Long-term
Efficacy and Safety of Adefovir in HBeAg-positive Hepatitis B Patients
Antiviral
treatment for chronic hepatitis B virus (HBV) infection
is limited by the emergence of drug resistance, which can develop over the course
of months or years.
As
presented at the 57th AASLD annual meeting taking place this week in Boston, an
international team of researchers* conducted a study of the long-term efficacy
and safety of adefovir (Hepsera)
for the treatment of chronic hepatitis B. Adefovir carries a risk of kidney toxicity,
though this appears uncommon at low doses.
The study originally included
more than 500 patients with HBV "e" antigen (HbeAg)-positive chronic
hepatitis B randomly assigned to receive 10 or 30 mg daily adefovir or placebo.
As previously reported, adefovir produced better virological, histological, and
biochemical responses compared with placebo over the first 48 weeks of therapy.
Among
the 171 subjects in the 10 mg adefovir arm, those with confirmed HBeAg loss or
seroconversion were followed off treatment, while those who did not seroconvert
in years 1 or 2 were given the option to continue therapy for 3 additional years.
A total of 65 patients continued therapy, and the AASLD report presented 5-year
follow-up data for 41 who completed the long-term study.
Results
Patients in the long-term follow-up study were 83% men, the median age was 34
years, 74% were Asian, the median serum HBV DNA level was 8.45 log copies/mL,
and the median ALT level was 2.0 x ULN.
Among the 41 patients still on adefovir after 5 years, the mean decrease in HBV
DNA from baseline was 4.05 log copies/mL.
The mean decrease in serum ALT was 50 U/L.
Markov 2-state probabilities of HBeAg loss and seroconversion at 240 weeks were
60% and 48%, respectively.
4 patients (2%) lost HBsAg and seroconverted to anti-HBs.
Repeat liver biopsies in 15 patients showed necroinflammation improvement in 67%
and fibrosis improvement in 60%.
Knodell necroinflammation and Ishak fibrosis scores decreased by a mean of 4 (P
= 0.014) and 1 (P = 0.022), respectively.
The adefovir-resistance mutations A181V and/or N236T were not detected in any
of the 171 patients at year 1, but developed in 13 long-term subjects (20%), beginning
at week 195.
12 of the 65 long-term patients (18%) developed virological resistance (defined
as resistance mutations with HBV DNA rebound or failure to ever attain HBV DNA
< 3 log copies/mL).
5 patients (8%) developed clinical resistance (virological resistance plus ALT
rebound after normalization).
There were no serious adverse events related to adefovir.
6 patients (9%) had a confirmed increase in serum creatinine of ? 0.5 mg/dL beginning
after 3.5 years, and 2 (3%) discontinued adefovir.
Conclusion
The
researchers concluded that, "Treatment with adefovir beyond 48 weeks produced
long-term virologic, biochemical, serologic, and histologic improvements and was
safe and well-tolerated in patients with HbeAg-positive chronic hepatitis B."
Service
d'Hepatologie, INSERM Unite 481, Hopital Beaujon, Clichy, France; Department of
Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan; Division
of Gastroenterology, National University Hospital, Singapore, Department of Medicine,
Monash University and Monash Medical Centre, Melbourne, VIC, Australia; Liver
Center, Huntington Medical Research Institute, Pasadena, CA; Gilead Sciences,
Foster City, CA.
P
Marcellin, T-T Chang, S G Lim, and others. Adefovir dipivoxil for the treatment
of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med 348(9):
808-816. February 27, 2003.
Patients in the long-term follow-up study were 83% men, the median age was 34
years, 74% were Asian, the median serum HBV DNA level was 8.45 log copies/mL,
and the median ALT level was 2.0 x ULN. 
