HBV Treatment - Standard of care

Introduction

Despite the availability of a prophylactic vaccine, with more than 350 million
chronically infected individuals worldwide, chronic hepatitis B virus (HBV) infection
remains a major global health concern (EASL 2002). Chronically infected individuals
carry a significantly increased risk of life-threatening liver complications
such as hepatic decompensation, liver cirrhosis and hepatocellular carcinoma
(HCC) (Beasley 1988). Recent studies have shown that the level of serum HBV
DNA for more than a decade correlates with the risk of developing cirrhosis and
HCC (Figure 1) (Iloeje 2006; Chen 2006). Therefore, suppressing the replication of
HBV to levels below the limit of detection of sensitive HBV DNA diagnostic tests
has become a major goal in HBV treatment.
For the treatment of chronic HBV infection two classes of agents are approved:
first, antiviral nucleos(t)ide analogues directly inhibiting HBV DNA replication and
second, interferon ƒ¿-based therapies that may modulate host immune response as
well as viral replication.
The number of agents approved for the treatment of chronic HBV infection has
steadily increased over recent years. In Europe seven medications for the treatment
of chronic hepatitis B are available: standard interferon ƒ¿-2a and ƒ¿-2b and PEGIFN
ƒ¿-2a, the nucleoside analogues lamivudine, telbivudine and entecavir and the
acyclic nucleotide analogues adefovir and tenofovir. More nucleos(t)ide analogues
with antiviral activity against HBV such as emtricitabine, clevudine, torcitabine,
amdoxovir and alamifovir are currently in clinical development.
Due to this significant expansion of therapeutic options, in most cases progression
of HBV infection and prevention of complications can be managed when the infection
is diagnosed in a timely manner and effectively treated. The early diagnosis of
chronic hepatitis B by HBS antigen (HBsAg) screening in high-risk groups and in
patients with elevated transaminases plays a crucial role in the management of HBV
infection.
Figure 1. Cumulative incidence of liver cirrhosis in untreated HBV-infected individuals within a
mean observation period of 11.4 years (REVEAL study). The incidence of liver cirrhosis increases
over time depending on the baseline HBV levels (Cornberg 2007).

Goals of antiviral therapy

Treatment endpoints
The aim of chronic hepatitis B therapy is to reduce the morbidity and mortality of
HBV infections such as liver failure and hepatocellular carcinoma (HCC) and increase
survival. To reach this goal surrogate markers must be used during and after
treatment to determine the success of therapy. This issue raises the question of
which of the different parameters (e.g., transaminases, liver histology, HBeAg and
HBsAg status, HBV DNA level) allows for a rapid prediction of favourable longterm
outcomes with respect to prevention of HBV-related complications
In two recent studies a close correlation between baseline HBV DNA levels and
progression of the disease has been demonstrated. In the REVEAL study, 3774 untreated
HBV-infected individuals were followed over a mean time period of 11.4
years in Taiwan (Iloeje 2006; Chen 2006). The entry HBV DNA level was the
strongest predictor of cirrhosis and HCC development (Figure 1). In multivariate
models, the relative risk of cirrhosis increased when HBV DNA reached levels
.300 copies/mL independent of whether HBeAg-negative or HBeAg-positive patients
were analysed. The relative risk was 1.4 in patients with HBV DNA levels of
300 to 1000 and increased to 2.4 in patients with 1000 to 10,000, 5.4 in patients
with 10,000 to 100,000 and 6.7 in patients with HBV DNA levels >1 million copies/
mL. In addition, individuals with HBV DNA .104 copies/mL (.2000 IU/ml)
were found to have a 3-15 fold greater incidence of liver cancer compared to those
with a HBV DNA <104 copies/mL. One can therefore conclude that the complete
and persistent suppression of HBV replication is a reliable surrogate endpoint for
clinical progression of liver disease. In a meta-analysis of 26 prospective studies,
treatment efficacy in patients with HBV infection revealed a statistically significant
and consistent correlation between viral load level while on therapy or change in
HBV DNA and histologic, biochemical and serologic response (Mommeja-Marin
2003).
In HBeAg-positive patients seroconversion from HBeAg to anti-HBe has been
found to be a reliable surrogate marker for prognosis of chronic HBV leading in
many cases to an inactive HBsAg carrier state (Figure 2). In these patients HBsAg
remains detectable but HBV replication is controlled at low or even undetectable
levels and transaminases are generally within normal ranges. Long-term observations
reveal, however, that HBeAg seroconversion cannot always be taken as a
guarantee for long-term remission of chronic hepatitis. A reactivation of the disease
with "sero-reversion" (i.e., HBeAg becoming positive again) as well as a transition
to HBeAg-negative chronic hepatitis B with increased (but often fluctuating) HBV
DNA levels can occur in up to 30% of patients. Therefore, HbeAg seroconversion
should be regarded as a stable treatment endpoint only in conjunction with (durable)
sustained and complete HBV DNA suppression.
no
seroconversion
seroconversion
HBeAg-/anti-HBe+
discontinuation of therapy
6-12 months
after seroconversion
HBeAg positive HBeAg negative
end of therapy with HBsAg seroconversion (HBs-Ag negative, Anti-HBs > 100 IU/l)
continue therapy long-term therapy
Figure 2. Possible endpoints of treatment of HBV infections. After achieving HBeAg or
HBsAg seroconversion, antiviral treatment can be stopped. However, it is recommended to
maintain treatment for a period of 6-12 months after the first sign of HBeAg or HBsAg seroconversion.
