Book on hepatitis from page 135 to 145

Book on hepatitis from page 135 to 145

134  Hepatology 2012
Long-term observations reveal, however, that HBeAg seroconversion cannot
always be taken as a guarantee of long-term remission. A reactivation of the disease
with “seroreversion” (HBeAg becoming detectable again) as well as a transition to
HBeAg-negative chronic hepatitis B with increased, often fluctuating, HBV DNA
levels, can occur in up to 30% of patients (Hadziyannis 1995, Hadziyannis 2001,
Hadziyannis 2006). Therefore, HBeAg seroconversion should be regarded as a
stable treatment endpoint only in conjunction with durable and complete
suppression of HBV replication.
In the natural course of HBV infection, the time point of HBeAg seroconversion
is important regarding the probability of long-term complications. In a recent long-term observational study in 483 HBeAg-positive patients achieving spontaneous
HBeAg seroconversion, it was shown that for 15 years after HBeAg seroconversion
the incidence of cirrhosis and HCC was lower for patients who had achieved
HBeAg seroconversion at an age <30 years old compared to patients achieving
seroconversion at an age >40 years old (Chen 2010). This observation raises the
question of whether HBeAg seroconversions during antiviral treatment in patients
older than 40 years are also associated with a higher risk of complications compared
to patients who achieve HBeAg seroconversion at a younger age.
Sustained response and “immune control”. The endpoint of therapy for patients
with HBeAg-negative disease is more difficult to assess. Long-term suppression of
HBV replication and ALT normalization are the only practical parameters of
response to therapy. Once antiviral therapy is stopped, durability of response is not
guaranteed due to the fluctuating course of HBeAg-negative chronic hepatitis B.
For treatment with PEG-IFN α in both, HBeAg-positive and -negative patients,
the inducing of a so-called ‘immune control’ status, characterized by persistent
suppression of viral replication with HBV DNA levels <2,000 IU/ml and
normalisation of ALT levels was recently defined as another, combined treatment
endpoint (Marcellin 2009). If this condition is maintained over time, it increases the
probability of HBsAg loss and reduces the development of liver fibrosis and HCC.
Late relapse beyond 6 months post-treatment has been described, but a sustained
response at 1 year post-treatment appears to be durable through long-term follow-up (EASL 2009, Marcellin 2009). However, the immune control status needs to be
regularly monitored, and treatment needs to be re-introduced in case of increase of
HBV replication. For patients presenting any signs of liver fibrosis or family
history of HCC, immune control should not be regarded as the treatment endpoint
but rather the complete suppression of HBV replication.
Induction of HBsAg loss. The ultimate goal of antiviral treatment is HBsAg loss
or even seroconversion to anti-HBs. Because HBsAg loss or seroconversion is
associated with a complete and definitive remission of the activity of chronic
hepatitis B and an improved long-term outcome, it is regarded as a cure from
chronic hepatitis B. 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 in PEG-INF α as well as nucleoside/nucleotide analog
treated patients an increase of the rates of HBsAg loss during long-term studies was
shown (Marcellin 2009, Marcellin 2011). However, as the probability of HBsAg
seroclearance during therapy with nucleoside or nucleotide analogs is linked to the
decrease of HBsAg levels during the early treatment period, it seems questionable
Hepatitis B Treatment  135
if after a treatment duration of 4-5 years significantly higher rates of HBsAg loss
can be expected (Marcellin 2011).
Reversion of liver fibrosis. With long-term treatment with different nucleoside
and nucleotide analogs it has been demonstrated that liver fibrosis and even
cirrhosis can be reverted in the majority of patients. This was recently impressively
shown in a subgroup of 59 patients from a rollover study including two Phase III
trials of the efficacy of ETV in treatment-naïve patients. Liver biopsies from
baseline and after a median treatment duration of 6 years (range, 3-7 years) found
an histologic improvement, defined as a decrease of 2 points or greater in the
Knodell necroinflammatory score in absence of worsening of the Knodell fibrosis
score, in 96% of patients. In addition, an improvement of more than 1 point in the
Ishak fibrosis score was seen in 88%, including all 10 patients who had advanced
fibrosis or cirrhosis when they entered the Phase 3 studies (Chang 2010a). More
recently, in a subanalysis of the tenofovir Trials 102 and 103 evaluating 348
patients who underwent biopsies before and after five years of therapy, 88%
experienced an improvement in overall liver histology as measured by an
improvement of at least two points in the Knodell score of HAI (histologic activity
index) (Figure 4). Of the 94 patients who had cirrhosis at the start of therapy, 73%
experienced regression of cirrhosis, and 72% had at least a two-point reduction in
fibrosis scoring (Marcellin 2011).
