Comparing P1101 to Entecavir in Patients With HBeAg(-) Hepatitis B Under Long-term Nucleos(t)Ide Analogue Therapy

Inclusion Criteria:

• Adults with age 20-75 years old; Subjects who are over 70 years of age must be ingenerally good health;
• Confirmed diagnosis of chronic hepatitis B (CHB) virus infection: with positive HBsAg ≧ 6 months prior to the study entry;
• Quantitative HBsAg level < 1,500 IU/ml at screening;
• Confirmed HBeAg (-) at screening;
• Stable disease: ALT < 3 x upper limit of normal (ULN), total bilirubin < 1.5 × ULN (except in Gilbert syndrome) and direct bilirubin < ULN at screening, serum HBV DNA < 50 IU/mL for ≧ 1 year prior to study entry;
• Stable treatment with nucleos(t)ide regimen (adefovir, entecavir, tenofovir or one ofthe following combinations: entecavir/adefovir or entecavir/tenofovir) for at least 2years prior to study entry;
• Interferon treatment naïve;
• Normal fundoscopic examination by ophthalmologist at screening; defined as nosignificant or major fundoscopic findings including but not limited to retinalexudates, hemorrhage, detachment, neovascularization, papilloedema, optic atrophy,microaneurysms and macular changes;
• Be able to attend all scheduled visits and to comply with all study procedures;
• Be able to provide written informed consent.

Exclusion Criteria:

• HBeAg-positive chronic hepatitis B;
• Documented history of drug resistance to any nucleoside/ nucleotide analogue;
• History of treatment with lamivudine or telbivudine prior to the study entry;
• Clinically significant abnormalities, other than HBV infection, based upon the resultsof a medical history, physical examination, vital signs, and a 12-leadelectrocardiogram (ECG) at screening as determined by the investigator;
• Other form of significant chronic liver disease apart from chronic hepatitis Binfection; Severe steatohepatitis by ultrasound or other examinations at thediscretion of investigators;
• Liver cirrhosis;
• Known positive for anti-HIV;
• Positive for anti-hepatitis C virus(HCV), Subject could be enrolled if no HCV RNAdetected within 1 year；
• Co-infection with hepatitis D;
• One of clinically significant abnormal laboratory test result at screening: whiteblood cell (WBC) < 3,000/mm^3, absolute neutrophil count (ANC) < 1500/mm^3, Hgb < 10g/dL, platelet < 90,000/mm^3, estimated Glomerular filtration rate < 60 mL/min;
• History of significant alcohol or illicit drug abuse within six months prior to thescreening visit (alcohol consumption of more than fourteen units of alcohol per week [1 Unit = 150 mL of wine, 360 mL of beer, or 45 mL of 40% alcohol]) or refusal toabstain from illicit drugs and minimize alcohol consumption throughout the study;
• History of severe allergic or hypersensitivity reactions (e.g bronchospasm,angioedema), asthma, or anaphylaxis
• Therapy with any systemic anti-viral treatment (except for treatment for HBV),anti-neoplastic, immunomodulatory treatment (including supraphysiologic doses ofsteroids and radiation) and immunosuppressants within 1 month (3 months for those withlong elimination half-lives) prior to the first dose of study drug;
• Use of an investigational drug within the last 4 weeks;
• Any history or presence of poorly controlled or clinically significant medicalconditions that are not suitable to receive interferon-based treatment, at thediscretion of the investigator: major psychiatric (including but not limited to thosewith severe depression, severe bipolar disorder, schizophrenia, suicidal ideation orhistory of suicidal attempt),neurological, cardiovascular (e.g. uncontrolledhypertension), pulmonary (including but not limited to chronic obstructive lungdisease), hematological, immunologic, endocrine, metabolic (e.g. diabetes mellituswith HbA1C > 8.0%), autoimmune disease, thyroid or other uncontrolled systemicdisease, coagulation disorders or blood dyscrasias;
• A depot injection or an implant of any drug within 3 months prior to administration ofstudy medication, other than contraception or hyaluronic acid injections in joints forosteoarthritis;
• History of solid organ transplantation;
• History of malignancy diagnosed or treated within 5 years prior to screening (exceptfor recent localized treatment of squamous or noninvasive basal cell skin cancers;cervical carcinoma in situ), cancer survivors not on maintenance therapy within thepast 5 years;
• History of opportunistic infection (e.g., invasive candidiasis or pneumocystispneumonia)
• Serious localized infection (e.g., cellulitis, abscess) or systemic andlife-threatening infection (e.g., septicemia) within the 3 months prior to screening;
• Pregnant subjects. Female subjects or the spouse of male subjects, with child-bearingpotential who are unwilling or unable to practice adequate contraception, defined asvasectomy in men, tubal ligation in women, or use of condoms and spermicides, or birthcontrol pills, or intrauterine devices from 4 weeks prior to Day 1 until 90 days afterthe last dose of study drug.