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Department of Gastroenterology, Liver Center, 2Department of Clinical Epidemiology and Biostatistics, Asan Medical Center,
Seoul, Republic of Korea; 3Department of Internal Medicine, Haeundae Paik Hospital, Inje University College of Medicine,
Busan, Republic of Korea
153
Serum Assays
Before 2007, serum HBV-DNA levels were measured using a
hybrid capture assay (lower limit of detection, 20,000 IU/mL;
Digene Diagnostics, Gaithersburg, MD); thereafter, levels were
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Lim et al
Statistical Analysis
All patients who met the eligibility criteria at baseline were
included in the analyses.
To reduce the effect of treatment selection bias and potential confounding, propensity score-matching was performed.
The use of propensity scores and matching produced 2 groups
of similar patients except for the treatment of interest and deal
with extraneous differences that were confounding the results.23 Propensity score-matching analyses allow simultaneous
adjustment for many covariates in situations in which conventional multivariable models might not be appropriate owing
to the multiple confounders and rare outcomes.24 The propensity scores for each cohort (the overall cohort and subcohorts comprising patients without cirrhosis, those with
cirrhosis, those with compensated cirrhosis, those with
decompensated cirrhosis, and those showing a complete virologic response) were derived nonparametrically using the
following variables: age; sex; HBeAg positivity; serum levels of
HBV DNA, alanine aminotransferase, albumin, total bilirubin,
and creatinine; international normalized ratio; platelet count;
diabetes mellitus; hypertension; cirrhosis; ascites; and Child
TurcottePugh scores. The same set of covariates was used for
propensity score modeling in the entire cohort and in the
subcohorts (cirrhosis was not included as a covariate in the
noncirrhosis and cirrhosis subcohorts). Propensity scorematching was performed by nearest-neighbor matching with
a caliper width of 0.1 multiplied by the standard deviation for
the linearly transformed propensity scores (logit-transformation). The propensity score-matching method is described
in detail in the Supplementary Materials and Methods section.
Basal laboratory data were missing in 0.02%6.22% of patients: HBeAg status was missing in 1 patient (0.02%), creatinine levels were missing in 8 patients (0.15%), platelet counts
were missing in 15 patients (0.28%), and INR was missing in
334 patients (6.22%). Missing values were imputed using
linear interpolation.25 Imputed values were constrained within
plausible ranges.
The baseline characteristics of the 2 treatment groups were
compared using the chi-square test and the t test for categoric
and continuous variables, respectively. For the propensity
score-matched cohorts, the baseline characteristics of the 2
groups were compared using the McNemar test and the paired
t test for categoric and continuous variables, respectively.
The differences between the 2 groups in terms of clinical
outcome were assessed using a multivariable Cox proportional
hazards model. Multivariable models were tted using the
Results
Characteristics of the Overall Study Population
The study population comprised 5374 CHB patients who
started their rst treatment with entecavir (n 2000) or
lamivudine (n 3374) and who met the inclusion criteria
(Figure 1). The 2 groups differed signicantly in terms of
baseline characteristics (Table 1). The patients in the entecavir group were signicantly older (mean, 47 vs 43 y),
were less likely to be HBeAg positive (58.4% vs 71.8%), had
lower levels of serum HBV DNA (median, 7.14 vs 7.49 log10
IU/mL), and were more likely to have cirrhosis (53.6% vs
48%). The HCC risk assessment scores for the 2 groups also
were compared. The CU-HCC score was similar between the
groups (P .99), whereas the GAG-HCC score was signicantly higher for the entecavir group than for the lamivudine group (mean, 95.3 vs 91.2; P < .001) (Table 1).
Follow-up Evaluation
Complete follow-up evaluation was dened as following
up a patient until the time of death, transplantation, or the
last follow-up date (March 31, 2013). These data were
available for 99.8% of the entire cohort. For the lamivudine
and entecavir groups, the median follow-up periods were
8.7 (interquartile range, 6.511.5) and 3.1 (interquartile
range, 2.24.3) years, respectively. To minimize inequalities
in follow-up duration between the 2 groups, patients who
were followed up for more than 6 years were censored at
6 years of follow-up evaluation. In the resulting follow-up
period (ie, up to 6 years), 302 patients (5.6%) died, 169
patients (3.1%) received a transplant, and 525 patients
(9.8%) developed HCC.
