In the original phase 3 studies, histological improvement was observed in the majority of patients (73%) as early as week 48, but only a minority (32%) demonstrated an improvement in fibrosis. The current analyses of the long-term histology cohort summarize the effects of continued entecavir therapy on hepatic necroinflammation and fibrosis in nucleoside-naive, HBeAg-positive and HBeAg-negative CHB patients.
After a median exposure to entecavir therapy of approximately 6 years, histological improvement and improvement of fibrosis increased to 96% and 88% of patients, respectively. Most patients (75%) in the cohort who had a baseline HAI score ≥4 achieved a score ≤3 by the time of long-term biopsy. These histological analyses GSK-3 activity extend previous observations PR-171 manufacturer of the clinical efficacy of entecavir at 48 weeks in patients with advanced fibrosis or cirrhosis.38 All
patients who had evidence of advanced fibrosis or liver cirrhosis at the phase 3 baseline demonstrated improvement in fibrosis at the long-term assessment. Suppression of viral replication below the level of polymerase chain reaction assay detection (serum HBV DNA level <300 copies/mL) occurred in all patients, and most patients (86%) also had a normal serum ALT level at the time of long-term biopsy. Because of the sustained suppression of HBV DNA to a level <300 copies/mL, these patients were at
minimal risk for antiviral drug resistance, and no evidence of virological rebound or genotypic resistance to entecavir was observed in this study. A majority of patients (55%) lost HBeAg, and 33% experienced HBe seroconversion at the time of long-term biopsy. medchemexpress Patients who did not demonstrate HBe seroconversion during long-term treatment also experienced improvements in liver histology and reversal of fibrosis, and this suggests that these outcomes are more closely associated with HBV DNA suppression than the immunological response to therapy. The baseline demographics of the patients in the long-term histology cohort and the phase 3 studies suggest that the two populations are comparable; however, the current data set has some limitations. For all patients who entered the rollover study, the dose of entecavir increased from 0.5 mg in the phase 3 studies to 1.0 mg daily in the rollover study, and 51 of 57 patients (89%) in this cohort received a median of 29 weeks of concurrent lamivudine before they continued on entecavir monotherapy for the remainder of the observation period. Because amendments were made to the long-term rollover study as new data emerged, it is not possible to evaluate any potential contribution of the increased dose of entecavir or the brief period of concurrent lamivudine to the results.