In contrast, the endpoint of therapy for patients with HBeAg-negative disease is
more difficult to assess and HBV DNA suppression and ALT normalization are the
only practical measures of response to therapy. But still, normal ALT levels and
suppression of HBV DNA levels do not guarantee sustained remission. Once therapy
is stopped, durability of the response remains a concern considering the fluctuating
course of HBeAg-negative chronic hepatitis B. It is well known that maintenance
of undetectable HBV DNA and of normal ALT activity declines progressively
the longer patients are followed after treatment.
HBsAg loss or seroconversion to anti-HBs is the ultimate goal and most desirable
endpoint of antiviral therapy and signals the cure of the chronic infection. The loss
of HBsAg or HBsAg-seroconversion is associated with a complete and definitive
remission of chronic hepatitis B activity and an improved long-term outcome.
However, HBsAg loss or seroconversion can be induced in only a limited number
of patients after short-term treatment (<5%). Interestingly, in recent follow-up
studies of PEG-IFN ƒ¿ as well as nucleos(t)ide analogue-treated patients an increase
of the rate of HBsAg-loss over long-term studies was demonstrated. The rate of
HBsAg seroclearance during therapy with nucleos(t)ide analogues is probably
linked to the duration of the period with low HBV replication. It therefore seems
likely that with increasing treatment durations in the future, higher rates of HbsAg
loss/seroconversion will be observed.
Nevertheless, due to the unique life cycle of HBV, which involves nuclear deposition
of episomal covalently closed circular DNA (cccDNA), in all patients with
HBV infection a cellular template of the viral genome persists in hepatocytes even
decades after HbsAg seroconversion (Rehermann 1996). Therefore, it is beleived
that due to cccDNA persistence complete eradication of HBV infection is impossible.
Reactivation of HBV infection can occur in certain circumstances from these
Indication for antiviral therapy 123
nuclear reservoirs even decades after HbsAg loss, for instance during immunosuppressive
therapy or chemotherapy, in particular with agents such as rituximab.
Criteria for response to therapy:
Virologic:
. sustained decrease of HBV DNA, to at least <104 copies/ml (2x103 IU/ml),
ideally to
<300 copies/ml (60 IU/ml).
. sustained Hbe seroconversion in HBeAg-positive patients
. ideally, loss of HBsAg
Biochemical:
. sustained ALT normalization
Histologic:
. reduction of fibrosis stage in histology or absence of progression
. reduction of inflammatory activity in histology
Potential long-term effects:
. avoidance of cirrhosis, hepatocellular carcinoma (HCC), transplantation,
and death
Indication for antiviral therapy
In acute hepatitis B
Acute hepatitis resolves spontaneously in 95-99% of cases. The effect of antiviral
therapy in acute hepatitis B has been never definitively established but due to the
high rate of spontaneous remission in adults, therapy with the currently available
drugs is not indicated. There is only one randomized placebo-controlled study from
India showing no advantage of lamivudine therapy for acute hepatitis B over placebo
(Kumar 2007). Data from Europe and the US on antiviral therapy of acute
hepatitis B with compensated liver function are not available.
Several case reports, however, reveal that patients with severe and fulminant hepatitis
B may benefit from early antiviral therapy with lamivudine or other nucleos(
t)ide analogues by reducing the need for high-urgency liver transplantation
(Tillmann 2006; Lisotti 2008). An immediate oral antiviral therapy seems justified
to prevent fulminant liver failure in cases where signs of liver synthesis impairment
(drop of TPZ value, increase in INR) during acute hepatitis B are present.
In chronic hepatitis B
Patients with HBsAg-positive chronic hepatitis should be considered as possible
candidates for antiviral therapy especially in situations when there is a significant
level of HBV replication. According to current guidelines it is no longer necessary
to differentiate between HBeAg-positive (wild type) and HBeAg-negative (precore
mutants) chronic hepatitis B as far as concerns treatment indication. However, with
respect to the choice of the proper antiviral drug(s), the HBe-Ag status may be still
useful.
In Table 1 (Key recommendation guidelines for indication for antiviral treatment
for HBV infection, see http://hepatologytextbook.com/link.php?id=1) the recommendations
of the different national and international societies are shown. The
views have shifted from focusing on histologically proven disease activity to the
importance of evaluating HBV DNA levels as the most relevant variable for a decision
to initiate therapy. Thus most of the recently published guidelines recommend
antiviral treatment for patients with HBV DNA levels of >10,000 copies/mL
(>2000 IU/mL), coupled with ALT levels of greater than 2 times the upper limit of
normal, and significant liver fibrosis, demonstrated by liver histology greater than
A1/F1.
Liver biopsy prior to the initiation of treatment can be useful for the treatment decision
in some patients, as it can provide important information on disease prognosis
and can help in the planning of subsequent therapeutic decisions if/when first line
treatment fails. However, a liver biopsy is not mandatory to make a decision concerning
treatment for the majority of patients based on the guidelines listed in Table
1 (Arkaca 2008; Buster 2008; Carosi 2008; Colle 2007; Cornberg 2007; EASL
2008; Juszczyk 2008; Keefe 2007; Liaw 2008).
Patients with liver cirrhosis or high-grade liver fibrosis and any measurable HBV
DNA should be considered for antiviral therapy. A flow chart showing the indication
for antiviral treatment according to the recently published German guidelines is
depicted in Figure 3 (Cornberg 2007). In patients with decompensated cirrhosis
(Child B or C) PEG-IFN ƒ¿ is contraindicated.
