Current Antiviral Therapy of Chronic Hepatitis B: Efficacy and Safety.

Abstract

The treatment of chronic hepatitis B is in constant evolution. Interferon, the first agent licensed for chronic hepatitis B treatment, has been superseded by the growing popularity of nucleoside/nucleotide analogues (NA). However, resistance to these agents is a major challenge. Newer NAs, such as entecavir and tenofovir dipivoxil fumarate, have very low resistance rates and favorable safety profiles. Long-term use of these agents can effectively suppress hepatitis B virus DNA, leading to decrease in incidence of hepatitic flares, as well as in the development of cirrhosis and hepatocellular carcinoma. The efficacy and safety of various antiviral agents is discussed in this review.

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Current Antiviral Therapy of Chronic Hepatitis B: Efficacy
and Safety
Yuk-Fai Lam & Man-Fung Yuen & Wai-Kay Seto &
Ching-Lung Lai
Published online: 9 August 2011
# The Author(s) 2011. This article is published with open access at Springerlink.com
Abstract The treatment of chronic hepatitis B is in constant
evolution. Interferon, the first agent licensed for chronic
hepatitis B treatment, has been superseded by the growing
popularityofnucleoside/nucleotideanalogues(NA).However,
resistance to these agents is a major challenge. Newer NAs,
such as entecavir and tenofovir dipivoxil fumarate, have very
low resistance rates and favorable safety profiles. Long-term
use of these agents can effectively suppress hepatitis B virus
DNA, leading to decrease in incidence of hepatitic flares, as
well as in the development of cirrhosis and hepatocellular
carcinoma. The efficacy and safety of various antiviral agents
is discussed in this review.
Keywords Hepatitis B.Nucleos(t)ide Analogs.
Resistance.HBV DNA
Introduction
Chronic hepatitis B (CHB) infection is a major health
burden worldwide, with around 400 million people affected
[1]. Patients with CHB have a 15% to 40% chance of
developing cirrhosis, hepatic decompensation and hepato-
cellular carcinoma in their lifetime [2, 3]. The risk of
having hepatocellular carcinoma is increased by more than
100–200 fold compared to healthy subjects [4]. Currently
two classes of agents are available for treatment of chronic
hepatitis B, namely immunomodulatory therapy (conven-
tional interferon and pegylated interferon) and nucleoside/
nucleotide analogs (NA).
Conventional Interferon and Pegylated Interferon
The first agent approved for treatment of chronic hepatitis
B was conventional interferon-α [5]. Pegylated-interferon,
which was licensed in 2005, has the advantage of ease of
administration when compared to conventional interferon.
They mainly work through immunomodulation.
These agents decrease viral loads and increase rates of
hepatitis B e antigen (HBeAg) seroconversion to antibody
against HBeAg (anti-HBe) [6]. They also have the advantage
of use for a finite duration. However, the course of treatment
has been extended from 16 weeks with the conventional
interferon to 48 weeks with pegylated interferon.
Interferons are poorly tolerated because of their severe
side effects. The side effects include influenza-like illness,
anorexia, flares of autoimmune disease, thyroid dysfunc-
tion, myelosuppression, hepatitis flare, hepatic decompensa-
tion, and neuropsychiatric adverse events like depression,
irritability, and even suicidal tendency. High relapse rate and
costs are also drawbacks of immunomodulatory therapy [7, 8].
On long-term follow-up, a majority of patients still have
detectable hepatitis B virus (HBV) DNA after interferon
treatment [9, 10]. In addition, most studies fail to demon-
strate a reduction in incidence of hepatocellular carcinoma
with conventional interferon on long term follow-up [11–13].
Nucleoside/Nucleotide Analogue
Currently five NAs are approved for the treatment of
CHB. They are lamivudine, adefovir dipivoxil (ADV),
HEPATITIS B: EPIDEMIOLOGY, NATURAL HISTORY, TREATMENT, AND TRANSPLANTATION (THOMAS BERG AND STEVEN-HUY HAN, SECTION EDITORS)
Y.-F. Lam (*):M.-F. Yuen:W.-K. Seto:C.-L. Lai
Department of Medicine,
The University of Hong Kong Queen Mary Hospital,
Pokfulam Road,
Hong Kong, Hong Kong
e-mail: lamyukfai@hotmail.com
Curr Hepatitis Rep (2011) 10:235–243
DOI 10.1007/s11901-011-0109-z

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telbivudine, entecavir and tenofovir disoproxil fumarate
(TDF) (Tables 1 and 2)
They are effective in suppressing viral loads, facilitating
HBeAg seroconversion, achieving alanine aminotransferase
(ALT) normalization, and improving liver fibrosis.
They are generally well tolerated and serious adverse
events are rarely encountered [14–17].
There is growing evidence that prolonged and effective
suppressionofHBVDNAcandecreasetheriskofcirrhosisand
hepatocellular carcinoma. Therefore the current trend of
treatment for chronic hepatitis B is to use long term NA
therapy to achieve permanent virologic suppression, with loss
of hepatitis B surface antigen (HBsAg) as the ideal end-point
[18•].
The comparative efficacy and resistance rates of the five
nucleoside and nucleotide analogues are shown in Table 1
and 2 respectively.
Lamivudine
Lamivudine was originally used for HIV infection. It was
approved by the United States Food and Drug Administration
(FDA)in1998asthefirstnucleosideanalogueforthetreatment
of CHB. Lamivudine is the (−) enantiomer of 2′,3′- dideoxy 3′-
thiacytidine. It is phosphorlyated into the triphosphate form
(3TC-TP) and is incorporated into the growing chain of DNA
during reverse transcription of the first strand of HBV DNA
and synthesis of the second strand of HBV DNA, resulting in
chainterminationandinhibitingHBVDNA synthesis [15, 19].
Efficacy and Resistance
Lamivudine is effective in suppressing viral replication in
both HBeAg-positive and HBeAg-negative patients.
