar-
ing the efficacy of adefovir and tenofovir disoproxil
in HBeAg positive and negative patients is under
way.

Small substudies in HBV monoinfected and
HIV-HBV coinfected patients have demonstrated
the activity of tenofovir against HBV. In the
ACTG 5127 study, 26 HIV-HBV coinfected
patients with lamivudine resistance were rando-
mised to tenofovir vs 25 to adefovir. Tenofovir
treated patients showed a greater time weighted
average DNA change (DVAG48) and log suppres-
sion of HBV with tenofovir 300 mg (4.0 log vs 23.1
log compared with adefovir 10 mg). Recent trials
show a favourable effect of tenofovir (72 to 130
weeks) and adefovir (60 to 80 weeks) in patients
with lamivudine resistant HBV infection and high
baseline HBV DNA (.10
6
copies/ml).
141 142
Patients
treated with tenofovir (300 mg/day) have a faster
and greater suppression of HBV DNA than those
treated with adefovir (10 mg/day). The absence of
phenotypic HBV resistance to tenofovir suggests a
favourable resistance profile. The licensing of
tenofovir would expand the HBV therapy arma-
mentarium.
Although tenofovir has not yet been licensed for
HBV treatment, it may become an important
treatment of highly replicative HBV infection and
HIV/HBV coinfection. The pharmacokinetics of
tenofovir are altered in patients with renal impair-

ment, and it is recommended that the dosing
intervals of tenofovir be adjusted for creatinine
clearance. Lactic acidosis, hepatomegaly, steatosis,
and renal impairment have been reported rarely in
patients with HIV infection treated with antire-
troviral agents and tenofovir. Exacerbations of
hepatitis B may occur. Decreases in bone mineral
density have rarely been reported in HIV positive
patients.
EMTRICITABINE
Emtricitabine (2939-dideoxy-59fluoro-39-thiacyti-
dine or FTC) is a 5-fluoro-oxathiolane derivative,
closely related to lamivudine. Like lamivudine,
emtricitabine is a cytosine nucleoside analogue.
Early studies indicate that it is effective in both
HBeAg positive and HBeAg negative patients.
143 144
Emtricitabine shows a dose related efficacy with an
average 3 log
10
decrease in HBV DNA levels after
eight weeks of treatment on the highest doses. In a
48 week randomised study assessing treatment
with 25, 100, or 200 mg for the first year, and 200
mg for the second year, the median decreases in
viral load were 2.6 log
10
, 3.1 log
10
, and 2.9 log

10
,
respectively. HBeAg seroconversion rates were
23%, 24%, and 23%, respectively.
A major double blind study has been completed.
Patients were treated with either 200 mg of
emtricitabine (n = 167) or placebo (n = 81) once
daily for 48 weeks. At the end of treatment, 62% of
167 patients receiving emtricitabine had improved
hepatic histological findings vs 25% of 81 receiving
placebo. HBV DNA concentrations were fewer
than 400 copies/ml in 54% of patients in the
emtricitabine group vs 2% in the placebo group. At
week 48, 13% patients in the emtricitabine group
who had HBV DNA measured at the end of
treatment had detectable virus with resistance
mutations. The rates of seroconversion to anti-
HBe (12%) and HBe antigen loss were not different
between arms.
145
Owing to its resemblance to lamivudine, emtri-
citabine selects the same mutations associated
with resistance to HBV polymerase. These rates
of resistance are relatively high and limit its role as
a monotherapy regimen. Like lamivudine, FTC
emtricitabine may form a backbone of combina-
tion therapy.
CLEVUDINE
Clevudine (L-FMAU or 29-fluoro-5-methyl-b-L-
arabinofuranosyluracil), is a novel L-nucleoside

analogue derived from deoxythymidine.
57 146–148
RECENT ADVANCES IN CLINICAL PRACTICE
116 Gut 2008;57:105–124. doi:10.1136/gut.2005.077891
on 11 August 2008 gut.bmj.comDownloaded from
Clevudine has potent anti-HBV activity. The
mechanism of action is mainly inhibition of viral
+ strand DNA synthesis. A marked decrease of
9 log
10
in the viral load was observed in the
woodchuck model. In the same model, clevudine
combined with emtricitabine resulted in a sharp
decrease in viraemia levels, which was more
pronounced than with single drugs alone.
149
A
unique characteristic of clevudine is the slow
rebound of viraemia after cessation of treatment,
which was also observed in patients; in an early
phase II trial, the median decrease of HBV DNA
levels varied from 2.48 to 2.95 log
10
with three
different doses after 28 days of treatment. At the
end of the 20 weeks follow up period, a slow
increase of HBV DNA levels was noticed. The drug
does not accumulate.
In a further study HBeAg positive patients were
randomised to placebo 30 mg or 50 mg clevudine.

150
Patients were followed up after 12 weeks of
treatment for a further 24 weeks off therapy.
Median serum HBV DNA reductions from baseline
at week 12 were 0.20, 4.49, and 4.45 log
10
copies/
ml in the placebo, 30 mg clevudine, and 50 mg
clevudine groups, respectively. HBV DNA log
10
reductions of 3.32 and 2.99 at week 12 off therapy
and 2.28 and 1.40 at week 24 off therapy were
noted in the 30 mg and 50 mg clevudine groups,
respectively.
Phase III placebo controlled trials of 24 weeks’
duration have been completed. HBV DNA levels
were significantly lower at the end of treatment
(24.2 log
10
) and at 24 weeks of follow up for
patients receiving clevudine. HBV DNA was
undetectable at the end of treatment in 59% of
patients receiving clevudine.
In vitro studies suggest that there may be cross
resistance with lamivudine resistant HBV mutants.
In animal studies resistance occurred in the
B domain of the polymerase gene, within 12
months of treatment.
OTHER NEW AGENTS
LB80380 is an oral nucleotide prodrug and is

chemically similar to adefovir dipivoxil and teno-
fovir disoproxil fumarate. LB80380 is rapidly
converted to the parent drug LB80331 in the liver
and intestine. LB80331 is further metabolised to
LB80317, a nucleotide analogue of guanosine
monophosphate. After phosphorylation to the di-
and triphosphate forms, the molecule inhibits viral
replication following incorporation into viral DNA.
The antiviral efficacy of a four week course of
LB80380 has been reported. The mean maximum
HBV DNA changes during the four week treat-
ment period were 23.02 to 23.80 log
10
copies/ml
for doses ranging from 30 to 240 mg daily. LB80380
has also been shown to be effective against YMDD
mutants, including rtM204I and rtM204V, in both
in vitro and in vivo studies. Further trials of
LB80380 are being conducted for efficacy in
patients with lamivudine resistant HBV (Lai CL,
et al. Interim report for a phase II, multi-centre,
dose-escalating study of LB80380/ANA380 in
hepatitis B patients with lamivudine resistant
YMDD mutant HBV. J Hepatol 2005;42(suppl
2):72A.)
Pradefovir mesylate, a PMEA prodrug that was
formerly known as remofovir, is preferentially
metabolised into its active form in the liver,
resulting in targeting to the liver and higher
PMEA concentrations in that organ. The lower

concentrations in kidney, result in a potentially
lower risk of nephrotoxicity than with adefovir.
The efficacy, pharmacokinetics, and safety of
pradefovir at various doses compared with adefovir
in patients with chronic hepatitis B has been
evaluated in 242 patients randomised to receive
pradefovir 5, 10, 20, or 30 mg/day or adefovir 10
mg/day. A week 24 interim analysis has been
reported. The responses were greater with prade-
fovir 30 mg than with adefovir at week 24,
measured by the decline in HBV DNA. In addition,
metabolism of pradefovir in the liver was asso-
ciated with less systemic drug exposure than with
adefovir. HBV DNA viral load reduction was
5 log
10
with the highest dose of 30 mg/day.
PMEO-DAPym, a novel acyclic pyrimidine ana-
logue, has been assessed in vitro. Most drug
resistant mutants, including multidrug resistant
strains, remained sensitive to tenofovir and PMEO-
DAPym. Therefore this agent deserves further
evaluation for the treatment of HBV infection,
given the need for drugs that do not share cross
resistance.
151
IMMUNOMODULATORY APPROACHES
Enhancers of the specific immune response, using
cytokines like IFNa, IFNc, tumour necrosis factor
alpha (TNFa), and interleukin 12 (IL12) have been

