Journal of Viral Hepatitis, 2013, 20 (Suppl.

1), 4045

doi:10.1111/jvh.12062

Efficacy and safety of telbivudine plus adefovir dipivoxil

combination therapy and entecavir monotherapy
for HBeAg-positive chronic hepatitis B patients with
resistance to adefovir dipivoxil
Jia-Jie Lu,1,2 Kai Liu,1,2 Yuan-Ji Ma,1,2 Juan Wang,1,2 En-Qiang Chen1,2 and Hong Tang1,2
1

Center of Infectious Diseases, West China Hospital, Sichuan University; and 2Division of Infectious Diseases, State Key Laboratory of Biotherapy,
Sichuan University, Chengdu, Sichuan, China
Received May 2012; accepted for publication December 2012

SUMMARY. The objective of this study was to compare the

efficacy and safety of two rescue strategies for hepatitis B e

antigen (HBeAg)-positive chronic hepatitis B (CHB) patients
with resistance to adefovir dipivoxil (ADV). This prospective study included 58 HBeAg-positive CHB patients with
resistance to ADV; 30 patients underwent telbivudine
(LdT) plus ADV combination therapy and 28 patients
switched to entecavir (ETV) monotherapy. After 48 weeks
of treatment, the rates of hepatitis B virus (HBV) DNA <3
log10 copies/mL in the LdT plus ADV group and the ETV
group were not significantly different (73.3% vs 57.1%,
P = 0.195). Six patients receiving LdT plus ADV had
HBeAg seroconversion, while none of the patients receiving
ETV alone had HBeAg seroconversion (20% vs 0%,
P = 0.039). During the 48-week treatment period, two
patients in the ETV monotherapy group had viral break-

INTRODUCTION
Chronic infection with the hepatitis B virus (HBV) affects
350 million people worldwide and is a leading cause of
liver-related morbidity and mortality [1,2]. It is estimated
that over 1 million HBV-infected patients die annually
because of hepatic decompensation, cirrhosis and hepatocellular carcinoma (HCC) [3,4]. Evidence-based medicine
has demonstrated that effective antiviral treatment of

Abbreviations: ADV, adefovir dipivoxil; ALT, alanine aminotransferase; CHB, chronic hepatitis; CK, creatine kinase; Etv, entecavir;
HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; ULN, upper limit of normal.
Correspondence: Hong Tang, MD, Center of Infectious Diseases,
West China Hospital, Sichuan University, No. 37 Guo Xue Xiang,
Wuhou District, Chengdu, Sichuan 610041, China.
E-mail: htang6198@hotmail.com

through and the strains were confirmed to be of a variant

associated with ETV resistance (rtM204V+ rtL180M+
rtT184G), while one patient receiving LdT plus ADV had
viral breakthrough and an LdT-associated resistance mutation (rtM204I) was detected. For the majority of the
patients, both LdT plus ADV combination treatment or
ETV monotherapy were generally well tolerated, and no
serious side effects were observed. Both LdT plus ADV combination therapy and ETV monotherapy led to significant
decreases in serum HBV DNA in HBeAg-positive CHB
patients with resistance to ADV, and LdT plus ADV combination therapy exhibited a significantly higher rate of
HBeAg seroconversion compared with ETV monotherapy.
Keywords: adefovir resistance, chronic hepatitis B, combination therapy, telbivudine plus adefovir.

chronic hepatitis B (CHB) reduces the risk of long-term

complications and improves patient survival [5,6].
Currently, oral nucleos(t)ide analogues have demonstrated success in suppressing virus replication with few
side effects [7]. All guidelines share a common principle
regarding nucleos(t)ide analogues treatment for CHB: longterm viral suppression by drugs with potent antiviral activity and low rates of drug resistance to achieve a durable
response that prevents hepatic decompensation, reduces or
prevents progression to cirrhosis and/or HCC, and prolongs
survival [3,5,79]. However, a major shortcoming of nucleos(t)ide analogue therapy is the development of drugresistant strains that develop with increasing frequency as
treatment progresses.
Adefovir dipivoxil (ADV) is a synthetic acyclic adenine
nucleotide analogue. It is a potent inhibitor of HBV reverse
transcriptase in the wild-type HBV strains as well as in
lamivudine (LAM) LdT- and entecavir (ETV)-resistant
mutants [913]. For this reason, ADV has been used
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Rescue therapy for ADV-resistant patients

