Entecavir
Proves
Superior
to
Lamivudine
in
HBeAg-positive
Chronic
Hepatitis
B Worldwide,
chronic
hepatitis
B inflicts
an
almost
incredulous
toll
on
the
planet,
affecting
greater
than
350
million
people.
HBV-related
liver
cancer
and
cirrhosis
cause
more
than
one
million
deaths
each
year.
As
in
the
treatment
of
HIV
infection,
the
primary
objective
of
anti-HBV
therapy
is
suppression
of
viral
replication.
Several
studies
have
shown
that
HBV
suppression
with
use
of
long-term
treatment
with
lamivudine
in
HBeAg-positive
patients
can
produce
histologic
improvement
in
the
liver,
delay
the
progression
of
liver
disease
and
lower
the
risk
of
development
of
hepatocellular
carcinoma. There
are
currently
five
FDA-approved
drugs
for
the
treatment
of
patients
with
HBeAg-positive
chronic
hepatitis
B.
These
include
standard
interferon
alfa
(Intron
A),
lamivudine
(Epivir-HBV),
pegylated
interferon
alfa-2a
(Pegasys),
adefovir
dipivoxil
(Hepsera),
and
entecavir
(Baraclude).
Standard
interferon
alfa
is
curative
in
30-40
percent
of
patients,
but
is
associated
with
a high
incidence
of
adverse
events.
Lamivudine
is
effective
in
up
to
56
percent
of
patients,
but
within
four
years,
the
onset
of
lamivudine-
resistant
virus
reaches
nearly
70
percent,
usually
resulting
in
HBV
DNA
rebound
and
hepatitis
flares.
Pegylated
interferon
alfa-2a
is
superior
to
lamivudine
in
patients
6 months
post
48-week
treatment,
but
as
with
standard
interferon,
there
is
a higher
incidence
of
adverse
events
than
with
lamivudine.
Adefovir
dipivoxil
offers
a significant
reduction
in
HBV
DNA
levels,
improves
liver
histology
in
greater
than
50
percent
of
patients
and
HBeAg
seroconversion
in
12
percent.
However,
after
three
years
of
treatment,
resistance
to
adefovir
develops
in
up
to
3 percent
of
HBeAg-positive
patients
and
5.9
percent
of
HBeAg-negative
patients,
according
to
the
authors
of
the
present
study. | [Editor's
Note:
Regarding
experimental
agents,
both
tenofovir
and
telbivudine
show
promise
for
the
treatment
of
chronic
HBV.
Both
these
drugs
are
in
Phase
3 efficacy
trials.] |
Table
of
Contents
BEHoLD
Study
Design
Study
Population
Efficacy
End
Points
Results
Discussion
Summary
and
Conclusion
References
BEHoLD
Study
Design
 The
current
study
was
a double-blind,
randomized,
controlled,
multi-national
trial
conducted
in
709
patients
from
137
centers
worldwide,
including
Europe
(41
centers),
North
America
(40),
Asia
(26),
Australia
(12),
and
South
America
(18).
Study
participants
received
entecavir
at
a dose
of
0.5
mg
once
daily
or
lamivudine
at
a dose
of
100
mg
once
daily
for
a minimum
of
52
weeks.
The
study
was
designed
by
entecavir's
sponsor,
Bristol-Myers
Squibb,
in
collaboration
with
a group
of
expert
hepatologists
who
comprised
the
Benefits
of
Entecavir
for
Hepatitis
B Liver
Disease
(BEHoLD)
Study
Group.
Study
Population
Inclusion
Criteria
16
years
of
age
or
older
and
had
HBeAg-positive
chronic
hepatitis
B and
compensated
liver
function
and
no
history
of
variceal
bleeding
or
hepatic
encephalopathy.
Detectable
hepatitis
B surface
antigen
(HBsAg)
for
at
least
24
weeks
before
screening;
Evidence
of
chronic
hepatitis
on
a baseline
liver-biopsy
specimen
obtained
within
52
weeks
before
randomization;
HBV
DNA
level
of
at
least
3 MEq
per
milliliter
by
the
branched-chain
DNA
assay
at
screening;
and
Serum
alanine
aminotransferase
ALT
level
1.3
to
10.0
times
the
upper
limit
of
normal
at
screening.
