Journal of Viral Hepatitis, 2013, 20 (Suppl. 1), 5864
12065
Forty-eight-week retrospective study of telbivudine and
lamivudine treatment in patients with hepatitis B-related
cirrhosis
Z. Han,1, Y. Shi,1, J. Zhu,1 Y. Chen,1 F. Yin,1 L. Xia,1 G. Luo,1 Z. Gao,1 J. Liu,1 G. Jia,1
C. Li,2 X. Zhou1 and Y. Han1 1Xijing Hospital of Digestive Diseases, State Key Laboratory of Cancer Biology, Fourth Military
Medical University, Xian; and 2College of Postgraduate Students, Fourth Military Medical University, Xian, China
Received June 2012; accepted for publication December 2012
SUMMARY. The aim of this study was to evaluate the effi-
cacy and safety of telbivudine 600 mg/day compared with
lamivudine 100 mg/day for 48 weeks of treatment in
patients with hepatitis B-related cirrhosis. Data were
reviewed retrospectively from 165 hepatitis B-related cir-
rhotic patients (55 compensated patients and 110 decom-
pensated) who received antiviral therapy with telbivudine
or lamivudine. Serum alanine aminotransferase (ALT) and
hepatitis B virus (HBV) DNA levels, hepatitis B e antigen
(HBeAg) loss and seroconversion, histological improvement
and various adverse events (AEs) were evaluated. Baseline
characteristics were comparable. ALT levels declined but
showed no significant difference in treatment with telbivu-
dine or lamivudine (P > 0.05). Reduction in serum HBV
DNA levels was evident by week 4 in compensated HBV-
related cirrhosis patients (telbivudine, 2.34 log10 copies/
mL; lamivudine, 2.07 log10 copies/mL; P = 0.02) and per-
sisted by week 8. Patients administrated with telbivudine
INTRODUCTION
Approximately 350400 million people have been infected
chronically with hepatitis B virus (HBV) worldwide, mainly
in the Asia-Pacific region [13]. Prognosis is poor when
patients have progressed to cirrhosis. At 5 years of infec-
tion, the incidence of cirrhosis in hepatitis B e antigen
(HBeAg)-positive and HBeAg-negative patients with
chronic hepatitis B (CHB) is 1338%. Nearly 20% of
patients with cirrhosis reach decompensation stage at 5-
Abbreviations: HBV, hepatitis B virus; ALT, alanine aminotransfer-
ase; HCC, hepatocellular carcinoma; INR, international normalized
ratio; PCR, polymerase chain reaction.
Correspondence: Ying Han and Xinmin Zhou, Xijing Hospital of
Digestive Diseases, State Key Laboratory of Cancer Biology, 127
West Changle Road, Xian, Shaanxi 710032, China.
E-mail: hanying@fmmu.edu.cn; zhouxm@fmmu.edu.cn
These authors contributed equally to this work.
doi:10.1111/jvh.
had slightly greater HBeAg loss and seroconversion than
patients with lamivudine, but the difference was not statis-
tically significant (P > 0.05). Accumulative HBeAg loss
was seen at week 48 (25.0% vs 25.0% and 13.3% vs
10.0% for telbivudine vs lamivudine in compensated and
decompensated cirrhotic groups, respectively), as well as
HBeAg seroconversion (15.0% vs 8.3% and 8.9% vs 6.7%).
Mean Knodell Histologic Activity Index scores decreased in
both compensated and decompensated cirrhotic patients
(3.92 vs 3.64, 3.85 vs 3.73, for telbivudine vs lamivudine).
Telbivudine and lamivudine were both well tolerated with
minor AEs. The results of this study support telbivudine as
an effective therapy for patients with both compensated
and decompensated HBV-related cirrhosis.
Keywords: hepatitis B e antigen, hepatitis B virus (HBV)
DNA, hepatitis B-related cirrhosis, histological improve-
ment, lamivudine, telbivudine.
year follow-up, while only 1435% with decompensated
cirrhosis can survive for more than 5 years [4].
According to the guidelines, there are currently seven
available drugs for the treatment of CHB: lamivudine, ente-
cavir, adefovir dipivoxil, tenofovir disoproxil fumarate, tel-
bivudine, as well as pegylated and standard interferon-a
[5,6]. While treatment options for cirrhosis are limited,
well-tolerated antiviral treatment to induce rapid viral sup-
pression and improve clinical outcomes is needed urgently.
New clinical practice guidelines recommend oral antiviral
medicine in patients with HBV-related cirrhosis. However,
increase in creatinine with tenofovir and lactic acidosis
with entecavir has been observed recently [7,8]. Lamivu-
dine is well tolerated in cirrhosis patients and remains a
worldwide prescribed therapy [9]. Telbivudine is a syn-
thetic thymidine nucleoside anti-HBV DNA polymerase
drug, which has significant anti-HBV activity. In preclini-
cal toxicologic trials, telbivudine has shown no mutagenic
or carcinogenic effect and no evidence of embryonic toxic
2012 Blackwell Publishing Ltd