Inactive chronic HBsAg carriers, characterised by negative HBeAg status (anti-
HBeAg-positivity), low HBV DNA levels (<10,000 copies/mL) together with normal
serum aminotransferase levels and normal liver histology can be excluded from
antiviral therapy. However, it may be difficult to differentiate between patients who
are inactive HBsAg carriers and those presenting with chronic HBeAg-negative
hepatitis. Elevated transaminase levels are not a reliable parameter for assessing the
stage of liver fibrosis and long-term prognosis of HBV-infected patients. Even in
patients with slightly elevated or even normal transaminases there is a significant
risk for development of HBV-associated complications (Lok 2000; Werle-
Lapostolle 2004). Therefore, control of HBV DNA levels at 3-6 months intervals is
indicated, reflecting that disease activity can fluctuate. Liver biopsy may be necessary
in cases where HBV DNA levels are low and ALT levels elevated.
HBsAg-positive
Figure 3. Pathway for indication for antiviral treatment according to the German guidelines for
the treatment of HBV infections.16 Treatment should be considerated if HBV DNA levels exceed
104 copies/mL and if a sign of ongoing hepatitis as elevated ALT > 2x upper limit of normal or
liver histology > A1/F1 is present. Of note, also asymptomatic carriers with family history of
HCC should receive treatment even if signs of hepatitis are absent.
HBV immunotolerant patients are mostly under 30 years of age and can be recognized
by having high HBV DNA levels, by being HBeAg-positive and by normal
ALT levels without any significant histological changes. According to most of the
clinical practice guidelines immediate therapy is not required. However patients at
higher risk for HCC - those with a positive family history, and those coming from
high endemic areas like Asia or Africa - may perhaps benefit from early antiviral
therapy. Studies are under way to further clarify this issue, especially to answer the
question of whether early intervention by antiviral therapy can positively influence
the long-term HCC risk.

Treatment indication: Summary of the German
guidelines recommendations

. All patients with chronic hepatitis B are candidates for antiviral therapy.
The level of viral replication in serum (limit 104 virus copies/ml, corresponding
to 2x103 IU/ml), the status of inflammation and fibrosis in the
biopsy, and the level of serum transaminases are primarily considered.
. Especially patients with advanced fibrosis or cirrhosis need consistent antiviral
therapy after detection of viremia.
. Reactivation of hepatitis B viral replication due to immunosuppression increases
the risk of acute decompensation and cirrhosis. It should be
avoided by preventive therapy.
. Alcohol and drug consumption are not a contraindication for treatment
with nucleos(t)ide analogues.
. Pregnancy is usually a contraindication for all available drugs. Therapy
with nucleos(t)ide analogues during pregnancy may be considered if the
benefit outweighs the risk.
. Occupational and social aspects and extrahepatic complications may justify
therapy in individual cases.
Treatment options for HBV infection
There are two classes of drug available for the treatment of HBV infections: interferon-
alpha (standard or pegylated IFN ƒ¿) and inhibitors of the HBV polymerase,
the nucleoside and acyclic nucleotide analogues.
While IFN ƒ¿ has been a mainstay in the treatment of chronic HBV infection for
many years it is limited by its tolerability and significant side effect profile that allows
its administration only for a limited period of time (6-12 months, maximum 24
months). Nucleos(t)ide analogues have a better tolerability and are therefore used in
long-term therapy of chronic hepatitis B. However, the efficacy of these oral agents
can be hampered by the risk of the emergence of resistance. Two interferons and
five oral antivirals are currently approved for the treatment of chronic HBV infections:
interferon ƒ¿-2b and peg-interferon (PEG-IFN) ƒ¿-2a, lamivudine, adefovir,
telbivudine, entecavir and tenofovir (Table 2).
Table 2: Drugs currently approved for the treatment of HBV infection
Substance Name Dose Duration
Interferon--ƒ¿
Standart Interferon-ƒ¿2a Roferon R 2.5-5 mio.IU/m2 body surface
3x/week
4-6 months
Standart Interferon-ƒ¿2b Intron A R 5-10 mio. IU 3x/week 4-6 months
Pegylated Interferon-ƒ¿2a Pegasys R 180 ƒÊg/week 48 weeks
Nucleoside analogues
Lamivudin Zeffix R 100 mg/day long-term*
Telbivudine Sebivo R 600 mg/day long-term*
Entecavir Baraclude R 0,5 mg/day long-term*
1 mg/day for patients with
lamivudine resistance
long-term*
Nucleotide analogues
Adefovir dipivoxil Hepsera R 10 mg/day long-term*
Tenofovir disoproxil fumarate Viread R 245 mg/day** long-term*
* see figure 6
** 300 mg tenofovir disoproxil fumarate corresponds to245 mg tenofovir disoproxil
Treatment indication: Summary of the German guidelines
recommendations 127
The efficacy of the available drugs, after one year of treatment, assessed by the proportion
of individuals with HBV DNA below the limit of detection, normalized
transaminases and HBeAg- seroconversion is shown in Figure 4.
1
2
3
4
5
6
7
8
9
3 6 9 12 15 18 21 24 27
months of antiviral treatment
HBV DNA log10 copies/mL
Nachweisgrenze
3) Re-increase of HBV DNA . 1 log
A) Plateau
2) Complete suppression of HBV DNA
B) Continous decrease, HBV DNA still positive at month 12
1) Incomplete suppression of HBV DNA:
Figure 4. Summary of treatment efficacy of different agents for the treatment of HBV infection
after one year of suppression of HBV DNA to below the limit of detection, ALT normalization
and HBeAg seroconversion. Differences in results have to be interpreted with the proviso that
these are not direct comparison studies.