Exclusion
Criteria
coinfection
with
hepatitis
C,
hepatitis
D or
HIV
or
the
human
immunodeficiency
virus;
the
presence
of
other
forms
of
liver
disease;
use
of
interferon
alfa,
thymosin,
or
antiviral
agents
with
activity
against
hepatitis
B within
24
weeks
before
randomization;
prior
lamivudine
therapy
lasting
more
than
12
weeks;
an
alpha
fetoprotein
level
greater
than
100
ng
per
milliliter;
a history
of
ascites
requiring
diuretics
or
paracentesis;
and
previous
treatment
with
entecavir.
Efficacy
End
Points The
primary
efficacy
end
point
was
the
proportion
of
patients
with
histologic
improvement.
This
was
defined
as
improvement
by
at
least
two
points
in
the
Knodell
necroinflammatory
score
with
no
worsening
in
the
Knodell
fibrosis
score
at
week
48,
relative
to
baseline.
Biopsies
were
scheduled
to
be
performed
at
baseline
(unless
one
had
been
performed
within
one
year
before
randomization)
and
at
week
48.
Liver-biopsy
specimens
were
evaluated
by
an
independent
histopathologist
who
was
unaware
of
patients'
treatment
assignment,
biopsy
sequence
and
clinical
outcome.
Secondary
efficacy
end
points
at
week
48
included
the
reduction
in
HBV
DNA
level
from
baseline
and
the
proportion
of
patients
with
undetectable
HBV
DNA,
as
measured
by
the
Roche
COBAS
Amplicor
PCR
assay
(version
2.0;
lower
limit
of
quantification,
300
copies
per
milliliter);
the
decrease
in
the
Ishak
fibrosis
score;
HBeAg
loss;
HBeAg
seroconversion
(HBeAg
loss
and
the
appearance
of
HBe
antibody);
and
normalization
of
serum
alanine
aminotransferase.
Normalization
of
alanine
aminotransferase
was
defined
by
the
protocol
as
an
alanine
aminotransferase
value
less
than
1.25
times
the
upper
limit
of
normal;
the
data
were
subsequently
reanalyzed
according
to
a more
stringent
definition
of
normalization
(an
alanine
aminotransferase
value
no
greater
than
the
upper
limit
of
normal).
Patients
who
had
a response
at
week
48
and
discontinued
treatment
were
followed
for
24
weeks
after
treatment.
This
served
to
indicate
whether
the
virologic
and
serologic
benefits
of
antiviral
therapy
were
sustained.
Safety
Analysis
Primary
safety
end
point
was
the
proportion
of
patients
who
discontinued
the
study
medication
because
of
clinical
or
laboratory-determined
adverse
events.
Analyses
of
adverse
events,
serious
adverse
events,
and
deaths.
Hepatitis
flares
during
treatment
were
defined
as
elevations
in
the
alanine
aminotransferase
level
to
more
than
twice
the
baseline
level
and
to
more
than
10
times
the
upper
limit
of
normal.
Post-treatment
flares
were
defined
as
elevations
in
alanine
aminotransferase
to
more
than
twice
the
reference
level
and
to
more
than
10
times
the
upper
limit
of
normal.
Resistance
Analysis
An
extensive
resistance
analysis
was
undertaken
to
identify
emerging
HBV
polymerase
substitutions
that
may
be
associated
with
reduced
susceptibility
to
entecavir.
All
339
available
paired
samples
from
patients
in
the
entecavir
group
were
submitted
for
genotypic
analysis.
In
the
lamivudine
group,
genotypic
and
phenotypic
analyses
were
performed
only
on
samples
from
patients
meeting
the
criterion
for
virologic
rebound.
Statistical
Analysis
Noninferiority
to
lamivudine
was
tested,
and
if
noninferiority
was
established,
a second
test
for
superiority
was
conducted.
Planned
sample
size,
315
per
group,
had
90
percent
power
to
demonstrate
noninferiority
with
respect
to
the
primary
efficacy
end
point,
assuming
response
rates
of
60
percent
for
lamivudine
and
64
percent
for
entecavir,
a 25
percent
rate
of
missing
biopsy
specimens
obtained
at
week
48,
and
a -10
percent
boundary
for
the
95
percent
lower
confidence
limit
for
the
difference
in
proportions.
