HIVandHepatitis.com Highlights from the
56th Annual AASLD Conference
 November 11 - 15, 2005 San Francisco, California

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Five-year Treatment with Adefovir Results in Regression of Liver Fibrosis in Patients with HBeAg-negative Chronic Hepatitis B

Adefovir dipivoxil/ ADV [Hepsera] has shown efficacy and safety in HBeAg-negative patients in a randomized, placebo-controlled trial over 96 weeks.

Patients on ADV in year 2 were offered 3 more years of open label ADV. Efficacy and safety were analyzed after 4 years (Y4, n=55) and 5 years (Y5, n=70) of ADV, among patients randomized to placebo or ADV for the initial 48 weeks and then ADV thereafter.

The histologic data presented herein represent the first 5-year prospective, systematic set of biopsy results published from a trial of an oral antiviral.

Assessments included HBV DNA (Roche Amplicor Monitor LLQ 1000 copies/mL) and ALT every 12 weeks; liver biopsies at baseline (BL), Y1, Y2 (optional), and end of study (either Y4 or Y5); and annual resistance surveillance if HBV DNA >LLQ. All analyses were of observed data except histology (ITT last observation carried forward for Y2).

Results

  • Baseline (BL) characteristics (n=125) were: 82% male; 70% Caucasian; 27% Asian; median age 47 years; median serum HBV DNA 7.10 log10 copies/ml; median Ishak fibrosis score 2.0.
  • Liver histology was available from 46 patients who received either 4 (n=22) or 5 (n=24) years of ADV treatment; Y2 biopsies were not performed in all patients.
  • Necroinflammation showed improvement from the first year of therapy, and by ranked assessment over 80% of patients improved at Y4 or Y5 compared to BL.
  • The proportion of patients with >=1 point decrease in Ishak fibrosis consistently increased over 5 continuous years of ADV treatment (8/24 [33%] at Y1, 11/24 [46%] at Y2, and 17/24 [71%] at Y5; p=0.005 Cochran-Armitage exact test).
  • Among 12 patients with bridging fibrosis or cirrhosis at BL, 7 improved >=2 points after 4 or 5 years of treatment.
  • Six patients (5%) had HBsAg loss, 5 with anti-HBs at the last available time point.
  • The percentage of patients with HBV DNA <1000 copies/mL was 26/40 (65%) at Y4 and 37/55 (67%) at Y5, and ALT normalized in 21/30 (70%) and 38/55 (69%), respectively.
  • The cumulative probability of ADV resistance (A181V and/or N236T mutations) was 0%, 3%, 11%, 18%, and 28% at weeks 48, 96, 144, 192, and 240, respectively.
  • By year 5, 1 patient (<1%) had confirmed serum phosphorus <2.0 mg/dL and 4 patients (3%) had confirmed increase in serum creatinine >=0.5 mg/dL above BL.
  • Serious adverse events not related to ADV were reported in 22 patients (18%).

Conclusions

Treatment with ADV 10 mg QD for 5 years produced significant and increasing improvement in hepatic fibrosis confirming that durable viral suppression impacts fibrosis over time. The 5-year treatment was generally well-tolerated and the onset of resistance delayed.

Reference
S Hadziyannis and others. Long-term adefovir dipivoxil treatment induces regression of liver fibrosis in patients with HBeAg-negative chronic hepatitis B: Results after 5 years of therapy. Abstract LB 14. Program and Abstracts of the 56th annual meeting of the American Association for the Study of Liver Diseases. November 11-15, 2005. San Francico, CA.

Gilead Announcement on Study 438

Following is the text of an announcement released by Gilead after presentation of the 5-year data on study 438 at the 56th AASLD in San Francisco (November 11-15, 2005):

Gilead Sciences presented data [at the 56th AASLD] describing the sustained efficacy and safety of its oral antiviral drug Hepsera (adefovir dipivoxil) for up to five years of treatment among patients with hepatitis B "e" antigen-negative, presumed precore mutant chronic hepatitis B.

In this analysis, which includes the first prospective set of liver biopsies following five years of oral antiviral therapy, treatment with Hepsera resulted in regression of liver fibrosis in 75 percent of patients. Liver fibrosis is a serious consequence of chronic liver inflammation.

Study results were presented as a late breaker poster (#LB12) at the 56th American Association for the Study of Liver Diseases Annual Meeting in San Francisco, CA.

"This study offers long-term evidence of antiviral efficacy and clinical benefit among patients with a difficult-to-treat form of chronic hepatitis B," said Stephanos Hadziyannis, MD, Department of Medicine, Henry Dunant Hospital, Athens, Greece, and a lead investigator for Study 438.

"Long-term therapy is often the rule for patients with HBeAg-negative hepatitis B, and other oral antiviral therapies either lack long-term data in this population or lead to the development of genotypic resistance at high rates after only a few years. The data presented indicate that Hepsera may be able to reverse signs of liver damage in patients who received up to five years of continuous treatment, with a relatively low rate of resistance."

Dr. Hadziyannis presented efficacy, tolerability, resistance and safety data from an open-label extension of Study 438, in which patients with HBeAg-negative chronic hepatitis B received Hepsera monotherapy continuously for up to 240 weeks.

Liver biopsies at years one, two, four and five (240 weeks) showed continual improvement in inflammation and regression of fibrosis:

- Eighty-three percent (20/24) and 75 percent (18/24) of patients showed improvement in inflammation and regression of fibrosis following 240 weeks of Hepsera treatment, respectively.

- Sixty-nine percent (38/55) of patients who received Hepsera for 240 weeks exhibited improvement in liver function, as measured by normalization of serum alanine transferase (ALT) levels.

- Sixty-seven percent (37/55) of patients had suppression of viral replication, indicated by undetectable levels of serum HBV DNA (less than 1,000 copies/mL).

- In addition, four patients experienced HBsAg loss.

- Three of the four patients showed sAg seroconversion (complete loss of HBsAg and the development of antibodies to the HB "surface" antigen) by the end of the evaluation.

Data from this study also showed that biochemical, virologic, serological and histological results in the 240-week treatment group were similar to those in a separate cohort of patients treated with placebo for the first year and Hepsera monotherapy for four years (192 weeks), indicating that therapy with Hepsera is associated with sustained improvements in patients with HBeAg-negative chronic hepatitis B.

Two mutations (rtN236T and rtA181V) in the HBV polymerase enzyme have been associated with genotypic resistance to Hepsera. According to a life-table analysis, the cumulative probability of selecting these viral mutations with Hepsera was 0, 3, 11, 18 and 29 percent after 48, 96, 144, 192 and 240 weeks of treatment, respectively. These mutations are indicators of the potential for clinical breakthrough.

The safety profile of Hepsera remained favorable through 240 weeks of treatment:

- Four patients (3 percent) had a confirmed increase in serum creatinine of greater than or equal to 0.5 mg/dL from baseline by week 240 and of those one patient discontinued the study.

- One patient had a serum phosphorous level less than 2.0 mg/dL, which was observed after discontinuation of therapy.

- Serious adverse events were reported in 19 percent (24/125) of patients in the study; none were determined to be related to Hepsera.

- Three patients (2 percent) discontinued from the study due to adverse events.

For more information about Hepsera, including prescription information, visit www.hepsera.com.

 

FDA-Approved Drugs for HBV infection
Epivir-HBV
(lamivudine; 3TC)
Intron A
(interferon alfa-2b)
 Hepsera
(adefovir dipivoxil)
 Baraclude
(entecavir)
 Pegasys
(peginterferon alfa-2a)

 

 

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