Journal of Viral Hepatitis, 2012, 19, 732743 doi:10.1111/j.1365-2893.2012.01600.

Randomized clinical trial: efficacy and safety of telbivudine and

lamivudine in treatment-nave patients with HBV-related
decompensated cirrhosis
H. L.Y. Chan,1 Y. C. Chen,2 E. J. Gane,3 S. K. Sarin,4 D. J. Suh,5 T. Piratvisuth,6 B. Prabhakar,7
S. G. Hwang,8 G. Choudhuri,9 R. Safadi,10 T. Tanwandee,11 A. Chutaputti,12 C. Yurdaydin,13
W. Bao,14 C. Avila15 and A. Trylesinski15 1Department of Medicine and Therapeutics, The Chinese University of Hong Kong,
Hong Kong, China; 2Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan; 3Liver Unit,
Auckland City Hospital, Auckland, New Zealand; 4Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India; 5Department of
Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; 6NKC Institute of Gastroenterology and Hepatology,
Songklanagarind Hospital, Prince of Songkla University, Hat Yai, Thailand; 7Osmania Medical College and General Hospital, Hyderabad, India;
8
Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea; 9Sanjay Gandhi Post Graduate Institute of Medical
10 11
Sciences, Lucknow, India; Holy Family Hospital, Nazareth & Hadassah Medical Center, Jerusalem, Israel; Siriraj Hospital, Bangkok, Thailand;
12 13 14
Phramongkutklao Hospital, Bangkok, Thailand; University of Ankara Medical School, Ankara, Turkey; Novartis Pharmaceuticals Corporation, East
15
Hanover, NJ, USA; and Novartis Pharma AG, Basel, Switzerland

Received 2 November 2011; accepted for publication 4 January 2012

SUMMARY. Patients with decompensated cirrhosis owing to
chronic hepatitis B viral (HBV) infection have a high mor-
bidity/mortality rate, and the treatment remains a challenge.
We studied the safety and efficacy of telbivudine and lami-
vudine in such patients. This noninferiority, double-blind
trial randomized 232 treatment-naive patients with decom-
pensated HBV (1:1) in 80 academic hospitals to receive
once-daily telbivudine 600 mg or lamivudine 100 mg for
104 weeks. Primary composite endpoint was proportion of
patients with HBV DNA <10 000 copies/mL, normal ala-
nine aminotransferase (ALT) and Child-Turcotte-Pugh score
improvement/stabilization at week 52. Response rates using
a post hoc modified endpoint (HBV DNA <300 copies/mL
[57 IU/mL] and ALT normalization) in intent-to-treat anal-
ysis (missing = failure) were 56.3% vs 38.0% after 76 weeks
(P = 0.018) and 45.6% vs 32.9% after 104 weeks (P =
0.093) for telbivudine vs lamivudine. Telbivudine treatment
was an independent predictive factor for HBV DNA
<300 copies/mL and ALT normalization (P = 0.037).
Response rates with protocol-defined composite endpoint in
intent-to-treat analysis (M = F) were 56.2 vs 54.0% (non-
inferiority not achieved) and 39.1% vs 36.4% (noninferiority
achieved) in telbivudine and lamivudine groups at 52 and
104 weeks. Telbivudine treatment was associated with a
significant improvement in glomerular filtration rate com-
pared to lamivudine treatment and was also associated with
a trend for improvement in survival (87% vs 79%). No cases
of lactic acidosis were reported. Telbivudine compared to
lamivudine was associated with a higher rate of patients
with both viral suppression and ALT normalization, a trend
towards a higher rate of survival and significant improve-
ment in glomerular filtration.
Keywords: chronic hepatitis B, decompensated hepatitis, tel-
bivudine.

Abbreviations: ALT, normal alanine aminotransferase; CHB, INTRODUCTION

chronic hepatitis B; CTP, Child-Turcotte-Pugh; eGFR, estimated
glomerular filtration rate; HBeAg, hepatitis B e antigen; HBsAg,
hepatitis B surface antigen; HBV, hepatitis B viral; MDRD, modifi-
cation of diet in renal disease; MELD, model for end-stage liver
disease.
Correspondence: Dr Henry Lik-Yuen Chan, Department of Medicine
and Therapeutics, The Chinese University of Hong Kong, 9/F Prince
of Wales Hospital, 3032 Ngan Shing Street, Shatin, Hong Kong
SAR, China. E-mail: hlychan@cuhk.edu.hk
Liver cirrhosis is the end stage of the natural history of
chronic hepatitis B (CHB) virus (HBV) infection with a high
incidence of complications including hepatocellular carci-
noma and decompensation of liver functions. CHB is the
major cause of liver-related mortality with more than 1 mil-
lion deaths each year from either hepatocellular carcinoma or
decompensated cirrhosis. Without treatment, decompensated
CHB in patients with HBV-related cirrhosis is associated with