widely in the treatment of CHB. The rate of ADV resistance
in HBeAg-positive CHB patients has been reported to be
0% in the first year of treatment, increasing to 1.6% in the
second year and 3.1% in the third year [14]. For the management of ADV resistance, evidence from small case
reports and in vitro testing [1518] suggests that management should be based on the pattern of ADV-resistant
mutations present [15,19,20].
The recommendation for CHB patients with ADV resistance is to use add-on therapy with a second drug without
cross-resistance (e.g. LAM, LdT, ETV) or to switch to tenofovir disoproxil fumarate (TDF) plus emtricitabine (FTC)
[3,79]. For LAM-nave patients who develop drug resistance while on ADV, switching to ETV is indicated [9]. In
fact, addition of LAM or LdT or switch to ETV is commonly
used to treat patients with ADV resistance in China
because TDF and FTC are not available in China, and the
cost of ETV plus ADV therapy is prohibitively high.
The rate of LAM resistance is high [2123]. However,
LAM should not be used in patients with the rtA181T
mutation due to its cross-resistance with the rtA181T
mutation [15,24]. Therefore, long-term use of LAM is limited. LdT exhibited significantly greater antiviral and clinical efficacy, while leading to fewer resistant patients than
LAM. In addition, in HBeAg-positive patients, a significantly higher rate of seroconversion was observed with
LdT therapy than with LAM [25]. ETV is a drug with a
high genetic barrier to resistance, and a very low rate of
antiviral resistance in nucleoside-nave patients has been
reported in ETV-treated patients: 0% after 1 year of therapy and 1.2% after 5 years [26,27].
Much less is known about the efficacy of LdT plus ADV
combination therapy versus a switch to ETV monotherapy
as a rescue for CHB patients resistant to ADV. The purpose
of the present study was to compare the efficacy and safety
of LdT plus ADV combination therapy versus ETV monotherapy for HBeAg-positive CHB patients with resistance to ADV.

MATERIALS AND METHODS

41

immunodeficiency virus; other forms of liver disease;

breast-feeding, pregnancy or inadequate contraceptive
measures; coexisting serious medical disease; and evidence
of hepatic decompensation, pancreatitis or HCC.

Study design
This is a prospective controlled study, aimed to evaluate
and compare the efficacy and safety of LdT plus ADV with
that of ETV monotherapy in patients with resistance to
ADV. All patients were administered daily 600 mg LdT
(Novartis) plus 10 mg ADV or 0.5 mg ETV (Bristol-Myers
Squibb) alone, according to each patients choice, and were
followed up in the hospitals outpatient clinic. Patient histories were obtained, physical examinations were conducted and venipuncture samples for laboratory
assessment were obtained at baseline and at weeks 4, 12,
24, 36 and 48. The primary efficacy outcomes were alanine aminotransferase (ALT) normalization, undetectable
HBV DNA and HBeAg seroconversion. Secondary efficacy
outcomes included resistance and safety.
This study was approved by the institutional review
board at West China Hospital and was conducted in accordance with the 1975 Declaration of Helsinki.

Serum assay methodology

Hepatitis B e antigen (HBeAg) and serum HBV DNA were
measured by enzyme-linked immunosorbent assay (ELISA;
Intec Stone, Xiamen, China) and real-time polymerase
chain reaction (PCR) (DA AN Gene Co. Ltd., Guangzhou,
China), respectively, according to the manufacturers
instructions. Serum ALT, creatinine (Cr) and creatine
kinase (CK) were measured with an automatic biochemistry analyser (Olympus AU5400, Tokyo, Japan) according
to standard laboratory procedures. HBV mutations associated with resistance to LdT (rtM204I) and ETV (rtI169T,
rtL180M, rtT184G, rtS202I, rtM204V/I and rtM250V)
were analysed by direct sequencing if virological breakthrough occurred.