assessed. HBV vaccine using viral recombinant
protein or plasmid DNA based vaccine is being
assessed as a therapeutic tool to trigger an immune
response and break immune tolerance. The combi-
nation of nucleoside analogues to inhibit viral
production and immunomodulatory approaches
may prove useful. Phase I–II trials are in progress.
At present, immunomodulatory therapy remains
an unrealised goal of treatment. Use of a DNA
vaccine approach relying on the administration of a
DNA plasmid encoding for the viral envelope gene
with a prime boost strategies is perhaps most
advanced.
STRATEGIES AND CHOICES FOR TREATMENT
No clear paradigms of treatment for hepatitis B
have yet emerged, compounding the difficulty in
treating patients. There are six licensed therapies,
and more in the offing. Many questions remain
unanswered. For example, which antiviral is most
appropriate for particular patients and how can
treatment be tailored to optimise response? In
whom should combination therapy be considered
de novo, and for whom might monotherapy or an
add-on therapy suffice? Which patients can realis-
tically expect a finite course of treatment, com-
pared with those requiring long term maintenance
RECENT ADVANCES IN CLINICAL PRACTICE
Gut 2008;57:105–124. doi:10.1136/gut.2005.077891 117
on 11 August 2008 gut.bmj.comDownloaded from
suppression? In whom will a strategy of simply

continuing viral suppression eventually culminate
in HBeAg seroconversion, and hence cessation of
therapy?
Ideally for a monotherapy to be contemplated,
the drug should rapidly reduce levels of viraemia,
engender very few ‘‘suboptimal’’ responses, and
have a very low rate of resistance. The potent
agents in current use appear safe. However,
resistance may later force the sequential use of
drugs, engendering the risk of multidrug resistant
hepatitis B. Different patterns of viral resistance
will need effective treatment.
THE PLACE OF COMBINATION THERAPY
The concept of combination therapy of persistent
viral infections is not new, but is rapidly emerging
as an important issue to avoid and overcome the
problem of selection of HBV drug resistant
mutants. The arguments for and against combina-
tion therapy continue in the absence of data to
suggest the most appropriate combinations. In the
best case, a theoretical synergistic effect would be
achieved using agents with dissimilar structures
and actions, thus enhancing rates of viral suppres-
sion and preventing or delaying the occurrence of
drug resistance. Although there are no existing data
to show that any combinations tested to date are
synergistic, a proof of principle exists to suggest
that, for example, resistance to lamivudine and
adefovir are reduced when these drugs used in
combination, though the combination is imperfect,

given that a proportion of patients will show poor
primary responses to adefovir. There is some
urgency to establish the efficacy of potent and
appropriate combination therapies, but these
will need necessarily large and hence expensive
trials. Thus we may need to glean the efficacy of
potent monotherapies versus combination thera-
pies from direct clinical experience over the coming
years.
The following strategies could be suggested for
patients with high levels of viral replication or
advanced disease. The first choice to be made is
whether a nucleoside analogue or pegylated inter-
feron should be used. Young patients with
markedly raised ALT may be the most suitable
candidates for interferon. However, it is correct
that these patients respond similarly to nucleo-
sides, and the options should be explained to them.
In HBeAg positive patients, or anti-HBe positive
patients with high levels of viral replication, or
patients with decompensated cirrhosis, rapid sup-
pression of HBV DNA replication to confer a low
risk of primary non-response or resistance is
important, and only a single agent capable of 5–
6 log
10
suppression within one year in the majority
of patients, and very low rates of resistance after
three years, should be considered as monotherapy.
Combinations of drugs may be advantageous.

For patients with lower levels of viral replication,
similar questions and arguments apply. Guidelines
based on clinical trial data and experience perhaps
suggest that many anti-HBe positive patients could
be treated with single agents which have low rates
of resistance, for example adefovir, tenofovir,
entecavir, and perhaps telbivudine. This strategy
is currently being debated, however, and may not
be optimal. Long term treatment is required,
making interferon perhaps less attractive. A sui-
table additional agent should be added if patients
do not show a rapid viral decline—for example, if
HBV DNA concentrations are .10
4
log
10
after 24
weeks—because of the high risk of resistance.
CIRRHOSIS
Treatment of cirrhosis should not be based on ALT
as it may be normal in advanced disease. IFN
increases the risk of sepsis and decompensation in
patients with advanced cirrhosis; it is a proin-
flammatory cytokine. However, interferon can be
used for the treatment of well compensated
cirrhosis in selected patients with sufficient hepatic
reserve and acceptable levels of hepatic function.
Hepatic decompensation may occur with exacer-
bations of disease following the use of nucleoside
analogues, and these patients should be carefully

monitored.
Immediate, prolonged, and profound suppres-
sion of viraemia confers benefit, reducing the risk
of progression to decompensated liver disease, and
possibly hepatocellular carcinoma. Clinical studies
indicate that prolonged and adequate suppression
of viraemia may stabilise patients and delay or
even obviate the need for transplantation. Recent
longer term studies have suggested the clinical
utility of HBV DNA suppression with lamivudine.
Kaplan–Meier estimates of disease progression
after three years treatment of patients with
cirrhosis are reduced to 5% in treated vs 21% in
placebo recipients.
73
However, the development of
lamivudine resistance significantly reduces the
clinical benefit in treated patients. Hepatocellular
carcinoma remains a persistent risk, albeit the risk
is lessened.
Decompensated cirrhosis and liver transplantation
Patients with decompensated cirrhosis should be
treated in specialist liver units, as the applica-
tion of antiviral therapy is complex. Interferon is
Box 5 Some controversies in management of hepatitis B
c What are the indications for treatment in HBeAg positive and negative
disease?
c What HBV DNA concentrations necessitate treatment and indicate response
in HBeAg negative disease?
c Should initial evaluation include HBV genotypes?

c In HBeAg positive disease, for whom is PEG interferon or a nucleoside optimal
as first line therapy?
c Should first line treatment include a combination therapy or will some
monotherapies suffice in some?
c What is the appropriate end point of therapy: HBeAg loss or HBeAg
seroconversion?
RECENT ADVANCES IN CLINICAL PRACTICE
118 Gut 2008;57:105–124. doi:10.1136/gut.2005.077891
on 11 August 2008 gut.bmj.comDownloaded from
problematical in patients with decompensated
cirrhosis. Prophylactic therapy with a nucleoside
is recommended for all patients undergoing liver
transplantation for end stage hepatitis B, to lower
levels of HBV DNA to at least less than 10
5
copies/
ml before transplantation. End stage liver disease
should be treated as a matter of urgency. Patients
may show slow clinical improvement over a period
of three to six months. However, some patients
with advanced hepatic disease with a high Child-
Pugh score and jaundice have progressed beyond
the point of no return and will not benefit. A slow
onset of action with suboptimal viral suppression
can be detrimental in patients with hepatic
decompensation. Patients with cirrhosis run the
risk of exacerbation with the development of
resistance. All such patients require long term
treatment, with careful monitoring for resistance
and flares. Regression of fibrosis has been reported.

There are fewer data on the efficacy and safety of
newer potent agents such as entecavir, telbivudine,
and tenofovir in this group, but these could be
used.
Recurrent HBV infection in the transplanted
liver has previously been a major problem.
Lamivudine for pre-transplant prophylaxis, in
combination with hepatitis B immunoglobulin
(HBIG), reduces the risk of graft infection to less
than 10%, as long as the HBV virus is suppressed
before transplantation. With the advent of lami-
vudine and adefovir, outcomes have improved
further.
152 153
Currently both HBIG and lamivudine or adefovir
are used prophylactically, and recurrent HBV is
now rare. Other licensed nucleosides could also be
considered; profound suppression and low rates of
resistance are advantageous.
154–156
Cases associated
with lamivudine resistance used to be problematic,
as patients with recurrent hepatitis B post-trans-
plant may develop fibrosing cholestatic hepatitis, a
manifestation of high levels of viral replication in
immunosuppressed patients. This complication is
currently rare, and should not occur.
157 158
Adefovir
has proved to be in important additional antiviral

drug to salvage patients with lamivudine resistance
pre- or post-transplant in the peritransplant
setting. The optimal timing of transplantation
has not been established, but selection of resistant
strains before surgery should be avoided. Shorter
courses of HBIG and other forms of prophylaxis,
including adefovir in combination with lamivu-
dine, are being studied. Antiviral therapy for
prophylaxis of recurrence post-transplantation
probably requires life long continuation of treat-
ment.
Pregnancy
Recent studies suggest that lamivudine therapy of
pregnant women with high levels of viraemia
during the last trimester of pregnancy reduces the
risk of transmission to the newborn infant, who
should receive HBIg and vaccine at birth. These
studies require confirmation.
Extrahepatic disease
HBsAg positive patients with extrahepatic mani-
festations and active HBV replication may respond
to antiviral therapy.
HDV coinfection
The mainstay of treatment remains long term
interferon. A proportion of patients become HDV
RNA negative, or even HBsAg negative, with
accompanying improvement in histology. To date
treatment with nucleoside analogues has proved
disappointing. IFN remains the only feasible
treatment. Newer agents such as clevudine or