The Asia Hepatitis Lamivudine Study Group concluded
that lamivudine 100 mg, when compared to placebo,
achieved a higher rate of HBeAg seroconversion (16%
versus 4%) and sustained ALT normalization (72% versus
24%) at 1 year. Greater proportion of patients in the group
receiving lamivudine 100 mg daily, when compared to
placebo, achieved improvement of necroinflammatory
activity by 2 points or more at 1 year (56% versus 25%)
[20]. The efficacy of lamivudine is confirmed by another
multicentre trial performed in the United States. HBeAg-
positive patients on lamivudine 100 mg daily, as compared
to placebo, have higher rates of histological improvement
(52% versus 23%), HBeAg seroconversion (32% versus
11%), undetectable HBV DNA (44% versus 16%) and
alanine aminotransferase normalization (41% versus 16%)
at 48 weeks [21]. For extended lamivudine therapy to
3 years, more patients achieved HBeAg seroconversion,
alanine aminotransferase normalization and sustained HBV
DNA suppression [22].
Lamivudine is also efficacious in HBeAg-negative
patients. After 1 year of treatment, 96% of patients achieved
alanine aminotransferase normalization and 68% achieved
undetectable HBV DNA [23].
Lamivudine is effective in preventing progression of
cirrhosis and developing of hepatocellular carcinoma [24–
26]. A large prospective study for patients with established
cirrhosis [27] showed that patients on lamivudine 100 mg
daily, compared to placebo, were less likely to have
increase in Child-Turcotte- Pugh (CTP) score (3.4% versus
8.8%) and development of hepatocellular carcinoma (3.9%
versus 7.4%). In fact, this study, originally planned for a
follow-up period of 5 years, was terminated at median of
32.4 months because of the significant differences
observed between the treatment group and the placebo
group.
Table 1 Efficacy of nucleoside/nucleotide analogs treatment for chronic hepatitis B (HBeAg-positive/HBeAg-negative)
Lamivudine [20, 22, 23, 32]ADV [39–41, 45] Telbivudine [48, 52] Entecavir [59–63]TDF [71, 72, 74, 75]
Rate of HBeAg seroconversion (%)
1 year
2 year
4 (or 5a) year
ALT normalization (%)
1 year
2 year
4 (or 5a) year
Undetectable HBV DNA by PCR (%)
1 year
2 year
4 (or 5a) year
16/−
29/−
47/−
12/−
29/−
48/−a
23/−
30/−
NA/−
21/−
31/−
44/−a
21/−
27/−
29/−
72/96
NA/60
69/NA
48/72
74/73
NA/69a
77/74
70/77
NA/NA
68/78
87/89
80/NAa
68/76
NA/NA
NA/NA
36/68
NA/42
NA/NA
21/51
40/71
NA/67a
60/88
56/82
NA/NA
67/90
80/94
94/NAa
76/93
89/91
96/100
ALT alanine aminotransferase, HBeAg hepatitis B e-antigen, NA not available
adenotes 5 year data
236Curr Hepatitis Rep (2011) 10:235–243

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The major problem with long-term lamivudine therapy is
drug resistance. Lamivudine is known to have a low genetic
barrier. The classical mutation associated with lamivudine is
rtM204V/I and rtL180M located in the YMDD locus of
hepatitis B virus polymerase [20, 21, 28, 29].
TherateofundetectableHBVDNAdecreasedfrom77%at
12 months of lamivudine treatment, to 52% at 24 months and
42% at 36 months, mainly due to development of drug
resistance [23, 30]. For cirrhotic patients on lamivudine,
those who have drug resistance are more likely to have
increase CTP score when compared to patients without
lamivudine resistance [27]. Hepatitic flares and even liver
failure were described in patients with lamivudine resistance.
Hepatitic flare was noted in 10% of lamivudine- treated
patients at 1 year and 18% at 2 years [30, 31].
Safety
Lamivudine has excellent safety profile. Long term study up
to 6 years showed no major adverse events and complications
associated with lamivudine treatment [30, 32].
Current Roles of Lamivudine Therapy
In view of the low genetic barrier of lamivudine, it is not
recommended as the first line treatment for CHB [33•, 34•].
However, lamivudine may have a role as monotherapy for
those with these favorable parameters: Baseline HBV DNA
less than 9 log, ALT higher than or equal to 2 times upper
limit of normal and good viral suppression of less than 4
log at week 4. The rate of lamivudine resistance for patients
who have these favorable parameters is low [35].
Lamivudine also has a role as preemptive treatment for
CHB patients receiving a finite course of immunosuppres-
sion or chemotherapy [36, 37]. The American Association
for the Study of Liver Disease guidelines recommends that
lamivudine can be used as prophylactic treatment if the
anticipated duration of immunosuppression or chemotherapy
is less than 12 months and the baseline HBV DNA is
undetectable [33•].
Although lamivudine is classified as a pregnancy
Category C drug, lamivudine has long term safety data in
pregnancy. Pregnant women on lamivudine have the same
rate of birth defect compared to the general population [38].
Lamivudine is also useful for patients who have resistance
toward adefovir dipivoxil as they have different pattern in
viral resistance [33•]. However, entecavir is superior to
lamivudine for patients with adevfovir resistance.
Adefovir Dipivoxil
ADV was approved by the United States FDA for treatment
of chronic hepatitis B in 2002. ADV is a nucleotide analog.
It is converted into adefovir and phosphorylated into its
active form in the body. Adefovir diphosphonate is
incorporated into the viral DNA and thus inhibits HBV
DNA reverse transcription and viral replication [14].
Efficacy and Resistance
In a phase III trial involving 515 HBeAg-positive
patients who were treated with ADV or placebo, more
patients in the adefovir group achieved undetectable
HBV DNA (21% versus 0%), alanine aminotransferase
normalization (48% versus 16%), histological improve-
ment (53% versus 25%) and HBeAg seoconversion (12%
versus 6%) at 48 weeks of treatment [39]. A second study
confirmed the efficacy of ADV in HBeAg-negative patients.