The
study
had
a single
primary
end
point
(histologic
improvement).
There
were
no
interim
analyses
of
efficacy.
Results Study
Population
Of
1056
patients
who
were
enrolled
and
screened:
715
were
randomly
assigned
(357
to
the
entecavir
group
and
358
to
the
lamivudine
group),
and
709
(354
in
the
entecavir
group
and
355
in
the
lamivudine
group)
received
at
least
one
dose
of
study
drug.
340
patients
assigned
to
the
entecavir
group
(95
percent)
and
321
patients
assigned
to
the
lamivudine
group
(90
percent)
completed
52
weeks
of
treatment.
Histologic
and
Biochemical
End
Points
The
primary
analysis
met
the
initial
test
for
noninferiority
of
entecavir,
and
the
investigators
proceeded
to
test
for
superiority.
Entecavir
treatment
resulted
in
a significantly
higher
rate
of
histologic
improvement
than
lamivudine
treatment
at
week
48,
with
72
percent
and
62
percent
of
the
patients,
respectively,
reaching
this
primary
end
point.
Treatment
with
entecavir
and
lamivudine
resulted
in
improved
Ishak
fibrosis
scores
in
39
percent
and
35
percent
of
the
patients,
respectively
(P=0.41).
In
8 percent
of
the
entecavir-treated
patients
and
10
percent
of
the
lamivudine-treated
patients,
the
Ishak
fibrosis
score
worsened.
The
alanine
aminotransferase
(ALT)
level
was
normalized
in
a higher
proportion
of
entecavir-treated
patients
than
lamivudine-treated
patients
at
week
48
(68
percent
vs.
60
percent,
P=0.02).
Virologic
and
Serologic
End
Points
HBV
DNA
levels
in
the
entecavir
group
fell
throughout
treatment;
HBV
DNA
was
undetectable
by
PCR
assay
in
67
percent
of
the
patients
in
this
group
at
week
48.
In
contrast,
viral
loads
in
the
lamivudine
group
remained
distributed
over
a wide
range
of
values,
and
by
week
48,
HBV
DNA
was
undetectable
by
PCR
assay
in
36
percent
of
the
patients
in
that
group.
The
mean
reduction
from
baseline
in
the
serum
HBV
DNA
level
by
PCR
assay
at
week
48
was
also
greater
in
the
entecavir
group
(6.9
log
copies
per
milliliter)
than
in
the
lamivudine
group
(5.4
log
copies
per
milliliter).
HBeAg
loss
and
seroconversion
occurred
in
22
percent
and
21
percent,
respectively,
of
the
patients
in
the
entecavir
group.
These
rates
were
similar
to
those
in
the
lamivudine
group
(20
percent
and
18
percent,
respectively);
HBsAg
loss
occurred
in
six
patients
in
the
entecavir
group
(2
percent)
and
four
in
the
lamivudine
group
(1
percent).
Responses
at
Week
48
and
after
Treatment
At
week
48,
74
patients
in
the
entecavir
group
(21
percent)
and
67
in
the
lamivudine
group
(19
percent)
had
a protocol-defined
response
(HBV
DNA
level
of
less
than
0.7
MEq
per
milliliter
and
HBeAg
loss).
Two
hundred
forty-seven
patients
in
the
entecavir
group
(70
percent)
and
165
in
the
lamivudine
group
(46
percent)
had
a virologic
response
(HBV
DNA
level
of
less
than
0.7
MEq
per
milliliter,
without
HBeAg
loss).
There
was
a non
response
(HBV
DNA
level,
0.7
MEq
per
milliliter)
in
19
patients
in
the
entecavir
group
(5
percent)
and
94
in
the
lamivudine
group
(26
percent).
Among
the
patients
with
a protocol-defined
response,
82
percent
of
those
in
the
entecavir
group
(61
of
74)
and
73
percent
of
those
in
the
lamivudine
group
(49
of
67)
had
a sustained
response
24
weeks
after
the
discontinuation
of
treatment.