or lethal effect. In initial clinical trials, groups treated with
telbivudine have had greater reduction in HBV DNA levels
and have been much slower to develop resistance than
groups treated with lamivudine in both HBeAg-positive
and HBeAg-negative patients [1013].
Few studies have focused on HBV cirrhotic patients and
histological outcomes. Our objective was to evaluate the
efficacy and safety of telbivudine or lamivudine in patients
with HBV-related cirrhosis, as well as their histological
response.
PATIENTS AND METHODS
Patients
This was a retrospective study. From July 2008 to Decem-
ber 2010, 587 patients were diagnosed with HBV-related
cirrhosis at the Department of Digestive Diseases, Xijing
Hospital, China. Of those patients, 165 who received con-
secutive monotherapy (55 with compensated HBV-related
cirrhosis, 110 with decompensated HBV-related cirrhosis),
administrated with telbivudine or lamivudine, were
enrolled in the study. The diagnosis of HBV-related cirrho-
sis was based on previously described criteria [14], ultra-
sound or computed tomography. Inclusion criteria were 18
69 years of age, HBV DNA  103 copies/mL, CTP
score  12 at screening, no history of treatment with
nucleotide acid analogues, alanine aminotransferase (ALT)
< 10 times the upper limit of normal (ULN), calculated
serum creatinine clearance  50 mL/min, haemoglobin
 7.5 g/dL, total white blood cell (WBC)
count  1 500/mm, platelet count  30 000 mm, a-
fetoprotein  10 ng/mL and no evidence of hepatocellular
carcinoma (HCC). Patients were excluded if they were HIV,
HCV or HDV positive, had prior nucleotide acid analogue
exposure, history within 2 months of variceal bleeding, he-
patorenal syndrome, hepatic encephalopathy, spontaneous
bacterial peritonitis, solid organ or bone marrow transplant
or use of hepatotoxic or nephrotoxic drugs, including those
affecting renal tubular secretion.
Data collection
Clinical and laboratory data were retrospectively collected
from the Patient History Record System. The following
parameters were evaluated for efficacy assessment: serum
HBV DNA, ALT, HBeAg/HBsAg loss and seroconversion,
and CTP score. Serum HBV DNA levels were quantified
using a real-time polymerase chain reaction (PCR) kit (Da
An Gene Co. Ltd, Guangzhou, Guangdong, China), with a
detection limit of 3 log10 copies/mL. Serum HBeAg/HBsAg
were quantified using Roche Modular Analytics, with a
detection limit of l0 IU/L. HBV serology was evaluated at
screening from baseline and every 12 weeks through week
48. Serum chemistry, haematology, prothrombin time
2012 Blackwell Publishing Ltd
Telbivudine in patients with hepatitis B-related cirrhosis 59
(PT), international normalized ratio (INR), urinalysis and
serum HBV DNA were collected every 4 weeks through
week 48. Patients received liver biopsy at baseline (within
3 months before treatment) and at study endpoint (48
52 weeks), and histological improvement was evaluated.
Various adverse events (AEs) including AEs and serious
AEs, laboratory abnormalities, death and discontinuation
of the study drug due to AEs were evaluated for 48 weeks
in all patients who received at least one dose of a study
drug. AEs and concomitant medications were recorded
every 4 weeks. Complete physical examination was per-
formed every 12 weeks. Serum a-fetoprotein was measured
at baseline, and at weeks 24 and 48.
No response was defined as a decrease of < 2 log10 cop-
ies/mL in HBV DNA at week 12 (and greater than entry
value) or serum HBV DNA levels remaining at  3
log10 copies/mL at or after 24 weeks of treatment. Viro-
logic breakthrough was defined as an increase of no < 1
log10 copies/mL from nadir on two consecutive determina-
tions or consecutive HBV DNA  3 log10 copies/mL after
being < 3 log10 copies/mL. Resistance was defined as viral
breakthrough with treatment-induced resistance muta-
tions. Conserved amino acid mutations of HBV polymerase
region were evaluated to determine whether they occurred
at polymorphic or conserved sites. Patients with no
response or with breakthrough or resistance could receive
add-on ADV.
Statistical analysis
Continuous variables were summarized using mean and
standard deviations (laboratory tests, ChildPugh score at
baseline and every 12 weeks). Binary variables were sum-
marized by counts and percentages. Efficacy data were
analysed for the intention-to-treat population. Independent
sample t-test and one-factor analysis of variance were used
for normally distributed quantitative variables. Percentage
changes in prognostic variables were calculated and com-
pared using chi-square test. In all tests, P < 0.05 was con-
sidered statistically significant. The descriptive statistics
were presented for safety analyses, including all AEs during
the 48 weeks. All statistical analyses were conducted using
SPSS version 12 (SPSS Inc., Chicago, IL, USA).
RESULTS
Patients
Among 55 compensated cirrhotic patients, 31 received tel-
bivudine (600 mg/day) and 24 received lamivudine
(100 mg/day), while in 110 decompensated cirrhotic
patients, 62 patients received telbivudine and 48 received
lamivudine. The treatment groups were matched at base-
line for age, sex and disease characteristics (Table 1).
Thirty-three compensated cirrhotic patients and 24
60 Z. Han et al.