 2012 Blackwell Publishing Ltd


a survival rate of 14% at 5 years [1]. Although liver trans-
plantation is the accepted therapeutic option for decompen-
sated cirrhosis, access to this treatment is restricted by the
lack of sufficient donor organs and prohibitive costs [2].
In contrast to decompensated CHB, survival in compen-
sated CHB is excellent, approaching 85% after 5 years,
which is similar to other types of compensated cirrhosis [1].
Therefore, therapies that can rescue decompensated CHB
could improve survival and remove the need for liver
transplantation.
The primary goal of antiviral therapy in CHB is sustained
viral suppression, preferably to undetectable levels of serum
HBV DNA by polymerase chain reaction (PCR). The
achievement of this endpoint can reduce necroinflammation,
halt fibrosis progression and prevent the development of
cirrhosis. Sustained viral suppression also improved out-
comes in patients with established cirrhosis. Lamivudine was
the first oral nucleoside demonstrating viral suppression,
hepatic function stabilization/improvement and morbidity
reduction in HBV-related decompensated cirrhosis [36].
When compared to untreated historical controls, survival of
nontransplanted patients with decompensated cirrhosis
treated by lamivudine improved [7]. Emergence of drug
resistance reduced the clinical benefit of lamivudine in end-
stage liver disease [8]. Early add-on therapy with adefovir
helped patients with lamivudine resistance, but its use in
decompensated patients was limited by nephrotoxicity [9].
Recent results indicated the new nucleoside/nucleotide
analogues entecavir and tenofovir were effective in treating
decompensated HBV cirrhosis [1012].
Most patients with decompensated cirrhosis have some
functional renal insufficiency, related to hepatorenal syn-
drome a condition associated with a high mortality [13].
This may be exacerbated by prerenal (overdiuresis, sepsis)
and renal injury (HBV-related glomerulonephritis and
nephrotoxicity from concomitant medications). Adefovir and
tenofovir are associated with direct renal injury, and ente-
cavir has shown an increased risk of lactic acidosis when
used in decompensated patients [11,1417].
Despite a dramatic reduction in viral load in the treated
patients, 2025% of the HBV-decompensated cirrhotic
patients still died or required liver transplantation within the
first 6 months of treatment [11]. There is no clear expla-
nation for the deterioration of liver function despite effective
antiviral therapy. However, it has been shown that patients
who developed this severe outcome have a higher viral load
assessed by serum HBV DNA, a higher level of serum bili-
rubin and a higher serum creatinine level. Thus, patients
with HBV-decompensated cirrhosis still have a mortality
risk, and treatment is a matter of urgency. In addition, the
use of nucleoside/nucleotide analogue in HBV-decompen-
sated cirrhotic patients is more challenging with a risk of
increased toxicity in comparison with patients with well-
compensated liver disease. These patients frequently have an
impaired renal function, the dosing of nucleoside/nucleotide
 2012 Blackwell Publishing Ltd
Telbivudine for decompensated HBV cirrhosis 733
analogue should be adapted to renal clearance, and the risk
of overdosing and renal toxicity is increased. Overall toxicity
can be increased owing to the impaired liver and renal
function of these patients in association with a high bilirubin
level. This might explain the lactic acidosis complications
observed in patients with decompensated liver cirrhosis
treated with entecavir [15]. Thus, HBV-decompensated cir-
rhotic patients need to be treated rapidly with a potent
nucleoside/nucleotide analogue treatment able to rapidly
decrease viral load and without toxicity.
Independent of serum levels of alanine aminotransferase
(ALT) and HBV DNA, current guidelines recommend an oral
nucleoside/nucleotide analogue for patients with decom-
pensated cirrhosis to improve/stabilize liver disease and
delay the need of liver transplantation [18,19]. These rec-
ommendations are largely based upon open-label studies of
lamivudine and adefovir [2023].
Treatment options remain limited in HBV-related decom-
pensated cirrhosis with a need for well-tolerated antiviral
treatments inducing rapid viral suppression and improving
clinical outcomes in these difficult-to-treat patients. In CHB
patients with compensated cirrhosis, telbivudine treatment
has demonstrated greater antiviral and clinical efficacy than
lamivudine [24,25]. The aims of this study were to evaluate
the clinical and virologic outcomes and safety of telbivudine
and lamivudine treatment in decompensated CHB patients.
PATIENTS AND METHODS
Design overview
This multicenter, phase 3, prospective, randomized, double-
blind clinical trial had a main objective to compare the
clinical efficacy of telbivudine vs lamivudine in adults with
decompensated CHB at 52 weeks and confirmed the findings
at 104 weeks.
Written informed consent was obtained from each patient.
The protocol was conducted in accordance with the Decla-
ration of Helsinki and approved by each local independent
ethics committee. This trial is registered with ClinicalTri-
als.gov, number NCT00076336.
Setting and participants
The trial was conducted in 80 medical academic centres in
21 countries. Patients were eligible to participate if between
18 and 70 years of age, had documented decompensated
CHB (defined by a clinical history compatible with decom-
pensated CHBrelated cirrhosis, Child-Turcotte-Pugh [CTP]
score 7, evidence of hepatic cirrhosis or portal hyperten-
sion), serum HBV DNA level 5 log10 copies/mL, not preg-
nant or breastfeeding, not coinfected with hepatitis C virus,
hepatitis D virus or human immunodeficiency virus (HIV).
