Comparison of Telbivudine Plus Adefovir With Lamivudine Plus Adefovir for the Treatment of Lamivudine-resistant Chronic Hepatitis B at 52 Weeks: A Pilot Study

Study Overview
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Brief Summary
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Lamivudine had been widely used for treatment-naïve chronic hepatitis B patients. However, development of antiviral resistance has been known as the major drawback: Incidence of lamivudine resistance was reported to be approximately 70% after 5 years (Lok AS et al, 2003). For the treatment of lamivudine resistance, adefovir has been widely used (Lok AS and McMahon B, 2009). However, switching to adefovir monotherapy was also reported to be at high risk of resistance, 25% at year 2 (Yeon JE et al, 2006). Recently, adding adefovir on lamivudine was shown to be superior to switching to adefovir monotherapy by decreasing the adefovir resistance (Rapti I et al, 2007, Lampertico P et al, 2007). However, combination of adefovir and lamivudine does not increase antiviral activity compared with adefovir monotherapy in patients with lamivudine resistance (Peters MG et al, 2004). As many patients are still viremic with the treatment of lamivudine and adefovir over 1 year, the investigators need more potent combination of the drugs. Telbivudine is a new nucleoside analogue with potent antiviral activity. The previous phase III study has shown the superiority of telbivudine over lamivudine in HBeAg positive and negative subjects (Lai CL et al, 2007). Therefore, telbivudine plus adefovir may be a better treatment option than lamivudine plus adefovir for the lamivudine-resistant chronic hepatitis B patients. No study assessing the efficacy of telbivudine plus adefovir has been conducted for these patients. The aim of this study is to evaluate the safety and efficacy of telbivudine plus adefovir compared with lamivudine plus adefovir in lamivudine resistant chronic hepatitis B patients at the end of 1 year follow-up,

Official Title
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Comparison of Telbivudine Plus Adefovir With Lamivudine Plus Adefovir for the Treatment of Lamivudine-resistant Chronic Hepatitis B at 52 Weeks: A Pilot Study

Conditions
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Chronic Hepatitis B

Intervention / Treatment
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* Drug: telbivudine plus adefovir
* Drug: lamivudine plus adefovir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HBeAg positive or negative chronic hepatitis B patients (positive HBsAg more than 6 months) Age ≥ 18 years old, and ≤70 years old Previous treatment with lamivudine more than 6 months Being on lamivudine at the time of screening Confirmed genotypic resistance to lamivudine by RFMP (rtM204V or I) Presence of virologic breakthrough ≥1 log increase of HBV DNA above na dir) HBV DNA ≥ 20,000 IU/mL Patient willing to give an informed consent (If patient is <20 years old, the parent or legal guardian also need to give an informed consent) Exclusion Criteria: Out of inclusion criteria Presence of adefovir resistance (rtA181T or V, rtN236T) by RFMP assay Laboratory abnormalities as follows at screening: AFP>100 ng/mL, serum phosphorous level<2.4 mg/dL, serum creatinine level> 1.5 mg/dL or creatinine clearance < 50 mL/min Patient with a history of decompensated liver disease: Any patients with a history of ascites, hepatic encephalopathy, variceal bleeding, jaundice, or CTP>7 points should be excluded. History of treatment with nucleos(t)ide analogues other than lamivudine more than 4 weeks History of immune modulatory drugs (interferon, thymosin-alfa) within 24 weeks of screening Liver transplant patient Patient co-infected with HIV, HCV, or HDV Patient with metabolic or genetic liver disease that may affect serum ALT level Habitual alcohol consumption (>140 g/week for male, >70 g/week for female) Patient not able to stop drugs that may affect ALT or HBV DNA level during study periods (ie. Steroid, immune-suppressants, non-steroidal anti-inflammatory drugs, acetaminophen,) Pregnant or lactating woman Menstruating woman unwilling to use appropriate methods of contraception (ie. Condom, oral contraceptives, tubal ligation) Patient with hepatocellular carcinoma (treated or not treated) Patient with any untreated malignancy Patient with history of malignancy cured within 5 years of screening

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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 |
| --- | --- |
| Active Comparator: Telbivudine plus adefovir<br>study drugs | Drug: telbivudine plus adefovir<br>* telbivudine 600 mg qd plus adefovir 10 mg qd<br>* Other names: adefovir (hepsera);|
| Active Comparator: Lamivudine plus adefovir<br>standard drugs | Drug: lamivudine plus adefovir<br>* lamivudine 100 mg qd plus adefovir 10mg qd<br>* Other names: adefovir (hepsera);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The mean reduction of serum HBV DNA from the baseline at week 52. |  | up to the end of year 1 (52 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HBV DNA undetectability(<20 IU/mL) | At the end of year 1 in the two groups, HBV DNA undetectability by real time PCR will be assessed. | up to the end of year 1 (52 weeks) | 
| mean serum HBV DNA level |  | up to the end of year 1 (52 weeks) | 
| rate of ALT normalization |  | up to the end of year 1 (52 weeks) | 
| rates of HBeAg loss |  | up to the end of year 1 (52 weeks) | 
| rate of HBeAg seroconversion at week 52. |  | up to the end of year 1 (52 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Hepatitis B, Telbivudine, Adefovir, Lamivudine resistance