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

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

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.

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

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

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

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.

Table 1. Baseline Characteristics

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

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

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%)

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).

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% (0.09- 0.73) 17.9 (5.2 ~ 30.7 hours)

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

Viral Kinetic Assessment Proportion of patients who achieve HBV DNA 300 copies/mL for each HBV DNA category on exploratory analysis (P-values <0.0001 ) 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%)

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

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