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Clinical Medicine: Therapeutics 2009:1 1115 11

REVIEW
Correspondence: Emilio Palumbo, Via dell Arc. Michele, 4 71100 Foggia Italy. Tel: +39 0881 685023;
Fax: + 39 0881 685023; Email: emipalu2003@yahoo.it
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Pharmacotherapy of Chronic Hepatitis B with Entecavir
Emilio Palumbo
Clinic of Paediatric, Hospital of Sondrio, Italy.
Abstract: Actually three nucleotide/nucleoside analogues are used for chronic hepatitis B: lamivudine, adefovir dipivoxil,
entecavir and telbivudine. Lamivudine and adefovir are advantageous for oral administration and safety, but they induce
a sustained response after withdrawal of therapy in only a minority of patients. Telbivudine is a new drug and further studies
are need to evaluate its real efcacy. Entecavir, a cyclopentyl guanosine analog, is a potent inhibitor of HBV-DNA polymerase
and it inhibits both priming and elongation steps of viral DNA replication. In phase II and III clinical trials, entecavir was found
to be superior to lamivudine for all primary endpoints evaluated in both nucleoside-naive and lamivudine-resistant patients
and it was effective in both HBeAg-positive and HBeAg-negative nucleoside-naive patients. Only one trial has evidenced cases
of viral resistance to entecavir. The approved dosage in treatment-naive patients is 0.5 mg/day orally, while in patients who
have failed lamivudine therapy or are known to harbour lamivudine-resistant mutants, the approved dosage is 1.0 mg/day.
Keywords: entecavir, hepatitis B, pharmacology, pharmacokinetics
Despite the use of HBV vaccine, chronic hepatitis B virus (HBV) infection occurs in approximately 5% of
the global population. This infection may lead to chronic hepatitis, cirrhosis and hepatocellular carcinoma in
25% to 40% of infected patients, it is among the principle 10 causes of death throughout the world.
1,2
Until recently, the only generally approved treatment for chronic hepatitis B was alpha-interferon, but
it has demonstrated moderate efcacy in terms of sustained response (biochemical, virological and his-
tological). In fact, only 20% to 40% of treated patients responded to therapy, with lower percentages
(10%) among patients infected with precore-mutant strains of HBV (HBeAb HBV-DNA positive).
3,4

This form is prevalent in mediterranean area (90% of the all patients with HBV infection) and it is due
to a mutation at nucleotide 1896 in the precore region of the HBV-DNA genome. The result of this muta-
tion is a stop codon that blocks HBeAg synthesis but still permits HBV replication and hepatitis B core
antigen production, leading to persistence of viremia and persistent or intermittent elevated serum alanine
aminotransferase (ALT) levels with frequent evolution into cirrhosis and hepatocellular carcinoma. The
suboptimal response of this form to alpha-interferon with a high rate of non-responders or relapses has
led to the research and development of new antiviral drugs to be used as alternative therapies.
The use of nucleot(s)ide analogues is a milestone in the treatment of chronic hepatitis B (CHB) and
they are considered as an alternative to interferon-treatment. The FDA of the USA approved the use of
lamivudine in adult patients in 1998, adefovir dipivoxil in 2002. These agents are advantageous for oral
administration and safety, but they induce a sustained response (after withdrawal of therapy) in only a
minority of patients. In addition, the long-term efcacy of lamivudine is limited by the frequent emer-
gence of drug-resistant HBV mutants.
57
Adefovir is associated with a low frequency of resistance but
its antiviral effect is not optimal.
8
For these reasons new drugs for treatment of chronic hepatitis B are
needed. A recent study has evidence entecavir is a selective inhibitor of HBV-DNA and it is less effec-
tive against lamivudine-resistant mutants than against wild-type HBV effective in combating lamivu-
dine-resistant mutant. This review focuses on the pharmacodynamic and pharmacokinetic
characteristics and on the efcacy and tolerability of entecavir in the treatment of chronic hepatitis B.
Relevant literature was identied through searches of MEDLINE (2002-May 2007).
Pharmacodynamic and Pharmacokinetic
Entecavir, a guanosine nucleoside analogue with activity against HBV polymerase, is efciently phos-
phorylated to the active triphosphate (TP) form, which has an intracellular half-life of 15 hours. By competing
12
Palumbo
Clinical Medicine: Therapeutics 2009:1
with the natural substrate deoxyguanosine TP,
entecavir-TP functionally inhibits the 3 activities of
the viral polymerase: (1) priming of the HBV poly-
merase, (2) reverse transcription of the negative
strand DNA from the pregenomic messenger RNA,
and (3) synthesis of the positive strand HBV DNA.