Figure 4. Changes in liver histology after five years of TDF treatment. In a study looking at
348 patients with paired liver biopsies, regression of liver fibrosis and even liver cirrhosis (Ishak
score 5 and 6) was found in the majority of patients.
136  Hepatology 2012
Criteria for treatment response
Virologic response
–  sustained decrease of HBV DNA, to at least <2,000 IU/mL (corresponding to
<10,000 copies/mL), ideally to <60 IU/mL (<300 copies/mL).
–  sustained HBe seroconversion in HBeAg positive patients
–  ideally, loss of HBsAg
Biochemical response
–  sustained ALT normalization
Histologic response
–  reduction of fibrosis (histological staging)
–  reduction of inflammatory activity (histological grading)
Potential long-term effects
–  avoidance of cirrhosis, hepatocellular carcinoma (HCC), transplantation, and
death
How to treat
Therapy of chronic hepatitis B is possible with PEG-INF α in order to induce an
immunologic long-term control by finite treatment or with nucleos(t)ide analogs by
long-term inhibition of HBV replication (Figure 5) (Table 2).
At first, the option of interferon therapy should be evaluated. However, if a
patient does not fulfil the criteria for a higher likelihood for treatment success with
PEG-INF  α, has contraindications, or is intolerant, long-term therapy with
nucleos(t)ide analogs is recommended (Figure 5). If a nucleos(t)ide analog  is
chosen, several parameters have to be considered prior to therapy: 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 LAM, however, should be restricted to patients with
mild fibrosis and HBV DNA levels <105
copies/ml. For patients with high-level
HBV replication (>10
9
copies/ml) only drugs with a high genetic barrier should be
used (i.e., ETV or TDF) (Table 3).
Treatment options
Because of a limited tolerability due to adverse events, duration with PEG-IFN α is
limited for a period of 6-12 months (maximum 24 months). Nucleoside and
nucleotide analogs have a good tolerability and are used in long-term treatment.
However, the efficacy of these oral agents can be hampered by emergence of
resistance. Two interferons and five oral HBV polymerase inhibitors are currently
approved for the treatment of chronic HBV infections: standard IFN α-2b and PEG-IFN  α-2a, lamivudine (LAM), adefovir dipivoxil (ADV), telbivudine (LdT),
entecavir (ETV) and tenofovir disoproxil fumarate (TDF) (Table 2). 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, normalised transaminases
and HBeAg seroconversion is shown in Figure 6.
Hepatitis B Treatment  137
Figure 5. Treatment algorithm for chronic HBV infection according to the German
Guidelines (Cornberg 2011). The indication for interferon therapy should always be
considered. For treatment with nucleoside or nucleotide analogs, agents with high genetic
barrier against resistance such as entecavir or tenofovir should be preferred.
Table 2. Overview of interferons and oral antiviral drugs currently approved for the
treatment of HBV infection.
Drug  Name  Dose  Duration
Interferon α
Standard Interferon α-2a Roferon
®
2.5-5 mio. U/m
2
body surface
3x/week
4-6 months
Standard Interferon α-2b  Intron A
®
5-10 mio. IU 3x/week  4-6 months
Pegylated Interferon α-2a  Pegasys
®
180 µg/week  48 weeks
Nucleoside analogs
Lamivudine Zeffix
®
100 mg/day long-term*
Telbivudine  Sebivo
®
600 mg/day  long-term*
Entecavir  Baraclude
®
0.5 mg/day  long-term*
1 mg/day for patients with
lamivudine resistance
long-term*
Nucleotide analogs        
Adefovir dipivoxil  Hepsera
®
10 mg/day  long-term*
Tenofovir disoproxil fumarate  Viread
®
300 mg/day  long-term*
* see Figure 6
138  Hepatology 2012
Table 3. Recommendations for the use of nucleos(t)ide analogs in clinical practice.