Patients receiving ADV 10 mg daily when compared with
placebo, achieved greater response in terms of histologic
improvement (64% versus 33%), undetectable HBV DNA
(51% versus 0%) and normalization of alanine aminotrans-
ferase (72% versus 29%) at 48 weeks [40]. Further clinical
studies show that extended ADV monotherapy up to 5 years
can achieve better histological, virologic and biochemical
outcomes [41].
For patients who have lamivudine resistance, combi-
nation therapy of lamivudine and adefovir or adefovir
monotherapy can achieve alanine aminotransferse nor-
malization and HBV DNA suppression [42]. However
recent studies favor the approach of adding adefovir to
lamivudine in lamivudine resistant patients instead of
switching to adefovir monotherapy because the latter
approach may lead to a higher risk of adefovir resistance
(7% versus 18% at 2 years) [43].
ADV is efficacious in decompensated cirrhosis. In a
study involving 226 lamivudine-resistant patients with
Lamivudine
[20, 22, 32]
ADV
[39–41, 45]
Telbivudine
[48, 52]
Entecavir
[59–63]
TDF
[71, 72, 74, 75]
Resistance (%)
1 year
2 year
5 year
14
39
60–70
0
3
20–29
2.2–5
10.8–25.1
NA
0
<1
1.2
0
0
NA
Table 2 Resistance rate of
nucleoside/nucleotide analogs
for treatment of chronic
hepatitis B
NA not available
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decompensated cirrhosis awaiting liver transplant, HBV
DNA became undetectable in 59% and 65% at week 48 and
96 with ADV treatment [44]. In the same study with 241
post-liver transplantation lamivudine-resistant CHB patients,
HBV DNA became undetectable in 40% and 65% at weeks
48 and 96 with ADV treatment. There is also improvement
of CTP score with adefovir treatment in lamivudine-resistant
chronic hepatitis B cirrhosis.
Cumulative rate of genotypic resistance to ADV at
5 years for HBeAg-positive and HBeAg-negative patients
are 20% and 29%, respectively [41, 45]. The mutations
associated with adefovir are N236T and A181V/T [46].
Viruses with these 2 mutations remain susceptible to
entecavir whereas viruses with A181V/T mutations are
cross-resistant to lamivudine [47].
Safety
The major side effect of ADV is nephrotoxicity. Studies
using ADV 10 mg versus ADV 30 mg found that the higher
dose is associated with greater impairment of renal function
[39]. ADV at 10 mg is well tolerated and renal side effects
are reported in 3% of patients with compensated liver
disease after 5 years of treatment [41]. The renal impair-
ment is reversible with dose reduction or drug withdrawal.
For patients receiving ADV, renal function should be
monitored every 3 months or more frequently if there is
pre-existing renal impairment [33•].
Current Role of Adefovir Therapy
With the availability of newer agents, such as entecavir and
TDF with high antiviral efficacy and high genetic barrier,
ADV monotherapy is no longer recommended as the first
option for treatment-naïve patients [33•, 34].
In the case of lamivudine or telbivudine resistance,
adefovir therapy is shown to be useful. It is recommended
that ADV is added to lamivudine/telbivudine instead of
switching to ADV monotherapy [43]. However, TDF is
superior to ADV for these patients. In the case of renal
impairment, ADV is best avoided. If it is used, dosage
should be adjusted and close monitoring of renal function is
necessary.
Telbivudine
Telbivudine was approved by the United States FDA for
treatment of CHB in 2006. Telbivudine is the L-enantiomer
of thymidine. After phosphorylation into active triphos-
phate form, it is incorporated into HBV viral DNA and
causes termination of chain synthesis, thereby suppressing
HBV DNA replication.
Efficacy and Resistance
In the GLOBE trial [48], 1367 patients including both
HBeAg-positive and HBeAg-negative patients were ran-
domized to telbivudine 600 mg daily and lamivudine
100 mg daily for 1 year. In HBeAg-positive patients,
patients on telbivudine, when compared to lamivudine, are
more likely to achieve undetectable HBV DNA (<300
copies/mL) (60% versus 40.4%) and HBeAg seroconver-
sion (22.5% versus 21.5%). For HBeAg-negative patients,
there was also a higher rate of undetectable HBV DNA
for patients on telbivudine compared with lamivudine
(88.3% versus 77.4%). Less patients on telbivudine
developed drug resistance when compared to lamivudine
in both HBeAg-positive (5.0% versus 11.0%) and
HBeAg-negative patients (2.2% versus 10.7%). HBeAg-
positive patients on telbivudine had better histologic
response than those on lamivudine at 1 year (64.7%
versus 56.3%). Another similar study performed in China
also demonstrated superiority of telbivudine to lamivu-
dine in terms of undetectable HBV DNA [49]. For
chronic hepatitis B patients with cirrhosis, telbivudine can
improve CTP score at 48 weeks of treatment [49, 50].
One of the major drawbacks with long-term telbivudine
treatment is the development of drug resistance. The main
mutation is rtM204I in the YMDD motif. Secondary
mutations rtL80I/Vand L80I/V + L180M may be associated
with the rtM208I mutation. Unlike lamivudine, rtM204V is
not associated with telbivudine resistance [48, 51].
After 2 years of therapy, the resistance is found in
25.1% of HBeAg-positive and 10.8% of HBeAg-negative
patients [52].
Safety
One of the major concerns with telbivudine use is elevation
of creatine kinase (CK) and myopathy. According to the
Novartis global database for patients treated over 4 years,
14% to 17% of patients have grade3/4 CK elevation, most
of which are transient [52]. A total of 1.1% of patients have
myopathy and myositis, presenting with muscle weakness
and pain. There is poor correlation between CK elevation
and myopathy/myositis as only 30% of these patients have
concomitant grade 3/4 CK elevations [53].
In addition, there is also the development of peripheral
neuropathy with the use of telbivudine, especially when used
together with pegylated interferon [54]. The clinical trial of
telbivudine and pegylated interferon was terminated because
of the high incidence (18%) of peripheral neuropathy.
