By Liz Highleyman

Prior research has shown that treatment-naive hepatitis B "e" antigen (HBeAg) positive or negative chronic hepatitis B patients treated with 0.5 mg daily entecavir for 1 year showed significantly more improvement in virological (HBV DNA), biochemical (ALT level), and liver histology (tissue damage) endpoints than those using lamivudine (Epivir-HBV).

Ting-Tsung Chang from National Cheng Kung University Medical College in Taiwan and colleagues looked at liver biopsy findings for patients who received at least 3 years of cumulative entecavir in Phase 3 clinical trials and a long-term rollover study (participants entered the rollover study after completing the randomized part of the trials). During the Phase 3 trials patients received entecavir at a dose of 0.5 mg once-daily, and during the rollover study they received 1.0 mg once-daily. Some participants received lamivudine in addition to entecavir for a brief period.

A total of 69 patients -- 50 HBeAg positive and 19 HBeAg negative -- underwent liver biopsies to evaluate improvement in histological appearance, or extent of liver damage including fibrosis and cirrhosis (scarring), after long-term entecavir therapy. Biopsies were done after a median 6 years of entecavir use (range 3-7 years). Histological improvement was analyzed for 57 patients who had adequate baseline and long-term biopsy samples available for comparison. All these participants had baseline Knodell necro-inflammatory scores of 2 or higher.

Results

	At the time of the long-term biopsies, all participants had undetectable HBV DNA < 300 copies/mL.
	86% had normalized ALT levels at this point.
	55% experienced HBeAg loss and 33% achieved HBe antibody seroconversion.
	Almost all analyzed patients -- 97% -- showed histological improvement, defined as at least a 2 point decrease in Knodell necro-inflammatory score and no worsening of Knodell fibrosis score.
	88% of patients achieved at least a 1 point improvement in Ishak fibrosis score, including all 10 participants who had advanced fibrosis or cirrhosis at the start of Phase 3 trials.
	Long-term entecavir therapy was generally well-tolerated, with no unexpected drug-related adverse events.

Based on these findings, the study authors concluded, "The majority of nucleoside-naive patients with chronic hepatitis B who were treated with entecavir in this long-term cohort achieved substantial histological improvement and regression of fibrosis or cirrhosis."

The likelihood of improvement increased with longer treatment, they added in their discussion. At the end of the Phase 3 studies, 73% of patients had shown histological improvement (as early as week 48), but only 32% demonstrated improvement in fibrosis.

"These data support the conclusion that in most nucleoside-naive patients, long-term entecavir therapy leads to potent suppression of HBV DNA, normalization of ALT and improvement in liver histology with accompanying regression of fibrosis, including those with advanced fibrosis or cirrhosis at baseline," Chang said in a press release issued by Hepatology publisher Wiley. "Substantially more patients demonstrated histologic improvement at the time of the long-term biopsy compared to week 48, confirming the value of long-term treatment for chronic HBV infection."

Noting that even participants who did not achieve HBe antibody seroconversion during long-term treatment still experienced improvements in liver histology and reversal of fibrosis, the researchers suggested that these benefits are probably more closely associated with HBV DNA suppression than with immunological response to therapy.

Investigator affiliations: National Cheng Kung University Medical College, Tainan, Taiwan; Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan; University of Miami Hospital and Clinics, Miami, FL; Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea; Department of Medicine, Queen Mary's Hospital, University of Hong Kong, Hong Kong, China; Division of Medicine, Hadassah Medical Center, Jerusalem, Israel; Liver Unit, University of Calgary, Calgary, Canada; Nicolaus Copernicus University, Collegium Medicum, Bydgoszcz, Poland; Armed Forces Institute of Pathology, Washington, DC; Department of Statistics, National Cheng Kung University, Tainan, Taiwan; Research and Development, Bristol-Myers Squibb Co., Princeton, NJ.

9/14/10

Reference
TT Chang, YF Liaw, SS Wu, and others. Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatology 52(3): 886-893 (Abstract). September 2010.

Other source
Wiley Publishers. Long-term Entecavir Therapy Reverses Fibrosis and Cirrhosis in Chronic Hepatitis B Patients. Press release. August 17, 2010.