Bruce Kreter

Long‐term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B

One year of treatment with entecavir (0.5 mg daily) in nucleoside‐naive patients with hepatitis B e antigen (HBeAg)‐positive or HBeAg‐negative chronic hepatitis B (CHB) resulted in significantly improved liver histology and virological and biochemical endpoints in comparison with lamivudine. Patients who received at least 3 years of cumulative entecavir therapy in phase 3 studies and a long‐term rollover study and underwent long‐term liver biopsy were evaluated for improvements in histological appearance. Sixty‐nine patients [50 HBeAg‐positive and 19 HBeAg‐negative] receiving entecavir therapy underwent long‐term liver biopsy (median time of biopsy = 6 years, range = 3‐7 years). Histological improvement was analyzed for 57 patients who had adequate baseline biopsy samples, baseline Knodell necroinflammatory scores ≥2, and adequate long‐term biopsy samples. At the time of long‐term biopsy, all patients in the cohort had a hepatitis B virus DNA level <300 copies/mL, and 86% had a normalized alanine aminotransferase level. Histological improvement (≥2‐point decrease in the Knodell necroinflammatory score and no worsening of the Knodell fibrosis score) was observed in 96% of patients, and a ≥1‐point improvement in the Ishak fibrosis score was found in 88% of patients, including all 10 patients with advanced fibrosis or cirrhosis at the phase 3 baseline. Conclusion: The majority of nucleoside‐naive patients with CHB who were treated with entecavir in this long‐term cohort achieved substantial histological improvement and regression of fibrosis or cirrhosis. (HEPATOLOGY 2010)

Entecavir therapy for lamivudine‐refractory chronic hepatitis B: Improved virologic, biochemical, and serology outcomes through 96 weeks

In hepatitis B e antigen (HBeAg)‐positive chronic hepatitis B patients who were refractory to current lamivudine therapy, switching to entecavir was superior to continued lamivudine at week 48 for histologic improvement, viral load reduction by polymerase chain reaction and alanine aminotransferase normalization. We assessed the efficacy, safety, and resistance profile of entecavir through 96 weeks of treatment. A total of 286 patients were randomized and treated with entecavir 1 mg (n = 141) or continued lamivudine 100 mg (n = 145). At week 52, 77 entecavir‐treated patients who had a protocol‐defined virologic response (HBV branched DNA [bDNA] < 0.7 MEq/mL but HBeAg‐positive) continued blinded therapy for up to 96 weeks. Patients were assessed for efficacy, safety, and emerging resistance. Cumulative proportions of all treated patients who achieved confirmed efficacy endpoints were also analyzed. Between week 48 and the end of dosing, the proportions of patients with HBV DNA <300 copies/mL by polymerase chain reaction increased from 21% to 40%, and alanine aminotransferase normalization (≤1× upper limit of normal) increased from 65% to 81%. In the second year, HBeAg seroconversion was achieved by 10% of patients. Of the 77 patients in the second year treatment cohort, entecavir resistance emerged in six patients, and seven experienced virologic breakthrough (five with genotypic resistance acquired before year 2). The safety profile of entecavir in the second year of therapy was consistent with that reported during year 1. Conclusion: Through 96 weeks of treatment, 1 mg entecavir resulted in continued clinical benefit in lamivudine‐refractory HBeAg‐positive chronic hepatitis B patients with a safety profile comparable to lamivudine. (HEPATOLOGY 2008.)

Cross-Study Analysis of the Relative Efficacies of Oral Antiviral Therapies for Chronic Hepatitis B Infection in Nucleoside-Naive Patients