Telbivudine is a pregnancy category B drug. In a study
involving 61 pregnant women in China to determine the
efficacy of telbivudine in decreasing maternal transmission
of the hepatitis B virus to their infants, no adverse effects
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were observed in both the mothers and the newborns in
telbivudine-treated patients [55].
Current Role of Telbivudine Therapy
Both the American Association for the Study of Liver
Disease and European Association for the Study of the
Liver guidelines do not recommend telbivudine as the first
line of treatment due to the high rate of drug resistance with
long-term use [33•, 34•]. In multivariate analyses of the
GLOBE study data, low baseline HBV DNA (<9 log10 for
HBeAg positive patients, <7 log10 for HBe-negative
patients) and undetectable HBV DNA at 24 weeks (<300
copies per mL) are associated with low rate of resistance at
2 years (HBeAg positive: 1.8%; HBeAg negative: 2.3%)
[56]. A recent study showed that HBV DNA level of less
than 200 IU/mL at week 12 of telbivudine therapy was also
predictive of higher chance of undetectable HBV DNA
(78.6%) and lower chance of resistance (0%) at year 3 [57].
Telbivudine may have a role in patients with these favorable
characteristics.
Entecavir
Entecavir was approved by the FDA as the third nucleoside
analog for the treatment of chronic hepatitis B in 2005.
Entecavir is a guanosine analogue. It undergoes phosphory-
lation into di-phosphate and tri-phosphate metabolites, which
is then incorporated into HBV DNA polymerase to inhibit
viral replication. It also inhibits the priming of HBV DNA
polymerase, a step which involves guanosine [58]. The
inhibition of the priming of HBV DNA polymerase is
unique among the currently licensed nucleoside/nucleotides.
Efficacy and Resistance
Entecavir has significant antiviral activity against chronic
hepatitis B. In a double blinded prospective study, 715
HBeAg-positive patients were randomized to receive the
standard doses of entecavir or lamivudine. More patients in
the entecavir group achieve undetectable HBV DNA levels
(67% versus 36%), alanine aminotransferase normalization
(68% versus 60%) and histological improvement (72%
versus 62%) at 48 weeks of treatment. The reduction of
HBV DNA from baseline to week 48 was greater with
entecavir than with lamivudine (6.9 versus 5.4 log copies
per mL). HBeAg seroconversion rate at 48 weeks with
entecavir group was 21%, while that for lamivudine group
was 18% [59]. Entecavir is also effective for HBeAg-
negative patients. In a parallel prospective study involving
648 HBeAg-negative CHB patients, who were randomized
to the standard doses of entecavir or lamivudine for
52 weeks, more patients in the entecavir group achieved
undetectable HBV DNA (90% versus 72%), normalization of
ALT (78% versus 71%) and histological improvement (70%
versus61%).The meanreductionofHBVDNAwashigherin
entecavir group (5.0 versus 4.5 log copies per mL) [60].
While the efficacy of earlier generation nucleoside/
nucleotide analogs decreases with time due to development
of resistance, entecavir demonstrates potent antiviral efficacy
for up to 5 years [61–63]. For patients taking entecavir up to
5 years, 94% achieved undetectable HBV DNA and 80%
had normal ALT levels. After 96 weeks of treatment, 31%
had HBeAg seroconversion; 5.1% also had HBsAg serocon-
version. After 5 years, an additional 23% had HBeAg
seroconversion; and 1.4% had HBsAg seroconversion [63].
Long term monitoring showed entecavir has a low
resistance rate in treatment-naïve patients up to 5 years.
The cumulative probability of genotypic entecavir resis-
tance was 1.2% [64•]. Entecavir resistance only occurs
when, in addition to the two substitutions associated with
lamivudine resistance (M204I/V +/− L180M), a third
“signature” substitution develops at positions T184, S202
or M250 [65]. Therefore, for patients who have lamivudine
resistance, there is lower genetic barrier for development of
entecavir resistance. For this group of patients, the
cumulative probability of genotypic entecavir resistance
and genotypic resistance associated with virological break-
through was 51% and 43%, respectively at 5 years. Because
of this, entecavir is not recommended in patients with
lamivudine resistance [64•].
Safety
Entecavir has similar safety profile with lamivudine.
Serious adverse events are rarely seen [59, 60]. In a
preclinical animal study, there is a higher incidence of
species-specific solid tumors with doses of entecavir above
the therapeutic range compared to placebo [66]. However,
post-market surveillance up to 2009 failed to show any
increase in incidence of malignancy with entecavir use [67].
Five cases of lactic acidosis on entecavir for decompensated
HBV cirrhosis were reported [68]. However, the lactic
acidosis was reversible in 4 of the patients. It is not certain
whether the lactic acidosis was related to the multiorgan
failure of the patients or to entecavir.
Current Role of Entecavir Therapy
Sustained effective virologic suppression is essential in
prevention of complications of chronic hepatitis B.
Entecavir has high antiviral potency, low resistance rate,
and excellent safety profile with prolonged use. Entecavir
is therefore one of the “ideal” treatment options for
CHB, especially for treatment-naïve individuals. Both the
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AASLD and EASL guidelines recommend entecavir as
one of the first line agents for treatment of chronic
hepatitis B [33•, 34•].
Tenofovir Disoproxil Fumarate
TDF is a nucleotide analogue initially approved for the
treatment of HIV infection. It was approved by the United
States FDA in 2008 for treatment of CHB. TDF is a
prodrug of tenofovir. Tenofovir is phosphorylated into its
active form and binds directly with viral polymerase and
thereby suppressing viral replication [69, 70].
Efficacy and Resistance
Tenofovir and adefovir share similar molecular structure;
tenofovir is found to be as potent as adefovir in an equal
molar basis in in-vitro study. As tenofovir is less nephro-
toxic, the approved daily dose of tenofovir is 300 mg which
is more potent than adefovir at 10 mg.In a pivotal trial
comparing tenofovir and adefovir, more patients achieved
undetectable HBV DNA (HBV DNA <400 copies per mL)
at 48 weeks in tenofovir group in both HBeAg-positive
(76% versus 13%) and HBeAg-negative (93% versus 63%)
patients [71]. All patients were put on open-label tenofovir
after 48 weeks. At week 144 of tenofovir treatment, 93% of
HBeAg-positive and 99% of HBeAg-negative patients have
undetectable HBV DNA [72]. Furthermore, no resistance to
tenofovir was detected up to week 192 [73•, 74, 75].