prenylation inhibitors may prove useful but this is
unproven.
159–169
HIV-HBV coinfection
The management of hepatitis B is made more
complex with coinfection with HIV. HBV has little
effect on the natural history or treatment on HIV
infection; however, HIV and HIV treatment
profoundly affect the natural history of HBV.
Therefore it is usually important to target treat-
ment of HBV to alter the outcome and take into
account the impact of HBV treatment on HIV.
Reactivation of hepatitis B may occur with HIV
infection.
170
HIV and HBV coinfection is more
likely to lead to lower rates of HBeAg seroconver-
sion and higher HBV DNA concentrations.
Coinfected patients should be monitored care-
fully at appropriate intervals if HIV disease is
untreated. Treatment of HIV may lead to more
severe hepatitis B with immune restitution.
Patients with active HBV disease should be treated.
It may be possible to achieve seroconversion in
HBeAg positive disease. Patients with normal ALT
are poor responders to interferon and nucleoside
analogue monotherapy, and treatment in isolation
is seldom indicated in these patients. Response
rates in HBeAg positive patients are higher for all
currently licensed agents for those patients with

higher baseline ALT. Responses may be higher in
patients with higher CD4 counts.
171 172
Appropriate treatment should be given for HIV
infection if indicated, or if treatment of HBV is
expected to have an impact on HIV therapy. Long
term suppressive therapy of HIV and HBV will be
required for HBeAg patients who fail to serocon-
vert, and for anti-HBe positive patients. This
should be factored in before starting treatment.
The timing of acquisition of HBV vs HIV will
have a bearing on considerations about treatment.
HIV superinfection may occur in patients with
chronic hepatitis B; alternatively, reactivation of
hepatitis B may occur in an HIV positive patient,
or the patient may be coinfected at diagnosis. The
patient may be naive or experienced, or have
resistant HBV at the time of superinfection. ALT
elevations in coinfected patients may be the result
of opportunistic infections, HAART (highly active
antiretroviral therapy) hepatotoxicity, mitochon-
drial toxicity, HBV clearance, immune reconstitu-
tion, emergence of drug resistance, reactivation
RECENT ADVANCES IN CLINICAL PRACTICE
Gut 2008;57:105–124. doi:10.1136/gut.2005.077891 119
on 11 August 2008 gut.bmj.comDownloaded from
after withdrawal of therapy, or superinfection
with HDV, HAV, or HCV.
173
Other general causes

include alcohol or drugs.
Adefovir has proven useful for HIV positive
patients with lamivudine (3TC) resistance. Longer
term follow up of a cohort of infected patients has
shown that by week 192, 58% of patients had HBV
DNA levels of ,1000 copies/ml and 70% had
normal ALT.
174
However, the cohort of patients
followed in this study continued HAART and
particularly lamivudine therapy (3TC).
If HAART is indicated for a patient coinfected
with HIV, lamivudine can be used, as this drug is
active against HIV and HBV. Tenofovir also is
active against HBV and HIV. Thus treatment of
coinfection offers the opportunity of utilising
combination treatments for hepatitis B. Adefovir
is a useful agent for the treatment of hepatitis B in
HIV coinfected patients where treatment of HIV is
not deemed necessary, as the drug has no effect on
HIV at a dose of 10 mg/day, or for lamivudine
resistant HBV. For HIV HBV coinfection where
treatment of HIV is necessary, tenofovir is the
better option as it is active against both viruses.
Entecavir may have activity against both HIV and
HBV.
VACCINATION
Hepatitis B can be prevented by vaccination.
Immense benefits and pay-offs have already been
achieved in endemic areas, and vaccination remains

a supreme example of preventive medicine
achieved through new biotechnology. Most gov-
ernment programmes worldwide, supported by the
WHO, have elected to consider universal vs
selective vaccination. There are some notable
exceptions in Europe.
CONCLUSIONS
Restoration or stimulation of the host immune
response and clearance of infected hepatocytes
occurs in only a small but critical proportion of
HBeAg positive patients. These patients are more
likely to lose HBeAg on treatment within one year.
This effect is unfortunately not significant or
sufficient for the majority of patients, explaining
the lack of short term finite efficacy of nucleosides
and interferons. The majority of these patients,
and anti-HBe positive patients, will require pro-
longed inhibition of HBV replication—that is,
maintained suppression of HBV DNA.
Suppression of viral replication reduces disease
progression. The continued use of single nucleo-
tides in sequence, as in the past, may lead to the
presence of multidrug resistant hepatitis B. There
are disadvantages to using a monotherapy with
high rates of resistance. These include the fact that
treatment failure is likely, and that failure is
associated with an exacerbation of disease. Use of
a single drug as first line agent will place great
selection pressure on HBV, and will reduce the
benefit of the drug in a total treatment approach

and future effectiveness. However, treatment at
present is confounded by relatively low rates of
resistance with some agents—for example, enteca-
vir and ostensibly tenofovir, and older agents in
patients with lower levels of replication. The
efficacy of effective combination therapy, however,
has not been fully explored. Synergisms have not
been easy to demonstrate, particularly because
similar classes of drugs have been assessed.
Nevertheless, reduced resistance with combination
therapy has been shown, and this should lead to
new clinical and theoretical paradigms for treat-
ment and assessments of cost-effectiveness. It may
be beneficial in the longer term to allow some
redundancy to avoid resistance. Treatment costs in
both developing and developed countries remain
high.
At present clinicians, patients, and public health
authorities must make choices on the basis of data
that are not fully matured. Treatments that are
constantly changing are not easily assimilated into
an algorithm. It remains possible that in the future
L-nucleoside mutations are best prevented by a de
novo combination. Definitions of true resistance
versus polymorphisms, and genotypic, phenotypic,
and clinical resistance remained incomplete.
Treatment optimisation will require sensitive
techniques to detect the emergence of viral
resistance at a stage before the risk of clinically
adverse events.

175
Although treatment decisions
remain challenging for clinicians, it is encouraging
that considerable progress has been made in the
development of potent inhibitors of HBV, which
have greatly facilitated the treatment of this
disease.
Competing interests: Declared (the declaration can be viewed on
the Gut website at />REFERENCES
1. Brooks EA, Lacey LF, Payne SL, et al. Economic evaluation of
lamivudine compared with interferon-alpha in the treatment of
chronic hepatitis B in the United States. Am J Manag Care
2001;7:677–82.
2. Yang BM, Kim CH, Kim JY. Cost of chronic hepatitis B infection
in South Korea. J Clin Gastroenterol 2004;38(10 suppl):S153–7.
3. Keeffe EB, Marcellin P. New and emerging treatment of chronic
hepatitis B. Clin Gastroenterol Hepatol 2007;5:285–94.
4. Keeffe EB, Dieterich DT, Han SH, et al. A treatment algorithm for
the management of chronic hepatitis B virus infection in the
United States: an update. Clin Gastroenterol Hepatol 2006;4:936–
62.
5. Hoofnagle JH, Doo E, Liang TJ, et al. Management of hepatitis
B: summary of a clinical research workshop. Hepatology
2007;45:1056–75.
6. Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology
2007;45:507–39.
7. Webster GJ, Reignat S, Maini MK, et al. Incubation phase of
acute hepatitis B in man: dynamic of cellular immune
mechanisms. Hepatology 2000;32:1117–24.
8. Rehermann B, Fowler P, Sidney J, et al. The cytotoxic T

lymphocyte response to multiple hepatitis B virus polymerase
epitopes during and after acute viral hepatitis. J Exp Med
1995;181:1047–58.
9. Rehermann B. Immune responses in hepatitis B virus infection.
Semin Liver Dis 2003;23:21–38.
10. Rehermann B, Ferrari C, Pasquinelli C, et al. The hepatitis B virus
persists for decades after patients’ recovery from acute viral
hepatitis despite active maintenance of a cytotoxic T-lymphocyte
response. Nat Med 1996;2:1104–8.
11. Boni C, Fisicaro P, Valdatta C, et al. Characterization of hepatitis
B virus (HBV)-specific T-cell dysfunction in chronic HBV infection.
J Virol 2007;81:4215–25.
RECENT ADVANCES IN CLINICAL PRACTICE
120 Gut 2008;57:105–124. doi:10.1136/gut.2005.077891
on 11 August 2008 gut.bmj.comDownloaded from
12. Ferrari C, Penna A, Bertoletti A, et al. Cellular immune response
to hepatitis B virus-encoded antigens in acute and chronic
hepatitis B virus infection. J Immunol 1990;145:3442–9.
13. Ferrari C, Penna A, Bertoletti A, et al. Immune pathogenesis of
hepatitis B [review]. Arch Virol Suppl 1992;4:11–18.
14. Webster GJ, Reignat S, Brown D, et al. Longitudinal analysis of
CD8+ T cells specific for structural and nonstructural hepatitis B
virus proteins in patients with chronic hepatitis B: implications for
immunotherapy. J Virol 2004;78:5707–19.
15. Aylward B, Kane M, McNair-Scott R, et al. Model-based
estimates of the risk of human immunodeficiency virus and
hepatitis B virus transmission through unsafe injections.
Int J Epidemiol 1995;24:446–52.
16. Berger A, Braner J, Doerr HW, et al. Quantification of viral load:
clinical relevance for human immunodeficiency virus, hepatitis B