Interferons
IFN ƒ¿ is a natural-occurring cytokine with immunomodulatory, antiproliferative
and antiviral activity. The therapeutic efficacy of IFN ƒ¿ can be clinically often recognised
by an increase in ALT levels at least twice the baseline level. These flares
often precede virologic response.
The main aim of standard or PEG-IFN ƒ¿ treatment is to induce long-term remission
via its finite treatment duration. Overall a long-term response defined by either
HBeAg seroconversion or durable suppression of HBV DNA to undetectable levels
can be achieved in approximately 30% of treated patients (Cooksley 2003). In these
responder patients the chance for HBsAg loss in the long-term is relatively high.
Use of Standard IFN:
Standard IFN ƒ¿ was approved as therapy of chronic hepatitis B in 1992. IFN ƒ¿ is
applied in dosages ranging from 5 million units (MU) to 10 MU thrice weekly (or
every other day). Using a meta-analysis, a significant improvement in endpoints
was shown in patients with HBeAg-positive chronic hepatitis B treated with standard-
interferon alpha in comparison to patients with no treatment. Complete remis
sion of fibrotic changes was observed and was often associated with the loss of
HBsAg. Furthermore, there is a trend towards reduction of hepatic decompensation,
development of hepatocellular carcinoma and liver-associated deaths (Lau 2007).
A significant decrease in ALT as well as HBV DNA concentration was also shown
for standard interferon alpha for the therapy of HBeAg-negative chronic hepatitis B.
However, these patients relapse frequently after the end of treatment (25-89%), as
evidenced by elevation of ALT levels and hepatitis B viral load (Hadziyannis 2006;
Lok 2007). The relapse rate seems to be higher when treatment duration is short (16
to 24 weeks) compared to longer (12 to 24 months). A retrospective comparison of
therapies lasting 5 and 12 months showed that with longer treatment the chance of a
long-term response was 1.64 times as high (normalization of ALT, HBV DNA
<1x106 copies/ml 1-7 years after end of therapy). The response rates were 54%
overall at the end of therapy, 24% 1 year after therapy, and 18% 7 years after therapy
(Hadziyannis 2006; Lok 2007).
In several studies, patients who had a long-term response to treatment demonstrated
a more favorable course with respect to progression to liver cirrhosis, liverassociated
death, and development of hepatocellular carcinoma than patients who
were untreated, unresponsive, or who had a relapse after taking interferon alpha.
The use of pegylated interferon ƒ¿ (PEG-IFN)
The addition of a polyethylene glycol molecule (PEG) to IFN results in a significant
increase in half-life, thereby allowing administration once weekly. In many centers
standard IFN ƒ¿ has now widely been replaced by PEG-IFN ƒ¿. Two types of PEGIFN
have been developed (PEG-IFN ƒ¿-2a and PEG-IFN ƒ¿-2b), of which PEG-IFN
ƒ¿-2a has been licensed for the treatment of chronic HBV infection in a weekly dose
of 180 ƒÊg (subcutaneous) for 48 weeks in both HBeAg-positive and HBeAgnegative
patients. The safety profiles of PEG-IFN and standard IFN are similar.
Following therapy termination a relatively high relapse rate can be expected
(>50%). The intermediate and long-term course after termination of therapy has not
been sufficiently studied. The questions of optimal dose of PEG-IFN ƒ¿-2a (90ƒÊg
vs. 180ƒÊg) and optimal duration of therapy have not been conclusively defined.
However, this is currently being studied in a prospective study.
For the treatment of HBeAg-positive chronic hepatitis B using pegylated interferon
alpha, four randomized controlled studies have been done. These studies compared
PEG-IFN ƒ¿ to standard-interferon, lamivudine, and/or a combination therapy of
PEG-IFN alpha and lamivudine for a duration of 24, 48, 52, or 60 weeks (Lok
2007). In the phase III international approval trial a 48-week course of PEG-IFN
alpha-2a (180 ƒÊg / week) with or without LAM was compared to LAM monotherapy
in HBeAg-positive patients. Sustained HbeAg seroconversion at the end of
follow up (week 72) was significantly higher in patients treated with PEG-IFN ƒ¿-2a
alone or in combination with LAM than in patients treated with LAM alone (32%
and 27% vs. 19%) (Lau 2005).
The efficacy and safety of PEG-IFN ƒ¿-2a (180 ƒÊg once weekly) plus placebo, PEGIFN
ƒ¿-2a plus lamivudine (100 mg daily), and lamivudine alone was compared in
177, 179, and 181 patients with HBeAg-negative chronic hepatitis B, respectively
(Marcellin 2004). Patients were treated for 48 weeks and followed for an additional
24 weeks. After 24 weeks of follow-up, the percentage of patients with normalization
of ALT levels or HBV DNA levels below 20,000 copies/mL was significantly
higher with PEG-IFN ƒ¿-2a monotherapy (59 percent and 43 percent, respectively)
and PEG-IFN alfa-2a plus lamivudine (60% and 44%) than with lamivudine
monotherapy (44% and 29%). Rates of sustained suppression of HBV DNA to below
400 copies/mL were 19% with PEG-IFN ƒ¿-2a monotherapy, 20% with combination
therapy, and 7% with lamivudine alone. Loss of HBsAg occurred in 12 patients
in the PEG-IFN groups, but not in the group of patients who received lamivudine
monotherapy. There was no significant difference in the histologic response
between the 3 treatment groups. In a follow up of this study the HbsAg seroconversion
rate increased over time, particularly in the PEG-IFN group with up to 11%
compared to 2% in the lamivudine monotherapy group 3 years after the end of the
treatment period (Gaspar 2004; Marcellin 2008).