Several studies have demonstrated antiviral efficacy of
tenofovir in lamivudine resistant patients. An Australian
prospective study involving 60 patients with incomplete
virologic response to both lamivudine and adefovir were
given TDF or combination of TDF and lamivudine, 64% of
patients achieved undetectable HBV DNA (<15 IU/mL) [76].
HBV mutation associated with adefovir resistant
rtN236T and rtA181V/T are associated with decrease in
response to tenofovir in in-vitro studies [77, 78]. However,
clinical studies on tenofovir showed mixed results in
adefovir resistant patients [76, 79, 80]. A retrospective
multicenter study involving patients with treatment failure
with lamivudine, adefovir, entecavir, either as sequential or
add-on therapy, showed that TDF was less efficacious in
patients with adefovir-associated mutations compared to
lamviduine-associated mutations (52% versus 100%) in
achieving undetectable HBV DNA (<400 copies per mL)
[79]. However, no patients had virological breakthrough in
the observed period of the study. In another German study
involving 105 adefovir treated patients, 81% of patients
have undetectable HBV DNA (<400 copies per ml) at week
48. The treatment response was not affected by baseline
ADV- resistance or lamivudine resistance [80].
In decompensated liver disease, TDF has comparable
improvement of virological, biochemical and clinical
parameters compared to entecavir. Both agents achieved
similar rates of HBV DNA undetectability (HBV DNA <400
copies per mL) at week 48, normal alanine aminotransferase
and improvement of CTP score [81].
There isno report ofvirologic resistance ofTDF in chronic
hepatitis B monoinfection [73•]. In a study involving patients
with HBV-HIV coinfection, rtA194T is found to be
associated with reduced susceptibility to TDF in-vitro when
lamivudine mutations rtM204V and rtL180m were present
[82]. However, this is not confirmed by another study [83].
The role of rtA194T in TDF resistance is still unknown.
Safety
From the experience in HIV infection, tenofovir is
associated with a small decline in renal function of
9.8 mL/min/1.37 m2 in 5 years [84]. However, large scale
clinical studies showed there is no evidence of compro-
mised renal function with tenofovir in patients with chronic
hepatitis B monoinfection [72]. TDF is also associated with
renal proximal tubular disfunction and renal phosphate
wasting [85]. Cases of acute renal failure and nephrogenic
diabetes insipidus have been reported [86]. Renal toxicity is
usually reversible when tenofovir is stopped.
TDF is a pregnancy category B drug. There is no
increase in rate of birth defects in HIV infected mother
taking tenofovir compared to baseline [34].
Current Role of TDF Therapy
TDF is recommended as the one of the first line agents
for treatment naïve patients. Given the potent antiviral
efficacy, low resistance rate and minimal toxicity, it can
achieve long term effective HBV DNA suppression and
has the potential to become one of the “ideal” treatment
options for chronic hepatitis B. Tenofovir is also useful
in patients with lamivudine, telbivudine and entecavir
resistance.
Conclusions
Over the past 10 years, there has been considerable
improvement in the treatment of chronic hepatitis B.
Interferon-based immunomodulatory therapy is gradually
being replaced by nucleoside/nucleotide analogs which
have better antiviral potency and safety profiles.
Newer nucleoside/nucleotide analogs including entecavir
and TDF have potent antiviral potency and high genetic
barrier to resistance, and thus are superior to agents such as
lamivudine, telbivudine, and adefovir.
240 Curr Hepatitis Rep (2011) 10:235–243

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Current treatment strategy of chronic hepatitis B is to
achieve prolonged and effective viral suppression [18•].
Due to the presence of intracellular covalently closed
circular DNA in hepatocytes, there is a chance of viral
rebound if NA is discontinued even when the serum HBV
DNA have declined to levels below the detectable limits of
polymerase chain reaction assays.
With the availability of entecavir and more recently TDF,
prolonged effective viral suppression can be achieved with
long-term treatment. It is likely that the complications with
CHB including cirrhosis and hepatocellular carcinoma will
decrease in the future with these newer agents.
However, more studies on the safety profiles and
efficacy on long term use of these newer agents are needed.
Disclosure
Bristol Myers-Squibb and Gilead; Man-Fung Yuen acted as consultant/
speaker and received research grants from Bristol Myers-Squibb,
GlaxoSmithKline, Novartis and Roche Diagnostics; Yuk-Fai Lam and
Wai-Kay Seto reported no potential conflicts of interest relevant to this
article.
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References
Papers of particular interest, published recently, have been
highlighted as:
• Of importance
1. Lai CL, Yuen MF. The natural history and treatment of chronic
hepatitis B: a critical evaluation of standard treatment criteria and
end points. Ann Intern Med. 2007;147:58–61.
2. Beasley RP. Hepatitis B virus. The major etiology of hepatocellular
carcinoma. Cancer. 1988;61:1942–56.
3. Bosch FX, Ribes J, Cleries R, et al. Epidemiology of hepatocellular
carcinoma. Clin Liver Dis. 2005;9:191–211. v.
4. Beasley RP, Hwang LY, Lin CC, et al. Hepatocellular carcinoma
and hepatitis B virus. A prospective study of 22 707 men in
Taiwan. Lancet. 1981;2:1129–33.
5. Hoofnagle JH, di Bisceglie AM. The treatment of chronic viral
hepatitis. N Engl J Med. 1997;336:347–56.
6. Wong DK, Cheung AM, O’Rourke K, et al. Effect of alpha-
interferon treatment in patients with hepatitis B e antigen-positive
chronic hepatitis B. A meta-analysis. Ann Intern Med.
1993;119:312–23.