virus and hepatitis C virus infection. Intervirology 1998;41:24–34.
17. Saldanha J, Gerlich W, Lelie N, et al. An international
collaborative study to establish a World Health Organization
international standard for hepatitis B virus DNA nucleic acid
amplification techniques. Vox Sang 2001;80:63–71.
18. Shyamala V, Cottrell J, Arcangel P, et al. Detection and
quantitation of HBV DNA in the WHO International Standard for
HIV-1 RNA (NIBSC code: 97/656). J Virol Methods 2004;118:69–
72.
19. Kao JH, Chen PJ, Lai MY, et al. Hepatitis B genotypes correlate
with clinical outcomes in patients with chronic hepatitis B.
Gastroenterology 2000;118:554–9.
20. Lindh M, Hannoun C, Dhillon AP, et al. Core promoter mutations
and genotypes in relation to viral replication and liver damage in
East Asian hepatitis B virus carriers. J Infect Dis 1999;179:775–
82.
21. Orito E, Mizokami M, Sakugawa H, et al. A case–control study
for clinical and molecular biological differences between hepatitis
B viruses of genotypes B and C. Hepatology 1901;33:218–23.
22. Tsubota AK, Arase Y, Ren FR, et al. Genotype may correlate
with liver carcinogenesis and tumor characteristics in cirrhotic
patients infected with hepatitis B virus subtype adw. J Med Virol
2001;65:257–65.
23. Lefkowitch JH. The liver in AIDS. Semin Liver Dis 1997;17:335–
44.
24. Hadziyannis SJ, Lieberman HM, Karvountzis GG, et al. Analysis
of liver disease, nuclear HBcAg, viral replication and hepatitis B
virus DNA in liver and serum of HBeAg versus anti-HBe positive
carriers of hepatitis B virus. Hepatology 1983;3:656–62.
25. Hadziyannis SJ, Vassilopoulos D. Hepatitis B e antigen-negative

chronic hepatitis B. Hepatology 2001;34:617–24.
26. Fattovich G, Giustina G, Realdi G, et al. Long-term outcome of
hepatitis B e antigen-positive patients with compensated cirrhosis
treated with interferon alfa. Hepatology 1997;26:1338–42.
27. Tsukuma H, Hiyama T, Tanaka S, et al. Risk factors for
hepatocellular carcinoma among patients with chronic liver
disease. N Engl J Med 1993;328:1797–801.
28. Yang HI, Lu SN, Liaw YF, et al. Hepatitis B e antigen and the risk
of hepatocellular carcinoma. N Engl J Med 2002;347:168–74.
29. Iloeje UH, Yang HI, Su J, et al. Predicting cirrhosis risk based on
the level of circulating hepatitis B viral load. Gastroenterology
2006;130:678–86.
30. Kondili LA, Osman H, Mutimer D. The use of lamivudine for
patients with acute hepatitis B (a series of cases). J Viral Hepat
2004;11:427–31.
31. Schmilovitz-Weiss H, Ben Ari Z, Sikuler E, et al. Lamivudine
treatment for acute severe hepatitis B: a pilot study. Liver Int
2004;24:547–51.
32. Petrelli E, Balducci M, Pieretti C, et al. Lamivudine treatment
failure in preventing fatal outcome of de novo severe acute
hepatitis B in patients with haematological diseases. J Hepatol
2001;35:823–6.
33. Reshef R, Sbeit W, Tur-Kaspa R. Lamivudine in the treatment of
acute hepatitis B. N Engl J Med 2000;343:1123–4.
34. Hessol NA, Koblin BA, Van Griensven GJP, et al. Progression of
human immunodeficiency virus type 1 (HIV-1) infection among
homosexual men in hepatitis B vaccine trial cohorts in
Amsterdam, New York City, and San Francisco, 1978–1991.
Am J Epidemiol 1994;139:1077–87.
35. Niederau C, Heintges T, Lange S, et al. Long-term follow-up of

HBeAg-positive patients treated with interferon alfa for chronic
hepatitis B. N Engl J Med 1996;334:1422–7.
36. Dibisceglie A, Lai CL, Gane E, et al. Telbivudine globe trial:
maximal early HBV suppression is predictive of optimal two-year
efficacy in nucleoside-treated hepatitis B patients. Hepatology
2006;44:230–1A.
37. Lai CL, Gane E, Hsu CW, et al. Two-year results from the globe
trial in patients with hepatitis B: greater clinical and antiviral
efficacy for telbivudine (LDT) vs. lamivudine [abstract].
Hepatology 2006;44:222A.
38. Perrillo RP, Gish RG, Peters M, et al. Chronic hepatitis B: a
critical appraisal of current approaches to therapy. Clin
Gastroenterol Hepatol 2006;4:233–48.
39. McMahon BJ. Selecting appropriate management strategies for
chronic hepatitis B: who to treat. Am J Gastroenterol
2006;101(suppl 1):S7–12.
40. Lok AS, McMahon BJ. [AASLD Practice Guidelines. Chronic
hepatitis B: update of therapeutic guidelines]. Rom J Gastroenterol
2004;13:150–4.
41. EASL. International Consensus Conference on Hepatitis B,
Geneva, 13–14 September 2002. Consensus statement (short
version). J Hepatol 2003;38:533–40.
42. Dusheiko G, Dibisceglie A, Bowyer S, et al. Recombinant
leukocyte interferon treatment of chronic hepatitis B. Hepatology
1985;5:556–60.
43. Samuel CE. Antiviral actions of interferons. Clin Microbiol Rev
2001;14:778–809.
44. Dusheiko GM, Zuckerman AJ. Therapy for hepatitis B. Curr Opin
Infect Dis 1991;4:785–94.
45. Wong DKH, Cheung AM, O’Rourke K et al. Effect of alpha-

interferon treatment in patients with hepatitis B e antigen-positive
chronic hepatitis B: a meta-analysis. Ann Intern Med
1993;119:312–23.
46. Lok AS, McMahon BJ. Chronic hepatitis B: update of
recommendations. Hepatology 2004;39:857–61.
47. Lok AS, Heathcote EJ, Hoofnagle JH. Management of hepatitis
B: 2000 – summary of a workshop. Gastroenterology
2001;120:1828–53.
48. Manesis EK, Hadziyannis SJ. Interferon a treatment and
retreatment of hepatitis B e antigen-negative chronic hepatitis B.
Gastroenterology 2001;121:101–9.
49. Oliveri F, Santantonio T, Bellati G, et al. Long term response to
therapy of chronic anti-HBe-positive hepatitis B is poor
independent of type and schedule of interferon. Am J Gastroenterol
1999;94:1366–72.
50. Lau GK, Piratvisuth T, Luo KX, et al. Peginterferon Alfa-2a,
lamivudine, and the combination for HBeAg-positive chronic
hepatitis B. N Engl J Med 2005;352:2682–95.
51. Janssen HL, van Zonneveld M, Senturk H, et al. Pegylated
interferon alfa-2b alone or in combination with lamivudine for
HBeAg-positive chronic hepatitis B: a randomised trial. Lancet
2005;365:123–9.
52. Marcellin P, Lau GK, Bonino F, et al. Peginterferon alfa-2a alone,
lamivudine alone, and the two in combination in patients with
HBeAg-negative chronic hepatitis B. N Engl J Med
2004;351:1206–17.
53. Bonino F, Marcellin P, Lau GK, et al. Predicting response to
peginterferon {alpha}-2a, lamivudine and the two combined for
HBeAg-negative chronic hepatitis B. Gut 2007;56:699–705.
54. Wursthorn K, Lutgehetmann M, Dandri M, et al. Peginterferon

