By Liz Highleyman

Several antiviral agents have potent activity against hepatitis B virus (HBV), but the ability of the virus to develop resistance mutations as it evolves is a potential challenge to long-term treatment success.

Evidence continues to accumulate, however, showing that newer anti-HBV agents appear to have a higher barrier to resistance that the old standard of care, lamivudine (Epivir-HBV). Furthermore, combination therapy -- the mainstay of antiretroviral therapy for HIV -- can help slow or halt the emergence of resistance mutations.

Several presentations this week at the 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in San Francisco looked at long-term data in chronic hepatitis B patients treated with entecavir (Baraclude).

Study ETV-901 is an extended follow-up analysis of individuals with chronic HBV who were initially treated in earlier clinical trials. The multinational studies ETV-022 and ETV-027 previously found that 0.5 mg once-daily entecavir monotherapy decreased HBV viral load and improved liver histology more than lamivudine at 48 weeks in hepatitis B "e" antigen (HBeAg) positive and HBeAg negative patients, respectively. Participants could then opt to remain on entecavir (1.0 mg daily) in ETV-901.

Yun-Fan Liaw and colleagues presented histological results for a subset of 69 ETV-901 participants (47 HBeAg positive, 16 HBeAg negative) with at least 3 years of cumulative entecavir treatment and evaluable liver biopsy samples at baseline. Within this group, 56 also had evaluable biopsies at 48 weeks and 57 had long-term biopsies, with a median interval of 6 years (range 3-7 years).

The long-term cohort was mostly male (82%), predominantly Asian (67%), and the mean age was 40 years. HBV genotypes were well distributed (ranging from 13% for genotype D to 33% for genotype C).

The primary histology endpoints were proportion of patients with histological improvement (> 2 point decrease in Knodell necroinflammatory score and no worsening of Knodell fibrosis score) and improvement in Ishak fibrosis score (> 1 point decrease) compared with baseline. Secondary endpoints included proportions with HBV DNA < 300 copies/mL, ALT normalization (< 1 x upper limit of normal), and those with a baseline histological activity index (HAI) score > 4 who achieved a score of < 3 during follow-up.

Results

• 44 of 56 patients (73%) showed histological improvement at 48 weeks and 55 of 57 (96%) did so long-term.

• 18 patients (32%) and 50 patients (88%), respectively, showed > 1 point improvement in Ishak fibrosis score.

• 3 of 42 patients (7%) at 48 weeks and 25 of 43 (58%) experienced > 2 points improvement in fibrosis score.

• The mean change from baseline is Ishak fibrosis score was -0.2 at 48 weeks and -1.53 in the long-term biopsies.

• All 10 patients with advanced fibrosis or cirrhosis (Ishak fibrosis score 4-6) at baseline experienced > 1 point improvement.

• 4 patients with cirrhosis at baseline (Ishak score ? 5) experienced improvement, with a median change of -3 (range -1 to -4).

• The mean change in Knodell necroinflammatory scores was -3.39 at week 48 and -6.37 long-term.

• Among patients with a baseline Knodell HAI score > 4 at baseline, 12 of 54 patients (22%) had a score < 3 at 48 weeks, and 41 of 55 (75%) did so long-term.

• 40 of 57 patients (70%) had HBV DNA < 300 copies/mL at 48 weeks, and 57 of 57 (100%) did so long-term.

• ALT normalization occurred in 38 of 57 patients (67%) at 48 weeks, and 49 of 57 (86%) long-term.

• 1 of 41 (2%) HBeAg positive patients experienced HBeAg loss at 48 weeks, rising to 22 of 40 (55%) long-term.

• 1 of 41 (2%) experienced HBe seroconversion at 48 weeks, increasing to 13 of 40 (33%) long-term.

• The safety profile of entecavir was consistent with previous experience.

• 25% experienced serious adverse events (AEs) and 3% experienced ALT flares while on treatment, but none discontinued due to AEs.

Based on these findings, the investigators concluded, "Long-term treatment with entecavir in a cohort of nucleoside-naive chronic hepatitis B patients treated for a median of 6 years resulted in profound and durable virologic suppression, histologic improvement, and normalization of liver histology, with regression of fibrosis/cirrhosis.

"These data suggest that long-term treatment with Baraclude has the potential to stop liver damage and may even improve liver fibrosis caused by chronic hepatitis B infection," said Dr. Liaw in a press release issued by Bristol-Myers Squibb. "The ability to provide effective long-term treatment with a potent antiviral with minimal resistance represents a positive step forward."

Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan; National Cheng Kung University Medical College, Tainan, Taiwan; Changhua Christian Hospital, Changhua, Taiwan; University Of Miami Hospital & Clinics, Miami, FL; Yonsei University College of Medicine, Seoul, South Korea; Queen Mary's Hospital, University of Hong Kong, Hong Kong, China; Hadassah Medical Center, Jerusalem, Israel; University of Calgary, Calgary, Alberta, Canada; Klinika Chorob Zakaznych AM, Bydgoszcz, Poland; Armed Forces Institute of Pathology, Washington, WA; Research & Development, Bristol-Myers Squibb, Wallingford, CT and Princeton, NJ.

Entecavir Discontinuation

In another ETV-901 analysis, Daniel Shouval and colleagues looked at 3-year outcomes in HBeAg negative patients who re-initiated entecavir after discontinuing therapy. In ETV-207, participants who met protocol-defined response endpoints were taken off therapy after 52 weeks. Those who relapsed within 6 months could re-enroll in ETV-901.

The re-treatment cohort included 99 patients who enrolled in ETV-901 with a treatment gap of at least 60 days between studies and were re-treated with 1 mg daily entecavir; 76 and 66 patients, respectively, were included in 2-year and 3-year analyses.

Results

• After 2 years of entecavir re-treatment, 91% of patients had HBV DNA < 300 copies/mL and 95% did so after 3 years.

• 79% experienced ALT normalization at 2 years and 86% did so at 3 years.

• Here, too, safety data was consistent with previous experience.

In conclusion the researchers stated, "ETV-027 demonstrated that discontinuation of effective antiviral therapy in HBeAg negative patients after 52 weeks of treatment results in rebound of viremia and increases in ALT."

Liver Unit, Hadassaha Medical Organization, Jerusalem, Israel; Queen Mary Hospital, University of Hong Kong, Hong Kong, China; National Cheng Kung University Medical College, Tainan, Taiwan; Hospital Italiano, Buenos Aires, Argentina; Changhua Christian Hospital, Changhua, Taiwan; Klinika Chorob Zakaznych AM, Bydgoszcz, Poland; Monash University, Melbourne, Victoria, Australia; University of Hawaii, Honolulu, HI; Research & Development, Bristol-Myers Squibb Company, Wallingford, CT.

11/04/08

References

Y Liaw, T Chang, S Wu, and others. Long-term entecavir therapy results in reversal of fibrosis/cirrhosis and continued histologic improvement in patients with HBeAg(+) and (-) chronic hepatitis B: Results from studies ETV-022, -027 and -901. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 894.

D Shouval, C Lai, T Chang, and others. Three years of entecavir (ETV) re-treatment of HBeAg(-) ETV patients who previously discontinued ETV treatment: Results from study ETV-901. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 927.

Other source
Bristol-Myers Squibb. New Data Suggest Long-Term Treatment with BARACLUDE (entecavir) May Reduce Liver Damage Caused by Chronic Hepatitis B. Press release. November 2, 2008.