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155
Lamivudine
(n 3374)
47 11
1288 (64.4%)
1168 (58.4%)
7.14 1.64
101 (53190)
3.8 (3.44.1)
1.2 (0.91.6)
1.10 (1.001.20)
0.80 (0.701.00)
142 (96183)
77 (3.9%)
102 (5.1%)
1071 (53.6%)
758 (70.8%)
313 (29.2%)
253 (12.7%)
5 (56)
19.8 13.9
95.3 22.1
2.6 (1.83.9)
3.1 (2.24.3)
43 11
2386 (70.7%)
2421 (71.8%)
7.49 1.17
128 (68244)
3.8 (3.24.1)
1.1 (0.91.6)
1.10 (1.001.30)
0.90 (0.801.00)
147 (96195)
122 (3.6%)
134 (4.0%)
1621 (48.0%)
958 (59.1%)
663 (40.9%)
532 (15.8%)
5 (56)
19.8 14.8
91.2 22.7
6.1 (2.79.0)
8.7 (6.511.5)
P value
<.001
<.001
<.001
<.001
.13
<.001
.79
<.001
.02
.03
.66
.05
<.001
<.001
.002
<.001
.99
<.001
<.001
<.001
ALT, alanine aminotransferase; CTP, ChildTurcottePugh; INR, international normalized ratio; IQR, interquartile range.
The cumulative rates of documented genotypic resistance mutations to lamivudine and/or entecavir during
the follow-up period (up to 6 years) were 1.5% and 50.8%
for the entecavir and lamivudine groups, respectively
(P < .001). Overall, 1.8% of the entecavir-treated patients
and 39.3% of the lamivudine-treated patients needed rescue
therapy (P < .001). Most of these patients were switched to
a combination therapy that included adefovir. Tenofovir was
not available during the study period.
Multivariable Analyses
Multivariable analyses to identify factors predictive of
clinical outcomes were performed for the entire cohort
(Table 2). Entecavir treatment was associated independently
with a signicantly lower risk of death or transplantation
(hazard ratio [HR], 0.49; 95% condence interval [CI],
0.380.64; P < .001). However, the risk of HCC was similar
between the 2 treatment groups (HR, 1.08; 95% CI,
0.871.34; P .48).
Table 2.Multivariable Analyses Showing Signicant Predictive Factors of Death or Transplantation and Hepatocellular
Carcinoma in the Entire Cohort
Death or transplantationa
Hepatocellular carcinomab
Variables
HR
95% CI
P value
HR
95% CI
P value
0.49
1.02
1.58
0.73
0.989
2.18
2.51
2.14
0.72
0.380.64
1.001.03
1.271.96
0.570.93
0.9860.991
1.592.99
1.713.68
1.692.70
0.690.75
<.001
.006
<.001
.01
<.001
<.001
<.001
<.001
<.001
1.08
1.06
1.81
0.70
0.995
1.51
2.59
1.53
0.94
0.871.34
1.051.07
1.482.20
0.610.80
0.9930.997
1.102.08
1.973.41
1.231.91
0.920.97
.48
<.001
<.001
<.001
<.001
.01
<.001
<.001
<.001
NOTE. A time-dependent multivariable Cox proportional hazards model with a backward variable selection approach was used
for all analyses.
a
Total number of patients, 5374; number of events, 457.
b
Total number of patients, 5374; number of events, 525.
c
Overall duration of treatment with any nucleoside/nucleotide analogue.
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performed. There were 575 and 275 matched pairs of patients with compensated and decompensated cirrhosis,
respectively. The entecavir- and lamivudine-treated groups
within each matched cohort did not differ signicantly in
terms of baseline characteristics (Supplementary Table and
Supplementary Figure 1).
In matched pairs of patients with compensated cirrhosis
and decompensated cirrhosis, entecavir was associated with
a signicantly lower risk of death or transplantation than
lamivudine (HR, 0.37; 95% CI, 0.210.65; P < .001; and HR,
0.43; 95% CI, 0.300.63; P < .001, respectively) (Table 4
and Supplementary Figure 3A and B). However, none of
the treatment groups within any of the subcohorts differed
in terms of HCC risk (P .66 and P .38 for the
compensated and decompensated cirrhosis subcohorts,
respectively) (Table 4 and Supplementary Figure 3A and B).
Discussion
Here, we compared midterm clinical outcomes for a
large cohort of CHB patients after they started treatment
with entecavir or lamivudine. This observational study
showed that entecavir was associated with a minimal risk of
drug resistance, a minimal need for rescue therapy, and a
signicantly lower risk of death or transplantation. By
contrast, entecavir was no better than lamivudine at
reducing the risk of HCC. These results were observed
consistently in the analyses by multivariable Cox proportional hazards model for the entire cohort and for propensity score-matched cohorts.
