Entecavir Superior to Lamivudine for Treatment of Nucleoside-Naive, HBeAg- Negative Patients Slideset on: Lai CL, Shouval D, Lok AS, et al. Entecavir versus lamivudine for patients with HBeAg- negative chronic hepatitis B. N Engl J Med. 2006;354:

clinicaloptions.com/hep Entecavir Superior to Lamivudine in Nucleoside-Naive, HBeAg-Negative Patients Background and Rationale  Goals of treatment in HBeAg-negative patients include long-term viral suppression and ALT normalization  Lamivudine effective during initial anti-HBV therapy, but resistance develops at rate of ~ 70% at 4 years, typically resulting in HBV rebound and hepatitis disease progression  Entecavir a potent inhibitor of HBV  Current study compared efficacy, safety of 48 weeks of treatment with entecavir vs lamivudine in nucleoside- naive, HBeAg-negative chronic hepatitis B patients Lai CL, et al. N Engl J Med. 2006;354:

clinicaloptions.com/hep Entecavir Superior to Lamivudine in Nucleoside-Naive, HBeAg-Negative Patients Summary of Study Design Lai CL, et al. N Engl J Med. 2006;354: Nucleoside-naive, HBeAg-negative patients with chronic hepatitis B (N = 638) Entecavir 0.5 mg/day (n = 325) Lamivudine 100 mg/day (n = 313) Week 52 Management decision Discontinuation/ continuation of therapy* Week 481:1 Randomization ULN, upper limit of normal. *Patients with response (HBV DNA < 0.7 MEq/mL and ALT < 1.25 x ULN) or nonresponse (HBV DNA ≥ 0.7 MEq/mL) to treatment discontinued therapy at Week 52 but were followed for an additional 24 weeks; patients with virologic-only response (HBV DNA < 0.7 MEq/mL and ALT ≥ 1.25 x ULN) allowed to continue study therapy up to 96 weeks.

clinicaloptions.com/hep Entecavir Superior to Lamivudine in Nucleoside-Naive, HBeAg-Negative Patients Histologic Improvement With Entecavir vs Lamivudine  Among patients with baseline biopsy showing Knodell necroinflammatory score ≥ 2, more patients receiving entecavir achieved histologic improvement by Week 48 Histologic Outcome Among Patients With Necroinflammatory Score ≥ 2 at Baseline Entecavir (n = 296) Lamivudine (n = 287) P Value Histologic improvement by Week 48, n (%)208 (70)174 (61).01 No histologic improvement by Week 48, n (%)57 (19)76 (26) Mean Knodell necroinflammatory score(n = 265)(n = 250)  Baseline  Week Ishak fibrosis score improvement by Week 48, % Lai CL, et al. N Engl J Med. 2006;354:

clinicaloptions.com/hep Entecavir Superior to Lamivudine in Nucleoside-Naive, HBeAg-Negative Patients Virologic, Biochemical Outcomes With Entecavir vs Lamivudine  Mean change in HBV DNA from baseline with entecavir vs lamivudine: -5.0 vs -4.5 log 10 copies/mL (P <.001) Week 48 Outcome Entecavir, n (%) (n = 325) Lamivudine, n (%) (n = 313) P Value HBV DNA undetectable by PCR*293 (90)225 (72)<.001 ALT normalization † 253 (78)222 (71).045 HBsAg loss1 (< 1) PCR, polymerase chain reaction. *< 300 copies/mL. † ≤ 1 x upper limit of normal. Lai CL, et al. N Engl J Med. 2006;354:

clinicaloptions.com/hep Entecavir Superior to Lamivudine in Nucleoside-Naive, HBeAg-Negative Patients Adverse Events With Entecavir vs Lamivudine Safety Outcome Entecavir, n (%) (n = 325) Lamivudine, n (%) (n = 313) P Value Adverse event on treatment246 (76)248 (79).30 Serious adverse event on treatment 21 (6)24 (8).64 Treatment discontinuation due to adverse event 6 (2)9 (3).44 ALT flare (> 2 x baseline and > 10 x ULN)  During treatment3 (< 1)5 (2).50  During 6 months of posttreatment follow-up 23 (8) (n = 297) 29 (11) (n = 263).19 Death on treatment2 (< 1)*0 (0).50 *Considered to be unrelated to study treatment. Lai CL, et al. N Engl J Med. 2006;354:

clinicaloptions.com/hep Entecavir Superior to Lamivudine in Nucleoside-Naive, HBeAg-Negative Patients Development of Resistance With Entecavir vs Lamivudine  No detection of emerging entecavir resistance mutations through 48 weeks of treatment –Based on paired samples from 211 randomly selected entecavir-treated patients –5 entecavir-treated patients with virologic rebound had no evidence of emergent substitutions when compared with baseline sequence –Week 48 samples fully susceptible in phenotypic analysis  20 of 25 (80%) lamivudine-treated patients with virologic rebound had evidence of emergent YMDD lamivudine resistance mutations Lai CL, et al. N Engl J Med. 2006;354:

clinicaloptions.com/hep Entecavir Superior to Lamivudine in Nucleoside-Naive, HBeAg-Negative Patients Key Conclusions  Entecavir produced significantly better virologic, biochemical, and histologic improvement vs lamivudine in nucleoside-naive, HBeAg-negative patients  Safety profile comparable for entecavir and lamivudine  No viral resistance to entecavir detected after 48 weeks of treatment Lai CL, et al. N Engl J Med. 2006;354: