Thursday, September 30, 2010

Long-Term Entecavir Therapy Reverses Fibrosis and Cirrhosis

Long-Term Entecavir Therapy Reverses Fibrosis and Cirrhosis in Patients With Chronic Hepatitis B
Fran Lowry
August 25, 2010 — Long-term antiviral therapy for 3 years or more with entecavir reverses fibrosis and cirrhosis in patients with chronic hepatitis B virus (HBV) infection, according to a new study published online August 3 in Hepatology.

"Chronic hepatitis B (CHB) infection affects over 350 million people worldwide," write Ting-Tsung Chang, MD, from National Cheng Kung University Medical College, Tainan, Taiwan, and colleagues. "Viral replication is now recognized as the key driver of liver injury and disease progression, and thus the primary aim of treatment for chronic HBV infection is long-term suppression of HBV replication to undetectable levels."

Previous studies showed that continuous treatment with entecavir for periods ranging from 48 weeks to 3 years resulted in potent virologic suppression and improvement in virologic, histologic, and biochemical outcomes in nucleoside-naive patients, with minimal emergence of resistance.

The aim of the present study was to determine if long-term entecavir treatment continued to provide histologic improvement and reversal of fibrosis or cirrhosis in patients with chronic HBV infection.

The researchers evaluated nucleoside-naive patients from two phase 3 studies with entecavir who subsequently entered an open-label rollover study and received entecavir for a total duration of at least 3 years. During the phase 3 trials, patients received entecavir 0.5 mg daily, and during the long-term rollover study, they received 1.0 mg of entecavir daily. In addition, some patients received concurrent lamivudine 100 mg daily for a brief period early in the rollover study before continuing with entecavir monotherapy after the study protocol was amended.

The 69 patients, 50 of whom tested positive for hepatitis B e antigen (HBeAg) and 19 who tested negative for HBeAg, underwent long-term liver biopsies. The median time of liver biopsy was 6 years (range, 3 - 7 years).

The investigators analyzed histologic improvement in 57 patients who had an adequate baseline biopsy, an adequate long-term biopsy, and a baseline Knodell necroinflammatory score of 2 or greater.

At the time of the long-term biopsy, all patients had HBV DNA levels of less than 300 copies/mL, and 86% had normalized alanine aminotransferase (ALT) levels.

Histologic improvement, defined as a decrease of 2 points or greater in the Knodell necroinflammatory score and no worsening of the Knodell fibrosis score, was observed in 96% of patients. In addition, an improvement of more than 1 point in the Ishak fibrosis score was seen in 88%, including all 10 patients who had advanced fibrosis or cirrhosis when they entered the phase 3 studies, the authors report.

Most patients (96%) experienced at least 1 adverse event at some time during entecavir treatment. Serious adverse events occurred in 25% of patients. No patient stopped entecavir because of adverse events.

The authors point out their study limitations, which include changes to the long-term rollover study, which made it impossible to evaluate the effect of the increased dose of entecavir or concurrent lamivudine on the results.

"These data support the conclusion that in most nucleoside-naïve 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," the study authors conclude. "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. The safety profile, potent suppression of HBV replication, and low potential for antiviral drug resistance in nucleoside-naïve patients make long-term treatment of CHB with entecavir monotherapy possible."

Commentary: Study Supports Past Findings

Asked to provide independent commentary about this study by Medscape Medical News, Kapil Chopra, MD, clinical director of hepatology at the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, said the study was able to demonstrate clearly that long-term antiviral therapy with entecavir improves the inflammation and reverses the fibrosis that occurs with chronic HBV infection.

"The study supports the earlier observations that effectively suppressing hepatitis B viral replication provides tangible, histologic benefits. If the virus can be adequately suppressed or made undetectable by antiviral therapy, then these benefits are much more likely," he said. "It tells us that the longer the duration of antiviral therapy the more benefit in terms of reversing the damage caused by the virus."

Dr. Chopra added that the level of resistance to entecavir was low. "This is the first time that a potent drug like entecavir has shown such a very low level of resistance, unlike that seen with lamivudine and adefovir. The sustained benefit is lost if resistance develops during antiviral therapy, so if you can avoid resistance, there is more likelihood of long-term benefit."

That some patients also received concurrent treatment with lamivudine "makes it difficult to draw conclusions that monotherapy with entecavir alone leads to these good outcomes. And in patients with cirrhosis, there is a sampling error using histology alone. A more solid endpoint would have been improvement in portal pressure, but this was not used here," Dr. Chopra said.

He added that it remains unclear whether the good results seen with long-term entecavir therapy will lead to any change in the incidence of hepatocellular carcinoma.

The study was sponsored by Bristol-Myers Squibb Pharmaceutical Research Institute. Dr. Chang has disclosed various financial relationships with Gilead Sciences, Bristol-Myers Squibb Co, GlaxoSmithKline, Schering-Plough Corp, and Pfizer Inc. Dr. Chopra has disclosed no relevant financial relationships.

Hepatology. Published online August 3, 2010. Abstract

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