The entecavir-TP Ki for HBV DNA polymerase is
0.0012 M. Entecavir-TP is a weak inhibitor of
cellular DNA polymerases , , and with Ki values
of 18 to 40 M. In addition, high exposures of ente-
cavir had no relevant adverse effects on polymerase
or mitochondrial DNA synthesis in HepG2 cells
(Ki 160 M).
9
Entecavir inhibited HBV DNA synthesis (50%
reduction, EC50) at a concentration of 0.004 M
in human HepG2 cells transfected with wild-type
HBV. The median EC50 value for entecavir against
LVDr HBV (rtL180M and rtM204V) was 0.026 M
(range 0.0100.059 M). In contrast, no clinically
relevant activity was noted against HIV type 1
(EC50 value 10 M) grown in cell culture.
Recombinant viruses encoding adefovir-resistant
mutations at either rtN236T or rtA181V remained
fully susceptible to entecavir.
In HBV combination assays in vitro, abacavir,
didanosine, lamivudine, stavudine, tenofovir or
zidovudine were not antagonistic to the anti-HBV
activity of entecavir over a wide range of concentra-
tions. In HIV antiviral assays, entecavir was not
antagonistic to the in vitro anti-HIV activity of these
six NRTIs at 4 times the Cmax of entecavir. Rela-
tive to wild-type HBV, LVDr viruses containing
rtM204 V and rtL180 M substitutions within the
reverse transcriptase exhibit 8-fold decreased sus-
ceptibility to entecavir. Incorporation of additional
entecavir resistant amino acid changes rtT184,
rtS202 and/or rtM250 decreases entecavir suscepti-
bility in cell culture. Substitutions observed in
clinical isolates (rtT184 A, C, F, G, I, L, M or S;
rtS202 C, G or I; and/or rtM250 I, L or V) further
decreased entecavir susceptibility 16- to 741-fold
relative to wild-type virus. The entecavir resistant
substitutions at residues rtT184, rtS202 and rtM250
alone have only a modest effect on entecavir suscep-
tibility, and have not been observed in the absence
of lamivudine resistant substitutions in more than
1000 patient samples sequenced. Resistance is medi-
ated by reduced inhibitor binding to the altered HBV
reverse transcriptase, and resistant HBV exhibits
reduced replication capacity in cell culture.
5
Entecavir is rapidly absorbed with peak plasma
concentrations occurring between 0.51.5 hours.
The absolute bioavailability has not been determined.
Based on urinary excretion of unchanged drug, the
bioavailability has been estimated to be at least 70%.
There is a dose-proportionate increase in Cmax and
AUC values following multiple doses ranging from
0.11 mg. Steady-state is achieved between
610 days after once daily dosing with 2 times
accumulation. Cmax and Cmin at steady-state are
4.2 and 0.3 ng/ml, respectively, for a dose of 0.5 mg,
and 8.2 and 0.5 ng/ml, respectively, for 1 mg. The
tablet and oral solution were bioequivalent in healthy
subjects; therefore, both forms may be used inter-
changeably.
5
Administration of 0.5 mg entecavir with a stan-
dard high-fat meal (945 kcal, 54.6 g fat) or a light
meal (379 kcal, 8.2 g fat) resulted in a minimal delay
in absorption (11.5 hour fed vs. 0.75 hour fasted),
a decrease in Cmax of 44%46%, and a decrease in
AUC of 18%20%. The lower Cmax and AUC when
taken with food is not considered to be of clinical
relevance in nucleoside-naive patients but could
affect efcacy in lamivudine-refractory patients. The
estimated volume of distribution for entecavir is in
excess of total body water. Protein binding to human
serum protein in vitro is 13%. Entecavir is not a
substrate, inhibitor or inducer of the CYP450 enzyme
system. Following administration of 14C-entecavir,
no oxidative or acetylated metabolites and minor
amounts of the phase II metabolites, glucuronide and
sulfate conjugates, were observed. Entecavir is pre-
dominantly eliminated by the kidney with urinary
recovery of unchanged drug at steady-state of about
75% of the dose. Renal clearance is independent of
dose and ranges between 360471 ml/min suggest-
ing that entecavir undergoes both glomerular ltra-
tion and net tubular secretion. After reaching peak
levels, entecavir plasma concentrations decreased in
a bi-exponential manner with a terminal elimination
half-life of 128149 hours. The observed drug
accumulation index is 2 times with once daily dos-
ing, suggesting an effective accumulation half-life
of about 24 hours. Pharmacokinetic parameters in
patients with moderate or severe hepatic impairment
were similar to those in patients with normal hepatic
function.