alpha-2b plus adefovir induce strong cccDNA decline and HBsAg
reduction in patients with chronic hepatitis B. Hepatology
2006;44:675–84.
55. Keeffe EB, Dieterich DT, Han SH, et al. A treatment algorithm for
the management of chronic hepatitis B virus infection in the
United States. Clin Gastroenterol Hepatol 2004;2:87–106.
56. Hoofnagle JH, Di Bisceglie AM, Waggoner JG, et al. Interferon
alfa for patients with clinically apparent cirrhosis due to chronic
hepatitis B. Gastroenterology 1993;104:1116–21.
57. Chong Y, Chu CK. Understanding the unique mechanism of L-
FMAU (clevudine) against hepatitis B virus: molecular dynamics
studies. Bioorg Med Chem Lett 2002;12:3459–62.
58. De Clercq E. Perspectives for the treatment of hepatitis B virus
infections. Int J Antimicrob Agents 1999;12:81–95.
59. De Man RA, Heijtink RA, Niesters HGM, et al. New
developments in antiviral therapy for chronic hepatitis B infection.
Scand J Gastroenterol 1995;30(suppl 212):100–4.
60. Dusheiko GM. Treatment and prevention of chronic viral
hepatitis. Pharmacol Ther 1995;65:47–73.
61. Torresi J, Locarnini S. Antiviral chemotherapy for the treatment
of hepatitis B virus infections. Gastroenterology 2000;118:S83–
103.
62. Werle-Lapostolle B, Bowden S, Locarnini S, et al. Persistence
of cccDNA during the natural history of chronic hepatitis B and
decline during adefovir dipivoxil therapy. Gastroenterology
2004;126:1750–8.
63. Zoulim F. New insight on hepatitis B virus persistence from the
study of intrahepatic viral cccDNA. J Hepatol 2005;42:302–8.
64. Zoulim F. Antiviral therapy of chronic hepatitis B: can we clear
the virus and prevent drug resistance? Antivir Chem Chemother

2004;15:299–305.
RECENT ADVANCES IN CLINICAL PRACTICE
Gut 2008;57:105–124. doi:10.1136/gut.2005.077891 121
on 11 August 2008 gut.bmj.comDownloaded from
65. Boni C, Bertoletti A, Penna A, et al. Lamivudine treatment can
restore T cell responsiveness in chronic hepatitis B. J Clin Invest
1998;102:968–75.
66. Lai CL, Chien RN, Leung NW, et al. A one-year trial of lamivudine
for chronic hepatitis B. N Engl J Med 1998;339:61–8.
67. Perrillo RP, Lai CL, Liaw YF, et al. Predictors of HBeAg loss after
lamivudine treatment for chronic hepatitis B. Hepatology
2002;36:186–94.
68. Chien RN, Liaw YF, Atkins M. Pretherapy alanine transaminase
level as a determinant for hepatitis B e antigen seroconversion
during lamivudine therapy in patients with chronic hepatitis B.
Asian Hepatitis Lamivudine Trial Group. Hepatology 1999;30:770–
4.
69. Zollner B, Petersen J, Puchhammer-Stockl E, et al. Viral features
of lamivudine resistant hepatitis B genotypes A and D. Hepatology
2004;39:42–50.
70. Lai CL, Leung N, Teo EK, et al. A 1-year trial of telbivudine,
lamivudine, and the combination in patients with hepatitis B e
antigen-positive chronic hepatitis B. Gastroenterology
2005;129:528–36.
71. Yuen MF, Sablon E, Hui CK, et al. Factors associated with
hepatitis B virus DNA breakthrough in patients receiving
prolonged lamivudine therapy. Hepatology 2001;34:785–91.
72. Tassopoulos NC, Volpes R, Pastore G, et al. Efficacy of
lamivudine in patients with hepatitis B e antigen-negative
hepatitis B virus DNA-positive (precore mutant) chronic hepatitis

B. Hepatology 1999;29:889–96.
73. Liaw YF, Sung JJ, Chow WC, et al. Lamivudine for patients with
chronic hepatitis B and advanced liver disease. N Engl J Med
2004;351:1521–31.
74. Ling R, Mutimer D, Ahmed N, et al. Selection of mutations in the
hepatitis B virus polymerase during therapy of transplant
recipients with lamivudine. Hepatology 1996;24:711–13.
75. Locarnini S, Hatzakis A, Heathcote J, et al. Management of
antiviral resistance in patients with chronic hepatitis B. Antivir
Ther 2004;9:679–93.
76. Zollner B, Petersen J, Schafer P, et al. Subtype-dependent
response of hepatitis B virus during the early phase of lamivudine
treatment. Clin Infect Dis 2002;34:1273–7.
77. Dienstag JL, Goldin RD, Heathcote EJ, et al. Histological
outcome during long-term lamivudine therapy. Gastroenterology
2003;124:105–17.
78. Delaney WE, Edwards R, Colledge D, et al. Cross-resistance
testing of antihepadnaviral compounds using novel recombinant
baculoviruses which encode drug-resistant strains of hepatitis B
virus. Antimicrob Agents Chemother 2001;45:1705–13.
79. Delaney WE, Yang H, Westland CE, et al. In vitro cross
resistance testing of adefovir, entecavir, and b-L-thymidine
against drug-resistant strains of HBV [abstract]. Hepatology
2001;34:628A
80. Kramata P, Votruba I, Otova B, et al. Different inhibitory
potencies of acyclic phosphonomethoxyalkyl nucleotide analogs
toward DNA polymerases alpha, delta and epsilon. Mol
Pharmacol 1996;49:1005–11.
81. Heijtink RA, De Wilde GA, Kruining J, et al. Inhibitory effect of 9-
(2-phosphonylmethoxyethyl)-adenine (PMEA) on human and duck

hepatitis B virus infection. Antiviral Res 1993;21:141–53.
82. Cundy KC, Barditch-Crovo P, Walker RE, et al. Clinical
pharmacokinetics of adefovir in human immunodeficiency virus
type 1-infected patients. Antimicrob Agents Chemother
1995;39:2401–5.
83. Shaw JP, Louie MS, Krishnamurthy VV, et al. Pharmacokinetics
and metabolism of selected prodrugs of PMEA in rats. Drug
Metab Dispos 1997;25:362–6.
84. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Adefovir
dipivoxil for the treatment of hepatitis B e antigen-negative
chronic hepatitis B. N Engl J Med 2003;348:800–7.
85. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Long-
term therapy with adefovir dipivoxil for HBeAg-negative chronic
hepatitis B. N Engl J Med 2005;352:2673–81.
86. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Long-
term therapy with adefovir dipivoxil for HBeAg-negative chronic
hepatitis B for up to 5 years. Gastroenterology 2006;131:1743–
51.
87. Zoulim F. Assessing hepatitis B virus resistance in vitro and
molecular mechanisms of nucleoside resistance. Semin Liver Dis
2002;22(suppl 1):23–31.
88. Das K, Xiong X, Yang H, et al. Molecular modeling and
biochemical characterization reveal the mechanism of hepatitis B
virus polymerase resistance to lamivudine (3TC) and emtricitabine
(FTC). J Virol 2001;75:4771–9.
89. Angus P, Vaughan R, Xiong S, et al. Resistance to adefovir
dipivoxil therapy associated with the selection of a novel mutation
in the HBV polymerase. Gastroenterology 2003;125:292–7.
90. Delaney WE, Yang H, Miller MD, et al. Combinations of adefovir
with nucleoside analogs produce additive antiviral effects against

hepatitis B virus in vitro. Antimicrob Agents Chemother
2004;48:3702–10.
91. Villeneuve JP, Durantel D, Durantel S, et al. Selection of a
hepatitis B virus strain resistant to adefovir in a liver
transplantation patient. J Hepatol 2003;39:1085–9.
92. Westland CE, Yang H, Delaney WE, et al. Week 48 resistance
surveillance in two phase 3 clinical studies of adefovir dipivoxil for
chronic hepatitis B. Hepatology 2003;38:96–103.
93. Yeon JE, Yoo W, Hong SP, et al. Resistance to adefovir dipivoxil
in lamivudine resistant chronic hepatitis B patients treated with
adefovir dipivoxil. Gut 2006;55:1488–95.
94. Lee YS, Suh DJ, Lim YS, et al. Increased risk of adefovir
resistance in patients with lamivudine-resistant chronic hepatitis
B after 48 weeks of adefovir dipivoxil monotherapy. Hepatology
2006;43:1385–91.
95. Perrillo R, Schiff E, Yoshida E, et al. Adefovir dipivoxil for the
treatment of lamivudine-resistant hepatitis B mutants. Hepatology
2000;32:129–34.
96. Walsh KM, Woodall T, Lamy P, et al. Successful treatment with
adefovir dipivoxil in a patient with fibrosing cholestatic hepatitis
and lamivudine resistant hepatitis B virus. Gut 2001;49:436–40.
97. Mutimer D, Feraz-Neto BH, Harrison R, et al. Acute liver graft
failure due to emergence of lamivudine resistant hepatitis B virus:
rapid resolution during treatment with adefovir. Gut
2001;49:860–3.
98. Tillmann HL, Bock CT, Bleck JS, et al. Successful treatment of
fibrosing cholestatic hepatitis using adefovir dipivoxil in a patient
with cirrhosis and renal insufficiency. Liver Transpl 2003;9:191–6.
99. Peters MG, Hann HH, Martin P, et al. Adefovir dipivoxil alone or
in combination with lamivudine in patients with lamivudine-