AbstractBackground and objective: p]Lamivudine and adefovir were approved for treatment of chronic hepatitis B virus (HBV) infection based on placebo-controlled trials, and entecavir was recently approved on the basis of its superiority over lamivudine in phase II/III trials; however, to date, these three therapies have not been compared head to head. Methods: To evaluate the relative efficacy of these therapies, we applied a predefined protocol of established statistical techniques to compare data from phase III entecavir trials with published clinical trial results with lamivudine, adefovir and placebo in nucleoside-naive hepatitis B e antigen (HBeAg)-positive and -negative populations. Results: A comprehensive literature search identified 612 publications/data sources, of which 28 satisfied predefined inclusion criteria. Independent reviewers extracted week 48–52 histological, virological, biochemical and serological endpoints from these sources, which were analysed with a fixed-effects model. For each of the three histological endpoints in HBeAg-positive patients (Histological Improvement, Ranked Assessment of Necroinflammation [RA-N] and Ranked Assessment of Fibrosis [RA-F]), entecavir was superior to adefovir. Entecavir was superior to lamivudine for Histological Improvement and comparable to lamivudine for RA-N and RA-F. With respect to reducing HBV DNA levels, entecavir (−6.98 log10 copies/mL) was more effective than lamivudine (−5.46 log10 copies/mL, p < 0.0001) and adefovir (−3.60 log10 copies/mL, p < 0.0001), and lamivudine was more effective than adefovir (p < 0.0001). The parallel goals of HBV DNA reduction below the limit of quantitation (LOQ) [by polymerase chain reaction] and ALT normalisation were achieved more often with entecavir (69% and 67% of patients, respectively) than with lamivudine (38% and 59%, respectively; p < 0.0001 and p < 0.05, respectively) or adefovir (21% and 48%, respectively; both p < 0.0001), and more often with lamivudine than with adefovir (p < 0.0001 and p < 0.05, respectively). HBeAg seroconversion rates were higher with entecavir (21% of patients) and lamivudine (18%) than with adefovir (12%, p < 0.01 and p < 0.05, respectively). For each of the three histological endpoints in the HBeAg-negative population, entecavir was comparable to adefovir. Entecavir was superior to lamivudine for Histological Improvement, and comparable to lamivudine for RA-N and RA-F, and all three antivirals were superior to placebo. Entecavir proved superior to lamivudine and adefovir in lowering HBV DNA levels (−5.20 vs −4.66 vs −3.91 log10 copies/mL, respectively; p < 0.0005 and p < 0.0001, respectively) and in suppressing HBV DNA below the LOQ (91% vs 73% vs 51% of patients, respectively; both p < 0.0001); in the latter respect, lamivudine was in turn superior to adefovir (p < 0.0001). Entecavir was also superior to lamivudine in normalising ALT (76% vs 69% patients, respectively; p < 0.05). Conclusions: Over a 12-month treatment period, this analysis predicts that the antiviral efficacy of entecavir would be superior to that of lamivudine, which in turn would be superior to that of adefovir, in nucleoside-naive patients with chronic HBV infection.

W1808 Regression of Fibrosis/Cirrhosis with Long-Term Entecavir Therapy in Chronic Hepatitis B (CHB) Patients with Baseline Bridging Fibrosis or Cirrhosis: Results from Studies ETV-022, -027 and -901

Baseline Bridging Fibrosis or Cirrhosis: Results from Studies ETV-022, -027 and -901 Eugene R Schiff1, Samuel S Lee2,You-Chen Chao3, SeungKew Yoon4, Fernando Bessone5, Shun-Sheng Wu6, Wieslaw Kryczka7, Yoav Lurie8, Adrian Gadano9, George Kitis10, Suzanne Beebe11, Bruce Kreter12, Dong Xu11, Melissa Harris13, Hong Tang13, Uchenna Iloeje11 1University of Miami Hospital & Clinics, Miami, FL, USA; 2Liver Unit, University of Calgary, Calgary, AB, Canada; 3Tri-Service General Hospital, Taipei, Taiwan; 4Department of Internal Medicine, Kangnam St Mary’s Hospital, Seoul, Korea; 5Rosario, Santa Fe, Argentina; 6Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan; 7Wojewodzki Szpital Zespolony, Kielce, Poland; 8Department of Gastroenterology, Tel Aviv Medical Center, Tel Aviv, Israel; 9Hospital Italiano Regional Del Sur, Buenos Aires, Argentina; 10George Papanikolaou Hospital, Gastroenterology Department, Thessaloniki, Greece; 11Research & Development, Bristol-Myers Squibb Company, Wallingford, CT, USA; 12Research & Development, Bristol-Myers Squibb Company, Princeton, NJ, USA; 13Research & Development, Bristol-Myers Squibb Company, Plainsboro, NJ, USA

919 ENTECAVIR (ETV) THERAPY IN CHRONIC HEPATITIS B PATIENTS PREVIOUSLY TREATED WITH ADEFOVIR (ADV) WITH INCOMPLETE RESPONSE ON-TREATMENT OR RELAPSE OFF-TREATMENT

1Alice Ho Miu Ling Nethersole Hospital, Hong Kong, China; 2Department of Medicine, Queen Mary’s Hospital, University of Hong Kong, Hong Kong, China; 3Whitman-Walker Clinic, Washington, WA, USA; 4Toronto General Hospital, Toronto, ON, Canada; 5Liver Disease Prevention Center, Division of Gastroenterology and Hepatology, Thomas Jefferson University Hospital, Philadelphia, PA, USA; 6Health Sciences Center, Edmonton, AB, Canada; 7Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan; 8Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore; 9China Medical University Hospital, Taichung, Taiwan; 10Research and Development, Bristol-Myers Squibb Company, Wallingford, CT, USA; 11Research and Development, Bristol-Myers Squibb Company, Princeton, NJ, USA