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Peginterferon a-2a Plus adefovir vs Peginterferon a-2a for 48 Weeks in HBeAg-Negative Chronic Hepatitis B: Preliminary 24-Week Results of the PEG FOR B Randomized Multicenter Trial
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Reported by Jules Levin
EASL, April 2007, Barcelona, Spain
P Piccolo from Rome, Italy reported these data in the oral Hep B session at EASL. This study does not have a third arm of adefovir monotherapy.
AUTHOR CONCLUSIONS
In HBeAg-negative chronic HBV, after 24 weeks of treatment, peginterferon a-2a plus adefovir dipivoxil combination therapy compared to peginterferon a-2a monotherapy results in:
--a significantly more rapid decline of HBV DNA levels
--a significantly greater proportion of patients with undetectable HBV DNA
--no significant differences in ALT normalization
--no HBeAg loss
--no difference in safety
Followup data will confirm whether this advantage is sustained after treatment completion.
Intro by Piccolo: HBeAg-negative chronic hepatitis B represents the majority of HBV cases in the Mediterranean area, and in Italy it represents 90% of HBV cases. Progression to cirrhosis is frequent and spontaneous resolution is rare. Treatment for HBeAg-negative chronic hepatitis B is unsatisfactory with high rates of relapse after suspension of oral nucleos(t)ide antiviral drugs, which makes treatment necessary for long-term and even indefinitely raising the risk of drug-induced resistance. Interferon-based treatment can produce a sustained response; combination treatment with interferon plus nucleos(t)ide analogues could further improve response rates.
The aim of the study is to assess the efficacy and safety of 48 weeks of peginterferon plus adefovir vs peginterferon monotherapy in the treatment of HBeAg-negative chronic hepatitis B. The primary endpoint is HBV DNA <10,000 cp/ml after 24 weeks of post-treatment followup. Secondary endpoints are undetectable HBV DNA, ALT normalization, combined virological and biochemical response, and HBsAg loss.
60 patients are randomized to either Pegasys + ADV mg qd or Pegasys momotherapy for 48 weeks with 24 week followup.
INCLUSION CRITERIA: age >18 yrs; HBsAg+ >6 months; HBeAg negative; HBV DNA >10,000 cp/ml (Cobas Amplicor): ALT >upper limit of normal; histological diagnosis of chronic HVB within 2 yrs of enrollment; informed consent.
EXCLUSION CRITERIA: clinical signs of cirrhosis; co-infection with HCV, HDV, HIV; concomitant liver disease of other etiology; pregnancy or lactation; renal insufficiency; contraindication to IFN treatment; active substance abuse.
BASELINE CHARACTERISTICS
N=60
Male: 67%
Mean age: 47 (18-65)
Mean BMI: 25 (16.3-35.7)
Mean ALT: 3.3 x ULN (1-14))
Mean HBV DNA: 6.4 log cp/ml (4.5-8.8)
Mean grading: 5.5 (Ishak)
Mean staging: 2.4 (Ishak)
4 patients had advanced fibrosis (Ishak 5-6) (6.7%) at biopsy. 73% were treatment-naïve; those treated had received standard IFN and either lanivudine or ADV therapy as well. Baseline characteristics were well matched between the 2 groups.
INTERIM ITT ANALYSIS
WEEK 24
So far 52 patients have completed 24 weeks and are included in the analysis.
PROPORTION OF PATIENTS WITH >2 LOG DROP IN VIRAL LOAD
Week 4: 56.7% pegIFN+ADV, 44.8% pegIFN (pegifn+ADV n=27, PegIFN n=25)
Week 12: 90.0% pegIFN+ADV, 58,6% pegIFN (p<0.01)
Week 24: 92.6% pegIFN+ADV, 60.0% pegIFN (p<0.01)
VIROLOGICAL RESPONSE: UNDETECTABLE HBV DNA: <200 cp/ml
Week 4: 3.3% pegIFN+ADV, 3.4% pegIFN
Week 12: 26.7% pegIFN+ADV, 24.1% pegIFN
Week 24: 70.4% pegIFN+ADV, 32.0% pegIFN (p<0.01)
MEAN HBV DNA REDUCTION
For pegIFN+ADV reduction was -4.15 log at week 24 vs -2.78 for PegIFN (p<0.001). One half of those patients have completed 48 weeks and viral load decline is -4.1 for pegIFN+ADV vs -2.80 for pegIFN (p<0.01).
She said neither the 24 or 48 week data have so far shown any HBsAg loss.
SAFETY: 24 weeks
PegIFN+ ADV
Severe Adverse Events
Severe neutropenia (week 2)
Severe autoimmune thrombocytopenia (week 24): Piccolo highlighted this as she said there was 1 case previously reported related to adefovir.
Drop-Out (reason)
Persistent neutropenia (week 4)
Persistent depressiob (week 5)
Thrombocytopenia (week 21)
3 cases of Peg-IFN dose reduction due to neutropenia (wk 4), fatigue (wk 1), anemia (wk 1).
2 Peg-IFN dose suspensions: 1 due to neutropenia, 2nd due to persistent fever.
Peg-IFN
Severe Adverse Events
Severe dermatitis (week 10)
Kidney stone (week 24): not drug related she said
Drop-Out (reason)
Non compliance (week 2)
Persistent depression (week 10)
Severe dermatitis (week 10)
2 cases of Peg-IFN dose reduction: 1 due to ALT flare, 2nd due to thrombocytopenia.
2 Peg-IFN suspensions: 1 for neutropenia; 2nd for thrombocytopenia.
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