Drug  Advantage  Disadvantage  Recommendation
Lamivudine
(LAM)
•  Low treatment costs
•  Oral solution
available for children
or individual dosage
in case of renal
impairment
•  High risk of
resistance in long-term monotherapy
•  Cross-resistance to
ETV and LdT
•  Use as first-line
therapy only in
selected patients with
low viral load
•  Prevention of
exacerbation in
HBsAg+, HBV DNA-patients with
immunosuppression
•  Preemptive therapy in
case of HBsAg-negative, anti-HBc
positive patients with
immunosuppression
•  Use in pregnancy
possible
Adefovir
dipivoxil
(ADV)
•  Experience in
combination with LAM
•  No cross-resistance
to LAM
•  Moderate antiviral
activity
•  Primary non-response in 10-20%
of cases
•  Slow viral kinetics
during therapy
•  Risk of viral
resistance in long-term monotherapy
•  Nephrotoxicity
•  Not to be used as
first-line therapy
Telbivudine
(LdT)
•  High antiviral efficacy
•  Potentially no cross-resistance to
entecavir
•  Moderate risk for viral
resistance in long-term monotherapy
•  Neuropathy and
myopathy
•  First-line therapy
•  Can be combined
with TDF
Entecavir
(ETV)
•  High antiviral efficacy
•  Low risk for viral
resistance in long-term monotherapy in
lamivudine-naïve
patients
•  Combination therapy
with TDF as rescue
therapy
•  Oral solution
available for
individual dosage in
case of renal
impairment
•  In LAM-experienced
patients high risk for
the development of
viral resistance and
virologic failure in
long-term
monotherapy
•  First-line therapy
•  Can be combined
with TDF
Tenofovir
disoproxil
fumarate
(TDF)
•  High antiviral efficacy
•  Low risk for viral
resistance in long-term monotherapy
•  Nephrotoxicity
•  Decrease in bone
mineral density
•  First line therapy
•  Can be combined
with ETV, LdT or LAM
if needed
* in HBV-monoinfected patients no renal toxicity was observed in 5 years of TDF treatment
Hepatitis B Treatment  139
Interferons
INF α is a natural occurring cytokine with immunomodulatory, antiproliferative and
antiviral activity. During treatment, the therapeutic efficacy of INF α can often be
clinically recognised by an increase of ALT levels to at least twice the baseline
levels. These ALT flares often precede virologic response.
The main aim of INF α treatment is to induce a long-term remission by finite
treatment duration. Overall a long-term response defined by either HBeAg
seroconversion or durable suppression of HBV DNA to low or undetectable levels
can be achieved in approximately 30% of treated patients. In these responders the
chance for HBsAg loss in the long-term is relatively high.
Figure 6. One-year efficacy of medications currently approved for the treatment of
chronic HBV infection (Lok 2009). Treatment efficacy is expressed as suppression of HBV
DNA below the limit of detection, ALT normalisation and rates of HBeAg seroconversion. As no
head-to-head trials comparing the substances have been undertaken, differences in antiviral
efficacy have to be interpreted with caution.
Standard INF α. Standard IFN α was approved for treatment of chronic hepatitis
B in 1992. IFN α is applied in dosages ranging from 5 million units (MU) to 10 MU
every other day or thrice weekly. In a meta-analysis, a significant improvement in
endpoints was shown in patients with HBeAg-positive chronic hepatitis B being
treated with standard IFN compared to untreated patients (Craxí 2003). Complete
remission of fibrotic changes was observed in some patients and the loss of HBsAg
occurred comparatively often. Furthermore, there was a trend towards reduction of
hepatic decompensation (treated 8.9% vs. untreated 13.3%), hepatocellular
carcinoma (1.9 vs. 3.2%), and liver associated deaths (4.9 vs. 8.7%) (Craxí 2003).
A significant decrease in ALT and in HBV DNA serum levels was also shown for
standard IFN α in the treatment of HBeAg-negative chronic hepatitis B (Brunetto
2003). However, a high percentage (25-89%) of these patients relapses after the end
of treatment showing elevation of ALT levels and a return of HBV DNA levels. The
relapse rate seems to be higher when treatment duration is short (16 to 24 weeks)
140  Hepatology 2012
compared to longer treatment (12 to 24 months). A retrospective comparison of IFN
therapies lasting from 5 to 12 months showed that with longer treatment the chance
of a long-term response was 1.6 times higher (normalization of ALT, HBV DNA
<1x10
6
copies/ml 1-7 years after end of therapy). The overall response rates were
54% at the end of therapy, 24% at 1 year after therapy, and 18% 7 years after
therapy (Manesis 2001).