resistant chronic hepatitis B. Gastroenterology 2004;126:91–101.
100. Lampertico P, Vigano M, Manenti E, et al. Adefovir rapidly
suppresses hepatitis B in HBeAg-negative patients developing
genotypic resistance to lamivudine. Hepatology 2005;42:1414–
19.
101. Rapti I, Dimou E, Mitsoula P, et al. Adding-on versus switching-to
adefovir therapy in lamivudine-resistant HBeAg-negative chronic
hepatitis B. Hepatology 2007;45:307–13.
102. Schiff ER, Lai CL, Hadziyannis S, et al. Adefovir dipivoxil therapy
for lamivudine-resistant hepatitis B in pre- and post-liver
transplantation patients. Hepatology 2003;38:1419–27.
103. Schiff E. Adefovir dipivoxil for wait-listed and post-liver
transplantation patients with lamivudine-resistant hepatitis B:
final long-term results. 2007.
104. Schiff E, Lai CL, Hadziyannis S, et al. Adefovir dipivoxil for wait-
listed and post-liver transplantation patients with lamivudine-
resistant hepatitis B: final long-term results. Liver Transpl
2007;13:349–60.
105. Colonno RJ, Genovesi EV, Medina I, et al. Long-term entecavir
treatment results in sustained antiviral efficacy and prolonged life
span in the woodchuck model of chronic hepatitis infection.
J Infect Dis 2001;184:1236–45.
106. De Man RA, Wolters LMM, Nevens F, et al. Safety and efficacy
of oral entecavir given for 28 days in patients with chronic
hepatitis B virus infection. Hepatology 2001;34:578–82.
107. Honkoop P, De Man RA. Entecavir: a potent new antiviral drug
for hepatitis B. Expert Opin Investig Drugs 2003;12:683–8.
108. Marion PL, Salazar FH, Winters MA, et al. Potent efficacy of
entecavir (BMS-200475) in a duck model of hepatitis B virus
replication. Antimicrob Agents Chemother 2002;46:82–8.

109. Lai CL, Rosmawati M, Lao J, et al. Entecavir is superior to
lamivudine in reducing hepatitis B virus DNA in patients with
chronic hepatitis B infection. Gastroenterology 2002;123:1831–8.
110. Chang TT, Gish RG, De Man R, et al. A comparison of entecavir
and lamivudine for HBeAg-positive chronic hepatitis B.
N Engl J Med 2006;354:1001–10.
111. Lai CL, Shouval D, Lok AS, et al. Entecavir versus lamivudine for
patients with HBeAg-negative chronic hepatitis B. N Engl J Med
2006;354:1011–20.
112. Tenney DJ, Levine SM, Rose RE, et al. Clinical emergence of
entecavir-resistant hepatitis B virus requires additional
substitutions in virus already resistant to Lamivudine. Antimicrob
Agents Chemother 2004;48:3498–507.
113. Wang ZY, Zhang DZ, Shi XF, et al. [Investigation of entecavir
medication of chronic hepatitis B patients in the Chongqing area
who failed lamivudine treatment]. Zhonghua Gan Zang Bing Za
Zhi 2007;15:13–15.
RECENT ADVANCES IN CLINICAL PRACTICE
122 Gut 2008;57:105–124. doi:10.1136/gut.2005.077891
on 11 August 2008 gut.bmj.comDownloaded from
114. Villet S, Ollivet A, Pichoud C, et al. Stepwise process for the
development of entecavir resistance in a chronic hepatitis B virus
infected patient. J Hepatol 2007;46:531–8.
115. Liaw YF. Rescue therapy for lamivudine-resistant chronic
hepatitis B: when and how? Hepatology 2007;45:266–8.
116. Zoulim F. Hepatitis B virus resistance to entecavir in nucleoside
naive patients: does it exist? Hepatology 2006;44:1404–7.
117. Colonno RJ, Rose R, Baldick CJ, et al. Entecavir resistance is
rare in nucleoside naive patients with hepatitis B. Hepatology
2006;44:1656–65.

118. Ying C, Colonno R, De CE, et al. Ribavirin and mycophenolic acid
markedly potentiate the anti-hepatitis B virus activity of entecavir.
Antiviral Res 2007;73:192–6.
119. Bryant ML, Bridges EG, Placidi L, et al. Antiviral L-nucleosides
specific for hepatitis B virus infection. Antimicrob Agents
Chemother 1901;45:229–35.
120. Bryant ML, Bridges EG, Placidi L, et al. Anti-HBV specific beta-L-
29-deoxynucleosides. Nucleosides Nucleotides Nucleic Acids
2001;20:597–607.
121. Standring DN, Bridges EG, Placidi L, et al. Antiviral beta-L-
nucleosides specific for hepatitis B virus infection. Antivir Chem
Chemother 2001;12(suppl 1):119–29.
122. Bridges E. Telbivudine preclinical safety studies suggest minimal
risk of chronic toxicity, reproductive toxicity or carcinogenicity
[abstract]. Gastroenterology 2006;130:A847.
123. Dienstag JL. Looking to the future: New agents for chronic
hepatitis B. Am J Gastroenterol 2006;101:S19–25.
124. Golitsina N, Danehy F, Fellows R, et al. Telbivudine
phosphorylation by three enzymes: Implications for anti-hepatitis
B virus activity in vitro and in the clinic [abstract]. Hepatology
2006;44:561A.
125. Hu P, Jiang J, Wang HY, et al. Single-dose and multiple-dose
pharmacokinetics and safety of telbivudine after oral
administration in healthy Chinese subjects. J Clin Pharmacol
2006;46:999–1007.
126. Lai CL, Lim SG, Brown NA, et al. A dose-finding study of once-
daily oral telbivudine in HBeAg-positive patients with chronic
hepatitis B virus infection. Hepatology 2004;40:719–26.
127. Zhou XJ, Lloyd DM, Chao GC, et al. Absence of food effect on
the pharmacokinetics of telbivudine following oral administration

in healthy subjects. J Clin Pharmacol 2006;46:275–81.
128. Zhou XJ, Lloyd DM, Fielman BA, et al. Absence of
pharmacokinetic drug-drug interaction between telbivudine and
lamivudine or adefovir in healthy subjects. J Hepatol
2005;42:197–8.
129. Zhou XJ, Myers M, Chao G, et al. Clinical pharmacokinetics of
telbivudine, a potent antiviral for hepatitis B, in subjects with
impaired hepatic or renal function. J Hepatol 2004;40:134.
130. Zhou XJ, Marbury TC, Alcorn HW, et al. Pharmacokinetics of
telbivudine in subjects with various degrees of hepatic
impairment. Antimicrob Agents Chemother 2006;50:1721–6.
131. Zhou XJ, Lim SG, Lloyd DM, et al. Pharmacokinetics of
telbivudine following oral administration of escalating single and
multiple doses in patients with chronic hepatitis B virus infection:
pharmacodynamic implications. Antimicrob Agents Chemother
2006;50:874–9.
132. Zhou XJ, Fielman BA, Lloyd DM, et al. Pharmacokinetics of
telbivudine in healthy subjects and absence of drug interaction
with lamivudine or adefovir dipivoxil. Antimicrob Agents
Chemother 2006;50:2309–15.
133. Chan HLY, Lai CL, Cho M, et al. A randomized trial of telbivudine
(LDT) vs. adefovir for HBeAg-positive chronic hepatitis B: results
of the primary week 24 analysis. J Hepatol 2006;44:S24–5.
134. Dore GJ, Cooper DA, Pozniak AL, et al. Efficacy of tenofovir
disoproxil fumarate in antiretroviral therapy-naive and -
experienced patients coinfected with HIV-1 and hepatitis B virus.
J Infect Dis 2004;189:1185–92.
135. Lacombe K, Gozlan J, Boelle PY, et al. Long-term hepatitis B
virus dynamics in HIV-hepatitis B virus-co-infected patients
treated with tenofovir disoproxil fumarate. AIDS 2005;19:907–15.