Although combination of lamivudine plus PEG-IFN failed to demonstrate any benefit
when evaluated at the end of follow-up, a more pronounced on-treatment virologic
response (week 48) was observed with combination therapy vs. LAM or PEGIFN
ƒ¿ alone in all studies. This more profound HBV DNA suppression induced by
the combination regimen was associated with a lower incidence of LAM resistance
(presence of YMDD mutants in 1% vs. 18% at the end of therapy). In summary the
use of a fixed combination of lamivudine plus PEG-IFN ƒ¿ is presently not recommended.
Nucleos(t)ide analogues
Nucleos(t)ide analogues inhibit viral replication by blocking the nucleoside binding
site of the viral polymerase and competing with the natural substrate deoxyadenosine
triphosphate (dATP) and by terminating DNA chain prolongation after incorporation
into viral DNA. Nevertheless, their detailed mechanisms of action for inhibiting
HBV DNA synthesis varies greatly from one agent to another. Nucleoside
and acyclic nucleotide analogues represent different subclasses of reverse transcriptase
inhibitors: while both are based on purines or pyrimidines, acyclic nucleotide
analogues possess an open (acyclic) ribose ring which confers to greater binding
capacity to resistant HBV polymerase strains (Figure 7).
In contrast to interferon-based treatment strategies where a finite treatment duration
of 24-48 weeks is established, treatment duration for nucleos(t)ide analogues is not
well-defined and needs to be given for extended periods in order to control viral
replication over the long-term. Short-term application of these agents for only 48
weeks is normally associated with prompt relapse in hepatitis B viremia.
Studies with nucleos(t)ide analogues have clearly demonstrated that suppression of
HBV viremia is associated with a significant decrease in histologic inflammatory
activity and fibrosis, including partial reversion of earlier stages of liver cirrhosis
(Wursthorn 2006; Werle-Lapostolle 2004; Lok 2000). HBeAg-seroconversion rates
also increase with increasing treatment duration (Liaw 2000; Lok 2000). Most importantly,
effective long-term control of HBV replication by nucleos(t)ide analogues
is associated with a reduction of long-term complications such as HCC and
development of liver cirrhosis. There is also evidence that effective inhibition of
HBV replication can reduce HBV cccDNA, possibly running parallel to the decline
in serum HBsAg level (Werle-Lapostolle 2004; Wursthorn 2006). These findings
hopefully indicate that long-term antiviral therapy may lead to a complete response
in a significant number of patients.
Figure 7. Chemical structure of the nucleoside analogue lamivudine and the acyclic nucleotide
analogue adefovir dipivoxil as an example of purine- or pyrimidine-based viral transcriptase
inhibitors. Lamivudine is based on cytosine while adefovir is based on adenine. In contrast to
lamivudine, adefovir possesses an acyclic ribose ring that gives it a higher flexibility.
A central aspect of HBV polymerase inhibitor treatment is the prevention and the
management of HBV resistance to these drugs. Resistance to nucleos(t)ide analogues
can occur during suboptimal treatment and often leads to aggravation of
liver disease. Therefore nucleoside-naive and nucleoside-experienced patients have
to be distinguished. Since several nucleoside analogues have overlapping resistance
profiles, prior nucleoside experience should be taken into account when selecting a
next-line therapy.
Lamivudine
Lamivudine is a synthetic nucleoside analogue that was approved for the treatment
of chronic hepatitis B in 1998. Lamivudine is the (-) enantiomer of 2' -3' dideoxy-3'-
thiacytidine. The phosphorylated form (3TC-TP) exerts its therapeutic action by
competing with dCTP for incorporation into the growing viral DNA chains, causing
chain termination. By inhibiting both the RNA- and DNA-dependent DNA polymerase
activities, the synthesis of both the first strand and the second strand of
HBV DNA are interrupted. Lamivudine is an oral medication and its dose for
chronic hepatitis B is 100 mg daily. This dose was chosen based on a preliminary
trial that randomly assigned 32 patients to receive 25, 100, or 300 mg of lamivudine
daily for a total of 12 weeks (Dienstag 1995). In this study the dose of 100 mg was
more effective than 25 mg and was similar to 300 mg in reducing HBV DNA levels,
therefore the dose of 100 mg daily was chosen for hepatitis B therapy (Nevens
1997).
Long-term lamivudine treatment is associated with a reduced progression of liver
disease in patients with advanced liver fibrosis therefore demonstrating a favourable
effect on the natural course of the disease (Liaw 2004). However the use of lamivudine
suffers from a steadily increasing rate of antiviral drug resistance over time,
reaching approximately 70% after 5 years in patients with HBeAg.positive patients
(Mauss 2007). Therefore, in many guidelines lamivudine is not any more considered
a first-line agent in the treatment of chronic HBV infection. However, lamivudine
still may play a role in combination regimens or in patients with mild
chronic hepatitis B expressing low levels of HBV DNA (<105 copies/mL) (Cornberg
2007). An early and complete virologic response to lamivudine within 6
months of therapy (<400 copies/mL) constitutes a prerequisite for long-term control
of HBV infection without the risk of development resistance.
