Adding Adefovir Dipivoxil Versus Switching to Entecavir in Patients With Lamivudine-resistant Chronic Hepatitis B

Study Overview
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Brief Summary
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Antiviral resistance mutations limit the efficacy of therapy for chronic hepatitis B. At year 2, resistance to adefovir may occur as high as 25% in patients with history of lamivudine resistance. Resistance to entecavir is reported to be 10% in lamivudine refractory patients during the same period. However, combination of lamivudine and adefovir decreased the adefovir resistance rate as low as 0% in the recent studies. By overcoming the antiviral resistance, the efficacy of therapy will be maximized. This study is intended to compare the efficacy of two strategies, combination of lamivudine and adefovir vs. entecavir monotherapy in patients with lamivudine resistance.

Detailed Description
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Recently, published data showed combination of lamivudine and adefovir lead to PCR negativity (<1000 copies/mL) up to 80% in the treatment of lamivudine-resistant chronic hepatitis B at year 2 [Rapti et al. Hepatology 2007 Feb;45(2):307-13.]. Other studies also showed 76% and 69% PCR negativity in mostly HBeAg negative subjects [Lampertico et al. Hepatology 2006 Oct;44(4) Suppl 1:556A-557A, Lampertico et al. Hepatology 2006 Oct;44(4) Suppl 1:693A-694A]. In the study for the treatment of lamivudine-resistant chronic hepatitis B patients which included HBeAg positive subjects more predominantly, entecavir monotherapy showed 34% of PCR negativity (<300 copies/mL) at year 2 [Tenney DJ, et al. Antimicrob Agents Chemother. 2007 Mar;51(3):902-11]. Although it is assumed that combination of lamivudine and adefovir would be more effective than entecavir monotherapy for lamivudine resistant patients, we cannot verify the assumption, because there is no data directly comparing these two strategies until now. The aim of this study is to determine the most effective therapy for the patients with lamivudine resistant chronic hepatitis B. We will compare the PCR negativity (<60 IU/ml) of HBV DNA at year 2 in patients receiving 'the combination of lamivudine and adefovir' and 'entecavir monotherapy'. Since we are planning to include lamivudine-resistant chronic hepatitis B patients regardless of HBeAg status, we assumed the PCR negativity (<300 copies/mL or <60 IU/mL) in adefovir-lamivudine combination and entecavir monotherapy group as 55% and 34%, respectively, considering HBeAg status and lower detection limit of PCR. The result of this study will be able to clearly demonstrate the superiority of combination therapy with lamivudine and adefovir to entecavir monotherapy, which provide us the guide to rescue therapy for patients with lamivudine resistant HBV.

Official Title
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Prospective Randomized Study for the Comparison of Adding Adefovir Dipivoxil and Switching to Entecavir in Patients With Lamivudine-resistant Chronic Hepatitis B

Conditions
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Chronic Hepatitis B

Intervention / Treatment
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* Drug: combination of lamivudine+adefovir vs entecavir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Chronic hepatitis B patients (positive HBsAg > 6 months) Age > 16 year old Serum alanine aminotransferase (ALT) >1.5 x ULN History of treatment with lamivudine more than 6 months Proven lamivudine resistant mutation HBV DNA level> 20000 IU/mL Compensated liver disease (Child-Pugh-Turcotte score over 7; prothrombin time prolonged more than 3 sec above ULN or INR over 1.5; serum albumin >3 g/dL; total bilirubin <2.5 mg/dL; No history of variceal bleeding, ascites, or hepatic encephalopathy) Patients willing to give informed consent Exclusion Criteria: Out of inclusion criteria Any one of following Serum phosphorus level under 2.4 mg/dL Serum creatinine level over 1.5 mg/dL or creatinine clearance <50 mL/min Absolute neutrophil count lower than 1000 cell/mL Hb level under 10 g/dL (male), under 9 g/dL (female) Serum AFP >100 ng/mL History of treatment with interferon-a, thymosin-alfa 1, or nucleos(t)ide analogue other than lamivudine in 6 months of screening Recipient of organ transplantation Positive antibody test to HIV, HCV or HDV Pregnant or breast feeding women Patients with hepatocellular carcinoma or uncontrolled malignant disease Habitual alcohol drinker (>140 g/week for men, >70 g/week for women)

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br>combination therapy | Drug: combination of lamivudine+adefovir vs entecavir<br>* Lamivudine 100 mg/day, Adefovir 10 mg/day, Entecavir 0.5 mg/day<br>* Other names: Zeffix, Hepsera, Baraclude;|
| Active Comparator: B<br>entecavir | Drug: combination of lamivudine+adefovir vs entecavir<br>* Lamivudine 100 mg/day, Adefovir 10 mg/day, Entecavir 0.5 mg/day<br>* Other names: Zeffix, Hepsera, Baraclude;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PCR negativity (<60 IU/ml) of HBV DNA |  | At the end of year 2 (since starting rescue therapy for lamivudine resistance) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1. PCR negativity (<60 IU/ml) of HBV DNA at year 1 (interim analysis) 2. Degrees of HBV DNA reduction 3. ALT normalization 4. HBeAg seroconversion 5. Development of resistant mutation 6. Virologic breakthrough 7. Biochemical breakthrough |  | At the end of year 2 except interim analysis | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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lamivudine resistant mutations, rescue therapy