Patients ever treated with lamivudine, adefovir or any
investigational anti-HBV nucleoside/nucleotide analogue or
734 H. L.Y. Chan et al.
who had received interferon or other immunomodulatory
treatment within the previous 12 months were excluded.
Randomization and interventions
Eligible patients were randomized centrally (1:1 ratio) to
receive 600 mg of telbivudine or 100 mg of lamivudine once
daily as oral tablets. No treatment intensification was planned.
Treatment assignments were stratified according to
screening CTP score (9 or <9) and screening serum ALT
(within normal values or >1 ULN). This stratification
assured similar degrees of hepatic insufficiency and liver
inflammation in both groups.
Screening and baseline/follow-up visits included physical
examination, blood pregnancy test if appropriate, blood
chemistry tests, liver function tests, serum alpha-fetoprotein,
prothrombin time/international normalized ratio (INR), CTP
score, creatinine clearance, HBV serologies (hepatitis B sur-
face antigen [HBsAg], antibodies against HBsAg [anti-HBs],
hepatitis B e antigen [HBeAg], antibodies against HBeAg [anti-
HBe]) and serum HBV DNA. Serum HBeAg, anti-HBe, HBsAg,
anti-HBs and ALT levels were assessed at central reference
laboratories (Quintiles, Durham, NC, USA) using standard
methods. Serum for HBV DNA was analysed at the central
reference laboratories using the COBAS Amplicor HBV Mon-
itor (Roche, Basel, Switzerland) PCR assay with lower limit
of quantification at 300 copies/mL (57 IU/mL) (Roche
Molecular Diagnostics, Pleasanton, CA, USA).
The cumulative rate of viral breakthrough and genotypic
resistance was evaluated using an approach similar to that for
other antiviral products (e.g., entecavir, adefovir), including
only the patients who were PCR negative at the end of the
previous year. Indeed, according to the current clinical prac-
tice and guidelines, PCR-positive patients are not allowed to
continue therapy, and the treatment regimen is recommended
to be intensified with the addition of a second antiviral drug.
Following these guidelines, the 2-year resistance analysis in-
cluded patients who did not have confirmed genotypic resis-
tance during the first year and who had a confirmed decrease
in serum HBV DNA from baseline by at least 1 log10 with
respect to baseline in two consecutive measurements and had
confirmed viral rebound of >1 log above nadir at week 104 or
at the last available assessment (for patients who discontinued
treatment before week 104). Resistance for first year was
calculated considering all ITT patients. DNA sequencing was
performed at an independent laboratory (Delft Diagnostic
Laboratory, Rijswijk, the Netherlands). The complete RT
domain of the HBV polymeraseencoding gene was amplified
by PCR, using the Expand High Fidelity PCR system (Roche
Applied Science, Indianapolis, IN, USA). Pairwise sequence
comparisons of the HBV polymerase RT regions at baseline (on
frozen samples) and at the time of virologic breakthrough
were performed.
The HBV sequencing analysis was also performed for
patients with nonresponders to a predefined composite
endpoint at week 52 and at week 104. The composite end-
point was defined as HBV DNA <300 copies/mL and ALT
normalized. The nonresponders for a particular visit were
the patients who failed to achieve HBV DNA <300 copies/
mL, and ALT normalized at that visit.
At each visit, the investigator rated the compliance to
treatment (total drug received/total drug expected 100) by
a 3-point scale: good (80%), fair (7965%) and poor
(65%). The overall compliance was defined as compliant
when a patient had 80% on-treatment visits rated as good
by investigators.
Outcome and follow-up
The primary protocol-defined efficacy endpoint was a com-
posite endpoint termed clinical response, defined as the
achievement of all the following efficacy criteria: serum HBV
DNA <10 000 copies/mL (1900 IU/L), normal serum ALT
level (ALT <1 ULN), improvement in/stabilization of CTP
score. Primary and secondary analyses were performed at
weeks 52 and 104.
Guidelines for CHB management and treatment from the
major liver associations were recently updated to include
PCR nondetectability (<300 copies/mL [57 IU/mL]) as the
primary goal of antiviral therapy in CHB [18,19,26].
Therefore, the study team proposed a post hoc analysis to
reflect this new endpoint. This modified composite endpoint
was defined as the achievement of both HBV DNA
<300 copies/mL and serum ALT normalization (applicable
for patients with ALT 1 ULN at baseline).
Secondary efficacy endpoints included the individual com-
ponents of the protocol-defined efficacy endpoint, proportion
of patients with HBV DNA <300 copies/mL, proportion of
patients with ALT normalization (ALT <1 ULN), frequency of
virologic breakthrough, time to virologic breakthrough and
rates of genotypic resistance and patient survival. Virologic
breakthrough was defined as a confirmed HBV DNA increase
in 1 log10 above nadir (lowest postbaseline HBV DNA level)
in patients with a confirmed treatment response (two con-
secutive 1 log10 HBV DNA decrease below baseline).
Safety assessments consisted of collecting all adverse events
and serious adverse events, with their severity and relation-
ship to study drug. This included the regular monitoring of
haematology, blood chemistry and urine, and regular
assessments of vital signs, physical condition and body weight.
Statistical analysis
With a noninferiority margin set at )10% and assumed the
proportion of clinical response of 40% for lamivudine and
60% for telbivudine at week 52 (based upon historical data
and adjusted for 20% drop out rate during first year), it was
calculated that 120 subjects per treatment group would be
needed to show noninferiority (one-sided alpha risk, 5%;
power, 90%) of telbivudine group.
 2012 Blackwell Publishing Ltd