Patients
chronic hepatitis B (CHB) outpatients from West China
Hospital, Sichuan University with resistance to ADV were
screened, and patients who met the following criteria were
included in the study: serum hepatitis B e antigen positive
and serum HBV DNA level  1000 copies/mL. ADV resistance was defined on the basis of genetic testing
(rtA181V/T or rtN236T) or the presence of virological
breakthrough, which we defined as a documented rise in
serum HBV DNA by  1 log10 (tenfold) above the nadir,
or to a detectable level (  1000 copies/mL) after achieving
virological response while continuing ADV therapy. Exclusion criteria were previous treatment for hepatitis B with
LAM, LdT or ETV; coinfection with hepatitis C or human
2012 Blackwell Publishing Ltd

Definition
Virological response was defined as a decrease in serum
HBV DNA to levels undetectable by PCR analysis (<1000
copies/mL). Serological response was defined as loss or
seroconversion of HBeAg in patients who were initially
HBeAg-positive. Biochemical response was defined as ALT
returning to values within the normal range.

Statistical analysis
Statistical analysis was carried out using Students t-test or
chi-squared test (or Fishers exact test). Categorical and
continuous variables were presented as a proportion (%),

42

J. Lu et al.

mean  SD or median (range) as appropriate. HBV DNA

levels were log-transformed. A P-value of <0.05 (twotailed) was considered to indicate a statistically significant
difference. All statistical analyses were performed using
SPSS version 18.0 (SPSS Inc., Chicago, IL, USA).

RESULTS
Baseline characteristics
A total of 58 HBeAg-positive CHB patients were analysed:
30 patients receiving LdT plus ADV combination therapy
and 28 patients receiving ETV monotherapy. All patients
were Chinese. A family history of CHB and HCC was
reported in 46% and 18% of all patients, respectively. The
total duration of ADV treatment prior to the switch in the
LdT plus ADV group was 944 months, and the total
duration of ADV treatment prior to the switch in the ETV
group was 840 months. ADV-resistant mutations were
detected in 41 patients; the remaining patients experienced
viral breakthrough during the course of ADV treatment,
but refused to accept genetic testing. The treatment groups
were well matched at baseline in demographic and disease
characteristics (Table 1). The group receiving LdT plus
ADV combination therapy and the group undergoing ETV
monotherapy had a similar proportion of patients with
ALT levels more than twice the upper limit of normal
(ULN) (53.3% and 60.7%, P = 0.571). The ALT levels of
10 patients in the LdT plus ADV group and 11 patients in
the ETV group were normal, and ALT levels of four
patients in the LdT plus ADV group were between normal
and twice the ULN.

Virological response
In the LdT plus ADV group, the proportion of patients
with a virological response (HBV DNA <3 log10 copies mL1) at 4, 12, 24, 36 and 48 weeks of treatment was 10%,
30%, 60%, 73.3% and 73.3%, respectively. In the ETV
group, the proportion of patients with a virological
response (HBV DNA <3 log10 copies mL-1) at 4, 12, 24,
36 and 48 weeks of treatment was 3.6%, 17.9%, 32.1%,
46.4% and 57.1%, respectively. The difference in virological response between the two groups was statistically significant at 24 and 36 weeks (P = 0.034 for week 24 and
P = 0.036 for week 36). However, the rates of HBV DNA
<3 log copies mL-1 in the LdT plus ADV group and the
ETV group were not significantly different after 48 weeks
(P > 0.05) (Fig. 1).

Serological response
Among the 58 patients, 33.3% (10/30) of those in the LdT
plus ADV group and 10.7% (3/28) of those in the ETV
group experienced HBeAg loss at 48 weeks (P = 0.039).

Table 1 Baseline characteristics of the study population

Characteristic
Age, years,
mean  SD
Sex, males, n (%)
ALT, IU\L,
mean  SD
HBV DNA, log10
copies/mL,
mean  SD
Total treatment
duration
prior to switch,
months,
mean  SD

LdT plus ADV

(N = 30)

ETV
(N = 28)

P-value

39.8  9.2

37.2  7.8

0.579

23 (76.7)
23 (82.1)
0.607
118.8  91.6 114.1  88.4 0.846
4.8  1.2

5.0  1.3

0.816

22.2  11.0

19.5  7.7

0.274

ADV, adefovir dipivoxil; ETV, entecavir; HBV, hepatitis B

virus; LdT, telbivudine.