Entecavir clearance decreases with decreasing
creatinine clearance.
6,7
Efcacy and Tolerability
In the rst study (Lai CL et al) a 24-week, double-
blind, randomized, multicenter, phase II clinical trial,
the safety and efcacy of entecavir (0.01 mg/day,
13
Entecavir for HBV
Clinical Medicine: Therapeutics 2009:1
0.1 mg/day, or 0.5 mg/day orally) were compared
with lamivudine (100 mg/day orally). A total of 169
treatment-naive patients chronically infected with
HBV (HBeAg and anti-HBe positive) were evaluated
for efcacy. Compared with lamivudine, entecavir
reduced HBV DNA by an additional 0.97 log(10) at
the 0.1-mg/day dose and an additional 1.28 log(10)
at the 0.5-mg/day dose. A clear dose-response rela-
tionship was observed for entecavir with the higher
doses showing signicantly greater viral suppression.
In patients treated with entecavir 0.5 mg/day, 83.7%
had an HBV-DNA level below the lower limit of
detection of the Quantiplex branched DNA assay
(2.5 pg/ml), compared with 57.5% treated with
100 mg/day lamivudine. In both treatment arms, very
few patients achieved HBeAg loss and/or serocon-
version by week 22. More patients treated with the
0.1-mg/day and 0.5-mg/day doses of entecavir had
normalization of alanine transaminase levels at week
22 compared with lamivudine, without a signicant
statistical difference. Entecavir was well tolerated
and side effects were similar to lamividine. This
study showed that entecavir has potent antiviral
activity against HBV at 0.1-mg/day and 0.5-mg/day
doses, both of which were superior to lamivudine in
patients affected by chronic B hepatitis, both HBeAg
and anti-HBe-positive.
9
In a phase III clinical trial Sherman M et al. ran-
domized a total of 286 patients affected by chronic
HBeAg-positive hepatitis with lamivudine-resistance
to switch to entecavir 1 mg daily (141 patients) or
continue lamivudine 100 mg daily (145) for a mini-
mum of 52 weeks. Histological improvement
occurred in 55% (68/124) of entecavir-treated treated
for 52 weeks vs. 28% (32/116) of lamivudine-treated
patients. More patients on entecavir than lamivudine
achieved the composite end point: 55% (77/141) vs.
4% (6/145), respectively. Mean change from baseline
in HBV DNA was 5.11 log(10) copies/mL for
entecavir-treated patients and 0.48 log(10) copies/mL
for lamivudine-treated patients. HBV DNA was
determined by PCR-Real-Time (1.000 copies/ml).
Virologic rebound because of entecavir resistance
substitutions occurred in 2 of 141 of entecavir-treated
patients, and genotypic evidence of resistance was
detected in 10 patients. The safety prole of enteca-
vir was comparable to lamivudine with fewer ALT
ares on treatment.
10
In another phase 3, double-blind trial Lai CL et al.
randomly assigned 648 patients with HBeAg-negative
chronic hepatitis B who had not previously been
treated with a nucleoside analogue to receive 0.5 mg
of entecavir or 100 mg of lamivudine once daily for
a minimum of 52 weeks. The primary efcacy end
point was histological improvement with a decrease
by at least two points in the Knodell necroinamma-
tory score, without worsening of brosis. Histo-
logical improvement after 48 weeks of treatment
occurred in 208 of 296 patients in the entecavir group
who had adequate baseline liver-biopsy specimens
that could be evaluated (70%), as compared with 174
of 287 such patients in the lamivudine group (61%).
More patients in the entecavir group than in the
lamivudine group had undetectable serum hepatitis
HBV-DNA levels according to a polymerase-chain-
reaction assay (1000 copies/ml, 90% vs. 72%) and
normalization of alanine aminotransferase levels
(78% vs. 71%, P = 0.045). The mean reduction in
serum HBV DNA levels from baseline to week 48
was greater with entecavir than with lamivudine.
There was no evidence of resistance to entecavir.
Safety and adverse-event proles were similar in the
two groups. Therefore, this study evidences as among
patients with HBeAg-negative chronic hepatitis B
who had not previously been treated with a nucleo-
side analogue, the rates of histological improvement,
virologic response, and normalization of alanine
aminotransferase levels were signicantly higher at
48 weeks with entecavir than with lamivudine.
