| 144-Week Safety and Efficacy Data on Adefovir Dipivoxil in Chronic Hepatitis B
144-week safety and efficacy data on the use of adefovir dipivoxil (Hepsera) in chronic HBV patients with hepatitis B 揺?antigen-positive were presented at the 55th AASLD in Boston. Gilead Science抯 Study 347 is a clinical trial of adefovir dipivoxil 10mg in hepatitis B 揺?antigen-positive patients (HBeAg-positive). The 揺?antigen is a viral protein found in the blood of many people infected with HBV.
Approximately 400 million individuals worldwide have CHB, a leading cause of cirrhosis and HCC. ADV has potent activity against wild-type and lamivudine-resistant HBV. Treatment with ADV 10 mg over 48 wks demonstrated significant histological, virological, serological and biochemical improvement compared to placebo (PLB) in CHB.
Eligibility: HBsAg+ ≥ 6 months, HBeAg+, serum HBV DNA ≥106 c/mL (Roche Amplico Monitor PCR, LLQ 1,000 c/mL) and ALT 1.2-10 x ULN. Prior interferon therapy allowed, if > 6 months prior to enrollment.
Patients (pts) were randomized to receive ADV 10 mg or 30 mg, or PLB. The study continued to evaluate the long term safety and efficacy of ADV 10 mg in pts who received ADV 10 mg in the first 48 wks. Results were reported up to 144 wks of therapy. Most pts had ≥ 1 dose PLB in year 2 due to a misallocation of dosing error. As the length of on study follow-up varies, K-M* estimates were used to conservatively evaluate proportions of pts achieving HBV DNA undetectability, ALT normalization, HBeAg loss and seroconversion.
Results
309 pts received ≥ 1 dose ADV 10 mg; 296, 231, and 84 pts were followed through 48, 96, and 144 wks; 74% male, 57% Asian and 38% Caucasian; median age 34 years. Baseline (BL) median serum HBV DNA 8.11 log10 c/mL; median ALT was 85 IU/L (2 x ULN).
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Note: Pts with confirmed HBeAg seroconversion or HBeAg loss were followed off-treatment in an observational study.
* Kaplan-Meier analysis
Adverse Events
The frequency and nature of adverse events (AEs), serious AEs and laboratory abnormalities was similar to PLB over 48 wks. Over 96 and 144 wks safety was consistent with that seen in the first 48 wks. Through 144 wks, no pt had a confirmed serum creatinine increase from BL of ≥ 0.5 mg/dL or a serum phosphorus < 1.5 mg/dL. No pt developed resistance by 48 wks; 2 (3.1%) developed resistance (1 N236T, 1 A181V) through 144 wks.
Conclusions
Treatment with ADV 10 mg over 144 wks resulted in increasing HBeAg loss and seroconversion rates. Continued reductions in serum HBV DNA and ALT levels were demonstrated with increasing proportions of patients achieving undetectable serum HBV DNA and ALT normalization. Resistance was delayed and infrequent. ADV 10mg was well tolerated with a safety profile consistent with that seen in PLB. No nephrotoxicity was observed. This study continues to evaluate the long-term safety and efficacy of ADV 10 mg.
Commentary
揅hronic hepatitis B is a challenging disease that often requires long-term therapy,?said Patrick Marcellin, MD, head of the Claude Bernard Research Center on Viral Hepatitis, Service d'H閜atologie and INSERM Unit 481, H魀ital Beaujon, Assistance Publique H魀itaux de Paris, Clichy; Professor Universit?Paris VII, France, and a lead investigator in Study 437.
揟his study suggests that in first-line treatment, Hepsera offers tolerability, continued inhibition of viral replication and normalization of liver enzymes for up to 144 weeks, with an increasing percent of patients achieving HBeAg seroconversion.?
About Hepsera
In conjunction with the release of results of Study 437, a Gilead announcement offered a summary review of information on adefovir dipivoxil, which follows below:
揂defovir dipivoxil, a nucleotide analogue for the treatment of chronic hepatitis B, is administered as a once-daily 10 mg tablet and works by inhibiting HBV DNA polymerase, an enzyme involved in the replication of the virus in the body.?/span>
揌epsera is now available in the United States and 16 countries in Europe. In April 2002, Gilead signed a licensing agreement with GlaxoSmithKline (GSK), granting to GSK rights to commercialize Hepsera in Asia, Latin America and other territories. Hepsera has now been approved in 15 countries in these regions.?/span>
揑n the United States, Hepsera is indicated for the treatment of chronic hepatitis B in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.?/span>
揟he adverse reactions considered at least possibly related to treatment reported in 3 percent or greater of patients in the first 48 weeks in Hepsera pivotal clinical studies were asthenia, headache, abdominal pain, nausea, flatulence, diarrhea and dyspepsia?/span>
揥ith extended treatment, mild to moderate increases in serum creatinine were observed uncommonly in patients with chronic hepatitis B and compensated liver disease treated with Hepsera for a median of 49 weeks and a maximum of 109 weeks.?
揅hanges in serum creatinine were observed very commonly in patients with pre- and post-transplantation lamivudine-resistant liver disease and multiple risk factors for changes in renal function who were treated with Hepsera for up to 129 weeks, with a median time on treatment of 19 and 56 weeks, respectively.?/span>
揅linical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of treatment with antiviral therapies for hepatitis B, including Hepsera. Special warnings and precautions for use are included in the package insert regarding monitoring of renal function, posttreatment exacerbations of hepatitis, use in patients with underlying renal impairment, patients co-infected with HIV, the occurrence of nucleoside analogue-associated lactic acidosis and severe hepatomegaly with steatosis.?/span>
11/03/04
Reference
P Marcellin and others. LONG TERM EFFICACY AND SAFETY OF ADEFOVIR DIPIVOXIL (ADV) 10 MG IN HBEAG+ CHRONIC HEPATITIS B (CHB) PATIENTS: INCREASING SEROLOGIC, VIROLOGIC AND BIOCHEMICAL RESPONSE OVER TIME. Abstract 1135 (poster). 55th AASLD. October 29-November 2, 2004. Boston, MA
[此贴子已经被作者于2004-11-4 10:42:58编辑过] | 
发表于 2004-11-5 00:42