The main analysis of the primary endpoint was performed
on the intent-to-treat analysis set, which included all ran-
domized patients who received at least one dose of study
treatment. Patients with missing data for the primary end-
point were considered treatment failures in the intent-
to-treat analysis. Missing data were treated as failure for
discrete endpoints, and the last available assessment was
used for continuous endpoints.
The difference in the proportions of clinical response
between treatment groups and its confidence interval was
estimated according to the CochranMantelHaenszel
method, adjusting for baseline strata. The hypothesis of
noninferiority of the two treatment groups was tested by
comparing the lower limit of the one-sided 95% confidence
interval (CI) of the difference of proportions between groups
to the margin set at )10%.
Multivariate analyses was performed using a logistic
regression model (backward selection method with P = 0.10
for selection of variables) to evidence predictive factors of
success for modified composite clinical endpoint (patients
with both HBV DNA <300 copies/mL and serum ALT nor-
malization) and predictive factors of success for HBV DNA
undetectable at week 104.
Survival rate was assessed by KaplanMeier analysis.
The safety population included patients who received at
least one dose of the study drug. The safety analysis was
based on the adverse events, laboratory values, physical
examinations and vital signs.
Modification of diet in renal disease (MDRD) and CKP-EPI
(Chronic Kidney DiseaseEpidemiology Collaboration) for-
mulae were used for the calculation of estimated glomerular
filtration rate (eGFR) [27,28]. LS means for eGFR and
serum creatinine levels were calculated at each post-
baseline time point with ANCOVA model including treat-
ment, country and baseline values; for baseline, the
ANOVA model included treatment and country as
cofactors.
The analyses were performed using SAS version 9.1 (SAS
Institute, Inc., Cory, NC, USA).
RESULTS
Patient disposition at baseline
Of the 232 randomized patients, one patient in the telbivu-
dine group discontinued the study prior to commencing
treatment (excluded from intent-to-treat and safety popula-
tions) and three patients (one telbivudine treated and two
lamivudine treated) were excluded from the intent-to-treat
population owing to no HBV DNA assessments after baseline
(Fig. 1). The intent-to-treat population consisted of 228
patients: 114 in the telbivudine group and 114 in the
lamivudine group. The main cause for study discontinuation
was death (10% in telbivudine group vs 15% in lamivudine
group at week 104) (Fig. 1).
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Telbivudine for decompensated HBV cirrhosis 735
Patient characteristics at baseline
Baseline characteristics of the intent-to-treat population are
described in Table 1. The treatment groups were balanced at
baseline for demographic and disease characteristics.
Efficacy assessments
Composite efficacy response
In the intent-to-treat population, the proportion of patients
achieving the primary efficacy endpoint for clinical
response (defined as both HBV DNA <300 copies/mL and
serum ALT normalization) was always higher in telbivudine-
treated compared to lamivudine-treated patients from 24 to
104 weeks (Fig. 2 and Table 2). At 76 weeks of treatment,
the clinical response rate was significantly higher in
telbivudine-treated patients vs lamivudine-treated patients.
Using a multivariate analysis, the following predictive
factors of achieving this new combined endpoint at week
104 were identified: treatment with telbivudine (odds-ratio
[OR] = 2.09; 95% CI, 1.054.18; P = 0.037) and week 24
HBV DNA <300 copies/mL (OR = 3.48; 95% CI, 1.428.53;
P = 0.0064) (Table 3).
Virologic response
The proportion of patients with HBV DNA <300 copies/mL
was numerically higher for telbivudine groups than for
lamivudine groups at 52 and 104 weeks (Table 2).
In a multivariate analysis, predictive factors for achieving
undetectable HBV DNA at week 104 were baseline HBV
DNA <7 log10 copies/mL (OR = 2.29; 95% CI, 1.304.06;
P = 0.0044) and HBeAg negative status (OR = 0.41; 95%
CI, 0.230.74; P = 0.0032) (Table 3).
Rates of 2-year cumulative virologic breakthrough
(1 log10 above nadir) were 28% for telbivudine-treated
patients and 39% for lamivudine-treated patients. The
median time to initial breakthrough was 400 days for
telbivudine-treated patients and 367 days for lamivudine-
treated patients. No significant difference in survival at week
104 was observed between patients with or without viro-
logic breakthrough both in telbivudine-treated patients
(P = 0.23) and in lamivudine-treated patients (P = 0.22).
Genotypic resistance
Rates of cumulative genotypic resistance were 11% (n = 13)
in telbivudine-treated patients and 14% (n = 16) in lami-
vudine-treated patients during year 1; the new genotypic
resistance rates during year 2 were 17.4% (n = 12) in tel-
bivudine-treated patients and 25% (n = 17) in lamivudine-
treated patients. Cumulatively, 27% and 36% patients
developed genotypic resistance during the 2-year period, in
the telbivudine and lamivudine groups, respectively.
Patients with HBV DNA <300 copies/mL at week 24 were
less likely to develop genotypic resistance after 2 years of
treatment. Pairwise sequence comparisons of the HBV
736 H. L.Y. Chan et al.
Randomization of 232 patients with
decompensated chronic hepatitis B infection
116 patients allocated to telbivudine group
7 deaths up to week 52
12 study discontinuations up to week 52
Patient/investigator request (5)
Adverse event (2)
Liver transplantation (2)
Lost to follow-up (1)
No compliance (1)
No study drug received (1)
Week 52:
97 patients on telbivudine
114 patients in intent-to-treat population
12 deaths up to week 104
34 study discontinuations up to week 104
Virologic breakthrough (10)
Patient/investigator request (8)
Treatment failure (4)
Adverse event (4)
Lost to follow-up (4)
Liver transplantation (3)
Non compliance (1)
Week 104
70 patients on telbivudine
114 patients in intent-to-treat population
115 patients in safety population
Fig. 1 Disposition of participants of the study.
polymerase RT regions at baseline and at the time of viro-
logic breakthrough showed that the conversion from M to I
in position 204 was associated with virologic breakthrough
in the telbivudine-treated patients and remained the key
signature mutation selected by telbivudine. No M204V
mutation was reported in the telbivudine-treated popula-
tion. In the lamivudine-treated group, a conversion from M
to I or V remained the signature mutations responsible for
genotypic resistance.
Genotypic resistance at weeks 52 and 104 was analysed
for the nonresponders of the composite endpoint (defined as
patients who failed to achieve both HBV DNA <300 copies/
mL and ALT normalization) at week 52 and at week 104,
respectively (Table 4). At week 52, among nonresponders,
an absence of response was related to genotypic resistance
for 30% of patients of telbivudine group and 31% of patients
of lamivudine group. At week 104, the higher response rate
for the clinical composite response endpoint in telbivudine vs
lamivudine groups could be explained by the numerically
lower rate of resistance in telbivudine nonresponders group
compared to lamivudine nonresponders group (22% vs 30%,
respectively; P = 0.36) although the difference was not
statistically significant (Table 3).
116 patients allocated to lamivudine group
10 deaths up to week 52
12 study discontinuations up to week 52
Patient/investigator request (3)
Adverse event (3)
Liver transplantation (1)
Lost to follow-up (3)
Virologic breakthrough (1)
Creatinine clearance <30 or dialysis (1)
Week 52:
94 patients on lamivudine
114 patients in intent-to-treat population
17 deaths up to week 104
37 study discontinuations up to week 104
Virologic breakthrough (16)
Patient/investigator request (6)
Treatment failure (4)
Adverse event (4)
Lost to follow-up (3)
Liver transplantation (3)
Creatinine clearance <30 or dialysis (1)
Week 104
62 patients on lamivudine
114 patients in intent-to-treat population
116 patients in safety population
Protocol-defined composite efficacy response
The original primary efficacy endpoint for clinical response
(composite endpoint defined as serum HBV DNA
<10 000 copies/mL, normal serum ALT level and
improvement in or stabilization of CTP score) was achieved
at week 52 in the intent-to-treat population for 56.2% of
patients in the telbivudine group vs 54.0% in the lamivudine
group (Table 2). At week 104, 39.1% of patients in the
telbivudine group had a clinical response compared with
36.4% in the lamivudine group. Consequently, demonstra-
tion of noninferiority was not achieved at 52 weeks (primary
endpoint), but was achieved at 104 weeks (confirmatory
endpoint) (Table 2).
The CTP score was stabilized/improved for most patients
in both groups at week 104 (Table 2).
HBeAg loss and seroconversion
Among patients with baseline-positive HBeAg, cumulative
HBeAg seroconversion occurred in 25.5% (13/51) and
24.4% (11/45) in telbivudine and lamivudine groups at
week 52 and in 27.5% (14/51) and 35.6% (16/45) at week
104, respectively.
 2012 Blackwell Publishing Ltd
 Telbivudine for decompensated HBV cirrhosis 737