Patients with long-term response to treatment have a more favourable course than
patients who were untreated, unresponsive, or who had a relapse interferon α
therapy with respect to progression to liver cirrhosis, liver associated deaths, and
development of hepatocellular carcinoma (Brunetto 2003, Lampertico 2003).
However, due to higher antiviral efficacy PEG-IFN α  should be preferred to
standard IFN α.
PEG-INF α. The addition of a polyethylene glycol molecule to the IFN resulted
in a significant increase in half-life, thereby allowing administration once weekly.
Two types of subcutaneously administered PEG-IFN α were developed: PEG-IFN
α-2a and PEG-IFN α-2b, of which PEG-IFN α-2a was licensed for the treatment of
chronic HBV infections in a weekly dose of 180 µg for 48 weeks in both HBeAg-positive and HBeAg-negative patients. However, PEG-IFN α-2b shows similar
efficacy. After one year on treatment with PEG-IFN α-2a and α-2b, 22% to 27% of
patients were reported to achieve HBeAg seroconversion (Janssen 2005, Lau 2005).
The safety profiles of standard IFN α and PEG-IFN α are similar. Following
therapy termination a relatively high relapse rate is to be expected (>50%). The dose
of 180 µg per week applied for 48 weeks was recently shown to exert a stronger
antiviral efficacy compared to administration for 24 weeks or to administration of
90 µg per week (Liaw 2011). In a small Italian study it was shown that prolongation
of 48 weeks of treatment with 180 µg PEG-IFN α per week by another 48 weeks of
135 µg PEG-IFN α-2a may enhance antiviral efficacy and increase the rate of
patients achieving HBsAg loss, at least in HBeAg-negative patients with HBV
genotype D (Lampertico 2010). However, the optimal treatment duration for PEG-IFN α has not been defined yet and treatment beyond 48 weeks is not recommended
by current guidelines.
PEG-IFN α in HBeAg-positive patients. Four randomized, controlled studies
investigating the efficacy of PEG-IFN α in HBeAg-positive patients have been
conducted (Crespo 1994, Chan 2005, Janssen 2005, Lau 2005). These studies
compared 180 µg PEG-INF  α  per week to standard IFN, LAM, and/or a
combination treatment with PEG-INF α + LAM for 48 weeks. Sustained HBeAg
seroconversion at the end of follow-up (week 72) was significantly higher in
patients treated with PEG-IFN α-2a alone or in combination with LAM than in
patients treated with LAM alone (32% and 27% versus 19%) (Marcellin 2004).
Importantly, it was recently shown that PEG-IFN  α  can induce
immunomodulatory effects which persist beyond the end of therapy leading to high
HBsAg clearance rates in the follow-up period. In a recent study, 97 patients with
chronic HBV infection who had received treatment with standard IFN α were
retrospectively analyzed for a median period of 14 (range, 5-20) years. During the
observation period, 28 patients (29%) of this cohort lost HBsAg (Moucari 2009).
PEG-IFN α in HBeAg-negative patients. The efficacy and safety of 48 weeks
treatment with 180 µg PEG-IFN α-2a once weekly + placebo, + 100 mg LAM daily,
or LAM alone was compared in 177, 179, and 181 HBeAg-negative patients,
Hepatitis B Treatment  141
respectively. After 24 weeks of follow-up, the percentage of patients with
normalisation of ALT levels or HBV DNA levels below 20,000 copies/ml was
significantly higher with PEG-IFN α-2a monotherapy (59% and 43%, respectively)
and PEG-IFN α-2a plus LAM (60% and 44%) than with LAM monotherapy (44%
and 29%); the rates of sustained suppression of HBV DNA below 400 copies/ml
were 19% with PEG-IFN α-2a monotherapy, 20% with combination therapy, and
7% with LAM alone.
Also in HBeAg-negative patients HBsAg loss can be induced in some patients by
PEG-IFN α treatment. In a study in 315 patients who were treated with either PEG-IFN α-2a, LAM 100 mg or a combination of both drugs for 48 weeks, three years
after the end of treatment, the rate of HBsAg loss was 8.7% in those who had been
treated with PEG-IFN α-2a alone or in combination with LAM while no patient
treated with LAM as monotherapy cleared HBsAg (Marcellin 2009a). Of the pa-tients who had received a PEG-IFN α-2a and who still had undetectable HBV DNA
three years after treatment, 44% had lost HBsAg.