7. Brunetto MR, Oliveri F, Rocca G, et al. Natural course and
response to interferon of chronic hepatitis B accompanied by
antibody to hepatitis B e antigen. Hepatology. 1989;10:198–202.
8. Brunetto MR, Giarin M, Saracco G, et al. Hepatitis B virus unable
to secrete e antigen and response to interferon in chronic hepatitis
B. Gastroenterology. 1993;105:845–50.
9. Wong VW, Wong GL, Yan KK, et al. Durability of
peginterferon alfa-2b treatment at 5 years in patients with
hepatitis B e antigen-positive chronic hepatitis B. Hepatology.
2010;51:1945–53.
10. Marcellin P, Bonino F, Lau GK, et al. Sustained response of
hepatitis B e antigen-negative patients 3 years after treatment
with peginterferon alpha-2a. Gastroenterology. 2009;136:2169–
79. e1-4.
11. Yuen MF, Hui CK, Cheng CC, et al. Long-term follow-up of
interferon alfa treatment in Chinese patients with chronic hepatitis
B infection: the effect on hepatitis B e antigen seroconversion and
the development of cirrhosis-related complications. Hepatology.
2001;34:139–45.
12. Truong BX, Seo Y, Kato M, et al. Long-term follow-up of
Japanese patients with chronic hepatitis B treated with interferon-
alpha. Int J Mol Med. 2005;16:279–84.
13. Lin SM, Yu ML, Lee CM, et al. Interferon therapy in HBeAg
positive chronic hepatitis reduces progression to cirrhosis and
hepatocellular carcinoma. J Hepatol. 2007;46:45–52.
14. Dando T, Plosker G. Adefovir dipivoxil: a review of its use in
chronic hepatitis B. Drugs. 2003;63:2215–34.
15. Lai CL, Yuen MF. Profound suppression of hepatitis B virus
replication with lamivudine. J Med Virol. 2000;61:367–73.
16. Rivkin A. A review of entecavir in the treatment of chronic
hepatitis B infection. Curr Med Res Opin. 2005;21:1845–56.
17. But DY, Yuen MF, Fung J, et al. Safety evaluation of telbivudine.
Expert Opin Drug Saf. 2010;9:821–9.
18. • Lai CL, Yuen MF. Chronic hepatitis B—new goals, new
treatment. N Engl J Med. 2008;359:2488–91. This article
suggests the new goal of chronic hepatitis B treatment should be
prolonged and effective viral suppression. The authors also
provide evidence to support this.
19. Severini A, Liu XY, Wilson JS, et al. Mechanism of inhibition
of duck hepatitis B virus polymerase by (−)-beta-L-2′,3′-
dideoxy-3'-thiacytidine. Antimicrob Agents Chemother.
1995;39:1430–5.
20. Lai CL, Chien RN, Leung NW, et al. A one-year trial of
lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine
Study Group. N Engl J Med. 1998;339:61–8.
21. Dienstag JL, Schiff ER, Wright TL, et al. Lamivudine as initial
treatment for chronic hepatitis B in the United States. N Engl J
Med. 1999;341:1256–63.
22. Leung NW, Lai CL, Chang TT, et al. Extended lamivudine
treatment in patients with chronic hepatitis B enhances hepatitis B
e antigen seroconversion rates: results after 3 years of therapy.
Hepatology. 2001;33:1527–32.
23. Hadziyannis SJ, Papatheodoridis GV, Dimou E, et al. Efficacy of
long-term lamivudine monotherapy in patients with hepatitis B e
antigen-negative chronic hepatitis B. Hepatology. 2000;32:847–
51.
24. Di Marco V, Marzano A, Lampertico P, et al. Clinical outcome of
HBeAg-negative chronic hepatitis B in relation to virological
response to lamivudine. Hepatology. 2004;40:883–91.
25. Villeneuve JP, Condreay LD, Willems B, et al. Lamivudine
treatment for decompensated cirrhosis resulting from chronic
hepatitis B. Hepatology. 2000;31:207–10.
26. Yuen MF, Seto WK, Chow DH, et al. Long-term lamivudine
therapy reduces the risk of long-term complications of chronic
hepatitis B infection even in patients without advanced disease.
Antivir Ther. 2007;12:1295–303.
27. Liaw YF, Sung JJ, Chow WC, et al. Lamivudine for patients with
chronic hepatitis B and advanced liver disease. N Engl J Med.
2004;351:1521–31.
28. Stuyver LJ, Locarnini SA, Lok A, et al. Nomenclature for
antiviral-resistant human hepatitis B virus mutations in the
polymerase region. Hepatology. 2001;33:751–7.
Curr Hepatitis Rep (2011) 10:235–243241

Page 8

29. Yuen MF, Sablon E, Hui CK, et al. Factors associated with
hepatitis B virus DNA breakthrough in patients receiving
prolonged lamivudine therapy. Hepatology. 2001;34:785–91.
30. Lok AS, Lai CL, Leung N, et al. Long-term safety of lamivudine
treatment in patients with chronic hepatitis B. Gastroenterology.
2003;125:1714–22.
31. Liaw YF, Chien RN, Yeh CT, et al. Acute exacerbation and
hepatitis B virus clearance after emergence of YMDD motif
mutation during lamivudine therapy. Hepatology. 1999;30:567–72.
32. Chang TT, Lai CL, Chien RN, et al. Four years of lamivudine
treatment in Chinese patients with chronic hepatitis B. J Gastro-
enterol Hepatol. 2004;19:1276–82.
33. • Lok AS, McMahon BJ. Chronic hepatitis B: update 2009.
Hepatology. 2009;50:661–2. This is the American Association for
the Study of Liver Diseases Guideline, which gives a comprehen-
sive overview on the management of chronic hepatitis B.
34. • EASL Clinical Practice Guidelines: management of chronic
hepatitis. B. J Hepatol. 2009;50:227–42. This is the latest
European Association for the Study of the Liver Guideline on
the management of chronic hepatitis B.
