Adefovir and Lamivudine for Entecavir Resistance (ALTER Study)

Study Overview
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Brief Summary
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Entecavir has been one of the option for treatment of lamivudine resistant chronic hepatitis B (CHB). In case of entecavir resistance, adefovir could be used. However, sequential monotherapy may result in multidrug resistance. It is thought that adefovir and lamivudine combination therapy reduce the risk of adefovir resistance, thereby continued therapy will lead to suppression of hepatitis B virus (HBV) DNA to be undetectable in patients with entecavir resistance. This study aim to evaluate the efficacy of adefovir and lamivudine combination therapy in CHB patients with entecavir resistance.

Detailed Description
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Entecavir is a potent antiviral agent for the treatment of chronic hepatitis B (CHB). However, the incidence of entecavir resistance increases over 50% at 5th year in lamivudine-refractory CHB patients. Considering cross resistance profile, adefovir is a good option for managing entecavir resistance. However adefovir monotherapy may lead to adefovir resistance, because entecavir resistant hepatitis B virus (HBV) retain lamivudine resistance. Previously, combination of adefovir and lamivudine was reported to be effective in a patient with entecavir resistance, but only as a case report form. No further data are available on this combination therapy in a sufficient number of patients. It is thought that adefovir and lamivudine combination therapy reduce the risk of adefovir resistance, thereby continued combination treatment will result in suppression of HBV DNA to be undetectable in patients with entecavir resistance. The aim of this study is to evaluate the efficacy of adefovir and lamivudine combination therapy in CHB patients with entecavir resistance.

Official Title
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Efficacy of Adefovir and Lamivudine Combination Therapy in Patients With Entecavir Resistance

Conditions
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Chronic Hepatitis B

Intervention / Treatment
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* Drug: ADEFOVIR, LAMIVUDINE


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Chronic hepatitis B patients (positive HBsAg > 6 months) Age > 18 year old History of treatment with entecavir more than 6 months Proven entecavir resistant mutation (rtT184S/A/I/L/G/C/M, rtS202G/C/I, or rtM250I/V) HBV DNA level> 2000 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-alfa, thymosin-alfa 1, or nucleos(t)ide analogue other than entecavir in 6 months of screening History of adefovir resistance (detection of rtA181T/Vor rtN236T at screening or in the past) 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: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Adefovir and lamivudine combination<br> | Drug: ADEFOVIR, LAMIVUDINE<br>* Adefovir/10mg tablet/once a day/52week Lamivudine/100mg tablet/once a day/52week<br>* Other names: Lamivudine (Zeffix);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Degree of HBV DNA reduction from baseline | Degree of HBV DNA reduction from baseline during 52 week-period of adefovir and lamivudine combination therapy will be assessed. | at week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HBV DNA undetectability by PCR (<60 IU/mL) |  | at week 52 | 
| ALT normalization |  | at week 52 | 
| HBeAg loss |  | at week 52 | 
| HBeAg to anti- HBe seroconversion |  | at week 52 | 
| Development of adefovir resistance |  | at week 52 | 
| Virologic breakthrough | virologic breakthrough is defined by increase of HBV DNA above 10 times the lowest level (na dir). | at week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adefovir, lamivudine, entecavir resistance