icon-folder.gif   Conference Reports for NATAP  
 
  EASL
39th Annual European Association for the Study of the Liver Conference
Berlin, Germany
April 14-18, 2004
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Adefovir 3 Year Study Results in Presumed Precore Mutant Chronic Hepatitis B: safety and efficacy
 
 
  Adefovir 3 Year Study Results in Presumed Precore Mutant Chronic Hepatitis B: safety and efficacy
 
"Three Year Results from a Double-Blind, Randomized, Placebo-Controlled, Study of Adefovir for Presumed Precore Mutant Chronic Hepatitis B"
 
Reported by Jules Levin
 
S Hadziyannis (Henry Dunant Hospital, Athens, Greece) reported results from this study at EASL Conference (April 14-18, 2004, Berlin, Germany). Here is his report.
 
Adefovir is a chain terminator of HBV DNA. It has activity against wild-type and lamivudine-resistant (LAM-R) HBV. The dose is one 10 mg tablet, once daily orally (dose interval modified for creatinine <50 ml/min).
 
The purpose of this study is to evaluate safety and efficacy of ADV over 96 and 144 weeks.
 
Brief summary: 3 years of ADV resulted in significant and sustained reductions in HBV DNA and ALT. Increasing proportions of patients achieved undetectable HBV DNA & ALT. Safety profile over 144 weeks consistent with first 48 weeks. Resistance to adefovir isdelayed & infrequent: In this study, 5.9% experienced ADV resistance after 3 yrs on ADV; across ADV studies over 144 weeks 3.9% had ADV resistance.
 
KEY INCLUSION CRITERIA
 
HBeAg-, HbeAb+, and HBsAg+
Compensated liver disease
HBV DNA >=105 copies/ml
ALT x ULN >= 1.5-15
Adequate renal function
 
STUDY 438 (0-144 weeks)
STUDY DESIGN

 
185 patients randomized to ADV or placebo. After 48 weeks patients receiving placebo were offered ADV for 2 additional years. After 3 years of study patients are offered 2 additional years for a total of 5 years in this study/ Liver biopsies are at week 48, 96 (optional), and week 144 (optional).
 
 
 
   
 
 
 
BASELINE CHARACTERISTICS
 
Weeks 0-144
N=70
Median age 47 yrs
Male 81%
Asian 26%
Caucasian 70%
Black 4%
Prior IFN 37%
Prior LAM* 7%

 
*less than 12 weeks exposure
 
BASELINE HBV DISEASE CHARACTERISTICS
 
Weeks 0-144
N=70
Median HBV DNA (log10 copies/ml*) 7.08
Median ALT (x ULN) 2.3
Median ALT (IU/L) 99
Cirrhosis 11%

 
*Roche Amplicor Monitor PCR Assay, LLQ 3 log10 copies/ml
 
 
 
   
 
 
 
 
 
   
 
 
 
SERUM HBV DNA and ALT
 
Week 0:
0% HBV DNA <1000 copies/ml
3% ALT Normalization
 
Week 48:
68% HBV DNA <1000 copies/ml
73% ALT normalization
 
Week 96:
69% HBV DNA <1000 copies/ml
83% ALT normalization
 
Week 144:
79% HBV DNA <1000 copies/ml
88% ALT normalization
 
Patients with HBV DNA >1000 copies/ml at baseline, n=70
Kaplan Meier estimates for patients with ALT at baseline, n=64
 
 
 
   
 
 
 
CHANGE IN ISHAK FIBROSIS SCORE from BASELINE
 
Week 48:
35% of patients improved
11% worsened
 
Week 144:
63% of patients improved
9% worsened
 
Improvement defined as >=1 point reduction
Worsened defined as >=1 point increase
Median Ishak Fibrosis at baseline=2
 
 
 
   
 
 
 
CLINICAL ADVERSE EVENTS
 
Week 0-96
N=79
Week 0-144
n=70
% of patients w/any events 85% 86%
% w/AE possibly/probably related to study drug 47% 49%
Serious AE 6% 10%
SAE possibly/probably related to study drug 0% 0%

 

 
RENAL LAB PARAMETERS
 
Wks 0-96
N=79
Wks 0-144
n=70
Serum Creatinine
increase from baseline >=0.5 mg/dL* 2 (2.5%) 3 (2.4%)
median change from baseline (mg/dL) 0.1 0
Serum phosphorous
<1.5 mg/dL* 0 0
median change from baseline (mg/dL) -0.2 -0.2

 
*confirmed (two consecutive lab abnormalities)
 
RESISTANCE EVALUATION
 
ADV resistance mutation N236T:
0 patients had mutation in 1st year (n=123), 2 in 2nd year (n=134*), and 1 in third year (n=70).
 
ADV-resistance mutation A181V:
0 patients got mutation in 1st yr, 2 in 2nd yr, and 1 in 3rd yr.
 
Reduced susceptibility to adefovir in vitro:
4-14 fold in patients with N236T;
2.5 to 3-fold in patients with A181V.
 
All samples with detectable serum HBV DNA by PCR (>1000 copies/ml) at weeks 48, 96, and 144 were analyzed.
 
The overall incidence of adefovir resistance in study 438 at weeks 48, 96, and 144 was 0%, 3.0%, and 5.9%, respectively.
 
*includes 55 and 144 samples from patients who received placebo during the first year.
 
Integrated Resistance Surveillance Across ADV Studies (0-144 weeks)
INCIDENCE OF ADV COMPARED TO LAMIVUDINE RESISTANCE

 
Year 1: 0% ADV; 24% lamivudine
Year 2: 2.0% ADV; 42% lamivudine
Year 3: 3.9% ADV; 53% lamivudine
Year 4: …ADV; 70% lamivudine
 
ADV (N236T+A181V)
LAM (YMDD)