Adefovir Dipivoxil
Adefovir dipivoxil was approved for treatment of chronic hepatitis B in the US in
2002 and in Europe in 2003. It is an oral diester prodrug of adefovir, a nucleotide
adenosine analogue that, in its active form (adefovir diphosphate), inhibits HBV
DNA polymerase. Because the acyclic nucleotide already contains a phosphatemimetic
group, it needs only two, instead of three, phosphorylation steps to reach
the active metabolite stage. It does not depend on the virus-induced kinase to exert
its antiviral action. Adefovir dipivoxil was the first substance with simultaneous
activity against wild-type, pre-core, and lamivudine-resistant HBV variants, and is
active in vitro against a number of DNA viruses in addition to HBV, as well as retroviruses
(i.e., HIV). The dose of 10 mg per day was derived from a study comparison
with 30 mg per day, which led to stronger suppression of HBV DNA but also to
an increase of creatinine levels in some patients. At higher doses adefovir caused
Fanconifs syndrome in a considerable proportion of patients (Hadziyannis 2003).
Adefovir was the first acyclic nucleotide that was widely used in the treatment of
lamivudine-resistant HBV infections. However, the antiviral efficacy of adefovir is
rather low compared to other available antivirals and is most probably due to dose
limitation, because of nephrotoxicity (Figure 5). This disadvantage makes adefovir
vulnerable to HBV resistance (Hadziyannis 2006). Today, add-on therapy in cases
of lamivudine resistance is the preferred strategy for adefovir, as discussed below
(Lampertico 2005). With the recent approval of tenofovir, the importance of adefovir
is likely to diminish.
Peg-IFN LAM ADV ETV LdT TDF
percentage of patients
HBV DNA under the limit of detection normal ALT
a) HBeAg-positive patients
b) HBeAg-negative patients
Figure 5. Summary of treatment efficacy of agents approved for the treatment of HBV infection
after one year of suppression of HBV DNA below the limit of detection, ALT normalisation and
HbeAg seroconversion. Differences in the results of the studies have to be interpreted with the
provision that this is a cross-study comparison and may involve differently selected study
populations.
Telbivudine
Telbivudine is a thymidine analogue which is active again13st HBV but at least in
vitro not active against other viruses, including HIV and HCV. It is reported to be
non-mutagenic, non-carcinogenic, non-teratogenic, and to cause no mitochondrial
toxicity. The favourable safety profile of telbivudine in a daily dose of 600 mg was
demonstrated in previous studies. However, CK elevations were observed more
than in the group treated with lamivudine and neurotoxicity may be an issue when
telbivudine is administered in combination with PEG-IFN.
Telbivudine at 600 mg/day express higher antiviral acitivity as compared to either
lamivudine at 100 mg/day or adefovir at 10 mg/day (Figure 5) and more patients
achieved HBeAg loss with telbivudine compared to lamivudine (Lai 2006).
However, resistance against telbivudine has been seen in up to 21% of patients after
2 years of treatment (Lai 2006). Resistance was predominantly observed in patients
who did not achieve undetectable HBV DNA after 24 weeks of treatment (Di Bisceglie
2006). Telbivudine should be used cautiously in HBeAg-positive patients
with high HBV DNA levels (>109 copies/mL) because the risk of incomplete virologic
response at week 24 is especially high in this patient population. Furthermore,
in all patients, treatment with telbivudine should be modified when HBV DNA levels
do not become undetectable after 24 weeks of treatment (therefore, switching to
a more potent drug or adding in a second non-cross-resistant drug is advised). Telbivudine
shows cross resistance to lamivudine and entecavir. As a consequence
telbivudine should not be used in lamivudine or entecavir refractory patients.

Entecavir

Entecavir, a cyclopentyl guanosine nucleoside analogue, is a selective inhibitor of
HBV replication and was licensed in 2006. Entecavir blocks all three polymerase
steps involved in the replication process of the hepatitis B virus: first, base priming;
second, reverse transcription of the negative strand from the pregenomic messenger
RNA; third, synthesis of the positive strand of HBV DNA. In comparison to all
other nucleos(t)ide analogues, entecavir is more efficiently phosphorylated to its
active triphosphate compound by cellular kinesis. It is a potent inhibitor of wildtype
HBV but is less effective against lamivudine-resistant HBV mutants. Therefore,
entecavir was approved in the dose of 0.5 mg per day for treatment naive
HBeAg-positive and HBeAg.negative patients and in the dose of 1 mg per day for
patients with prior treatment with lamivudine.
Treatment-naive HBeAg-positive patients achieved HBV DNA undetectable levels
in 67% after one year and in 74% after two years (Figure 5) (Sherman 2008; Gish
2007). Long-term studies in entecavir-responding patients demonstrated that response
can be maintained in nearly all patients for up to five years. So far, the rate
of long-term resistance is estimated to be approximately 1% in the first years for
treatment-naive patients (Tenny 2008).
In lamivudine-resistant patients entecavir is less potent. Only 19% of these patients
achieved undetectable HBV DNA after one year and 40% after two years, despite
an increased entecavir dose of 1 mg/day (Sherman 2008; Gish 2007). Up to 45% of
patients with lamivudine resistance were shown to develop resistance against entecavir
after 5 years of treatment (Tenny 2008). Partial cross-resistance facilitates the
development of entecavir resistance, as only one or two additional mutations are
needed for the development of full entecavir resistance.

Tenofovir

Tenofovir disoproxil fumarate, an ester prodrug form of tenofovir (PMPA; (R)-9-
(2-phosphonylmethoxypropyl)), belongs to the group of acyclic nucleoside phosphonates
(or nucleotide analogues). Tenofovir (TDF) has selective activity against
retroviruses and hepadna-viruses and is currently approved for the treatment of human
immunodeficiency virus (HIV) infections and for treatment of chronic hepatitis
B. Tenofovir shows strong activity against both HBeAg-positive and HBeAg.
negative HBV infections in treatment-naive patients (Heathcote 2008; Marcellin
2008). In vitro studies have clearly demonstrated that lamivudine-resistant HBV
strains (mutations rtM204I/V, rtL180M and rtL173M) remain susceptible to TDF
(Lada 2004). These observations are consistent with clinical studies showing a high
efficacy of TDF in lamivudine-resistant HBV infections irrespectively of the kind
of mutation mediating lamivudine resistance (Van Boemmel 2008, Manns 2008).
