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Three year Results from a Double-Blind, Randomized, Pacebo-Controlled, Study of Adefovir (ADV) in HBeAg-negative Chronic Hepatitis B (CHB)
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Reported by Jules Levin
authors: Stephanos Hadziyannis (438 Study Group), Nicholas Tassopoulos, Ting-Tsung Chang, Jenny Heathcote, George Kitis, Mario Rizzetto, Patrick Marcellin, Seng Gee Lim, Shan Shan Chen, Sarah Arterburn, Jia Ma, Shelly Xiong, Michael Wollman, Craig James, Graeme Currie, Carol L Brosgart
Adefovir is a nucleotide analogue of adenosine monophosphate. It's a chain terminator of HBV DNA. It has activity against wild-type and lamivudine-resistant (LAM-R) HBV. It is dosed at one 10 mg tablet once daily.
Hepatitis B, HBeAg-negative individuals were initially randomized into ADV 10 mg (n=121) or placebo (n=62) for 48 weeks. For the next 96 weeks all patients received ADV 10 mg, this is a total of 96 weeks. Patients receiving ADV in the second 48 weeks were offered up to 3 additional years of ADV in this study. The objective was to evaluate the safety, efficacy and resistance profile of ADV over 96 and 144 weeks. Liver biopsies were performed at baseline, weeks 48, 96, and 144.
Brief summary: 64%, 71%, and 79% had undetectable HBV DNA (<1000 copies/ml) at weeks 48, 96, and 144. 34%, 53%, and 63% on ADV had improved fibrosis on Ishak Score at weeks 48, 96, and 144, and 4%, 5%, and 10% worsened, respectively. 3 patients (2%) had elevations in creatinine through 144 weeks. The overall incidence of ADV resistance mutations in study 438 at weeks 48, 96, and 144 was 0%, 3.0%, and 5.9%, respectively.
KEY STUDY INCLUSION CRITERIA
HBeAg-neg
HBeAb+
HBsAG+
HBV DNA >=105 copies/ml
ALT x ULN >= 1.5-15
Baseline liver biopsy
Adequate renal function (serum creatinine <1.5 mg/dL
BASELINE DEMOGRAPHICS
Median age 47 yrs
81% men
26% Asian
70% Caucasian
4% Black
Prior IFN 37%
Prior Lam 7% (<12 weeks prior exposure)
BASELINE HBV DISEASE CHARACTERISTICS
Median HBV DNA 7.08 log10 copies/ml
Median ALT 2.3 x ULN
Median ALT 99 IU/L
Cirrhosis 11%
The median serum HBV DNA was <3 log 1,000 copies/ml (LLQ) at week 24 and week 144 (Roche Amplicor Monitor PCR).
Median serum ALT was <40 by week 12 and <40, about 30 IU/L throughout the 144 weeks.
SERUM HBV DNA and ALT
HBV DNA <1000 copies/ml; ALT normalization
Week 0: 0% & 0%
Week 48: 64% & 73%
Week 96: 71% & 83%
Week 144: 79% & 88%
IMPROVEMENT in FIBROSIS -- ISHAK SCORE
Improvement defined as 1 pt or greater reduction; worsening defined as 1 pt or greater increase. Median Ishak Fibrosis Score at baseline=2.
Week 48 (n=112):
14% on placebo improved vs 34% on ADV.
36% worsened on placebo vs 4% on ADV.
Week 96 (n=19):
53% improved on ADV, about 5% worsened.
Week 144 (n=12): 63% improved on ADV, about 10% worsened.
CLINICAL ADVERSE EVENTS
| Wks 0-96 | Wks 0-144 | | N=79 | n=70 | | % of pts w/any events | 85% | 86% | | % w/AE possibly/prob related to study drug | 47% | 49% | | Serious AEs | 6% | 10% | | SAEs poss/prob related to study drug | 0% | 0% |
RENAL EVENTS
Elevations in serum creatinine >= 0.5 mg/dL: 3 pts (2%) through 144 weeks
--2 in yr 2, 1 in yr 3
--all resolved, 1 on treatment, 2 on disct.
No serum phosphorous changes seen through 144 weeks
RESISTANCE
LAM (V173L, L180M, M204V or I)
ADV (A181V, N236T)
| ADV-R | Wks | Wks | Wks | Reduced | | Mutation | 0-48 | 49-96 | 97-144 | Susc in vitro | | N=123 | n=134* | n=70 | | | N236T | 0 | 2 | 1 | 4-14 fold | | A181V | 0 | 2 | 1 | 2.5-3 fold |
*includes 55 week 144 samples from pts who received placebo during first year.
All samples with detectable serum HBV DNA by PCR (>1000 copies/ml) at weeks 48, 96, and 144 were analyzed.
The overall incidence of ADV resistance mutations in study 438 at weeks 48, 96, and 144 was 0%, 3.0%, and 5.9%, respectively.
AUTHOR'S CONCLUSIONS
3 yrs of ADV resulted in significant & sustained reductions in HBV DNA and ALT.
Increasing proportions of pts achieved undetectable HBV DNA and ALT normalization.
Safety profile over 144 weeks consistent with the first 48 weeks.
Resistance to ADV is delayed and infrequent.
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