Prolongation of PEG-IFN α treatment beyond 48 weeks may increase sustained
response rates. This was found in an Italian study in 128 mainly genotype D–
infected HBeAg-negative patients who were randomized to either treatment with
180 µg/week PEG-IFN α-2a for 48 weeks or a continuing treatment with PEG-IFN
α-2a at 135µg/week. Additionally, in a third arm patients received combination
treatment with PEG-IFN α-2a 180µg/week and LAM 100 mg/day, followed by 48
weeks of PEG-IFN α-2a in the dosage of 135 µg/week. As a result, 48 weeks after
the end of treatment 26% of patients who had received 96 weeks of PEG-IFN
treatment showed HBV DNA levels <2,000 IU/mL compared to only 12% of the
patients who had received PEG-IFN for 48 weeks. Combination with LAM showed
no additional effect (Lampertico 2010a).
Nucleoside and nucleotide analogs
Nucleoside and nucleotide analogs inhibit HBV replication by competing with the
natural substrate deoxyadenosine triphosphate (dATP) and causing terminating of
the HBV DNA chain prolongation. They represent two different subclasses of re-verse transcriptase inhibitors: while both are based on purines or pyrimidines,
acyclic nucleotide analogs have an open (acyclic) ribose ring that confers greater
binding capacity to resistant HBV polymerase strains.
Treatment duration for nucleos(t)ide analogs is not well-defined but a short-term
application of these agents for 48 weeks is associated with prompt relapse in
viremia and they should be administered for longer periods. Treatment efficacy of
nucleoside and nucleotide analogs implies complete suppression of HBV DNA
levels in serum. This should be achieved within six months if agents with high risk
for resistance development as LAM, ADV, and LdT are used.
Effective long-term control of HBV replication with nucleoside or nucleotide ana-logs is associated with a reduction of long-term complications such as HCC and
development of liver cirrhosis (Toy 2009). Studies with different nucleoside and
nucleotide analogs have demonstrated that suppression of HBV replication is
associated with a significant decrease in histologic inflammatory activity and fibro-sis, including partial reversion of liver cirrhosis (Chen 2006, Iloeje 2006, Mom-meja-Marin 2003, Chen 2010, Marcellin 2011, Schiff 2011). With increasing treat-ment duration HBeAg seroconversion rates increase (Liaw 2000, Lok 2000). Most
142  Hepatology 2012
importantly, there is also evidence that effective inhibition of HBV replication can
reduce HBV cccDNA, possibly running parallel to the decline in serum HBsAg
levels (Werle-Lapostolle 2004, Wursthorn 2006). These findings may indicate that
long-term antiviral therapy may lead to a complete response in a significant number
of patients.
A central aspect of HBV polymerase inhibitor treatment is the prevention and
management of HBV resistance to these drugs (see Chapter 10). Resistance against
nucleoside or nucleotide analogs can occur during suboptimal treatment and often
leads to aggravation of liver disease. Because of cross resistance between several
nucleoside and nucleotide analogs, nucleoside-naïve and nucleoside-experienced
patients have to be distinguished and prior nucleoside experience should be taken
into account when choosing a second line therapy. However, highly potent sub-stances such as ETV and TDF show minimal or even no resistance development in
treatment-naïve patients over 5-6 years (Snow-Lampert 2011).
Lamivudine (LAM). LAM, a (-) enantiomer of 2’ -3’ dideoxy-3’-thiacytidine, is
a nucleoside analog that was approved for the treatment of chronic HBV infection in
1988 with a daily dose of 100 mg. This dose was chosen based on a preliminary trial
that randomly assigned 32 patients to receive 25, 100, or 300 mg of LAM 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.
LAM exerts its therapeutic action in its phosphorylated form. 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.
Long-term LAM treatment is associated with an increasing rate of antiviral drug
resistance reaching approximately 70% after 5 years in patients with HBeAg-positive HBV infections. Therefore, in many guidelines LAM is not considered a
first-line agent in the treatment of chronic HBV infection any more. However, LAM
still may play a role in combination regimens or in patients with mild chronic
hepatitis B expressing low levels of HBV DNA (<10
5
copies/ml). An early and
complete virologic response to LAM within 6 months of therapy (<400 copies/mL)
constitutes a prerequisite for long-term control of HBV infection without the risk of
developing resistance.