Of
the
patients
with
a response
at
week
48
who
discontinued
therapy,
41
percent
(25
of
61)
of
those
in
the
entecavir
group
and
41
percent
(20
of
49)
of
those
in
the
lamivudine
group
had
undetectable
HBV
DNA
by
PCR,
and
84
percent
(51
of
61)
and
82
percent
(40
of
49),
respectively,
had
normalization
of
alanine
aminotransferase.
Resistance
There
was
no
evidence
of
emerging
resistant
variants
to
entecavir
by
week
48
among
the
339
evaluated
patients
assigned
to
receive
entecavir.
Six
patients
in
the
entecavir
group
(2
percent)
and
63
patients
in
the
lamivudine
group
(18
percent)
had
virologic
rebound
during
the
first
year
of
drug
administration.
Samples
obtained
at
week
48
retained
full
phenotypic
susceptibility
to
entecavir.
Genotypic
analysis
of
isolates
obtained
at
week
48
from
the
patients
in
the
lamivudine
group
with
virologic
rebound
revealed
that
45
of
63
(71
percent)
had
mutations
in
the
YMDD
motif
of
the
HBV
polymerase
gene.
Safety
and
Adverse
Events
The
frequency
of
adverse
events
during
treatment
was
similar
in
the
two
groups.
The
most
frequent
adverse
events
were
headache,
upper
respiratory
tract
infection,
nasopharyngitis,
cough,
pyrexia,
upper
abdominal
pain,
fatigue,
and
diarrhea,
most
of
which
were
of
mild-to-moderate
severity.
The
frequencies
of
serious
adverse
events
were
also
similar
in
the
two
treatment
groups.
There
were
fewer
discontinuations
due
to
adverse
events
in
the
entecavir
group
(one)
than
in
the
lamivudine
group
(nine);
four
of
the
nine
patients
in
the
lamivudine
group
and
the
patient
in
the
entecavir
group
discontinued
treatment
because
of
an
increase
in
alanine
aminotransferase.
Elevations
in
alanine
aminotransferase
were
observed
less
frequently
in
the
entecavir
group
than
in
the
lamivudine
group.
Alanine
aminotransferase
flares
during
treatment
were
observed
in
12
entecavir-treated
patients
(3
percent)
and
23
lamivudine-treated
patients
(6
percent).
In
the
entecavir
group,
all
the
alanine
aminotransferase
flares
during
treatment
were
associated
with
a reduction
in
HBV
DNA
by
at
least
2 log
copies
per
milliliter,
and
all
but
one
were
self-limiting
with
continued
treatment.
None
of
the
entecavir-treated
patients
had
hepatic
decompensation.
In
the
lamivudine
group,
approximately
half
the
alanine
aminotransferase
flares
during
treatment
(12
of
23)
were
associated
with
increasing
HBV
DNA
levels.
The
majority
of
the
flares
persisted
until
the
time
of
treatment
discontinuation.
One
of
the
lamivudine-treated
patients
had
hepatic
decompensation
associated
with
a flare
and
died
during
follow-up.
At
the
time
the
database
was
locked,
alanine
aminotransferase
flares
had
occurred
in
2 of
134
patients
(1
percent)
in
the
entecavir
group
and
9 of
129
patients
(7
percent)
in
the
lamivudine
group
who
underwent
post-treatment
follow-up.
Two
deaths
occurred
during
the
on-treatment
period,
both
in
the
lamivudine
group.
Neither
was
judged
to
be
related
to
study
therapy.
One
patient
died
from
sudden
dyspnea,
and
one
death
was
of
undetermined
cause.
Discussion Lamivudine
treatment
has
been
associated
with
histologic
improvement
and
with
reductions
in
both
Child-Pugh
score
and
the
development
of
hepatocellular
carcinoma.
This
reduction
in
disease
progression
probably
arises
from
the
effective
suppression
of
HBV
replication.
"However,"
the
authors
note,
"the
frequent
development
of
lamivudine
resistance
can
result
in
a rebound
in
viral
load
and
a loss
of
histologic
benefit."
In
the
current
study,
entecavir
was
associated
with
significantly
higher
rates
of
histologic,
virologic,
and
biochemical
improvement
than
was
lamivudine.