35. Yuen MF, Fong DY, Wong DK, et al. Hepatitis B virus DNA levels
at week 4 of lamivudine treatment predict the 5-year ideal
response. Hepatology. 2007;46:1695–703.
36. Hsu C, Hsiung CA, Su IJ, et al. A revisit of prophylactic
lamivudine for chemotherapy-associated hepatitis B reactivation
in non-Hodgkin's lymphoma: a randomized trial. Hepatology.
2008;47:844–53.
37. Loomba R, Rowley A, Wesley R, et al. Systematic review: the
effect of preventive lamivudine on hepatitis B reactivation during
chemotherapy. Ann Intern Med. 2008;148:519–28.
38. Antiretroviral Pregnancy Registry Steering Committee. Antiretro-
viral pregnancy registry international interim report for 1 January
1989 through 31 January 2010. Available at http://www.apregistry.
com/forms/interim_report.pdf. Accessed April 2011.
39. Marcellin P, Chang TT, Lim SG, et al. Adefovir dipivoxil for the
treatment of hepatitis B e antigen-positive chronic hepatitis B. N
Engl J Med. 2003;348:808–16.
40. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Adefovir
dipivoxil for the treatment of hepatitis B e antigen-negative
chronic hepatitis B. N Engl J Med. 2003;348:800–7.
41. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Long-term
therapy with adefovir dipivoxil for HBeAg-negative chronic
hepatitis B for up to 5 years. Gastroenterology. 2006;131:1743–
51.
42. Peters MG, Hann Hw H, Martin P, et al. Adefovir dipivoxil alone
or in combination with lamivudine in patients with lamivudine-
resistant chronic hepatitis B. Gastroenterology. 2004;126:91–101.
43. Fung J, Lai CL, Yuen JC, et al. Adefovir dipivoxil monotherapy
and combination therapy with lamivudine for the treatment of
chronic hepatitis B in an Asian population. Antivir Ther.
2007;12:41–6.
44. Schiff E, Lai CL, Hadziyannis S, et al. Adefovir dipivoxil for
wait-listed and post-liver transplantation patients with lamivudine-
resistant hepatitis B: final long-term results. Liver Transpl.
2007;13:349–60.
45. Marcellin P, Chang TT, Lim SG, et al. Long-term efficacy and
safety of adefovir dipivoxil for the treatment of hepatitis B e
antigen-positive chronic hepatitis B. Hepatology. 2008;48:750–8.
46. Angus P, Vaughan R, Xiong S, et al. Resistance to adefovir
dipivoxil therapy associated with the selection of a novel mutation
in the HBV polymerase. Gastroenterology. 2003;125:292–7.
47. Libbrecht E, Doutreloigne J, Van De Velde H, et al. Evolution of
primary and compensatory lamivudine resistance mutations in
chronic hepatitis B virus-infected patients during long-term
lamivudine treatment, assessed by a line probe assay. J Clin
Microbiol. 2007;45:3935–41.
48. Lai CL, Gane E, Liaw YF, et al. Telbivudine versus lamivudine in
patients with chronic hepatitis B. N Engl J Med. 2007;357:2576–
88.
49. Hou J, Yin YK, Xu D, et al. Telbivudine versus lamivudine in
Chinese patients with chronic hepatitis B: Results at 1 year of a
randomized, double-blind trial. Hepatology. 2008;47:447–54.
50. Liang J, Han T, Xiao SX, et al. Telbivudine treatment on cirrhosis
resulting from chronic hepatitis B. Chin J Hepatol. 2009;17:24–7.
51. Zoulim F, Locarnini S. Hepatitis B virus resistance to nucleos(t)
ide analogues. Gastroenterology. 2009;137:1593–608. e1-2.
52. Liaw YF, Gane E, Leung N, et al. 2-Year GLOBE trial results:
telbivudine Is superior to lamivudine in patients with chronic
hepatitis B. Gastroenterology. 2009;136:486–95.
53. Avila, Goncalves. Creatine kinase elevations during 4 years of
continuous telbivudine treatment are transient and not predictive of
uncommonly observed muscle related symptoms. [abstract] 60th
Annual Meeting of the American Association for the Study of the
Liver Diseases (AASLD); Oct 30–Nov 3 2009; Boston, USA
54. Marcellin P, Avila C, Wursthorn K, et al. Telbivudine (LDT) plus
Peg-interferon (PEGIFN) in HbeAg-positive chronic hepatitis B—
very potent antiviral efficacy but risk of peripheral neuropathy
(PN) [abstract]. J Hepatol. 2010;52(S1):S6–7.
55. Zhang LJ, Wang L. Blocking intrauterine infection by telbivudine
in pregnant chronic hepatitis B patients. Chin J Hepatol.
2009;17:561–3.
56. Zeuzem S, Gane E, Liaw YF, et al. Baseline characteristics and
early on-treatment response predict the outcomes of 2 years of
telbivudine treatment of chronic hepatitis B. J Hepatol.
2009;51:11–20.
57. Seto WK, Lai CL, Fung J et al. Significance of HBV DNA levels
at 12 weeks of telbivudine treatment and the 3 years treatment
outcome. J Hepatol 2010.
58. Seifer M, Hamatake RK, Colonno RJ, et al. In vitro inhibition
of hepadnavirus polymerases by the triphosphates of BMS-
200475andlobucavir.AntimicrobAgentsChemother.1998;42:3200–
8.
59. Chang TT, Gish RG, de Man R, et al. A comparison of entecavir
and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J
Med. 2006;354:1001–10.
60. Lai CL, Shouval D, Lok AS, et al. Entecavir versus lamivudine
for patients with HBeAg-negative chronic hepatitis B. N Engl J
Med. 2006;354:1011–20.
61. Gish RG, Lok AS, Chang TT, et al. Entecavir therapy for up to
96 weeks in patients with HBeAg-positive chronic hepatitis B.
Gastroenterology. 2007;133:1437–44.
62. Shouval D, Akarca US, Hatzis G, et al. Continued virologic and
biochemical improvement through 96 weeks of entecavir treat-
ment in HBeAg(−) Chronic Hepatitis B Patients (Study ETV-027).