Adefovir dipivoxil (ADV). 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, an acyclic nucleotide adenosine analog that is active in its
diphosphate form. Because the acyclic nucleotide already contains a phosphate-mimetic group, it needs only two, instead of three, phosphorylation steps to reach
the active metabolite stage. ADV was the first substance with simultaneous activity
against wild type, pre-core, and LAM-resistant HBV variants. It is active in vitro
against a number of DNA viruses other than HBV and retroviruses (i.e., HIV). The
dose of 10 mg per day was derived from a study comparing 10 mg versus 30 mg/d.
The higher dosage leads to stronger suppression of HBV DNA levels but also to
renal toxicity with an increase of creatinine levels (Hadziyannis 2003).
ADV was the first acyclic nucleotide that was widely used in the treatment of
LAM-resistant HBV infections. However, the antiviral effect of ADV in the
licensed dosage of 10 mg/day is rather low as compared to other available antivirals
(Figure 4); this disadvantage makes ADV vulnerable to  HBV resistance
Hepatitis B Treatment  143
(Hadziyannis 2006a). Now that TDF is approved, ADV should not be used as first-line monotherapy.
Telbivudine (LdT). Telbivudine is a thymidine analog which is active against
HBV but at least in vitro not active against other viruses, including HIV and
hepatitis C virus (HCV). LdT at 600 mg/day expresses higher antiviral activity
compared to either LAM at 100 mg/day or ADV at 10 mg/day (Figure 4). More
patients achieved HBeAg loss within 48 weeks as compared to other nucleos(t)ides.
LdT was reported to be non-mutagenic, non-carcinogenic, non-teratogenic, and to
cause no mitochondrial toxicity. A favourable safety profile at a daily dose of 600
mg was demonstrated (Hou 2008, Lai 2007). However, CK elevations were
observed more often as compared to the group treated with LAM and neurotoxicity
may be an issue when LdT is administered in combination with PEG-INF α
(Fleischer 2009). Thus, in the GLOBE trial, during a period of 104 weeks grades 3/4
elevations in CK levels were observed in 88 of 680 (12.9%) patients who received
LdT and in 28 of 687 (4.1%) patients who received LAM (p<0.001) (Liaw 2009).
However, rhabdomyolysis was not observed. Peripheral neuropathy was described
in 9 of 48 (18.75%) patients who received combination therapy of PEG-INF αnd
LdT and only in 10 of 3500 (0.28%) patients who received LdT monotherapy
(Goncalves 2009).
Resistance to LdT has been found to occur in up to 21% after 2 years of treatment
(Tenney 2009), predominantly in patients who did not achieve undetectable HBV
DNA level after 24 weeks of treatment (Zeuzem 2009). LdT shows cross-resistance
to LAM and ETV. As a consequence LdT should not be used in LAM or ETV
refractory patients.
Entecavir (ETV). Entecavir, a cyclopentyl guanosine nucleoside analog, 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 nucleoside and nucleotide analogs, ETV is more
efficiently phosphorylated to its active triphosphate compound by cellular kinases. It
is a potent inhibitor of wild-type HBV but is less effective against LAM-resistant
HBV mutants. Therefore, ETV was approved at a dose of 0.5 mg per day for
treating naïve HBeAg-positive and -negative patients at the dose of 1 mg per day for
patients with prior treatment with LAM (Lai 2005, Sherman 2008). ETV and LAM
are the only nucleoside analogs available as a tablet and an oral solution.
Treatment-naïve HBeAg-positive patients achieved undetectable HBV DNA
levels in 67% and 74% after one and two years of ETV treatment, reaching 94%
after five years, respectively (Figure 4, Figure 7) (Chang 2010). Long-term studies
in ETV responder patients demonstrated that response can be maintained in nearly
all patients over an observation period of up to six years. So far, the rate of
resistance at six years of treatment is estimated to be approximately 1.2% for
treatment-naïve patients (Tenney 2009). Loss of HBsAg occurs in 5% of treatment-naïve individuals after two years of ETV therapy (Gish 2010). A non-randomised
Italian study in a mixed population of predominantly HBeAg-negative patients
could demonstrate undetectable HBV DNA levels in 91% and 97% of patients at 1
and 2 years of ETV treatment, respectively (Lampertico 2010).