Table 1 Demographic and clinical char-

acteristics of the patients (intent-to-treat Characteristics Telbivudine Lamivudine All
population) Number of patients 114 114 228
Age, mean (SD), year 49.6 (10.9) 51.9 (10.0) 50.8 (10.5)
Sex, n (%) of male 87 (76.3) 81 (71.1) 168 (73.7)
Geographic origin, n (%)
Asian 74 (64.9) 74 (64.9) 148 (64.9)
Middle eastern/Indian 28 (24.6) 21 (18.4) 49 (21.5)
subcontinental
Caucasian 10 (8.8) 17 (14.9) 27 (11.8)
Other 2 (1.8) 2 (1.8) 4 (1.8)
HBeAg negative*, n (%) 63 (55.3) 68 (59.6) 131 (57.5)
HBV DNA, mean (SD), 7.6 (1.9) 7.6 (1.9) 7.6 (1.9)
log10 copies/mL
Serum ALT, IU/mL
Mean (SD) 75.1 (54.4) 84 (87.8) 79.4 (72.9)
1 ULN, n (%) 31 (27.2) 30 (26.3) 61 (26.8)
>1 ULN, n (%) 83 (72.8) 84 (73.7) 167 (73.2)
CTP scores
Mean (SD) 8.1 (1.6) 8.5 (1.8) 8.3 (1.7)
<7, n (%) 11 (9.6) 7 (6.1) 18 (7.9)
79, n (%) 81 (71.1) 74 (64.9) 155 (68.0)
>9, n (%) 22 (19.3) 33 (28.9) 55 (24.1)
MELD scores
Mean (SD) 14.7 (3.7) 15.5 (4.6) 15.1 (4.2)
56, n (%) 11 (9.6) 7 (6.1) 18 (7.9)
79, n (%) 81 (71.1) 74 (64.9) 155 (68.0)
1018, n (%) 22 (19.3) 33 (28.9) 55 (24.1)
Serum creatinine, 71 71 71
median, mg/dL
Genotype, n (%)
A 6 (5.3) 11 (10) 17 (7.5)
B 26 (22.8) 15 (13.2) 41 (18.0)
C 48 (42.1) 58 (50.9) 106 (46.5)
D 33 (28.9) 29 (25.4) 62 (27.2)
Other 1 (0.9) 1 (0.9) 2 (0.9)

ALT, alanine aminotransferase; CTP, Child-Turcotte-Pugh; MELD, model for end-

stage liver disease. *HBeAg was undetermined in one patient of lamivudine group.
% of patients with clinical response

80
Telbivudine Lamivudine
Survival of patients
(HBV DNA < 300 copies/mL

70 Survival rates for patients in the telbivudine group showed a

and ALT normalization)

60 54.7% 56.3% trend to be consistently higher over the entire study period
50.6%
50 P = 0.49 45.6% than those in the lamivudine group (P = 0.16; log-rank test)
40
49.3% P = 0.018 (Fig. 3).
44.8% P = 0.093
38.0%
30
32.9% Treatment compliance
20
Rates of overall compliance to treatment were high and not
10 different between groups: 98% (113/115) in telbivudine
0 group and 98% (114/116) in lamivudine group.
0 24 52 76 104
Weeks
Safety
Fig. 2 Composite endpoint for clinical response (patients
with both HBV DNA <300 copies/mL and ALT [alanine There were no significant differences between the treatment
aminotransferase] normalization) over 2 years groups for adverse events that led to study drug discontin-
(intent-to-treat analysis; missing = failure). uation. Only one serious event (myopathy) was considered

 2012 Blackwell Publishing Ltd

 738
H. L.Y. Chan et al.

Table 2 Clinical response and biochemical and virologic parameters after 52 and 104 weeks of telbivudine or lamivudine treatment (intent-to-treat population; miss-
ing = failure)

52 weeks 104 weeks

LdT LAM LdT LAM

Parameters n = 114 n = 114 Difference* (95% CI) P n = 114 n = 114 Difference* (95% CI) P

