Entecavir (Baraclude) Demonstrates Greater Antiviral Activity than Adefovir (Hepsera) in Hepatitis B Patients with Decompensated Liver Disease

		SUMMARY: Entecavir (Baraclude) exhibited greater antiviral activity against hepatitis B virus (HBV) than adefovir (Hepsera) in patients with decompensated liver cirrhosis, and was associated with clinical benefits including improved survival, according to a study presented this past weekend at the 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in Boston.

By Liz Highleyman

Treatment of chronic hepatitis B in patients with decompensated liver disease -- characterized by symptoms such as ascites (abdominal fluid accumulation), portal vein hypertension, and hepatic encephalopathy -- has not been extensively studied, but this group has an urgent need for effective therapy that can inhibit viral replication and slow further progression of liver damage.

To explore this issue, an international team of investigators conducted a randomized, open-label, Phase 3b study (ETV-048) comparing 1.0 mg/day entecavir versus 10 mg/day adefovir in this population.

A total of 100 participants randomly assigned to the entecavir arm and 91 assigned to the adefovir arm started treatment. Most patients (about 75%) were men and the mean age was about 52 years. About half were Asian and about one-third were white. Participants could have prior experience with interferon alfa or lamivudine (Epivir-HBV), but no other anti-HBV therapies. About one-third had lamivudine resistance.

Just over half the participants were hepatitis B "e" antigen (HBeAg) positive. The study population had highly advanced liver disease. The mean ALT level was about 100 U/L. The mean pre-treatment MELD score was about 16.0, and the mean Child-Pugh-Turcotte (CPT) score was about 8.5 (all had a score > 7). About 9% had CTP Class A, about 65% had CTP Class B, and about 25% had CTP Class C liver disease.

Results

	In the entecavir arm, 80 patients were treated for 24 weeks and 71 continued through 48 weeks.
	In the adefovir arm, 75 patients were treated for 24 weeks and 62 for 48 weeks.
	At Week 24, mean HBV DNA decreased by 4.48 log10 in the entecavir arm, compared with 3.40 log10 in the adefovir arm (P < 0.0001).
	At Week 48, HBV DNA decreases were 4.66 log10 and 3.90 log10, respectively.
	At Week 24, in a non-completer = failure analysis, 49% of participants in the entecavir arm achieved HBV DNA < 300 copies/mL, compared with 16% in the adefovir arm (P < 0.0001).
	At Week 48, the corresponding percentages were 57% and 20%, respectively (P < 0.0001).
	At Week 24, 59% of entecavir recipients achieved ALT normalization, compared with 39% in the adefovir arm (P = 0.0193).
	At Week 48, the corresponding percentages were 63% and 46%, respectively (P = 0.0425).
	At Week 24, no entecavir recipients achieved HBeAg loss or seroconversion, compared with 14% loss and 12% seroconversion in the adefovir arm.
	By Week 48, 11% of entecavir recipients achieved HBeAg loss and 6% experienced seroconversion, compared with 18% and 11%, respectively, in the adefovir arm.
	At Week 24, 1% of entecavir recipients (1 person) and no adefovir recipients achieved hepatitis B surface antigen (HBsAg) loss.
	By Week 48, 5% of entecavir recipients, but still no adefovir recipients, had achieved HBsAg loss.
	Mean MELD score fell by 2.0 points at Week 24 and by 2.6 points at Week 48 in the entecavir arm, compared with 0.9 and 1.7, respectively, in the adefovir arm.
	A majority of patients in both arms experienced either improvement or no further worsening of CTP scores (66% at Week 24 and 61% at Week 48 in the entecavir arm; 71% and 67%, respectively, in the adefovir arm).
	In the entecavir arm, 32% of patients at Week 24 and 35% at Week 48 experienced at least a 2-point decline in CTP score, compared with 24% and 27%, respectively, in the adefovir arm.
	Patients in the entecavir arm were more likely to survive and less likely to develop hepatocellular carcinoma (HCC) through 288 weeks.
	23% in the entecavir arm died during follow-up, compared with 33% in the adefovir arm.
	12% and 20%, respectively, developed HCC.
	Adverse event rates were high overall, 89% in the entecavir arm and 97% in the adefovir arm.
	54% and 47%, respectively, experienced grade 3-4 adverse events.
	1 entecavir recipient developed lactic acidosis (not requiring treatment) and 3 had low bicarbonate levels (vs 2 in the adefovir arm).

"Entecavir demonstrated superior antiviral activity to adefovir in this patient population," the researchers concluded. "Entecavir provided clinical benefit in patients with chronic hepatitis B infection and decompensated cirrhosis."

"This study represents an important first step in addressing an unmet medical need, as this is one of the first comparative studies to evaluate the safety and efficacy of antiviral therapy in this difficult-to-treat patient population," said ETV-048 study investigator Hugo Cheinquer in a press release issued by entecavir manufacturer Bristol-Myers Squibb. "Chronic hepatitis B is a lifelong disease and these data suggest that treatment with Baraclude may offer chronic hepatitis B patients with decompensated cirrhosis a treatment option."

Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan; Aristotle University of Thessaloniki, Thessaloniki, Greece; Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil; GB Pant Hospital, New Delhi, India; Siriraj Hospital, Mahidol University, Bangkok, Thailand; Alice Ho Miu Ling Nethersole Hospital, Hong Kong, China; University of Calgary, Calgary, Alberta, Canada; Columbia University Medical Center, Timisoara, Romania; McGuire VA Medical Center, Richmond, VA; Medical University, Lodz, Poland; Research and Development, Bristol-Myers Squibb Company, Wallingford, CT.

11/3/09

Reference
Y Liaw, M Raptopoulou-Gigi, H Cheinquer, and others. Efficacy and Safety of Entecavir versus Adefovir in Chronic Hepatitis B Patients with Evidence of Hepatic Decompensation. 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2009). Boston. October 30-November 1, 2009. Abstract 422.

Other source
Bristol-Myers Squibb. Baraclude (Entecavir) Demonstrated Greater Antiviral Efficacy Compared to Adefovir in New Study of Chronic Hepatitis B Patients with Evidence of Decompensated Cirrhosis. Press release. October 31, 2009.