Table 1 Baseline demographics and clinical characteristics

Compensated cirrhosis Decompensated cirrhosis

Group Lamivudine Telbivudine Lamivudine Telbivudine

Case no. 24 31 48 62
Age, years 43.83  9.56 45.25  7.67 54.67  10.41 53.00  8.25
Sex 18/6 25/6 43/5 51/11
HBeAg () 12/12 20/11 30/18 45/17
HBV DNA 8.67 E  06 1.30 E  07 2.34 E  06 7.25 E  06
ALT 140.83  74.53 133.32  82.74 45.87  25.10 58.83  23.83

ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus.

decompensated cirrhotic patients received liver biopsy at (a)

baseline; among them, 27 and 22 patients received liver
biopsy at week 48 and week 52, respectively.

Biochemical response
Serum ALT levels declined dramatically in both treatment
groups of patients with compensated HBV-related cirrhosis
at week 4 and returned to normal level at week 48. There
was no significant difference in treatment with telbivudine
or lamivudine (P > 0.05) (Fig. 1).

HBV DNA responses (b)

Among both compensated and decompensated HBV-related

cirrhosis patients, reduction in serum HBV DNA levels was
significant at week 48 in both the telbivudine and lamivu-
dine groups (Fig. 2). The difference between the two treat-
ments was evident by week 4 in compensated HBV-related
cirrhosis patients (reductions of 2.34 log10 copies/mL for
telbivudine and 2.07 log10 copies/mL for lamivudine,
P = 0.02) and persisted by week 8 (Fig. 2a). This difference
was not observed in decompensated HBV-related cirrhosis
patients. The mean time required for serum HBV DNA to
become undetectable by PCR assay was around 24 weeks
for each group, and there was no difference in treatment Fig. 1 Declines in serum alanine aminotransferase (ALT)
or disease progression. There was no primary treatment levels from baseline in (a) compensated hepatitis B virus
failure. (HBV)-related cirrhotic patients and (b) decompensated
HBV-related cirrhotic patients. Black bar, lamivudine;
white bar, telbivudine. Telbivudine versus lamivudine,
HBeAg loss and seroconversion
P > 0.05.
Patients administrated with telbivudine achieved slightly
greater HBeAg loss and seroconversion than patients with vudine groups, respectively (P = 0.66), and HBeAg sero-
lamivudine, although this difference was not statistically conversion appeared in 8.9% and 6.7% (P = 0.73, Fig. 3b,
significant. Among compensated HBV-related cirrhosis d), respectively. By week 24, of the compensated patients
patients, 25% in the telbivudine group and 25% in the who achieved HBeAg loss, 10% were in the telbivudine
lamivudine group had HBeAg loss (P = 1.00) and 15% in group and 16.7% were in the lamivudine group (P = 0.58)
the telbivudine group and 8.3% in the lamivudine group (Fig. 3a); the corresponding percentages for the decompen-
