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 Interferon, the first agent licensed for chronic hepatitis B treatment, has been superseded by the growing popularity of nucleoside/nucleotide analogues (NA).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.
Cancer 06/1988; 61(10):1942-56. · 4.77 Impact Factor
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ABSTRACT: Year 2000 estimates of the incidence of cancer indicate that primary liver cancer remains the fifth most common malignancy in men and the eighth in women. The number of new cases has been predicted as 564,000, corresponding to 398,000 in men and 166,000 in women. The geographic areas at highest risk are located in Eastern Asia, Middle Africa, and some countries of Western Africa. Changes in incidence among migrant populations underline the predominant role of environmental factors in the etiology of primary liver cancer. In high-risk countries, the early cases of primary liver cancer occur already at ages 20 and above, underlying the impact of viral exposures early in life. In countries at low risk, primary liver cancer is rare before the 50s, translating the impact of late exposures with moderate risks and long latency intervals. Sex ratios are typically between 2 and 4. The incidence of primary liver cancer is increasing in several developed countries including the United States, and the increase will likely continue for several decades. The trend has a dominant cohort effect related to exposures to hepatitis B and C viruses. The variability of primary liver cancer incidence is largely explained by the distribution and the natural history of the hepatitis B and C viruses. The attributable risk estimates for the combined effects of these infections account for well over 80% of liver cancer cases worldwide. Primary liver cancer is the first human cancer largely amenable to prevention using hepatitis B virus vaccines and screening of blood and blood products for hepatitis B and C viruses.Clinics in Liver Disease 06/2005; 9(2):191-211, v. · 3.18 Impact Factor
Article: Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22 707 men in Taiwan.The Lancet 12/1981; 2(8256):1129-33. · 38.28 Impact Factor
Current Antiviral Therapy of Chronic Hepatitis B: Efficacy
Yuk-Fai Lam & Man-Fung Yuen & Wai-Kay Seto &
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
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.
Chronic hepatitis B (CHB) infection is a major health
burden worldwide, with around 400 million people affected
. 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 . 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 . 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) . 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].
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,
Hong Kong, Hong Kong
Curr Hepatitis Rep (2011) 10:235–243
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
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
The comparative efficacy and resistance rates of the five
nucleoside and nucleotide analogues are shown in Table 1
and 2 respectively.
Lamivudine was originally used for HIV infection. It was
approved by the United States Food and Drug Administration
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%)
. 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 . For extended lamivudine therapy to
3 years, more patients achieved HBeAg seroconversion,
alanine aminotransferase normalization and sustained HBV
DNA suppression .
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 .
Lamivudine is effective in preventing progression of
cirrhosis and developing of hepatocellular carcinoma [24–
26]. A large prospective study for patients with established
cirrhosis  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
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 (%)
4 (or 5a) year
ALT normalization (%)
4 (or 5a) year
Undetectable HBV DNA by PCR (%)
4 (or 5a) year
ALT alanine aminotransferase, HBeAg hepatitis B e-antigen, NA not available
adenotes 5 year data
236Curr Hepatitis Rep (2011) 10:235–243
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].
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 . 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].
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 .
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
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 .
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.
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 .
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 . 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 . Further clinical
studies show that extended ADV monotherapy up to 5 years
can achieve better histological, virologic and biochemical
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 . 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) .
ADV is efficacious in decompensated cirrhosis. In a
study involving 226 lamivudine-resistant patients with
[20, 22, 32]
[71, 72, 74, 75]
Table 2 Resistance rate of
for treatment of chronic
NA not available
Curr Hepatitis Rep (2011) 10:235–243 237
decompensated cirrhosis awaiting liver transplant, HBV
DNA became undetectable in 59% and 65% at week 48 and
96 with ADV treatment . 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 .
Viruses with these 2 mutations remain susceptible to
entecavir whereas viruses with A181V/T mutations are
cross-resistant to lamivudine .
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
. 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 . 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 . 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
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 , 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 . 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
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 . 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 .
In addition, there is also the development of peripheral
neuropathy with the use of telbivudine, especially when used
together with pegylated interferon . 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
238Curr Hepatitis Rep (2011) 10:235–243
were observed in both the mothers and the newborns in
telbivudine-treated patients .
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%)
. 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 .
Telbivudine may have a role in patients with these favorable
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 . 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% . 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%
entecavir group (5.0 versus 4.5 log copies per mL) .
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 .
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 . 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•].
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 . However,
post-market surveillance up to 2009 failed to show any
increase in incidence of malignancy with entecavir use .
Five cases of lactic acidosis on entecavir for decompensated
HBV cirrhosis were reported . 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
Curr Hepatitis Rep (2011) 10:235–243239
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 . 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 . 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) .
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)
. 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 .
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 .
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
. However, this is not confirmed by another study .
The role of rtA194T in TDF resistance is still unknown.
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 . However, large scale
clinical studies showed there is no evidence of compro-
mised renal function with tenofovir in patients with chronic
hepatitis B monoinfection . TDF is also associated with
renal proximal tubular disfunction and renal phosphate
wasting . Cases of acute renal failure and nephrogenic
diabetes insipidus have been reported . 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 .
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
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
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.
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
Ching-Lung Lai acted as speaker for GlaxoSmithKline,
Creative Commons Attribution Noncommercial License which per-
mits any noncommercial use, distribution, and reproduction in any
medium, provided the original author(s) and source are credited.
This article is distributed under the terms of the
Papers of particular interest, published recently, have been
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