Many earlier studies including a randomized trial and
cohort studies have shown that treatment with nucleos(t)
ide analogues improves clinical outcomes in patients with
CHB compared with no treatment.36,29,30 Two recent
nationwide cohort studies also conrmed these ndings in
geographically and racially diverse patients with or without
cirrhosis.31,32 Among different nucleos(t)ide analogues,
entecavir and tenofovir show greater antiviral potency and
markedly lower resistance rates than lamivudine and
adefovir710; thus, they have been recommended as the
July 2014
Lamivudine
(n 1792)
P value
46.1 10.1
1193 (66.6%)
1133 (63.2%)
7.28 1.55
46.1 10.9
1179 (65.8%)
1107 (61.8%)
7.30 1.18
.98
.64
.32
.57
42.2
581
643
7.72
103 (55195)
3.8 (3.34.1)
1.2 (0.91.6)
1.10 (1.001.20)
0.86 (0.701.00)
143 (95184)
68 (3.8%)
77 (4.3%)
933 (52.1%)
632 (67.7%)
301 (32.3%)
244 (13.6%)
5 (56)
19.8 14.2
94.4 22.1
118 (65223)
3.8 (3.34.1)
1.1 (0.91.6)
1.10 (1.001.20)
0.90 (0.801.00)
140 (96184)
73 (4.1%)
91 (5.1%)
934 (52.1%)
634 (67.9%)
300 (32.1%)
239 (13.3%)
5 (56)
20.1 14.4
94.4 22.9
.93
.86
.59
.85
.59
.68
.73
.31
1.00
.95
156
3.9
1.1
1.07
0.9
175
25
28
.85
.65
.56
.97
Entecavir
(n 878)
10.6
(66.2%)
(73.2%)
1.61
(95290)
(3.64.1)
(0.91.4)
(1.001.10)
(0.71.0)
(143209)
(2.8%)
(3.2%)
0
0
5 (55)
8.8 8.4
74.6 12.3
Cirrhosis cohort
Lamivudine
(n 878)
42.2
578
656
7.68
P value
10.6
(65.8%)
(74.7%)
1.08
.93
.91
.45
.47
172
3.9
1.0
1.08
0.9
176
24
32
(96321)
(3.64.1)
(0.81.3)
(1.001.10)
(0.71.0)
(140208)
(2.7%)
(3.6%)
0
0
5 (55)
9.5 8.8
74.5 11.8
.77
.82
.52
.77
.79
.84
1.00
.98
NA
NA
NA
.09
.81
ALT, alanine aminotransferase; CTP, ChildTurcottePugh; INR, international normalized ratio; IQR, interquartile range.
Entecavir
(n 860)
49.9
565
437
6.92
8.5
(65.7%)
(50.8%)
1.31
Lamivudine
(n 860)
49.7
572
447
6.91
9.6
(66.5%)
(52.0%)
1.14
73 (44124)
91 (55153)
3.6 (3.04.0)
3.6 (3.04.0)
1.4 (1.01.9)
1.3 (0.91.9)
1.20 (1.101.30) 1.20 (1.101.30)
0.8 (0.70.9)
0.9 (0.71.0)
107 (73146)
104 (72140)
49 (5.7%)
43 (5.0%)
55 (6.4%)
49 (5.7%)
860 (100%)
860 (100%)
589 (68.5%)
572 (66.5%)
271 (31.5%)
288 (33.5%)
221 (25.7%)
216 (25.1%)
6 (57)
6 (57)
30.1 10.4
30.3 10.6
112.9 10.5
112.6 10.7
P value
.61
.76
.63
.72
.48
.76
.95
.98
.83
.51
.59
.62
NA
.38
.82
.66
.63
.49
Entecavir
(n 1792)
Noncirrhosis cohort
157
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Lim et al
CLINICAL LIVER
mutants are more likely to suffer hepatitis ares, disease progression, and to die than those without resistant mutants.3,5,6
Thus, our results showing that patients treated with entecavir
have a signicantly lower risk of death or transplantation than
those treated with lamivudine may reect the higher virologic
response rates and markedly lower resistance rates in entecavirtreated patients. These factors may reduce and prevent hepatitis
ares and hepatic necroinammation, thereby slowing progression to decompensation, which then may result in a further
reduction in the risk of liver failure and death.