had HBeAg seroconversion (P = 0.58) (Fig. 3a,c). Among sated patients were 4.4% and 6.7% (P = 0.68, Fig. 3b).
decompensated HBV cirrhotic patients, HBeAg loss The HBeAg seroconversion rates by week 24 were 10.0%
appeared in 13.3% and 10% of the telbivudine and lami- and 0.0% in the telbivudine and lamivudine groups

2012 Blackwell Publishing Ltd

 Telbivudine in patients with hepatitis B-related cirrhosis 61

(P = 0.26), respectively, in the compensated HBV-related

cirrhosis patients, and 2.2% and 0.0% (P = 0.41), respec-
tively, in the decompensated HBV-related cirrhosis patients.
(a)
Breakthrough and resistance
Viral breakthrough and genotypic resistance were signifi-
cantly less common in patients receiving telbivudine than
in those receiving lamivudine (Fig. 2). There were no cases
of resistance developed in compensated or decompensated
HBV-related cirrhosis patients who received telbivudine,
and one patient was detected with M204I mutation at
week 48. In comparison, 8.3% and 4.2% of patients who
received lamivudine developed resistance, and one and two
were detected M204I/V mutation, respectively (P < 0.01
for both comparisons).

(b)
Fig. 2 Reductions in serum hepatitis B virus (HBV)
DNA levels from baseline. Declines in serum alanine
aminotransferase (ALT) levels in (a) compensated
HBV-related cirrhotic patients and (b) decompensated
HBV-related cirrhotic patients.
Histologic responses
Of patients with histological data, 19 compensated CHB
patients receiving telbivudine and 14 receiving lamivudine
had histological exam data, and 15 and 12, respectively,
had a final histological exam between weeks 48 and 52;
the corresponding numbers were 12 each for decompensat-
ed CHB patients receiving telbivudine or lamivudine, and
12 and 10, respectively, had a final histological exam
between weeks 48 and 52. Among compensated CHB
patients, the mean Knodell Histologic Activity Index
(Knodell HAI) scores (range, 022, with higher scores indi-
cating more severe disease) decreased by 3.92 and 3.64
points in patients who were receiving telbivudine and
those receiving lamivudine, respectively (Fig. 4a); among
decompensated cirrhotic patients, the scores decreased by
3.85 and 3.73 points, respectively (Fig. 4b). Among com-
pensated patients, 81.25% with marked pretreatment

(a) (b)

(c) (d)

Fig. 3 Hepatitis B e antigen (HBeAg) response during treatment. HBeAg loss in (a) compensated hepatitis B virus (HBV)-
related cirrhotic patients and (b) HBV-related cirrhotic patients. HBeAg seroconversion in (c) compensated HBV-related
cirrhotic patients and (d) decompensated HBV-related cirrhotic patients. Solid line, lamivudine; dashed line, telbivudine.