Due to possibly existing cross-resistance to adefovir, the efficacy of tenofovir may
be hampered by the presence of adefovir resistance; however, a re-increase of HBV
DNA during tenofovir treatment in patients with previous adefovir failure has not
been observed (Berg 2008).
TDF is generally well tolerated and not associated with severe side effects to date.
In large randomized clinical trials in HBV/HIV coinfected patients the use of TDF
was associated with an excellent renal safety profile. However mild impairment of
renal function due to TDF treatment up and anecdotal cases of acute renal failure
and Fanconi syndrome have been reported in some HBV/HIV coinfected patients
(Gallant 2005; Verhelst 2002; Creput 2003; Karras 2003; Peyriere 2004; Coca
2002). In these patients the decline of creatinine clearance was significantly greater
than in those being exposed to other nucleoside-based antiviral drugs. Regular
monitoring of renal function is therefore recommended while on TDF therapy.
Two-year efficacy data are available for TDF in (mostly) treatment-naive HBeAgpositive
and -negative patients. TDF showed marked antiviral efficacy with complete
virologic response rates (HBV DNA <400 copies/mL) reaching nearly 100%
and 90% in HBeAg-negative and -positive patients, respectively. No drug resistance
has been observed so far. HBsAg loss was observed in 5% of the HBeAg-positive
patients after 15 months of therapy with TDF (Heathcote 2008). Similar efficacy
without development of resistance was also demonstrated when TDF was administered
to lamivudine-refractory patients or those showing incomplete response to
adefovir (Manns 2008; Van Boemmel 2008; Berg 2008).
Nucleos(t)ide analogue combination therapy
There is only one study that has compared combination therapy with lamivudine
plus adefovir to lamivudine monotherapy in naive patients. There was no difference
in the virologic and biochemical response between the groups. The rate of lamivudine
resistance was much lower in the combination group. However, the development
of resistance could not be completely avoided by adding adefovir (Sung
2003). Another study analysing the combination of lamivudine plus telbivudine
showed no benefit over a median observational period of two years (Schmutz
2006). Combining telbivudine and lamivudine did not improve antiviral efficacy or
protect against development of resistance (Lai 2005). No data are available on other
combination therapies.
Prognostic factors for therapeutic success
Several factors are positively associated with long-term remission and may help to
guide treatment decisions: Pretreatment factors predictive of HbeAg seroconversion
are low HBV DNA, high ALT levels (greater than 2-5 times ULN) and high inflammatory
activity scores on liver biopsy. These general baseline predictors are
relevant especially for treatment regimes with PEG-IFN ƒ¿ but may also be relevant
for nucleos(t)ide analogues (Fried 2008). In contrast HBV genotype, another baseline
predictor, has been shown to be associated only with differences in viral response
to interferon alpha. Thus patients with HBV genotype A, prevalent in northern
Europe and USA, show a much better rate of HBeAg-seroconversion (47-52%)
than patients with HBV genotype D (22-25%), prevalent in the south of Europe, or
HBV genotypes B or C, prevalent in Asia (30-40% resp. 28-30%) (Erhardt 2005;
Flink 2006).
How to treat
Basically two different treatment strategies can be chosen: One is to treat with (pegylated)
interferon alpha in order to induce long-term control via limited treatment.
The other concept is long-term inhibition of viral replication by nucleoside and nucleotide
analogues that inhibit HBV replication (Figure 6).
(Peg-)Interferon alpha ?
nucleos(t)die analogue with
high resistance barrier
or combination therapy
every approved nucleos(t)die analogue
choice according to: virus load, comorbidity, etc.
no liver cirrhosis liver cirrhosis
Figure 6. Suggestion for an algorithm for treatment of HBV infection with PEG-IFN according
to the German guidelines (Cornberg 2007).
First, the possibility of an interferon therapy should be evaluated. However when a
patient does not fulfill the criteria for PEG-IFN ƒ¿ or has contraindications or is intolerant
to IFN ƒ¿, long-term therapy with nucleos(t)ides analogues is recommended.
When an oral drug is chosen several parameters have to be considered -
the antiviral efficacy of the drug, the durability of response, the resistance barrier,
and the stage of liver disease.
If the initial viral load is low and liver cirrhosis has been excluded, any approved
drug may be used. The use of lamivudine, however, should be restricted to patients
with mild fibrosis and HBV DNA levels <105 copies/mL. For patients with highlevel
HBV replication (>109 copies/mL) only those drugs with a high genetic barrier
for resistance should be used (i.e., entecavir and/or tenofovir).
136 HBV Treatment - Standard of care
Monitoring of patients before and during antiviral therapy
Before therapy, HBV DNA levels should be measured with a highly sensitive assay
and these results should be confirmed 1-2 months after starting therapy. ALT levels
reflecting the inflammatory activity as well as creatinine levels should be measured.
HBV genotyping is only recommended in patients who are considered candidates
for treatment with interferon. HBV resistance testing can be useful in patients with
prior failure to more than one nucleos(t)ide analogue. HBV resistance has to be
expected when an increase of HBV DNA of >1 log during antiviral treatment is
observed. In cases of primary treatment failure an appropriate second line treatment
can be chosen without resistance testing.