By contrast, treatment with entecavir did not reduce the
risk of HCC to a greater extent than lamivudine in any of the
cohorts in any of the analyses. This may be explained, at
least partly, by the fact that rescue therapies were widely
used during treatment with lamivudine. However, other
viral or host factors that are not readily amenable to the
suppression of viral replication may be associated with a
continued risk of HCC. These factors may include the early
integration of HBV DNA into the host genome, which results
in genomic alterations and/or chromosomal instability, and
pre-existing cirrhosis.3538 In patients who have been
infected with HBV for a long time, or who already have
progressed to cirrhosis, many transformed hepatocyte
clones carrying genetic abnormalities that predispose to
cancer may be present before the onset of treatment.38,39
Thus, our results suggest that even after very effective
suppression of viral replication by oral antiviral agents, the
risk of HCC may not be reduced dramatically in CHB patients, particularly in those with cirrhosis. Further studies
are needed to determine whether these results are applicable to other potent antiviral agents, such as tenofovir.
The current consensus is that regular surveillance for
the early detection of HCC may be cost effective when the
annual risk exceeds 1.5% in patients with cirrhosis and 0.2%
in patients without cirrhosis.19,40 We showed that the annual
incidence of HCC in both the entecavir and lamivudine
cohorts was higher than 4% in patients with cirrhosis and
0.7% in those without cirrhosis. These observations, and
those of others,33 suggest that the risk of HCC persists
regardless of the drugs being used to treat CHB patients;
therefore, surveillance for early detection may be justied.
This study had several strengths. First, entecavir was
compared directly with lamivudine in a large cohort with a
high number of events. Second, there were very few missing
data and follow-up evaluation was almost complete. Third,
strict inclusion criteria were applied. Patients who died or
underwent liver transplantation within 6 months of treatment were assumed to be too sick to observe the clinical
benet from any antiviral treatment, and were excluded
from the study. Patients who were diagnosed as HCC within
the rst year of treatment also were excluded, based on the
assumption that these patients may have had pre-existing
undetected HCC on recruitment to the study. Finally, multiple strategies were used to minimize confounders (multivariable analyses, propensity score-matching analyses
adjusted for overall treatment duration) and competing
risks analyses were used to rigorously adjust for all risks.
The major limitation of this study was that it was based
on observational data. Thus, our ndings are potentially
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159
Table 4.Cumulative Incidence and Hazards Ratios for the Clinical Outcomes in the Propensity Score-Matched Cohorts
No.
No. of /100 patientyears
Outcomes Patient-years events
Overall cohort (N 1792 pairs)
Entecavir
5874
76
1.29
Lamivudine
9920
188
1.90
Noncirrhosis subcohort (N 878 pairs)
Entecavir
2975
9
0.30
Lamivudine
5109
17
0.33
Cirrhosis subcohort (N 860 pairs)
Entecavir
2779
60
2.16
Lamivudine
4530
162
3.58
Compensated cirrhosis subcohort (N 575 pairs)
Entecavir
1830
16
0.87
Lamivudine
3166
64
2.02
Decompensated cirrhosis subcohort (N 275 pairs)
Entecavir
900
44
4.89
Lamivudine
1286
101
7.86
Complete virologic responsea subcohort (N 275 pairs)
Entecavir
930
13
1.40
Lamivudine
1349
30
2.22
HR
(95% CI)
Hepatocellular carcinoma
No.
Patient- No. of /100 patientyears
P value years events
HR
(95% CI)
P value
0.49
(0.370.64)
<.001
5687
9503
137
234
2.41
2.46
1.01
(0.801.27)
.95
0.86
(0.391.89)
.71
2947
5031
21
40
0.71
0.80
1.26
(0.682.34)
.46
0.42
(0.310.57)
<.001
2635
4211
108
183
4.10
4.35
1.00
(0.781.28)
.999
0.37
(0.210.65)
<.001
1747
2957
58
105
3.32
3.55
0.92
(0.651.31)
.66
0.43
(0.30-0.63)
<.001
830
1182
49
75
5.90
6.34
0.84
(0.56-1.25)
.38
0.61
(0.321.17)
.14
875
1273
33
42
3.77
3.30
1.06
(0.651.74)
.81
NOTE. The hazards ratios and P values represent the entecavir group compared with the lamivudine group, adjusted for overall
treatment duration using a multivariable Cox regression model.
a
Serum HBV-DNA level <60 IU/mL at 1 year of treatment.
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Supplementary Material
Note: To access the supplementary material accompanying
this article, visit the online version of Gastroenterology at
www.gastrojournal.org, and at http://dx.doi.org/10.1053/
j.gastro.2014.02.033.
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J Hepatol 2006;45:529538.
2. Schiff ER. Prevention of mortality from hepatitis B and
hepatitis C. Lancet 2006;368:896897.
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