144  Hepatology 2012
In LAM-resistant patients ETV is less potent. Only 19% and 40% of these
patients achieved undetectable HBV DNA after one and two years, respectively,
despite an increased dose of 1 mg/day (Gish 2007, Sherman 2008). Due to cross-resistance up to 45% of patients with LAM resistance develop resistance against
ETV after 5 years of treatment (Tenney 2009).
ETV has a favourable tolerability profile and can be easily adjusted to renal
function. However, ETV may cause severe lactic acidosis in patients with impaired
liver function and a MELD score of >20 points (Lange 2009).
Figure 7. Percentage of patients achieving HBV DNA levels <400 copies/ml during long-term treatment with 1 mg ETV per day (Chang 2010). The long-term cohort ETV-901
consists of HBeAg-positive patients initially treated in the study ETV-022 (ETV 0.5 mg/day),
which was designed for a duration of one year.
Tenofovir  (TDF). Tenofovir disoproxil fumarate, an ester prodrug form of
tenofovir (PMPA; (R)-9-(2-phosphonylmethoxypropyl)), is an acyclic nucleoside
phosphonate, or nucleotide  analog  closely related to ADV. TDF has selective
activity against retroviruses and hepadnaviruses and is currently approved for the
treatment of HIV infection and of chronic hepatitis B. TDF showed marked antiviral
efficacy over five years with complete virologic response rates (HBV DNA <400
copies/ml) reaching nearly 100% in treatment-naïve HBeAg-negative and -positive
patients (Figure 8). In HBeAg-positive patients, 11% of patients experienced
HBsAg loss (Marcellin 2011). Other clinical studies showing a high efficacy of
TDF in LAM-resistant HBV infections irrespective of the mutation mediating LAM
resistance (van Bömmel 2010, Levrero 2010). Due to possibly existing cross-
Hepatitis B Treatment  145
resistance to ADV, the efficacy of TDF might be hampered by the presence of ADV
resistance in patients with high HBV viremia; however, a breakthrough of HBV
DNA during TDF treatment in patients with previous ADV failure or in treatment-naïve patients has not been observed (van Bömmel 2010, Levrero 2010, Snow-Lampert 2011).
Figure 8. Percentage of patients achieving HBV DNA levels <400 copies/mL during long-term treatment with 300 mg TDF per day (Marcellin 2010). Patients were originally
randomised to treatment with 300 mg TDF or 10 mg ADV per day. After one year, patients
receiving ADV were switched to TDF. Please note that the on-treatment analysis excluding the
missing patients showed undetectable HBV DNA in 96% of the TDF-TDF group and in 100% of
the ADV-TDF group.
TDF is generally well-tolerated and not associated with severe side effects. For
HBV-monoinfected, treatment-naïve patients, renal safety during TDF monotherapy
was investigated in three studies. In a randomized study comprising HBeAg-negative patients, none of 212 patients treated with TDF for three years and none of
112 patients who were treated with ADV for one year and then switched to TDF for
two years had a decrease in GFR to levels of <50 ml/min or an increase of serum
creatinine levels to >0.5 mg/dl (Marcellin 2009). In a similar study in HBeAg-positive patients, of 130 patients treated with TDF for 3 years and of 76 patients
treated with ADV for one year and consecutively with TDF for 2 years, only one
patients showed an increase in serum creatinine levels >0.5 mg/dl starting at year
two (Heathcote 2011). In a sub-analysis of both studies in 152 HBeAg-positive and
-negative Asian patients, no increase of serum creatinine >0.5 mg/dl or of eGFR
<50 ml/min was found in up to 3 years of TDF treatment (Liaw 2009a). In contrast,
in a recent study a benefit in renal function could be found in treated patients when
compared to untreated patients with HBV infection, which might reflect a lower
incidence of glomerulonephritis caused by HBsAg-induced immune complexes in
treated patients (Mauss 2011).
The use of tenofovir in HIV-coinfected patients is discussed in detail in Chapter
17.
Combination therapy as first-line treatment. As of now, first-line combination
treatments with nucleoside and nucleotide analogs or PEG-IFN α + nucleos(t)ide
analogs are not indicated. There is only one study comparing a combination therapy