J Hepatol. 2006;44n Suppl 2:S21–22.
63. Chang TT, Lai CL, Kew Yoon S, et al. Entecavir treatment for up
to 5 years in patients with hepatitis B e antigen-positive chronic
hepatitis B. Hepatology. 2010;51:422–30.
64. • Tenney DJ, Rose RE, Baldick CJ, et al. Long-term monitoring
shows hepatitis B virus resistance to entecavir in nucleoside-naive
patients is rare through 5 years of therapy. Hepatology.
2009;49:1503–14. This article describes a very low rate of viral
resistance with long term use of entecavir for treatment of chronic
hepatitis B.
65. Tenney DJ, Levine SM, Rose RE, et al. Clinical emergence of
entecavir-resistant hepatitis B virus requires additional substitu-
tions in virus already resistant to Lamivudine. Antimicrob Agents
Chemother. 2004;48:3498–507.
66. Entecavir Package Insert. Available at http://www.fda.gov.
Accessed 1 April 2011
67. Fontana RJ. Side effects of long-term oral antiviral therapy for
hepatitis B. Hepatology. 2009;49:S185–95.
242Curr Hepatitis Rep (2011) 10:235–243

Page 9

68. Lange CM, Bojunga J, Hofmann WP, et al. Severe lactic acidosis
during treatment of chronic hepatitis B with entecavir in patients
with impaired liver function. Hepatology. 2009;50:2001–6.
69. De Clercq E, Holy A. Acyclic nucleoside phosphonates: a key
class of antiviral drugs. Nat Rev Drug Discov. 2005;4:928–40.
70. Ying C, De Clercq E, Nicholson W, et al. Inhibition of the
replication of the DNA polymerase M550V mutation variant of
human hepatitis B virus by adefovir, tenofovir, L-FMAU, DAPD,
penciclovir and lobucavir. J Viral Hepat. 2000;7:161–5.
71. Marcellin P, Heathcote EJ, Buti M, et al. Tenofovir disoproxil
fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl
J Med. 2008;359:2442–55.
72. Heathcote EJ, Marcellin P, Buti M, et al. Three-year efficacy and
safety of tenofovir disoproxil fumarate treatment for chronic
hepatitis B. Gastroenterology. 2011;140:132–43.
73. • Snow-Lampart A, Chappell B, Curtis M, et al. No resistance to
tenofovir disoproxil fumarate detected after up to 144 weeks of
therapy in patients monoinfected with chronic hepatitis B virus.
Hepatology. 2011;53:763–73. This article describes zero resis-
tance with long term use of TDF in patients with chronic hepatitis
B monoinfection.
74. Heathcote EJ, Gane EJ, DdeMan RA, et al. Long term (4 year)
efficacy and safety of tenofovir disoproxil fumarate (TDF)
treatment in HBeAg-positive patients (HBeAg+) with chronic
hepatitis B (study 103): preliminary analysis (abstract). Hepatol-
ogy. 2010;52(4(Suppl)):556A.
75. Marcellin P, Buti M, Krastev Z, Gurel S, et al. Continued efficacy
and safety through 4 years of tenofovir disoproxil fumurate (TDF)
treatment in HBeAg-negative patients with chronic hepatitis B
(study 102): preliminary analysis (abstract). Hepatology. 2010;52
(4(Suppl)):555A.
76. Patterson SJ, George J, Strasser SI, et al. Tenofovir disoproxil
fumarate rescue therapy following failure of both lamivudine and
adefovir dipivoxil in chronic hepatitis B. Gut. 2011;60:247–54.
77. Qi X, Xiong S, Yang H, et al. In vitro susceptibility of adefovir-
associated hepatitis B virus polymerase mutations to other
antiviral agents. Antivir Ther. 2007;12:355–62.
78. Villet S, Pichoud C, Billioud G, et al. Impact of hepatitis B virus
rtA181V/T mutants on hepatitis B treatment failure. J Hepatol.
2008;48:747–55.
79. van Bommel F, de Man RA, Wedemeyer H, et al. Long-term
efficacy of tenofovir monotherapy for hepatitis B virus-
monoinfected patients after failure of nucleoside/nucleotide
analogues. Hepatology. 2010;51:73–80.
80. Berg T, Marcellin P, Zoulim F, et al. Tenofovir is effective alone or
with emtricitabine in adefovir-treated patients with chronic-
hepatitis B virus infection. Gastroenterology. 2010;139:1207–17.
81. Liaw YF, Sheen IS, Lee CM, et al. Tenofovir disoproxil fumarate
(TDF), emtricitabine/TDF, and entecavir in patients with decompen-
sated chronic hepatitis B liver disease. Hepatology. 2011;53:62–72.
82. Sheldon J, Camino N, Rodes B, et al. Selection of hepatitis B
virus polymerase mutations in HIV-coinfected patients treated
with tenofovir. Antivir Ther. 2005;10:727–34.
83. Delaney WEt, Ray AS, Yang H, et al. Intracellular metabolism and
in vitro activity of tenofovir against hepatitis B virus. Antimicrob
Agents Chemother. 2006;50:2471–7.
84. de Vries-Sluijs TE, Reijnders JG, Hansen BE, et al. Long-term
therapy with tenofovir is effective for patients co-infected with
human immunodeficiency virus and hepatitis B virus. Gastroen-
terology. 2010;139:1934–41.
85. Labarga P, Barreiro P, Martin-Carbonero L, et al. Kidney
tubular abnormalities in the absence of impaired glomerular
function in HIV patients treated with tenofovir. AIDS.
2009;23:689–96.
86. Karras A, Lafaurie M, Furco A, et al. Tenofovir-related nephro-
toxicity in human immunodeficiency virus-infected patients: three
cases of renal failure, Fanconi syndrome, and nephrogenic
diabetes insipidus. Clin Infect Dis. 2003;36:1070–3.
Curr Hepatitis Rep (2011) 10:235–243243