Entecavir Plus Adefovir in Lamivudine-Resistant Chronic Hepatitis B Patients Who Fail Lamivudine Plus Adefovir
Entecavir Plus Adefovir in Lamivudine-Resistant Chronic Hepatitis B Patients Who Fail Lamivudine Plus Adefovir
The presence of persistent inadequate or suboptimal virologic response is a strong risk
 factor for viral resistance and breakthrough and also for disease progression of chronic
 hepatitis B, and thus, a change in therapy is required. The combination of entecavir (ETV)
 and adefovir (ADV) is a promising treatment for patients with lamivudine (LAM)-resistance who
 show suboptimal response to the combination of LAM and ADV.

 In this randomized, open labeled trial,the investigators will compare the efficacy of
 continuation of ADV plus LAM versus switch to ADV plus ETV in adults with LAM-resistant
 chronic hepatitis B who shows suboptimal response to the combination treatment of ADV and
 LAM.
In this randomized, open label, two-arm, single center phase IV trial, the investigators will
 assess and compare the efficacy and safety of continuation of ADV plus LAM versus switching
 to ADV plus ETV up to 52-weeks in Korean adults with chronic hepatitis B who have resistant
 mutants to LAM and show suboptimal response to combination of ADV plus LAM.

 All study subjects who complete the initial treatments of 52-weeks will be thereafter treated
 with the combination of ADV plus ETV for 52 more weeks.

 Study period: Nov 2009 - October 2012 Patient enrollment period: November 2009 - December
 2010

 Study protocol

 1. Group A (ADV+LAM group): Adefovir (10 mg/day) + Lamivudine (100 mg/day) for 52 weeks,
 and thereafter, Adefovir (10 mg/day) + Entecavir (1 mg/day) for 52 more weeks

 2. Group B (ADV+ETV group): Adefovir (10 mg/day) + Entecavir (1 mg/day) for 104 weeks
Inclusion Criteria:

 1. Male or female, 16 to 75 years of age

 2. Compensated liver disease(Child-Pugh class A)

 3. HBsAg positive at least 6 months or more

 4. HBeAg positive or negative

 5. Confirmation of Lamivudine-resistance HBV mutation anytime before the study

 6. Patients with suboptimal response (HBV DNA > 2000 IU/mL despite combination of
 Adefovir [10 mg/day] plus Lamivudine [100 mg/day] for 6 months or more). Serum HBV DNA
 should be determined by the PCR assay at the local laboratory at screening for this
 study

 7. Patient is ambulatory.

 8. Patient is willing and able to comply with the study drug regimen and all other study
 requirements.

 9. The patient is willing and able to provide written informed consent to participate in
 the study.

 Exclusion Criteria:

 1. Patient has a history of hepatocellular carcinoma (HCC) or findings suggestive of
 possible HCC, such as suspicious foci on imaging studies or elevated serum alpha
 fetoprotein (AFP) levels. In patients with such findings, HCC should be ruled-out
 prior to randomizing the patient for the present study.

 2. Patient previously received oral antiviral agent other than Lamivudine or Adefovir

 3. Patient has received interferon or other immunomodulatory treatment for HBV infection
 within 12 months before screening for this study.

 4. Patient has concomitant other chronic viral infection (HCV or HIV)

 5. Patient has evidence of renal insufficiency defined as serum creatinine > 1.5 mg/dL

 6. Patient has medical condition that requires use of systemic prednisolone or other
 immunosuppressive agent (including chemotherapeutic agent)

 7. Patient is currently abusing alcohol or illicit drugs, or has a history of alcohol
 abuse or illicit substance abuse within the preceding two years.

 8. Patient is pregnant or breastfeeding or willing to be pregnant

 9. Patient has one or more additional known primary or secondary causes of liver disease,
 other than hepatitis B (e.g., alcoholism, autoimmune hepatitis, malignancy with
 hepatic involvement, hemochromatosis, alpha-1 antitrypsin deficiency, Wilson's
 Disease, other congenital or metabolic conditions affecting the liver, congestive
 heart failure or other severe cardiopulmonary disease, etc.).

 10. A history of treated malignancy (other than hepatocellular carcinoma) is allowable if
 the patient's malignancy has been in complete remission, off chemotherapy and without
 additional surgical intervention, during the preceding three years.

 11. Clinical signs of decompensated liver disease as indicated by any one of the
 following:

 -  serum bilirubin > 3 mg/dL

 -  prothrombin time > 6 seconds prolonged or INR >1.6

 -  serum albumin < 2.8 g/dL

 -  History of ascites, variceal hemorrhage, or hepatic encephalopathy

 -  Child-Pugh score ≥7