2012 Blackwell Publishing Ltd

62 Z. Han et al.

(a) (b)

(c) (d)

Fig. 4 Histological response during treatment. Knodell Histologic Activity Index in (a) compensated hepatitis B virus
(HBV)-related cirrhotic patients and (b) decompensated HBV-related cirrhotic patients. Ishak score in (c) compensated
HBV-related cirrhotic patients and (d) decompensated HBV-related cirrhotic patients.

Table 2 Frequency of main clinical adverse events during lamivudine (Table 2). Serious AEs (defined according to
treatment criteria adapted from the Division of AIDS, National Insti-
tute of Allergy and Infectious Diseases), regardless of attrib-
Telbivudine Lamivudine utability to study drug, were reported for six patients in
(n = 93) (n = 72) the telbivudine group (6.5%) and seven in the lamivudine
Death 1 2 group (9.7%). One and two patients in the telbivudine
Elevated creatine 2 0 group and lamivudine group, respectively, died because of
kinase levels disease progression. Two and one patients in the telbivu-
Muscle pain 2 0 dine group and lamivudine group, respectively, had mildly
Myolysis for striated muscle 0 0 elevated plasma creatinine, and one patient had HBV-
Renal function disorder 2* 1 related renal disease in the telbivudine group. Myopathy,
Lactic acidosis 0 0 characterized by muscle pain and weakness, and moder-
Viral breakthrough 1 4 ately elevated creatine kinase levels before and during
and resistance treatment, was reported in two patients at weeks 4648
Liver transplantation 0 0 after initiation of telbivudine. When telbivudine was dis-
continued, creatine kinase levels returned to normal within
*
One patient was diagnosed hepatitis B virus (HBV)-related 1 month and symptoms resolved in 912 months. Other
renal disease. patterns of clinical AEs, including infrequent mild nausea
and diarrhoea, were similar in the two study groups. There
bridging fibrosis or cirrhosis with Ishak fibrosis scores of 46 was no Grade 3 or 4 elevation in ALT and aspartate ami-
(where 0 indicates no fibrosis and 6 indicates cirrhosis) notransferase levels during treatment nor was there any
reduced to 37.5% with telbivudine, and 77.78% reduced liver transplantation.
to 38.89% with lamivudine (Fig. 4c); the corresponding
figures for decompensated cirrhotic patients were 100.0
DISCUSSION
63.63% and 90.080% (Fig. 4d).
The present study reports data on the efficacy and safety of
telbivudine or lamivudine treatment in HBV cirrhotic
Safety and adverse events
patients, as well as histological response. In patients with
Frequencies of AEs through week 48 were similar for compensated HBV-related cirrhosis, telbivudine had a mod-
patients who received telbivudine and those who received erately greater antiviral efficacy than lamivudine. In both