The upper limit of normal for serum alanine aminotransferase (ALT) was 55 IU\L for men and 38 IU\L for women.
Additionally, at 48 weeks, significantly more patients
receiving LdT plus ADV had HBeAg seroconversion compared with patients receiving ETV alone (6/30 vs 0/28,
P = 0.024) (Fig. 2).

Biochemical response
The rate of serum ALT normalization at week 48 was high
in both treatment groups. At 48 weeks, normal ALT levels
were achieved in 85% (17/20) of patients receiving LdT
plus ADV and in 70.6% (12/17) of patients receiving ETV
monotherapy. The difference in ALT normalization
between the two groups was not statistically significant
(P = 0.428).

Fig. 1 Virological response rates of hepatitis B e antigen

(HBeAg)-positive patients with resistance to adefovir
dipivoxil (ADV) receiving telbivudine (LdT) plus adefovir
dipivoxil (ADV) or entecavir (ETV) alone during 48-week
treatment.
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Rescue therapy for ADV-resistant patients

Fig. 2 hepatitis B e antigen (HBeAg) loss and

seroconversion rates of HBeAg-positive patients with
resistance to adefovir dipivoxil (ADV) receiving telbivudine
(LdT) plus ADV or entecavir (ETV) alone during 48-week
treatment.

Viral breakthrough and resistance

Two patients in the ETV monotherapy group experienced
viral breakthrough during the 48-week course of treatment, and the strains were confirmed to be a variant associated with ETV resistance (rtM204V+ rtL180M+
rtT184G). In patients receiving LdT plus ADV combination
therapy, viral breakthrough was found in one patient, in
whom an LdT-associated resistant strain (rtM204I) was
detected. After 48 weeks, the rates of viral breakthrough
and resistance showed no significant differences between
the LdT plus ADV group and the ETV group (P = 0.951).

Safety and adverse events

For the majority of the study patients, both combination treatment of LdT plus ADV and ETV monotherapy were generally
well tolerated. Elevations in CK levels were found in two
patients in the LdT plus ADV group at 36 weeks, but the LdT
regimen was continued because the patients had no musclerelated symptoms (e.g. muscle pain, weakness), and the CK
levels were lower than five times the ULN. After 1 month, the
CK levels of the two patients returned to normal. Elevated
serum CK was not found in the ETV group of patients, and
the difference in the rate of elevations in CK levels between
the two groups was not statistically significant (6.7% vs 0%,
P = 0.492). Elevated serum Cr was not found in either group
during the 48-week observation period.
Elevations in ALT levels were reported for one patient in
the LdT plus ADV group (3.3%) and two patients in the
ETV group (7.1%), and all of these ALT flares were associated with viral breakthrough. No patient developed HCC in
either of the two groups during the 48 weeks.

DISCUSSION
Oral nucleos(t)ide analogues have been widely used for
over 10 years, and the sustained suppression of serum
2012 Blackwell Publishing Ltd

