1. Early Hepatitis B Virus DNA Reduction in Hepatitis B e Antigen–Positive Patients with Chronic Hepatitis B : A Randomized International Study of Entecavir Versus Adefovir
Hepatology 2009 Vol. 49 No.1
R2 Lee Hongjoo
Prof. Kim Byungho

2. Background HBV ≥ 50 million/yr infected
≥ 1 million/yr deaths ← complications of CHB (cirrhosis, HCC…)
risk of developing cirrhosis and HCC vs serum HBV DNA level.
HBV DNA↓ → liver disease in patients with CHB↓
Lamivudine, Adefovir, Entecavir
Viral kinetic studies of nucleoside analogs have shown a biphasic decay in HBV DNA
half-life of circulating virus : 26.4 hours with ADV.
24 hours with lamivudine.
16 hours with ETV

3. Background
Object
Compare early antiviral activity of ETV with that of ADV
viral kinetic profiles of ETV with that of ADV
in HBeAg(+), nucleoside- naïve adults who are chronically infected with HBV.

4. Patients and Methods Study Design
open-label phase IIIb study : ETV 0.5 mg or ADV 10mg (for ≥ 52 weeks)
prospectively randomized (1:1)
Patients
Inclusion criteria
> 16 years old
HBeAg (+) CHB infection
compensated liver disease : ALT 1.3 ~ 10 times the ULN
never received treatment with nucleosides or nucleotides
sHBV DNA level of ≥ 108 copies/mL at screening,
Exclusion criteria
evidence of infection with HIV, HCV or HDV
recent history of acute pancreatitis.
serum Cr>1.5 mg/dL, Hb<10 g/L, platelet count<70,000/mm3

5. Patients and Methods Outcomes and Assessments.
Primary objective : early antiviral efficacy between ETV & ADV
Secondary efficacy end points : viral kinetics over first 12 weeks of therapy
mean change in HBV DNA from baseline to weeks 24 and 48
proportion of patients with undetectable sHBV DNA (300 copies/mL) at weeks 12, 24, 48
proportion of patients with normalization of serum ALT
HBe seroconversion at week 48
Safety
sHBV DNA : quantitative PCR assay (limit of quantification 300 copies/mL)
on day 1 → daily until day 14 → 3, 4, 6, 8, 10, 12, 24, 48 weeks

6. Patients and Methods Statistical Analysis.
Target sample size : >26 patients/treatment group
→ 90% power to demonstrate superiority at week 12
Efficacy analysis : assigned therapy for > 12 weeks
baseline and week 12 HBV DNA PCR measurements
Viral Kinetics.
Biphasic decay kinetics (previously described)
Spline regression : first-phase and second phase slopes for each therapy
t tests using the Satterthwaite method for unequal variances : Comparisons of the two slopes
Cochrane-Armitage trend test : Exploratory analyses for predicting HBV DNA < 300 copies/mL at weeks 24, 48 based on HBV DNA categories at day 10
Standard four-parameter exponential decay model
: estimate the following viral kinetic parameters

7. Results Fig. 1. Flow of patients through the trial.
January 2005 ~ January 2006 (first patient was enrolled ~ last patient completed 12 weeks of treatment)
Fig. 1. Flow of patients through the trial.

8. Table 1. Baseline Characteristics

9. Primary/Secondary Efficacy End Point
Table 2. Mean (SE) HBV DNA Reductions (log10 copies/mL) from Baseline During Treatment

10. Secondary Efficacy End Points
Fig. 2. Distribution of patients stratified by HBV DNA category by PCR
at weeks 12, 24, and 48.

11. Secondary Efficacy End Points
Serum ALT at 48 weeks
HBeAg loss and HBe seroconversion rates
NL (1< ULN)
ALT (1 ~2 ULN)
ETV-treated patients
25 (76%)
7(21%)
ADV-treated patients
20 (63%)
8 (25%)
HBeAg loss
HBe seroconversion rates
ETV-treated patients
6 of 33 (18%)
5 of 33(15%)
ADV-treated patients
7 of 32 (22%)

12. Viral Kinetic Assessment
Rapid first-phase decline
-0.329
-0.391
-0.034
Slower second-phase decline
-0.024
day10
Fig. 3. HBV DNA viral kinetics mean curves (SE, standard error).

13. Viral Kinetic Assessment
On four parameter exponential decay model
mean estimate of efficacy (ɛ)
estimated half-life
of circulating virus
ETV
99.9%
14.5 hours
ADV
99.5%
32.5 hours
M.D.
(95% C.I.)
0.41%
( )
17.9
(5.2 ~ 30.7 hours)

14. Viral Kinetic Assessment
Fig. 4. Mean HBV DNA profile during the first 12 weeks of therapy superimposed on individual profiles for each patient

15. Viral Kinetic Assessment
Proportion of patients who achieve HBV DNA 300 copies/mL for each HBV DNA category on exploratory analysis (P-values < )
HBV (copies/mDNA )
<106
106 ~ 107
107 ~ 108
>108
day 10
17 (26%)
15 (23%)
14 (22%),
19 (29%)
24 week
13 (76%)
4 (27%)
2 (14%)
48 week
14 (82%)
6 (40%)
4 (29%)
1 (5%)

16. Safety
Table 3. Safety According to Treatment Received to Week 48

17. Conclusions
Entecavir therapy resulted in earlier and superior reduction in HBV DNA compared with adefovir in nucleoside-naïve HBeAg-positive patients with CHB.