During therapy, HBV DNA, ALT and creatinine levels should be measured initially
at 4 to 6 weeks and then every 3 months. The early identification of viral resistance
and, thus, an early adjustment of therapy is crucial. Patients with suppression of
HBV replication to <300 copies/ml (60 IU/ml) for at least 2 years may perhaps be
monitored every 6 months. However, no studies have been done yet to support this
recommendation.
In HBeAg-positive patients, HBeAg and anti-HBe as well as HBsAg and anti-HBs
should also be measured when HBV DNA levels become undetectable, to identify
seroconversion as an endpoint (Table 3).
Table 3: Recommendation for laboratory tests for monitoring of antiviral therapy
Tests before antiviral treatment Interval
Quantitative HBV DNA
HBe-Ag, anti HBe
HBV genotype
ALT level
Creatinine level
Other chemistry tests
If IFN-based treatment is planned
Tests during antiviral treatment Interval
Quantitative HBV DNA After 4-6 weeks, after 12 weeks, then every 3-6 months
HBe-Ag, anti-HBe 3-6 months, if HBV DNA is undetectable
HBs-Ag, anti-HBs 3-6 months, in HBeAg-positive patients after HBeAg
seroconversion in and HBeAg-negative patients if HBV
DNA is undetectable
HBV resistance test If HBV DNA increases > 1 log during antiviral treatment
and pretreatment history is not known, but first check for
treatment adherence!
ALT level Initially every month, than every 3-6 months
Creatinine level* 3-6 months
Other chemistry tests 3-6 months
* Patients treated with TDF should initially be checked every 4 weeks to exclude decrease in
kidney function
Treatment indication: Summary of the German guidelines
recommendations 137
The level of HBV DNA as a parameter for response to antiviral therapy
During antiviral therapy, the decrease of HBV DNA from baseline is the most important
tool in monitoring treatment efficacy. Complete response to antiviral therapy
is defined as suppression of HBV DNA below the limit of detection of a sensitive
real time PCR assay (Figure 4). Incomplete suppression is characterized by
persistant HBV replication despite antiviral therapy. Ongoing HBV replication
should be avoided, to prevent selection of resistant HBV strains by replication of
the virus in the presence of drug in the so called gplateau phaseh. A re-increase of
HBV DNA despite continuous antiviral therapy is often caused by viral resistance.
Adherence to therapy is also important in preventing drug resistance.
In this respect, measuring HBV DNA kinetics early during therapy will help to
guide antiviral treatment and to establish early stopping rules or add-on strategies to
avoid antiviral failure.
In case of incomplete virologic response an appropriate rescue therapy should be
initiated. Timing and type of the rescue strategies differs with respect to the nucleos(
t)ide analogue which was previously used. For instance, selection of telbivudine
and lamivudine resistance can occur within a relatively short treatment period
of 6 months if complete suppression of viremia is not induced . leading to the
recommendation that therapy should be adapted in the case of incomplete HBV
DNA suppression at month 6. In contrast, entecavir and tenofovir and to a lesser
extent adefovir have not been shown to be associated with a significant risk for resistance
within the first two years of therapy in treatment-naive patients. In case of
incomplete viral suppression at week 48 continuation of monotherapy is advisable
for entecavir and tenofovir, as long as HBV DNA levels continue to decrease.
In treatment-naive patients with incomplete response to first line lamivudine, telbivudine
or adefovir, a switch to tenofovir has been shown to be quite successful. The
debate, however, is still ongoing on whether to switch or add in tenofovir as the
optimal management.
No definite therapeutic strategies have been evaluated yet for either tenofovir- or
entecavir-treated patients who show still ongoing viral replication even after 1-2
years. An add-on therapy with a non cross-resistant agent is recommended.
Treatment duration and stopping rules
In HBeAg positive patients continuous treatment with nucleos(t)ide analogues is
necessary as long as HBeAg-seroconversion is not achieved. Even after seroconversion
occurs, antiviral therapy should be continued for at least 12 months to avoid
the risk of gsero-reversionh after stopping the nucleos(t)ide analogue therapy.
Since only 30-35% of all patients treated with PEG-IFN ƒ¿ reached HBeAg seroconversion
after 48 weeks, studies have been conducted to predict the probability of
seroconversion in relationship to viral kinetcs. Fried and co-workers showed in a
retrospective analysis that early prediction of stable seroconversion was possible as
early as week 12 on therapy provided HBV DNA concentration had reached levels
below 5 log / ml in this time (Fried 2008). In 53% of these patients HBeAg seroconversion
was observed while patients with HBV DNA levels between 5 and 9 log
138 HBV Treatment - Standard of care
copies / mL or levels above 9 log / ml achieved HBeAg seroconversion only in 17%
and 14%, respectively. Thus, individualized PEG-IFN ƒ¿ strategies will certainly be
an interesting option in the future.
Criteria for optimal treatment duration are still lacking in patients with HBeAgnegative
chronic hepatitis B. PEG-IFN ƒ¿ should be given for 48 weeks and a possibly
unlimited long-term use of nucleos(t)ide analogues is recommended. The effect
of stopping therapy after 4 to 5 years of complete viral suppression in HBeAgnegative
patients on adefovir therapy was recently evaluated by Hadziyannis and
coworkers in a small preliminary study (Hadziyannis 2006). Despite all patients
suffering a slight virologic relapse within 3 months of stopping therapy, most patients
maintained clinical remission over the following 4 years without any therapy,
and 28% of them lost HBsAg. In patients with liver cirrhosis, however, oral antiviral
treatment should not be discontinued because of the risk of liver decompensation
during a virologic rebound and should be administered life-long or until HbsAg
loss/seroconversion is achieved.