New HBV treatment shows continued clinical benefit compared with lamivudine

January 2006

Entecavir (Baraclude, Bristol-Myers Squibb), the new chronic hepatitis B (HBV) agent, produced an increase in patients’ viral load suppression to undetectable levels compared with lamivudine (Epivir, GlaxoSmithKline) after 96 weeks of treatment, according to data presented at the 56th Annual Meeting of the American Association for the Study of Liver Disease.

“Data showed that 80% of patients taking Baraclude [for] up to 96 weeks experienced confirmed viral load reductions to undetectable levels compared to 39% of patients taking lamivudine,” said Robert Gish, MD, study investigator and medical director of the liver transplant program at the California Pacific Medical Center in San Francisco. “Viral load suppression to undetectable DNA means better histology, less inflammation and, in the long-term, a lower risk of cirrhosis and cancer.”

Also, none of the nucleoside-naive patients treated with entecavir experienced “virologic rebounds” due to drug resistance.

“We are making and breaking new ground here,” said Gish about the high rate of entecavir-treated patients who had undetectable levels of viral load (less than 300 copies/mL) and no drug resistance.

The development of resistance to antiviral treatment is “correlated with a high risk of disease progression” and occurs in about 20% of lamivudine-treated patients per year of use, according to Gish.

Clinical measures

The study consisted of 709 nucleoside-naive patients who were positive for the hepatitis B e antigen (HBeAg).

In patients treated for up to 96 weeks, therapy with entecavir also resulted in significant normalization of alanine aminotransferase (ALT) levels, an HBV marker, compared with lamivudine: 87% of patients treated with entecavir achieved normal ALT levels vs. 79% of lamivudine patients.

Entecavir’s HBeAg seroconversion, another clinical measure, compared favorably with lamivudine’s: 31% vs. 26%. The difference, however, was not statistically significant.

HBeAg conversion usually results in long-term suppression of HBV-DNA and allows patients to stop medication, explained Gish. Indeed, patients were responders and taken off the drug once they experienced HBeAg loss and suppression of HBV-DNA (less than 700 copies/mL). Thirty percent of entecavir-treated patients came off the drug in the second year of treatment vs. 25% of lamivudine-treated patients.

The 96-week data were an extension of the randomized study of 709 chronic HBV patients who were initially treated for 48 weeks with entecavir 0.5 mg once daily or lamivudine 100 mg once daily. Seventy-four entecavir and 67 lamivudine responders did not continue in the study, and 19 entecavir (HBV-DNA greater than 700 copies/mL) and 94 lamivudine nonresponders did not continue.

Patients only continued in the study past 48 weeks if they had very low HBV-DNA (less than 700 copies/mL) but had not yet achieved HBeAg loss. Two hundred forty-three entecavir and 164 lamivudine patients continued beyond 48 weeks.

The absence of virologic rebounds due to resistance in the second year of entecavir treatment among nucleoside-naive patients was likely due to the rapid and sustained suppression of viral replication, said Richard Colonno, MD, vice president of Infectious Diseases Drug Discovery at the Bristol-Myers Squibb Pharmaceutical Research Institute in Wallingford, Conn.

“If the virus is not replicating, it cannot create the mutations that give rise to resistant virus,” he said.

The phenomena of resistance helped foster the attitude that clinicians should use HBV antivirals as “drugs of last resort” instead of using them too early to “prevent downstream liver events,” said Colonno. “Entecavir has the potential to change that paradigm.”

Gish hopes that the new data will provide clinicians with further encouragement to treat chronic hepatitis B, which has been “grossly undertreated” in the past.

“Things are changing now. We know that the combination of a viral load greater than 105 copies/mL and elevated ALT causes a 12-fold increase in the likelihood of death due to cirrhosis or cancer. There is a huge change in attitude about treatment going on,” he said.

For more information:

• Gish R. Abstract 181. Presented at: 56th Annual Meeting of the American Association for the Study of Liver Disease; Nov. 11-15, 2005; San Francisco.