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Adefovir for HBV HBeAg-negative: 4 years- safety, antiviral efficacy, resistance, ALT normalization, creatinine & phosphorous
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Reported by Jules Levin
Adefovir is a similar drug to tenofovir (Viread). Tenofovir is used for HIV treatment, as you know, & it has antiviral activity against HBV. Several studies have been conducted examining tenofovir for HBV & in HBV/HIV coinfected patients & these studies show that tenofovir is at least as potent as ADV & perhaps more potent. Ongoing studies continue to examine tenofovir for HBV treatment. Unlike in HIV, treatment guidelines for HBV have not been established & continue in development. You can become familiar & educated about HBV diagnostics & treatment by reading the numerous articles in the HBV section of the NATAP website that discuss care & treatment for HBV & HBV/HIV coinfection.
"Adefovir Dipivoxil (ADV) B Demonstrates Sustained Efficacy in HBeAg-Negative Chronic Hepatitis B (CHB) Patients"
S Hadziyannis (Henry Dunant Hospital, Athens, Greece) reported in a poster (#492) at 40th annual meeting of EASL (April 2005, Paris) this information & study results. Also at EASL P Marcellin reported in an oral talk the 144 efficacy results for Adefovir in HBeAg-positive patients:
Adefovir Week 144 Efficacy in HBeAg+
"Increasing Serologic, Virologic and Biochemical Response Over Time to Adefovir (ADV) 10 mg in HBeAg+ Chronic Hepatitis (CHB) Patients"
http://www.natap.org/2005/EASL/easl_13.htm
AUTHOR SUMMARY
--4 yrs of ADV resulted in significant & sustained reductions in HBV DNA & ALT (77% <1000 copies/ml)
--increasing proportions of patients achieving undetectable HBV DNA & ALT normaliztion (91% at week 192)
--no change in safety profile with extended dosing up to 192 weeks
--cumulative incidence of resistance with ADV is less than incidence of resistance with lamivudine at year 1: cumulative ADV resistance in this study in HBeAg-negatives: 18% after 192 weeks; 11% after 144 weeks; 3% after 96 weeks; 0 after 1 year.
Background information about Adefovir provided by Hadziyannis:
--nucleotide analogue of adenosine monophosphate
--activity against wild-type & lamivudine (3TC)-resistant (LAM-resistant) HBV
--10mg daily
--durable HBV DNA suppression with a high thresold for the development of resistance
see NATAP Adefovir Resistance report from EASL
Adefovir Resistance report: 4 years update
"Incidence and predictors of emergence of HBV Muations Associated with ADV Resistance During 4 years of ADV Therapy for Patients with Chronic HBV"
http://www.natap.org/2005/EASL/easl_14.htm
--safety profile similar to placebo in 48 week controlled trials
KEY INCLUSION CRITERIA
--HBsAg+
--HBeAg-negative, anti-HBe+, and HBV DNA > 100,000 copies/ml
--compensated liver disease
--ALT x ULN >=1.5 to 15
--adequate renal function
STUDY DESIGN
Patients randomized 2:1 to receive ADV 10mg or placebo for 48 weeks. After which, placebo patients received ADV. Liver biopsies are performed at weeks 48 & 96. This report shows week 144 results & study is continuing for 2 additional years.
BASELINE DEMOGRAPHICS
Median age: 47
Male: 81%
Asian: 26%
Caucasian: 70%
Prior IFN: 37%
Prior LAM: 7% (less than 12 wks prior exposure)
The efficacy population in this study (n=70) has similar demographics to the Safety Population (n=125); the Safety population includes patients with up to 3-4 years cumulative ADV exposure. The Efficacy Population includes patients randomized to ADV in Year 1 & Year 2 of study.
BASELINE HBV DISEASE CHARACTERISTICS
Median HBV DNA: 7 log copies/ml (Efficacy population, 7 log copies/ml Safety Population
Median ALT: 2.3 x ULN (Efficacy Pop), 2.4 x ULN, (Safety Pop)
Cirrhosis: 11% (Efficacy Pop), 11% Safety Pop)
RESULTS
HBV DNA <1,000 copies/ml
Kaplan Meier estimates
Week 192: 77%
Week 144: 77%
Week 96: 77%
Week 48: 63%
HBsAg loss was observed in 4/125 (3.2%) of patients by week 192
ALT NORMALIZATION
Kaplan Meier Estimates
Week 192: 91%
Week 144: 88%
Week 96: 83%
Week 48: 73%
CLINICAL ADVERSE EVENTS
CREATININE & PHOSPHOROUS
Three patients in the long term safety & efficacy study had a confirmed increase in serum creatinine >+0.5 mg/dL from baseline through week 192: all resolved Ð 1 on treatment & 2 after discontinuation.
No patient developed confirmed serum phosphorous <2.0 mg/dL through 192 weeks.
RESISTANCE EVALUATION
ADV-Resistant mutation-
Weeks 0-48 (n=123): 0
Weeks 49-96 (n=134a): 4
Weeks 97-144 (n-124a): 10
Weeks 144-192 (n=67b): 5
a-includes patients who received placebo during the first year
b=includes only patients who received ADV 10mg in the first year.
All samples with detectable serum HBV DNA by PCR (>1000 copies/ml) at weeks 48, 96, 144 & 192 were analyzed.
The cumulative incidence of adefovir resistance mutations in study 438 at weeks 48, 96, 144 & 192 was 0%, 3%, 11%, & 18%, respectively.
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