11
Chang TT et al. randomly assigned 715 patients
affected by HBeAg-positive chronic hepatitis B who
had not previously received a treatment to receive
either 0.5 mg of entecavir or 100 mg of lamivudine
once daily for a minimum of 52 weeks. Also in this
study the primary efcacy end point was histological
improvement with a decrease by at least two points
in the Knodell necroinammatory score, without
worsening of brosis at week 48, while secondary
end points included a reduction in the serum HBV
DNA level, HBeAg loss and seroconversion, and
normalization of the alanine aminotransferase level.
Histological improvement after 48 weeks occurred
in 226 of 314 patients in the entecavir group (72%)
and 195 of 314 patients in the lamivudine group
(62%). More patients in the entecavir group than in
the lamivudine group had undetectable serum HBV
DNA levels according to a polymerase-chain-reaction
assay (1.000 copies/ml, 67% vs. 36%) and nor-
malization of alanine aminotransferase levels (68%
vs. 60%). The mean reduction in serum HBV DNA
from baseline to week 48 was greater with entecavir
than with lamivudine (6.9 vs. 5.4 log copies per
milliliter). HBeAg seroconversion occurred in 21%
of entecavir-treated patients and 18% of those treated
14
Palumbo
Clinical Medicine: Therapeutics 2009:1
with lamivudine. No viral resistance to entecavir was
detected. Safety was similar in the two groups. In
this study among patients with HBeAg-positive
chronic hepatitis B, the rates of histological, viro-
logic, and biochemical improvement are signicantly
higher with entecavir than with lamivudine in patients
affected by chronic HBeAg-positive hepatitis. The
safety prole of the two agents is similar, and there is
no evidence of viral resistance to entecavir.
12
The aim of a recent study was to assess the ef-
cacy and safety of entecavir in kidney- and liver-
transplant recipients with chronic hepatitis B virus
(HBV) infection. Ten male transplant patients with
chronic HBV infection (eight kidney- and two liver-
transplant patients), who have become adefovir
(n = 9) or lamivudine-resistant (n = 1) were given
entecavir at 0.5 to 1 mg/d. All patients were HBs Ag
positive: six were HBe Ag()/HBe Ab(+), and four
were HBe Ag(+)/HBe Ab(). After a median follow-
up of 16.5 months, entecavir therapy was associated
with a signicant decrease in HBV DNA viral load
and rate of HBV DNA clearance was 50% in both
HBeAg(+) and HBeAg() patients. The study
showed a decline of eGFR from 62 to 48 ml/min in
patients with renal transplant. This is doubtful since
the patients had received a renal transplant and many
reasons for declining renal function, however, a
cautionary remark might be justied.
13
The efcacy and safety of entecavir in patients
with chronic hepatitis B and advanced liver brosis/
cirrhosis was assessed from three large, randomized,
multicenter, phase III studies. These studies enrolled
patients (/ = 16 yr) with chronic hepatitis B, ele-
vated alanine aminotransferase (ALT) levels, and
compensated liver disease. Two trials enrolled
nucleos(t)ide-naive patients randomized to at least
48 weeks of treatment with entecavir 0.5 mg/day or
lamivudine 100 mg/day. The third trial randomized
lamivudine-refractory patients to 48 weeks of ente-
cavir 1 mg/day or lamivudine 100 mg/day. The
majority of patients were previously treated with
interferon. The efcacy and safety in patients with
advanced liver brosis/cirrhosis were examined for
consistency with those seen in the overall study
populations. Of the 1,633 treated patients, 245 had
advanced liver brosis/cirrhosis (120 entecavir and
125 lamivudine). Among entecavir-treated patients
with advanced liver brosis, improvement in Ishak
brosis was observed in 57% of nucleos(t)ide-naive
HBeAg-positive patients, 59% of nucleos(t)ide-naive
HBeAg-negative patients, and 43% of lamivudine-
refractory HBeAg-positive patients versus 49%,
53%, and 33% of lamivudine-treated patients with
advanced liver brosis. The overall trends in other
histologic, virologic, biochemical, and serologic
outcomes in entecavir- versus lamivudine-treated
patients with advanced liver brosis/cirrhosis were
consistent with those observed in the overall study
populations in each trial. The treatment was well
tolerated. This data conrms that the performance
of entecavir relative to that of lamivudine in patients
with advanced liver brosis/cirrhosis was consistent
with the relationship observed in the overall treated
population.
14
A recent randomized, double-blind, multicenter
study in Japan evaluated the efcacy and safety of
two doses of entecavir in adult patients with
lamivudine-refractory chronic hepatitis B infection.