Patients with clinical response,, n (%) 65 (56.2) 62 (54.0) 2.2 ()10.9; 15.3) 0.74 45 (39.1) 42 (36.4) 2.7 ()9.96; 15.45) 0.67
Patients achieving new endpoint,, n (%) 46 (54.7) 42 (49.3) 5.4 ()9.97; 20.9) 0.49 38 (45.6) 28 (32.9) 12.7 ()2.1; 27.5) 0.093
Individual endpoints**
HBV DNA <10 000 copies/mL, n (%) 85 (74.6) 82 (71.9) 2.6 ()9.4; 14.2) 0.69 65 (57.0) 55 (48.2) 8.8 ()4.5; 21.8) 0.20
HBV DNA <300 copies/mL, n (%) 74 (64.9) 70 (61.4) 3.5 ()9.1; 16.1) 0.62 56 (49.1) 45 (39.5) 9.6 ()3.5; 22.5) 0.15
Serum ALT normalization, n (%) 54 (65.1) 57 (67.9) )2.8 ()17.2; 11.8) 0.73 51 (61.4) 44 (52.4) 9.1 ()6.2; 24.1) 0.25
CTP score, n (%)
Improvement (decrease 2) 36 (31.6) 44 (38.6) )7.0 ()19.5; 5.4) 0.28 44 (38.6) 46 (40.4) )1.8 ()14.5; 11.0) 0.83
Stabilization (absolute change 1) 60 (52.6) 52 (45.6) 7.0 ()6.2; 19.9) 0.31 42 (36.8) 38 (33.3) 3.5 ()9.0; 15.9) 0.61
Worsening (increase 2) 18 (15.8) 18 (15.8) 0.0 ()9.7; 9.8) 1.0 28 (24.6) 30 (26.3) )1.8 ()13.3, 9.7) 0.80

ALT, alanine aminotransferase; CI, confidence interval; CTP score, Child-Turcotte-Pugh score; LdT, telbivudine; LAM, lamivudine. *LdT minus LAM. P-value for
superiority testing. Composite endpoint defined as: patients with HBV DNA <10 000 copies/mL, normal serum ALT and improvement in/stabilization of CTP score. For
the proportion estimates, the treatment difference and the 95% CI were calculated by CochranMantelHaenszel method adjusting for baseline strata. New composite
endpoint defined as: patients with HBV DNA <300 copies/mL and serum ALT normalization (applicable for patients with elevated ALT at baseline: n = 83 in LdT group and
n = 84 in LAM group). **Exact method. For patients with elevated serum ALT at baseline (n = 83 in LdT group and n = 84 in LAM group); patients with normal serum
ALT regardless baseline ALT level were 67.8% vs 70.9% at Week 52 and 63.7% vs 56.2% in LdT (n = 114) and LAM (n = 114) groups, respectively.

 2012 Blackwell Publishing Ltd

 Telbivudine for decompensated HBV cirrhosis 739

Table 3 Multivariate analyses of predictive baseline factors Hepatocellular carcinoma was reported during the 2-year
and week 24 HBV DNA level for efficacy endpoints at Week period in 17/115 telbivudine-treated patients (15%) and 18/
104 116 lamivudine-treated patients (16%). When the cases of
hepatocellular carcinoma diagnosed during the first year
Multivariate analysis were excluded, the proportions of patients with diagnosis of
Odds-ratios hepatocellular carcinoma were 3/115 (3%) and 8/116 (7%),
(95% CI)* P-value respectively.
The serum creatinine levels were analysed over 104-week
Efficacy endpoint: PCR negative + ALT normalization
Telbivudine (n = 83) 2.092 (1.0474.181) 0.0367 on-treatment period. In year 1, the serum creatinine levels in
vs lamivudine both telbivudine and lamivudine groups increased; in year 2,
(n = 84) serum creatinine levels decreased in telbivudine group to the
Baseline HBeAg 0.536 (0.2611.103) 0.0905 end of on-treatment period, while it continued increasing in
positive (n = 68) vs lamivudine group (P = 0.05 at week 60; P = 0.04 at week
negative (n = 98) 68; P = 0.08 at week 84) (Fig. 4A). Lamivudine-treated
Week 24 HBV DNA 3.483 (1.4218.534) 0.0064 patients showed a steady decline in MDRD-eGFR, whereas
<300 (n = 117) eGFR steadily improved in telbivudine-treated patients with
vs 300 copies/mL the greatest improvement seen during the second year of
(n = 39) treatment. The eGFR was significantly increased in the tel-
Efficacy endpoint: PCR negative bivudine group compared to the lamivudine group from
Telbivudine (n = 114) 1.530 (0.8692.696) 0.1409 week 60 of treatment to end of the study (P < 0.01 at week
vs lamivudine 60; P < 0.01 at week 68; P = 0.01 at week 84) (Fig. 4B).
(n = 114) The eGFR by CKD-EPI formula in both telbivudine and
Baseline MELD >22 0.244 (0.0471.254) 0.0911 lamivudine groups decreased during year 1, but at year 2, it
(n = 10) vs 22 started to increase in telbivudine group to the end of the
(n = 218) study, while it continued decreasing in lamivudine group to
Baseline HBeAg 0.414 (0.2310.744) 0.0032 the end of the study (P = 0.08 at week 60; P = 0.06 at week
positive (n = 96) vs 68; P = 0.07 at week 84) (Fig. 4C). The two curves were
negative (n = 131)
close to each other during year 1, while they separated with
Baseline HBV DNA <7 2.292 (1.2954.057) 0.0044
each other during year 2. This trend was similar as the
(n = 103) vs 7
results with the MDRD formula.
log10 copies/mL
There was 1 telbivudine-treated patient of 63 year-old
(n = 125)
with baseline eGFR <60 mL/min/1.73 m2 according to
CKD-EPI (44.9 mL/min/1.73 m2) and MDRD formula
ALT, alanine aminotransferase; CTP, Child-Turcotte-Pugh.
(46.5 mL/min/1.73 m2) at baseline. At the end of the
*Variables considered were treatment, age, race, gender,
baseline BMI, ALT, HBV DNA, HBeAg, CTP, MELD, genotype treatment, his serum creatinine level was reduced from 1.6
and week 24 HBV DNA. Only variables kept in the final to 0.9 mg/dL, and eGFR was improved to 90.2 mL/min/
model (P = 0.10 to stay) are presented in the table. 1.73 m2 (MDRD) or 89.8 mL/min/1.73 m2 (CKD-EPI). The