2012 Blackwell Publishing Ltd


compensated and decompensated HBV cirrhotic patients,
telbivudine was superior to lamivudine for HBeAg loss and
seroconversion. However, in aspects of biological and histo-
logical response in each group of patients, telbivudine and
lamivudine achieved similar therapeutic effects.
Serum HBV DNA serves as a good predictor of viral repli-
cation and is a great risk factor for cirrhosis [5,6,15]. High
serum HBV DNA levels always indicate disease progression.
The main endpoint of treatment in HBV-related cirrhosis is
complete and durable suppression of HBV to hold down pro-
gression of disease. Both 1- and 2-year results of the GLOBE
trial have demonstrated potent antiviral efficacy of telbivu-
dine against HBV in both HBeAg-positive and HBeAg-nega-
tive patients [1012]. Reduction in serum HBV DNA level
from baseline is an important measure. Consistent with
these results, our study of HBV-related cirrhosis also showed
greater potency of telbivudine in reduction in serum HBV
than of lamivudine.
Biochemical remission is one goal of antiviral therapy
against HBV and is related to favourable outcomes [5,6].
Serum ALT levels are typically used to evaluate liver cell
inflammation [16]. In our study, we observed a significant
decline of ALT levels in antiviral-treated HBV cirrhotic
patients, especially in compensated patients. The results of
lamivudine treatment groups were no better than those of
telbivudine treatment groups. These results indicate that
both telbivudine and lamivudine could be effective in
reducing liver inflammation. Discrepancy between ALT
activity and histological liver damage might be seen in
end-stage liver disease. In our study group, we only saw a
slight elevation of ALT in decompensated patients, which
might be due to cell death without ALT release such as
apoptosis with no membrane damage [17,18].
HBeAg loss and seroconversion, defined as loss of HBeAg
with the appearance of anti-HBe, are often associated with
clinical remission and transition to inactive liver disease
[19]. Consistent with previous findings, telbivudine treat-
ment seemed slightly superior to lamivudine for all HBeAg-
positive cirrhotic patients. Meanwhile, patients receiving
telbivudine could achieve earlier HBeAg loss and serocon-
version before week 24 compared with those who received
lamivudine. Although HBeAg is a nonparticulate secretory
protein, it is essential for the establishment of persistent
infection in vivo. Downregulation of innate immune
response indicated that it was accompanied by HBeAg
seroconversion [20]. Our and others data suggest that
patients treated with telbivudine might achieve better
immune remission than patients treated with lamivudine.
REFERENCES
1 Lee W. Hepatitis B virus infection. N 2 Lok ASF, McMahon BJ. Chronic hep-
Engl J Med 1997; 337: 1733 atitis B. Hepatology 2001; 34: 1225
1745. 1241.
2012 Blackwell Publishing Ltd
Telbivudine in patients with hepatitis B-related cirrhosis 63
Liver fibrosis is a dynamic process of fibrogenesis and fibr-
olysis. Persistence of necroinflammation leads to the accu-
mulation of matrix proteins and fibrosis will progress to
cirrhosis; on the contrary, suppression of necroinflammation
because of sustained HBV suppression leads to the activation
of fibrolysis mechanisms and fibrosis will regress [21]. Antiv-
iral reagents can suppress histological necroinflammation
activity in HBV cirrhosis, so it might lead to stabilization and
regression of fibrosis and reduce the risk of progression to
end-stage liver disease and even HCC [22]. We conducted a
descriptive assay of histological response in the treatment of
HBV cirrhotic patients. Telbivudine and lamivudine
improved liver necroinflammation to some extent, which
might indicate a reduction in risk of progress to end-stage
liver diseases and HCC.
HBV cirrhotic patients are recommended for continuous
and prolonged NUC therapy, while viral breakthrough and
resistance can result in great treatment problems. All
nucleoside therapies for CHB have shown various rates of
loss of response due to drug resistance. Within 2 years
after initiation of treatment, the cumulative incidence of
lamivudine resistance approaches 38% and 17% of telbivu-
dine, according to non-head-to-head studies [14]. The
lower resistance rates observed with telbivudine compared
to lamivudine are probably due to the greater antiviral effi-