The
efficacy
of
entecavir
appears
to
result
from
its
potent
suppression
of
HBV
replication.
Entecavir
suppressed
HBV
DNA
by
a mean
of
nearly
7 log
copies
per
milliliter,
and
67
percent
of
the
patients
in
the
entecavir
group
had
undetectable
levels
of
HBV
DNA
by
PCR
assay
within
48
weeks
after
the
start
of
treatment.
Histologic
examination
of
the
liver
remains
the
definitive
method
of
assessing
disease
progression,
and
arresting
or
reversing
liver
damage
is
a principal
goal
of
long-term
hepatitis
B therapy.
According
to
the
study
authors,
"The
improved
histologic
benefit
of
entecavir
as
compared
with
lamivudine
and
its
greater
effect
on
viral
suppression
suggest
that
with
long-term
treatment,
entecavir
might
also
reduce
the
risk
of
end-stage
liver
disease
and
hepatocellular
carcinoma."
At
week
48,
there
was
no
evidenc
od
an
emergence
of
drug
resistance.In
vitro
experiments
and
clinical
studies
have
demonstrated
that
resistance
to
entecavir
develops
only,
and
infrequently,
when
HBV
contains
preexisting
lamivudine-associated
resistance
substitutions
(rtL180M
and
rtM204V)
and
when
an
additional
substitution
(rtT184G,
rtS202I,
or
rtM250V)
is
selected.
The
possibility
of
resistance
after
longer-term
exposure
to
entecavir
treatment
is
currently
under
study.
Lamivudine
is
established
as
a well-tolerated
antiviral
therapy.
The
similar
tolerability
profiles
of
entecavir
and
lamivudine
in
this
study
show
that
entecavir
is
well
tolerated
by
patients
with
chronic
hepatitis
B.
Continued
monitoring
will
be
necessary
to
determine
it's
long-term
safety.
The
authors
point
out
that
fewer
patients
treated
with
entecavir
than
those
treated
with
lamivudine
experienced
ALT
flares
during
therapy.
The
flares
taking
place
during
entecavir
treatment
were
associated
with
reductions
in
HBV
DNA.
Flares
after
treatment
were
also
uncommon
among
the
entecavir-treated
patients.
Summary
and
Conclusion
Among
patients
with
HBeAg-positive
chronic
hepatitis
B,
the
rates
of
histologic,
virologic,
and
biochemical
improvement
are
significantly
higher
with
entecavir
than
with
lamivudine.
The
safety
profile
of
the
two
agents
is
similar,
and
there
is
no
evidence
of
viral
resistance
to
entecavir.
In
conclusion,
the
authors
write,
"The
advent
of
more
potent
antiviral
agents
for
the
treatment
of
chronic
hepatitis
B offers
the
potential
to
control
HBV
replication
and
to
arrest
or
halt
the
progression
of
liver
disease.
Entecavir,
which
provided
response
rates
that
were
significantly
higher
than
those
of
an
existing
oral
antiviral
agent
in
a large
population
of
patients
who
had
not
previously
received
a nucleoside
analogue,
has
demonstrated
benefit
as
a primary
therapy
for
HBeAg-positive
chronic
hepatitis
B."
03/10/06
References
1.
T-T
Chang,
R G
Gish,
R de
Man
and
others
(for
the
BEHoLD
AI463022
Study
Group).
A Comparison
of
Entecavir
and
Lamivudine
for
HBeAg-Positive
Chronic
Hepatitis
B.
The
New
England
Journal
of
Medicine
354(10):
1001-1010.
March
9,
2006.
2.
C-L
Lai,
D Shouval
and
A S
Lok
(for
the
BEHoLD
AI463027
Study
Group).
Entecavir
versus
Lamivudine
for
Patients
with
HBeAg-Negative
Chronic
Hepatitis
B.
The
New
England
Journal
of
Medicine
354(10):
1011-1020.
March
9,
2006.
|
Entecavir
(Baraclude)
Brand
Name:
Baraclude
Drug
Class:
Nucleoside
analogue
reverse
transcriptase
inhibitor
|
|
|
|