11 missing data. patient had ascites. There were four lamivudine-treated

by the investigator to be related to study treatment
(telbivudine group), which was untreated and resolved
completely while continuing on study drug. No case of
rhabdomyolysis or lactic acidosis was reported.
During the 104 weeks of the study and poststudy follow-
up (4 months after completion of the study), deaths occurred
in 15 (16%) patients treated with telbivudine and 22
patients (22%) treated with lamivudine. During the first
6 months of the study, four deaths occurred in the telbivu-
dine group and 10 in the lamivudine group. No death was
related to study drug. In the telbivudine group, the most
frequent causes of death were sepsis/septic shock, hepatic
failure and/or hepatorenal syndrome. In the lamivudine
group, the most frequent causes of death were related to
hepatic cirrhosis, haemorrhage of oesophageal varices or
gastrointestinal haemorrhages.
patients with baseline eGFR <60 mL/min/1.73 m2 (CKD-EPI
and MDRD formulae). Only one increased to 6090 mL/
min/1.73 m2 during the on-treatment period, and he did not
have ascites.
Improvement from baseline to end of study of eGFR
(MDRD formula) in telbivudine group correlated significantly
with the improvement in liver function assessed by decrease
in model for end-stage liver disease (MELD) score (r = )0.19;
P = 0.040; Pearsons correlation test). No significant corre-
lation was observed between eGFR and liver function in
lamivudine group.
DISCUSSION
In this study, we compared the clinical efficacy of telbivudine
and lamivudine in treatment-naive patients with HBV-
related decompensated cirrhosis. In the initial study design,

 2012 Blackwell Publishing Ltd

740 H. L.Y. Chan et al.

Table 4 Analysis of resistance rates among the nonresponders for the composite endpoint (HBV DNA <300 copies/mL and
ALT normalization) at weeks 52 and 104 (ITT population)

Analysis at week 52 Analysis at week 104

Genotypic resistance at Genotypic resistance at

week 52 week 104
Nonresponders* Nonresponders*
n (%) n (%)
at week 52 at week 104
(n) No Yes (n) No Yes

Total 79 55 (70) 24 (30) 101 74 (73) 27 (27)

Telbivudine 37 26 (70) 11 (30) 45 35 (78) 10 (22)
Lamivudine 42 29 (69) 13 (31) 56 39 (70) 17 (30)
P-value 0.91 0.36

ALT, alanine aminotransferase. *Nonresponders are defined as patients who failed to achieve both HBV DNA <300 copies/mL
and ALT normalization. Chi-square test.

Fig. 3 Survival in patients with hepatitis B virus-related decompensated cirrhosis treated by lamivudine or telbivudine over
2 years (KaplanMeier analysis).

the primary efficacy endpoint was a composite endpoint
combining virologic response (HBV DNA <10 000 copies/
mL), biochemical response (normal serum ALT) and stabil-
ization of/improvement in decompensated cirrhosis. During
the study, however, technological advances in HBV DNA
quantitative assays reduced the lower limit to 300 copies/
mL, and recent studies of new nucleoside/nucleotide ana-
logues demonstrated that CTP score could not accurately
discriminate between different potent antivirals [11,16].
This was modified; hence, we defined a post hoc composite
primary endpoint, which took into account the higher sen-
sitivity of new HBV DNA assays and did not include the CTP
score. In multivariate analyses, telbivudine treatment was
an independent predictive factor for achieving both HBV
DNA <300 copies/mL and serum ALT normalization.
Results with the protocol-defined composite endpoint were
nevertheless of interest: demonstration of noninferiority of
telbivudine compared to lamivudine was not achieved at
week 52, but noninferiority was achieved at week 104.
Over the full study period, the survival rates were con-
sistently higher for patients treated with telbivudine vs
lamivudine. Virologic and biochemical results in the
telbivudine group at the end of the study showed higher
rates for HBV DNA <300 copies/mL, higher rates for ALT
normalization and lower rates for virologic breakthrough.
However, there was no statistical difference in these outcome
measures between the two treatment groups, possibly
related to the sample size.
The virologic inhibition (HBV DNA <300 copies/mL)
observed at 52 weeks in our study is consistent with data
from recent studies in treatment-naive patients with
decompensated cirrhosis treated by nucleoside/nucleotide
analogues, although direct comparisons are limited by
differences in patient population and study design. In the

 2012 Blackwell Publishing Ltd

 Telbivudine for decompensated HBV cirrhosis 741

(a) 0.88
0.87
0.86

Serum creanine, mg/dL

0.85
0.84
0.83
0.82
0.81
0.80 Telbivudine
0.79 Lamivudine

0.78
0 2 4 8 12 16 54 32 40 48 52 60 68 76 84 92 100 104
Weeks
(b) 110

108
eGFR, mL/min/1.73 m2

106
(CKD-EPI formula)

104

102

100

98
Telbivudine
96 Lamivudine

94
0 2 4 8 12 16 54 32 40 48 52 60 68 76 84 92 100 104
Weeks
(c) 100
99
eGFR, mL/min/1.73 m2

98
(MDRD formula)

97

96

95

94

93 Telbivudine

92 Lamivudine

91
0 2 4 8 12 16 54 32 40 48 52 60 68 76 84 92 100 104
Weeks

Fig. 4 Evolution of renal function by treatment groups over 2 years as assessed by: (a) serum creatinine (P = 0.05 at week
60; P = 0.04 at week 68; P = 0.08 at week 84); (b) estimated glomerular filtration rate (eGFR) as calculated by modification
of diet in renal disease (MDRD) formula (P < 0.01 at week 60; P < 0.01 at week 68; P = 0.01 at week 84); (c) eGFR as
calculated by CKD-EPI formula (P = 0.08 at week 60; P = 0.06 at week 68; P = 0.07 at week 84). Creatinine clearance
(CKP-EPI or MDRD formula) and serum creatinine levels were calculated at each time point with ANCOVA modelling
including treatment, country and baseline values as cofactors.