43

HBV DNA to very low or undetectable levels has been

associated with the prevention of liver disease progression
and inhibition of the development of long-term complications [5,6,28,29]. However, drug resistance has presented
a serious challenge to CHB treatment. Insufficient antiviral
efficacy caused by drug resistance has resulted in attenuated viral suppression, which can lead to significant clinical deterioration [7,15,29]. Although some studies have
carried out direct comparisons of the antiviral efficacies
among the rescue strategies for LAM-resistant patients,
there is still limited information on managing resistance to
ADV. In China, major rescue therapies for CHB patients
with ADV resistance include adding LAM or LdT to the
treatment regimen and switching to ETV. In separate trials,
both LdT and ETV have shown greater antiviral effects
than ADV and LAM [26,3032]. Therefore, the aim of the
present study was to provide data regarding the efficacy
and safety of two rescue strategies (adding LdT and switching to ETV) for HBeAg-positive CHB patients with resistance to ADV.
In the present study, we explored and compared rescue
options for HBeAg-positive CHB patients with resistance to
ADV. During 48 weeks of rescue treatment, a higher proportion of patients treated with LdT plus ADV achieved
undetectable HBV DNA levels than in the ETV group (60%
vs 32.1% at 24 weeks, 73.3% vs 46.4% at 36 weeks and
73.3% vs 57.1% at 48 weeks). However, the only time
points where the difference between the two groups was
statistically significant were weeks 24 and 36 (P = 0.034
for week 24 and P = 0.036 for week 36), and there was
no significant difference at week 48 (P = 0.195). This suggested that LdT plus ADV combination therapy might produce a more rapid reduction in HBV DNA levels compared
with ETV monotherapy. As higher HBV DNA loads represent a greater risk factor for the development of HCC and
cirrhosis [33,34], the use of LdT plus ADV would be
expected to result in a better clinical outcome than that
observed in CHB patients presenting with ADV resistance
who were treated with only ETV. Nevertheless, we could
not conclude from our data that LdT plus ADV combination therapy exhibited significantly more rapid and greater
virological response compared with ETV monotherapy for
CHB patients with ADV resistance because of the limited
sample size, short course of treatment and short follow-up
survey. Therefore, further studies are needed to confirm
this hypothesis.
Hepatitis B e antigen (HBeAg) seroconversion is a key
goal in the treatment in HBeAg-positive CHB patients; this
event indicates good prognosis, including lower rates of cirrhosis and slower disease progression [3,79]. In the present
study, a higher proportion of patients experienced HBeAg
loss and HBeAg seroconversion in the LdT plus ADV group
than in the ETV group. Among the 30 patients receiving
combination therapy of LdT plus ADV, 10 patients obtained
HBeAg loss and six obtained HBeAg seroconversion; the

44

J. Lu et al.

rates of these events in this group were significantly

higher than in the ETV group. Some previous studies have
suggested that combination therapy did not improve
HBeAg seroconversion rates compared with monotherapy
[29,35]. We speculate that the higher rate of HBeAg loss
and seroconversion in the LdT plus ADV group may be
related to the effect of LdT, because a study of treatmentnave patients demonstrated that LdT could significantly
increase the rate of serological response compared with
other nucleos(t)ide analogues (i.e. LAM, ADV and ETV)
[36,37].
Evidence from several clinical studies suggests that combination therapy can decrease the rate of drug resistance
[29,35]. In our study, the proportion of patients experiencing viral breakthrough was 3.3% (1/30) in the LdT plus
ADV group, compared with 7.1% (2/28) of patients receiving ETV alone; an LdT-associated resistance mutation
(rtM204I) and ETV-associated resistance mutations
(rtM204V+ rtL180M+ rtT184G) were detected in these sets
of patients, respectively. The rates of viral breakthrough
and resistance were similar in both groups (P = 0.951).
These data are different from those reported in previous
clinical studies [29,35], which may due to the limited sample size in the present study.
In this study, LdT plus ADV combination therapy and
ETV alone were both well tolerated by patients. In spite of
the fact that two patients in the LdT plus ADV group had
elevated CK, they had no muscle-related symptoms, and
the CK levels were lower than five times the ULN. The LdT
plus ADV treatment was continued, and after 1 month,

the CK levels of the two patients returned to normal. The

rate of ALT flares was low in the two groups, which is in
accordance with the lower incidence of viral breakthrough
in the two groups. Although the long-term safety of LdT
plus ADV combination therapy in patients with resistance
to ADV is still unclear, our findings suggest that short-term
LdT plus ADV combination therapy appears to be safe in
this setting.
The long-term efficacy and safety of LdT plus ADV combination therapy or ETV monotherapy for CHB patients
with resistance to ADV is still not well understood.
Although our preliminary results are not randomized, they
indicate that the application of LdT plus ADV combination
therapy and ETV monotherapy for HBeAg-positive CHB
patients with resistance to ADV leads to significant
decreases in serum HBV DNA, and LdT plus ADV combination therapy exhibited a significantly higher rate of HBeAg
seroconversion compared with ETV monotherapy. The
present potentially favourable results may prompt further
randomized and larger sample size investigations to estimate the long-term efficacy and safety of the rescue therapies for CHB patients with resistance to ADV.

ACKNOWLEDGEMENT AND DISCLOSURES

This work was supported by National Science and Technology Major Project of China (2012ZX10002007-001-003,
2008ZX10002-006), and National S&T Major Project for
Infectious
Diseases
Control
(2012ZX10004-901,
2009ZX10004-905).

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