136. Nelson M, Portsmouth S, Stebbing J, et al. An open-label study
of tenofovir in HIV-1 and hepatitis B virus co-infected individuals.
AIDS 2003;17:F7–10.
137. Benhamou Y, Tubiana R, Thibault V. Tenofovir disoproxil
fumarate in patients with HIV and lamivudine-resistant hepatitis B
virus. N Engl J Med 2003;348:177–8.
138. Bruno R, Sacchi P, Zocchetti C, et al. Rapid hepatitis B virus-DNA
decay in co-infected HIV-hepatitis B virus ‘e-minus’ patients with
YMDD mutations after 4 weeks of tenofovir therapy. AIDS
2003;17:783–4.
139. Kuo A, Dienstag JL, Chung RT. Tenofovir disoproxil fumarate for
the treatment of lamivudine-resistant hepatitis B. Clin
Gastroenterol Hepatol 2004;2:266–72.
140. Van Bommel F, Zollner B, Sarrazin C, et al. Tenofovir for patients
with lamivudine-resistant hepatitis B virus (HBV) infection and
high HBV DNA level during adefovir therapy. Hepatology
2006;44:318–25.
141. Van Bommel F, Wunsche T, Mauss S, et al. Comparison of
adefovir and tenofovir in the treatment of lamivudine-resistant
hepatitis B virus infection. Hepatology 2004;40:1421–5.
142. Benhamou Y, Fleury H, Trimoulet P, et al. Anti-hepatitis B virus
efficacy of tenofovir disoproxil fumarate in HIV-infected patients.
Hepatology 2006;43:548–55.
143. Gish RG, Trinh H, Leung N, et al. Safety and antiviral activity of
emtricitabine (FTC) for the treatment of chronic hepatitis B
infection: a two-year study. J Hepatol 2005;43:60–6.
144. Korba BE, Schinazi RF, Cote P, et al. Effect of oral administration
of emtricitabine on woodchuck hepatitis virus replication in
chronically infected woodchucks. Antimicrob Agents Chemother
2000;44:1757–60.

145. Lim SG, Ng TM, Kung N, et al. A double-blind placebo-controlled
study of emtricitabine in chronic hepatitis B. Arch Intern Med
2006;166:49–56.
146. Kocic I. Clevudine. University of Georgia/Abbott/Bukwang/
Triangle/Yale University. Curr Opin Investig Drugs 2000;1:308–13.
147. Marcellin P, Mommeja-Marin H, Sacks SL, et al. A phase II
dose-escalating trial of clevudine in patients with chronic hepatitis
B. Hepatology 2004;40:140–8.
148. Peek SF, Cote PJ, Jacob JR, et al. Antiviral activity of clevudine
[L-FMAU, (1-(2-fluoro-5-methyl-beta, L-arabinofuranosyl) uracil)]
against woodchuck hepatitis virus replication and gene
expression in chronically infected woodchucks (Marmota monax).
Hepatology 2001;33:254–66.
149. Jacquard AC, Nassal M, Pichoud C, et al. Effect of a
combination of clevudine and emtricitabine with adenovirus-
mediated delivery of gamma interferon in the woodchuck model
of hepatitis B virus infection. Antimicrob Agents Chemother
2004;48:2683–92.
150. Lee HS, Chung YH, Lee K, et al. A 12-week clevudine therapy
showed potent and durable antiviral activity in hbeag-positive
chronic hepatitis B. Hepatology 2006;43:982–8.
151. Brunelle MN, Lucifora J, Neyts J, et al. In vitro activity of 2,4-
diamino-6-[2-(phosphonomethoxy)ethoxy]-pyrimidine against
multidrug-resistant hepatitis B virus (HBV) mutants. Antimicrob
Agents Chemother 2007;51:2240–3.
152. Grellier L, Mutimer D, Ahmed M, et al. Lamivudine prophylaxis
against reinfection in liver transplantation for hepatitis B cirrhosis.
Lancet 1996;348:1212–15.
153. Mutimer D, Dusheiko G, Barrett C, et al. Lamivudine without
HBIg for prevention of graft reinfection by hepatitis B: long-term

follow-up. Transplantation 2000;70:809–15.
154. Han SH, Kinkhabwala M, Martin P, et al. Resolution of recurrent
hepatitis B in two liver transplant recipients treated with
famciclovir. Am J Gastroenterol 1998;93:2245–7.
155. Markowitz JS, Martin P, Conrad AJ, et al. Prophylaxis against
hepatitis B recurrence following liver transplantation using
combination lamivudine and hepatitis B immune globulin.
Hepatology 1998;28:585–9.
156. Sousa JM, Pareja F, Serrano J, et al. Comparison between levels
of anti-HBS with a fixed administration dose of HBIG and a
combination of HBIG and lamivudine for the prophylaxis of
hepatitis B after liver transplantation. Transplant Proc
2003;35:723–4.
157. Davies SE, Portmann BC, O’Grady JG, et al. Hepatic histological
findings after transplantation for chronic hepatitis B virus
infection, including a unique pattern of fibrosing cholestatic
hepatitis. Hepatology 1991;13:150–7.
158. Lau JY, Bain VG, Davies SE, et al. High-level expression of
hepatitis B viral antigens in fibrosing cholestatic hepatitis.
Gastroenterology 1992;102:956–62.
159. Andreone P, Spertini F, Negro F. Lamivudine-associated
remission of chronic hepatitis delta. Ann Intern Med
2000;132:598.
160. Battegay M, Simpson LH, Hoofnagle JH, et al. Elimination of
hepatitis delta virus infection after loss of hepatitis B surface
antigen in patients with chronic delta hepatitis. J Med Virol
1994;44:389–92.
161. Berk L, De Man RA, Housset C, et al. Alpha lymphoblastoid
interferon and acyclovir for chronic hepatitis delta. Prog Clin Biol
Res 1991;364:411–20.

162. Bordier BB, Ohkanda J, Liu P, et al. In vivo antiviral efficacy of
prenylation inhibitors against hepatitis delta virus. J Clin Invest
2003;112:407–14.
163. Cariani E, Ravaggi A, Puoti M, et al. Evaluation of hepatitis delta
virus RNA levels during interferon therapy by analysis of
RECENT ADVANCES IN CLINICAL PRACTICE
Gut 2008;57:105–124. doi:10.1136/gut.2005.077891 123
on 11 August 2008 gut.bmj.comDownloaded from
polymerase chain reaction products with a nonradioisotopic
hybridization assay. Hepatology 1992;15:685–9.
164. Chen TZ, Wu JC, Au LC, et al. Specific inhibition of delta antigen
by in vitro system by antisense oligodeoxynucleotide: implications
for translation mechanism and treatment. J Virol Methods
1997;65:183–9.
165. Di Bisceglie AM, Negro F, Smedile A, et al. Alpha interferon
therapy of chronic delta hepatitis: a pilot study. Prog Clin Biol Res
1991;364:393–7.
166. Farci P, Mandas A, Coiana A, et al. Treatment of chronic hepatitis D
with interferon alfa-2a. N Engl J Med 1994;330:88–94.
167. Farci P, Roskams T, Chessa L, et al. Long-term
benefit of interferon alpha therapy of chronic hepatitis D:
regression of advanced hepatic fibrosis. Gastroenterology
2004;126:1740–9.
168. Casey J, Cote PJ, Toshkov IA, et al. Clevudine inhibits hepatitis
delta virus viremia: a pilot study of chronically infected
woodchucks. Antimicrob Agents Chemother 2005;49:4396–9.
169. Farci P. Treatment of chronic hepatitis D: new advances, old
challenges. Hepatology 2006;44:536–9.
170. Altfeld M, Rockstroh JK, Addo M, et al. Reactivation of hepatitis
B in a long-term anti-HBs-positive patient with AIDS following

lamivudine withdrawal. J Hepatol 1998;29:306–9.
171. Smit MC, Haverkamp MH, Weersink AJ, et al. [Patients co-
infected with HIV and hepatitis-B virus (HBV): the favourable
effect of lamivudine, as part of combined antiretroviral therapy, on
HBV may be dependent upon the number of CD4-cells]. Ned
Tijdschr Geneeskd 2004;148:2330–4.
172. Bruguera M, Cremades M, Salinas R, et al. Impaired response to
recombinant hepatitis B vaccine in HIV- infected persons. J Clin
Gastroenterol 1992;14:27–30.
173. Dore GJ, Cooper DA. The impact of HIV therapy on co-infection
with hepatitis B and hepatitis C viruses. Curr Opin Infect Dis
2001;14:749–55.
174. Benhamou Y, Bochet M, Thibault V, et al. Safety and efficacy of
adefovir dipivoxil in patients co-infected with HIV-1 and
lamivudine-resistant hepatitis B virus: an open-label pilot study.
Lancet 2001;358:718–23.
175. Pallier C, Castera L, Soulier A, et al. Dynamics of hepatitis B
virus resistance to lamivudine. J Virol 2006;80:643–53.
ANSWER
From question on page 103
Figure 1 (3.5 MHz convex probe abdominal ultrasonography)
shows a long tubular serpigenous structure (which appeared
mobile in real time) located in the second part of the duodenum.
Part of this structure is seen within the main pancreatic duct.
The head of the pancreas appears bulky. Figure 2 shows a high
frequency ultrasonograph (7.5 MHz linear probe) in which the
tubular structure is suggestive of a round worm.
Subsequent side viewing endoscopy confirmed the tubular
structure to be a live round worm (fig 3) which was removed
intact in the same sitting.

