SUMMARY: Entecavir (Baraclude), a nucleoside analog approved for treatment of hepatitis B virus (HBV) infection, continued to demonstrate good viral suppression, reduced necro-inflammation, and alanine aminotransferase (ALT) normalization for nearly 5 years among Asian patients in large clinical trials, researchers reported at the American Association for the Study of Liver Diseases "Liver Meeting" (AASLD 2010) this week in Boston. Entecavir was well-tolerated and no drug resistance was observed.

By Liz Highleyman

Entecavir (Baraclude) Tablet Entecavir Drug Summary Page

Several nucleoside/nucleotide analogs are approved for treatment of chronic hepatitis B, including entecavir, lamivudine (Epivir-HBV), adefovir (HepSera), and tenofovir (Viread). These agents have potent activity against HBV, but when used alone the virus may develop resistance that can compromise the effectiveness of long-term therapy. Newer drugs, however, generally have a higher barrier to resistance.

Asian Patients

Robert Gish from California Pacific Medical Center in San Francisco and colleagues looked at outcomes among Asian participants in a pair of Phase 3 studies of entecavir, ETV-022 and ETV-027.

HBV is endemic in many Asian countries; most people with hepatitis B in these regions are infected as infants, and the virus is much more likely to persist in people infected so young (about 90% chronic, compared with about 10% of those infected as adults).

In these 2 trials, previously untreated hepatitis B "e" antigen (HBeAg) positive and negative chronic hepatitis B patients were randomly assigned (1:1) to receive 0.5 mg entecavir or 100 mg lamivudine for a minimum of 52 weeks.

Overall, entecavir demonstrated superior histological (> 2-point reduction in Knodell necro-inflammatory score without worsening of Knodell fibrosis score), virological (decreased HBV DNA viral load), and biochemical (ALT normalization) responses compared with lamivudine; the safety profiles of the 2 drugs were similar.

At AASLD, researchers present safety and efficacy data for entecavir among 657 Asian patients, who made up about half of all participants in the 2 studies; 406 were HBeAg positive and 251 were HBeAg negative. A majority (70%-85% across study arms) were men and the average ages were 32 years in ETV-022 and 44 years in ETV-027. The most common HBV genotypes were B and C. The average Ishak fibrosis score at baseline was just over 2.0.

Results

	70% of Asian patients in the entecavir arms experienced histological improvement at week 48, compared with 64% in the lamivudine arm; rates were similar in ETV-022 and ETV-027.
	Overall, 80% taking entecavir achieved HBV DNA < 400 copies/mL, compared with 56% taking lamivudine, but response rates differed in the 2 studies:
	ETV-022: 69% vs 40%, respectively; ETV-027: 93% vs 77%, respectively.
	68% of entecavir recipients achieved ALT <1 x upper limit of normal, compared with 64% of lamivudine recipients; lamivudine response rates were the same in both studies, but entecavir response was better in ETV-027 than in ETV-022 (76% vs 63%).
	Patients in the entecavir arms had the following serological responses:
	16% experienced BeAg loss; 16% experienced HBeAg seroconversion; 1 person achieved hepatitis B surface antigen (HBsAg) loss.
	None of the Asian participants developed entecavir resistance.
	Safety profiles of the 2 drugs were similar, as was the case in the study as a whole:
	6% in both arms experienced serious adverse events; 2% in both arms experienced ALT flares; < 1% in the entecavir arms and 2% in the lamivudine arms discontinued therapy due to adverse events.

Based on these findings, the investigators concluded, "Entecavir demonstrated significant histologic, virologic, and biochemical responses in Asian chronic hepatitis B patients who were HBeAg-positive or -negative at week 48."

"The efficacy and safety profile of entecavir in Asians is consistent with its profile in the overall population as previously documented," they added.

Long-term Therapy

In the second poster presentation, C. Pan from Mount Sinai School of Medicine and colleagues looked at the long-term effectiveness of entecavir among treatment-naive Asian patients who participated in Study ETV-022 (receiving 0.5 mg entecavir) and subsequently rolled over into ETV-901 (receiving 1.0 mg entecavir). The analysis included 94 Asian participants with available 240-week (about 4.6 years) data.

Results

	The proportion of people with HBV DNA < 300 copies/mL rose steadily over the course of treatment:
	Week 48: 59%; Week 96: 84%; Week 144: 90%; Week 192: 93%; Week 240: 95%.
	Percentages with ALT <1 x upper limit of normal did not show a consistent pattern:
	Week 48: 63%; Week 96: 75%; Week 144: 73%; Week 192: 87%; Week 240: 76%.
	The cumulative rate of HBeAg loss at week 240 was 40%;
	The cumulative rate of HBeAg seroconversion was 18%.
	Even up to 5 years, no entecavir resistance was detected.
	Again, the safety profile for entecavir in this Asian cohort reflected that of the study as a whole.
	11% of patients experienced adverse events, but none discontinued therapy for this reason.

"Entecavir through 5 years achieved and maintained high rates of HBV DNA suppression and ALT normalization, with no resistance detected in [nucleoside/nucleotide-naive] HBeAg positive Asian chronic hepatitis B patients," the researchers concluded. "The safety profile of entecavir was consistent with the observations made in the overall population."

Investigator affiliations:

Gish study: Division of Hepatology and Complex GI, California Pacific Medical Center, San Francisco, CA; University of Hawaii, Honolulu, HI; Division of Gastroenterology, Mount Sinai School of Medicine, New York, NY; Center for Liver Disease, Virginia Mason Medical Center, Seattle, WA; Division of Gastroenterology, University of California, Irvine Medical Center, Orange, CA; Queen Mary Hospital, Hong Kong, China; National Cheng Kung University Medical College, Tainan, Taiwan; Severance Hospital, Yonsei University College of Medicine, Seoul, Korea; Research & Development, Bristol-Myers Squibb Company, Wallingford, CT and Plainsboro, NJ; Pfleger Liver Institute, University of California School of Medicine, Los Angeles, CA.

Pan study: Division of Gastroenterology, Mount Sinai School of Medicine, New York, NY; Pfleger Liver Institute, University of California School of Medicine, Los Angeles, CA; Center for Liver Disease, Virginia Mason Medical Center, Seattle, WA; Division of Gastroenterology, University of California, Irvine Medical Center, Orange, CA; National Cheng Kung University Medical College, Tainan, Taiwan; Queen Mary Hospital, Hong Kong, China; Kangnam St. Mary Hospital, Catholic University Medical College, Seoul, Korea; Foothills Provincial General Hospital, University of Calgary, Calgary, Alberta, Canada; Research & Development, Bristol-Myers Squibb Company, Wallingford, CT and Plainsboro, NJ; University of Hawaii, Honolulu, HI.

11/2/10

References

RG Gish, NC Tsai, C Pan, and others. Efficacy and Safety of Entecavir in Nucleos(t)ide Naive Asians with HBeAg-Positive and -Negative Chronic Hepatitis B: Results from Studies ETV-022/027. 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2010). Boston, October 29-November 2, 2010. Abstract 485.

C Pan, MJ Tong, KV Kowdley, and others. Long-term Entecavir Treatment for up to 5 Years in Asians with HBeAg-positive Nucleos(t)ide naive Chronic Hepatitis B: Results from ETV-022 and -901. 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2010). Boston, October 29-November 2, 2010. Abstract 478.