cacy of telbivudine. However, telbivudine effectively sup-
presses the robust M204V resistance pathway, which was
seen in lamivudine receivers. This leads to halving of the
resistance rate.
This study of HBV cirrhotic patients confirms previously
described associations between greater reduction in HBV
DNA levels and higher HBeAg seroconversion rate of tel-
bivudine compared to lamivudine. The AEs data in this
study were consistent with previous findings and suggest
that telbivudine and lamivudine have similar safety pro-
files. In conclusion, the present results support telbivudine
as an effective therapy for patients with both compensated
and decompensated HBV-related cirrhosis.
ACKNOWLEDGEMENT AND DISCLOSURES
This study was partly supported by the Chinese National
Nature Science Foundation (30970149, 30971116). The
authors thank all of the patients screened in this study.
The Digital Information Center, Xijing Hospital FMMU,
China provided much assistance in data collection for this
study.
3 Alter MJ. Epidemiology and preven-
tion of hepatitis B. Semin Liver Dis
2003; 23: 3946.
64 Z. Han et al.
4 Vallet-Pichard A, Mallet V, Costen-
tin CE, Pol S. Treatment of HBV-
related cirrhosis. Expert Rev Anti
Infect Ther 2009; 7: 527535.
5 Lok ASF, McMahon BJ. Chronic hep-
atitis B: update 2009 (AASLD Prac-
tice Guidelines). Hepatology 2009;
50: 136.
6 European Association for the Study
of the Liver. EASL clinical practice
guidelines: management of chronic
hepatitis B. J Hepatol 2009; 50: 227
242.
7 Antoniou T, Raboud J, Chirhin S
et al. Incidence of and risk factors
for tenofovir-induced nephrotoxicity:
a retrospective cohort study. HIV
Med 2005; 6: 284290.
8 Marzano A, Marengo A, Marietti M,
Rizzetto M. Lactic acidosis during
entecavir treatment in decompensat-
ed hepatitis B virus-related cirrhosis.
Dig Liver Dis 2011; 43: 10271028.
9 Hache C, Villeneuve JP. Lamivudine
treatment in patients with chronic
hepatitis B and cirrhosis. Expert Opin
Pharmacother 2006; 7: 18351843.
10 Liaw YF, Gane E, Leung N et al.
GLOBE Study Group. Two-year
GLOBE trial results: telbivudine is
superior to lamivudine in patients
with chronic hepatitis B. Gastroen-
terology 2009; 136: 486495.
11 Lai CL, Leung N, Teo EK et al. Tel-
bivudine Phase II Investigator
Group. A 1-year trial of telbivudine,
lamivudine, and the combination in
patients with hepatitis B e antigen
positive chronic hepatitis B. Gastro-
enterology 2005; 129: 528536.
12 Lai CL, Gane E, Liaw YF et al. Globe
Study Group. Telbivudine versus
lamivudine in patients with chronic
hepatitis B. N Engl J Med 2007;
357: 25762588.
13 Hou J, Yin YK, Xu D et al. Telbivu-
dine versus lamivudine in Chinese
patients with chronic hepatitis B:
results at 1 year of a randomized,
double-blind trial. Hepatology 2008;
47: 447454.
14 EASL International Consensus Confer-
ence on Hepatitis B. 1314 September,
2002: Geneva, Switzerland. Consen-
sus statement (short version). J Hepatol
2003; 38: 533540.
15 Iloeje UH, Yang HI, Su J, Jen CL,
You SL, Chen CJ. Risk Evaluation of
Viral Load Elevation and Associated
Liver Disease/Cancer-In HBV (the
REVEAL-HBV) Study Group. Pre-
dicting cirrhosis risk based on the
level of circulating hepatitis B viral
load.. Gastroenterology 2006; 130:
678686.
16 Kronenberger B, Zeuzem S, Sarrazin
C et al. Dynamics of apoptotic activ-
ity during antiviral treatment of
patients with chronic hepatitis C.
Antivir Ther 2007; 12: 779787.
17 Hotchkiss RS, Strasser A, McDunn
JE, Swanson PE. Cell death. N Engl J
Med 2009; 361: 15701583.
18 Farnik H, Lange CM, Hofmann WP
et al. Nucleos(t)ide analogue treat-
ment reduces apoptotic activity in
patients with chronic hepatitis B. J
Clin Virol 2011; 52: 204209.
19 Lau GK, Wang FS. Uncover the
immune biomarkers underlying hep-
atitis B e antigen (HBeAg) serocon-
version: a need for more translational
study. J Hepatol 2012; 56: 753755.
20 Lang T, Lo C, Skinner N, Locarnini S,
Visvanathan K, Mansell A. The hep-
atitis B e antigen (HBeAg) targets
and suppresses activation of the
toll-like receptor signaling pathway.
J Hepatol 2011; 55: 762769.
21 Serpaggi J, Carnot F, Nalpas B et al.
Direct and indirect evidence for the
reversibility of cirrhosis. Hum Pathol
2006; 37: 15191526.
22 Marcellin P, Heathcote EJ, Buti M et al.
Tenofovir disoproxil fumarate versus
adefovir dipivoxil for chronic hepatitis B.
N Engl J Med 2008; 359: 24422455.
2012 Blackwell Publishing Ltd
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