Necroinflammation and fibrosis were assessed with the original Knodell histology activity index (HAI) scoring system and the Ishak modification of this system.35, 36 The pathologist was blinded to treatment assignment, biopsy sequence, and clinical outcome for the phase 3 liver biopsy samples and remained blinded with respect to clinical outcomes when the long-term biopsy samples were being evaluated. Serum samples for virological, biochemical, and serological endpoints were matched in time (±12 weeks) with the corresponding long-term biopsy. Serum HBV DNA was assayed with the Roche Amplicor COBAS polymerase chain reaction assay [version 2.0, Pleasanton,

CA; lower limit of quantification = 300 copies/mL (57 IU/mL)] at 12-week intervals during the phase 3 studies and the first year of the rollover study and at 24-week intervals selleck kinase inhibitor thereafter. HBV serologies were assessed every 12 weeks, centrally during the phase 3 studies [Abbott AxSYM microparticle enzyme immunoassay (Abbott Laboratories, North Chicago, IL) and Diasorin enzyme immunoassay] and in local laboratories during the ETV-901 study. Alanine aminotransferase

(ALT) levels were assessed in local laboratories. The criteria for inclusion in the efficacy analyses were (1) an adequate baseline liver biopsy sample, (2) a baseline Knodell MLN0128 necroinflammatory score ≥2, and (3) an adequate long-term biopsy sample. The adequacy of the biopsy sample was determined by the histopathologist. The coprimary efficacy endpoints were histological improvement (≥2-point decrease in the Knodell necroinflammatory score and no worsening of the Knodell fibrosis score) and improvement in the Ishak fibrosis score (≥1-point decrease). Secondary histological endpoints included the mean change from the baseline in the Knodell necroinflammatory score, the mean change from the baseline in the Ishak fibrosis score, the proportion of patients with baseline advanced fibrosis/cirrhosis 上海皓元医药股份有限公司 (Ishak score ≥4) who demonstrated

improvement, and the proportion of patients with a baseline Knodell HAI score ≥4 points who achieved a final score ≤3 points. Nonhistological secondary endpoints included the proportion of patients achieving an HBV DNA level <300 copies/mL, an ALT level ≤1 times the upper limit of normal, HBeAg loss, HBe seroconversion, and hepatitis B s antigen (HBsAg) loss. All endpoints were assessed at week 48 in the phase 3 study and at the time of long-term biopsy. Safety analyses were performed for all patients who underwent long-term liver biopsy and were based on data collected during treatment in the long-term rollover study. Analyses included the incidence of adverse events, serious adverse events, laboratory abnormalities, and discontinuations due to adverse events. Continuous variables were summarized with the mean, median, standard error, standard deviation (SD), and minimum and maximum values.