Eighty-four patients with chronic hepatitis B who
were refractory to lamivudine therapy were switched
from lamivudine to daily oral doses of 0.5 mg ente-
cavir (41 patients) or 1 mg entecavir (43 patients)
for 52 weeks. The proportions of patients achieving
the primary end-point ( or = 2 log(10) reduction
in HBV-DNA from baseline by polymerase chain
reaction assay or undetectable HBV-DNA levels
[400 copies/mL] at week 48) were 90% and 93%
for entecavir 0.5 mg and 1 mg, respectively, with
33% of patients in each dosing group achieving
400 copies/mL. The mean reduction in HBV-DNA
from baseline was 3.58 and 3.75 log(10) copies/mL
for entecavir 0.5 mg and 1 mg, respectively. High
proportions of patients achieved alanine aminotrans-
ferase normalization at week 48 (0.5 mg 86%, 1 mg
78%). Histological improvement was observed in
most patients (0.5 mg 52%, 1 mg 60%). Virological
breakthrough (increase in HBV-DNA of or = 1
log(10) copies/mL from nadir) was observed in one
patient but was not associated with selection of
entecavir-associated resistance substitutions. Ente-
cavir was well tolerated, with no patients discon-
tinuing the study drug due to adverse events.
15
In another experiment a total of 286 patients were
randomized and treated with entecavir 1 mg (n = 141)
or continued lamivudine 100 mg (n = 145). At week
52, 77 entecavir-treated patients who had a protocol-
dened virologic response (HBV branched DNA
[bDNA] 0.7 MEq/mL but HBeAg-positive)
continued blinded therapy for up to 96 weeks.
Patients were assessed for efficacy, safety, and
emerging resistance. Cumulative proportions of all
treated patients who achieved conrmed efcacy
endpoints were also analyzed. Between week 48 and
the end of dosing, the proportions of patients with
15
Entecavir for HBV
Clinical Medicine: Therapeutics 2009:1
HBV DNA 300 copies/mL by polymerase chain
reaction increased from 21% to 40%, and alanine
aminotransferase normalization ( or = 1x upper
limit of normal) increased from 65% to 81%. In the
second year, HBeAg seroconversion was achieved
by 10% of patients. Of the 77 patients in the second
year treatment cohort, entecavir resistance emerged
in six patients, and seven experienced virologic
breakthrough (five with genotypic resistance
acquired before year 2). The safety prole of ente-
cavir in the second year of therapy was consistent
with that reported during year 1. Through 96 weeks
of treatment, 1 mg entecavir resulted in continued
clinical benet in lamivudine-refractory HBeAg-
positive chronic hepatitis B patients with a safety
prole comparable to lamivudine.
16
Using 500 patient HBV isolates from several
entecavir clinical trials, Baldick CJ et al. show that
phenotypic susceptibility correlates with genotypic
resistance and patient virologic responses. The
full-length HBV or reverse transcriptase gene was
amplied from patient sera, sequenced, and cloned
into an HBV expression vector. Entecavir suscep-
tibilities of individual virus clones and patient
quasispecies populations were analyzed in con-
junction with the sequenced resistance genotype
and the patients virologic response. Entecavir
susceptibility decreased approximately 8-fold for
isolates with various constellations of lamivudine
resistance substitutions. The spectrum of additional
substitutions that emerged during therapy at resi-
dues rtT184, rtS202, or rtM250 displayed varying
levels of entecavir susceptibility according to the
specic resistance substitutions and the proportion
of resistant variants in the quasispecies. Phenotypic
analyses of samples associated with virologic
breakthrough conrmed the role of these residue
changes in entecavir resistance. Additional longi-
tudinal phenotypic analyses showed that decreased
susceptibility correlated with both genotypic resis-
tance and increased circulating HBV DNA.
17
Conclusion
The goal of therapy for patients with HBV infection
is to prevent the progression of liver disease to
cirrhosis and hepatic cell cancer. Among analogue
nucleos(t)ise, lamivudine i is limited by the high
frequency of resistance. Adefovir has the advantages
of a very low frequency of resistance and effective-
ness both in wild-type and lamivudine-resistant
HBV infection. Entecavir has been proved effective
against wild-type and lamivudine-resistant mutants.
The treatment most likely needed for chronic hepatitis B
is to use multiple agents and entecavir must be used
in combination with lamivudine or adefovir. We do
not have information on treating interferon resistant
patients with entecavir. Futher studies are needed to
conrm the rate of resistance to this drug.
Disclosure
The author reports no conicts of interest.
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