The diagnosis is acute pancreatitis (as indicated by the raised
serum amylase level) caused by the round worm in the
pancreatic duct (pancreatic ascariasis).
Ascariasis is the most common helminthic infestation that
affects .1.4 billion people worldwide, and the majority of cases
hail from Asian and Latin American countries.
1
It is responsible
for 50–60% of paediatric admissions to the emergency depart-
ment, of which 10% is constituted by hepatobiliary and
pancreatic ascariasis.
2
Our case suggests that some varieties of
pancreatitis are a result of pancreatic ductal obstruction rather
than biliary reflux as per Opie’s common channel hypothesis.
Real-time ultrasonography is an efficient, reliable and non-
invasive diagnostic approach for pancreatic ascariasis.
3
Endoscopic removal of the ascaris from the pancreatobiliary
tract is possible in up to 73% of cases.
4
Gut 2008;57:124. doi:10.1136/gut.2006.110601a
REFERENCES
1. Khuroo MS. Hepatobiliary and pancreatic ascariasis. Indian J Gastroenterol
2001;20(Suppl 1):C28–32.
2. Malik AH, Saima BD, Wani MY. Management of hepatobiliary and pancreatic
ascariasis in children of an endemic area. Pediatr Surg Int 2006;22:164–8.
3. Ferreyra NP, Cerri GG. Ascariasis of the alimentary tract, liver, pancreas and biliary
system: its diagnosis by ultrasonography. Hepatogastroenterology 1998;45:932–7.
4. Chinh ND, Long NT, Bach TT, et al. Ascaris-induced acute pancreatitis. Ann Chir

2004;129:83–6.
G
Figure 1 Side viewing endoscopic picture showing a live round worm
in the second part of the duodenum.
Editor’s quiz: GI snapshot
RECENT ADVANCES IN CLINICAL PRACTICE
124 Gut January 2008 Vol 57 No 1
on 11 August 2008 gut.bmj.comDownloaded from
LETTER
Dosing azathioprine in thiopurine
S-methyltransferase deficient
inflammatory bowel disease
patients
With great interest we read the article by
Kaskas et al (Gut 2003;52:140–2) about safe
treatment of thiopurine S-methyltransferase
(TPMT) deficient Crohn’s disease patients
with azathioprine (AZA). In this paper it is
illustrated that TPMT-deficient patients can
be successfully treated with very low doses
of AZA (,10% of standard initial dose).
Unfortunately, this is not the case for all
homozygous mutant TPMT allele carriers.
This is demonstrated by the case report of
an exceptional thiopurine S-methyltransfer-
ase deficient patient with inflammatory
bowel disease who we identified recently.
A 19-year-old man with ulcerative colitis
who was attending the outpatient clinic was
treated with AZA 150 mg once daily and

cyclosporine 150 mg twice daily and devel-
oped severe pancytopenia (leukocyte count,
0.8610
9
/l; thrombocyte count, 44610
9
/l;
haemoglobin, 4.5 mmol/l) and sepsis conse-
quently 2 months after start of treatment.
Both drugs were discontinued immediately.
After long-term hospitalisation the patient
was discharged and after normalisation of
6-thioguanine nucleotides (6-TGNs) levels
and blood cell counts, AZA was carefully
restarted at a 25 mg daily dosage with
frequent monitoring. After 2 weeks AZA
was discontinued because of a decrease in
leukocyte (3.7610
9
/l) and thrombocyte
(66610
9
/l) counts. Cyclosporine and steroids
were administered but had no clinical effect.
Two months later infliximab was started
combined with AZA at an even lower dose
of 12.5 mg once daily. Ten weeks thereafter,
the patient developed leukopenia once again
(leukocyte count 3.7610
9

/l) and AZA was
discontinued once more. 6-TGN levels were
as high as 969 pmol per 8610
8
red blood cells
(RBCs), the proposed therapeutic window
being 250–500 pmol per 8610
8
RBC. TPMT
phenotyping revealed an intermediate meta-
boliser (0.76 pmol per 10
6
RBC/h), while
TPMT genotyping surprisingly revealed a
homozygous mutant (*3A/*3A). The patient
is currently being treated successfully with
infliximab monotherapy once every
8 weeks.
Three important lessons can be learned
from this case. First, despite very low AZA
dosing (approximately 5% of standard dose)
this IBD patient with homozygous TPMT
mutant alleles developed very high 6-TGN
levels and leucopenia consequently. We
totally agree with Kaskas et al that, in
specific cases, TPMT deficiency in patients
with inflammatory bowel disease (IBD) per
se does not preclude thiopurine treatment
and hence offers a further therapeutic option
for this group of patients. This should be

done with great caution, however; that is,
with very frequent blood tests and 6-TGN
monitoring, as in some cases even a 5%
starting dose can be dangerous.
Second, although TPMT genotype and
phenotype normally show very high correla-
tions,
1
there are exceptional cases. In our case,
6-TGN levels were a far better predictor of
TPMT deficiency than was TPMT activity.
Third, despite the TPMT *3A/*3A geno-
type, it lasted 2 months before leucopenia
developed on a standard AZA dose in our
patient. This is very unusual as most
patients with homozygous TPMT mutant
alleles develop myelotoxicity 1–2 weeks
after starting standard thiopurine treat-
ment.
23
A longer period of very frequent
monitoring is advisable when thiopurine
treatment is started in homozygous TPMT
mutant carriers. This rare group of patients
should be treated with the greatest caution.
L J J Derijks,
1
R B van Helden,
2
D W Hommes,

2
P C Stokkers
3,4
1
Department of Clinical Pharmacy, Ma´xima Medical Center,
Veldhoven, The Netherlands;
2
Department of
Gastroenterology & Hepatology, Leiden University Medical
Center, Leiden, The Netherlands;
3
Department of
Gastroenterology & Hepatology, Academic Medical Center,
Amsterdam, The Netherlands
Correspondence to: Dr Luc J J Derijks, Department of
Clinical Pharmacy, Ma´xima Medical Center, PO Box 7777,
5500 MB Veldhoven, The Netherlands;
Competing interests: None.
Gut 2008;57:872. doi:10.1136/gut.2007.145912
REFERENCES
1. Sanderson J, Ansari A, Marinaki T, et al. Thiopurine
methyltransferase: should it be measured before
commencing thiopurine drug therapy? Ann Clin
Biochem 2004;41(Pt 4):294–302.
2. Lennard L. TPMT in the treatment of Crohn’s disease
with azathioprine. Gut 2002;51:143–6.
3. Derijks LJ, Gilissen LP, Engels LG, et al.
Pharmacokinetics of 6-mercaptopurine in patients with
inflammatory bowel disease: implications for therapy.
Ther Drug Monit 2004;26:311–8.

CORRECTIONS
doi:10.1136/gut.2005.077891corr1
Dusheiko G, Antonakopoulos N. Current
treatment of hepatitis B. (Gut 2008;57:105–
24).
There are several mistakes in this article.
(1) In the section ‘‘Major patterns of chronic
hepatitis’’, under the heading ‘‘HBeAg posi-
tive chronic hepatitis B’’, the sentence
‘‘Spontaneous seroconversion rates remain
relatively low in this group at approximately
20% at one year’’ should read ‘‘at 5–15%’’.
(2) In table 1, reference 48 should be
reference 50 and reference 83 should be
reference 111. (3) In table 2, reference 50
should be 52 and reference 83 should
reference 111. (4) Also in table 2, the
entecavir 0.5 mg resistance rate in HBeAg
negative patients is 0–1%, not 8%.
doi:10.1136/gut.2006.gt114892corr1
Persiani R, Biondi A, Larocca L, et al.
Intussusception in a 51-year-old male. (Gut
2008;57:242). In this article the third
author’s name was published incorrectly as
Luigi L: it should be Larocca L.
PostScript
872 Gut June 2008 Vol 57 No 6
on 11 August 2008 gut.bmj.comDownloaded from