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
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.
the time of the long-term biopsies, all participants
had undetectable HBV DNA < 300 copies/mL.
had normalized ALT levels at this point.
experienced HBeAg loss and 33% achieved HBe antibody
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.
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.
entecavir therapy was generally well-tolerated, with
no unexpected drug-related adverse events.
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
"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.
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.
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).
Wiley Publishers. Long-term Entecavir Therapy Reverses Fibrosis
and Cirrhosis in Chronic Hepatitis B Patients. Press release.
August 17, 2010.