 2012 Blackwell Publishing Ltd

742 H. L.Y. Chan et al.
randomized open-label study of Liaw et al. [16], comparing
entecavir and adefovir, with a study population comparable
to ours, HBV DNA <300 copies/mL at 48 weeks was
achieved for 57% of patients treated with 1 mg daily of
entecavir vs 20% of patients treated with adefovir. Another
randomized double-blind study compared tenofovir, tenofo-
vir plus emtricitabine vs entecavir: HBV DNA <400 copies/
mL was achieved for 71%, 88% and 73% of patients,
respectively [11]. In this trial, the high proportions of
patients with virologic control were possibly explained by
lower CTP scores at inclusion, as well as a high proportion of
HBeAg negative patients and lower HBV DNA level, which
are positive predictors of achieving undetectable HBV DNA
[11].
The present study has some limitations mainly related to
statistical power. Study size was calculated assuming a
clinical response for 40% of patients in lamivudine group,
based on historical data [37]. The actual clinical response
observed in lamivudine group was much higher at 54%,
possibly reflecting recent advances in the medical manage-
ment of decompensated cirrhosis. Therefore, the study was
underpowered. Owing to the stringent inclusion criteria for
decompensated HBV infection, full recruitment was not
possible despite extension of recruitment to 2.5 years. There
was also a high expected loss of patients, consistent with the
severity of the liver disease. Of note, our study included a
high percentage of patients with genotype C, which is a
predictive factor of poor prognosis as compared to other
genotypes.
Patients who received lamivudine had a steady decline in
renal function as evidenced by the evolution of serum creat-
inine and eGFR (estimated by MDRD formula and CKD-EPI).
In contrast, renal function steadily improved in telbivudine-
treated patients, with the greatest improvement during the
second year of treatment. The three curves shown in Fig. 3
matched with each other, thus supporting that the changes in
eGFR in two treatment groups were actually triggered by the
changes in the serum creatinine levels. The improved eGFR
assessed by MDRD or CKD-EPI or serum creatinine levels in
the telbivudine-treated patients was consistent.
In contrast with the present study results, in the two
studies with tenofovir and entecavir in decompensated CHB,
there was no improvement in eGFR in either arm after up to
4 years with continuous entecavir treatment [11,16]. Renal
function is an important safety issue in decompensated end-
stage liver disease because most patients have some degree of
underlying renal insufficiency. In the study of Nair et al.,
33% of patients with end-stage liver disease had varying
renal impairment (creatinine clearance <70 mL/min);
moreover, renal function was shown to predict survival of
patients undergoing liver transplantation [29,30].
The explanation for the apparent benefit in improved
renal function remains speculative and is certainly multi-
factorial, possibly reflecting beneficial effects on liver func-
tion and/or lack of drug nephrotoxicity. A direct effect of
telbivudine on renal function, via improved renal blood flow
or tubular function cannot be excluded. Studies are planned
to further explore this effect. Although the potential
improvement in renal function and the improvement in liver
function assessed by MELD score appeared to be significantly
correlated, these results should be however interpreted
cautiously. Indeed, one of the parameters in the MELD score
is creatinine concentration. Therefore, the relationship
between creatinine-based eGFR improvement and liver
improvement remains uncertain.
The present study demonstrates that telbivudine is safe
and well tolerated in patients with decompensated CHB.
Adefovir use in decompensated cirrhosis has been limited by
the nephrotoxicity and relative weak antiviral potency of
this agent. Similarly, tenofovir, a more potent nucleotide
analogue than adefovir, is also associated with significant
nephrotoxicity in at-risk patient populations including those
with HIV infection or decompensated liver disease [31].
Entecavir has been associated with the life-threatening
complication of lactic acidosis, with the greatest risk in
patients with the poorest liver function [15,32].
In conclusion, in this 2-year study, the largest compara-
tive trial of two active nucleosides in patients with difficult-
to-treat HBV-related decompensated cirrhosis, telbivudine
was safe and well tolerated. Compared to lamivudine,
treatment with telbivudine for 104 weeks was associated
with a higher rate of patients with both viral suppression
and ALT normalization, a trend towards higher rate of
survival, similar stabilization of liver function and significant
improvement in calculated eGFR.
ACKNOWLEDGEMENTS
Declaration of personal interests: Henry L.Y. Chan was a
member of Advisory Boards and invited speaker for Bristol
Myers Squibb, Roche, Pharmasset, Abbott, Novartis and
Merck. Edward J. Gane was a member of Advisory Boards and
invited speaker for Roche, GSK, Pharmasset, Abbott, Novartis
and Merck. Seong Gyu Hwang received a research grant from
Idenix, Novartis, Bristol Myers Squibb, GSK, Bukwang, and
LG Life Sciences. Cihan Yurdaydin was on the speakers bu-
reau for Novartis, Bristol Myers Squibb, Gilead, Roche and a
member of Advisory Board for Bristol Myers Squibb, Gilead
and Merck. Yi Cheng Chen, Shiv K. Sarin, Dong Jin Suh,
Teerha Piratvisuth, Boddu Prabhakar, Gourdas Choudhuri,
Rifaat Safadi, Tawesak Tanwandee and Anuchit Chutaputti
have no conflict of interest to declare. Weibin Bao is an em-
ployee of Novartis Pharmaceuticals. Claudio Avila and Aldo
Trylesinski are employees of Novartis Pharma, AG. Declara-
tion of funding interests: This study was sponsored by Nov-
artis Pharma, AG. The sponsors were involved in the study
design and analysis of data. They provided financial support
for editorial assistance. Francis Beauvais from Scientific and
Medical Writing provided writing assistance, which was
provided by Novartis Pharma, AG.
 2012 Blackwell Publishing Ltd

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