Efficacy and Safety Study of Tenofovir Disoproxil Fumarate (TDF) in Chinese Chronic Hepatitis B (CHB) Subjects With Advanced Fibrosis & Compensated Cirrhosis

A Prospective, Multi-center, Cohort Study to Evaluate the Efficacy and Safety of Tenofovir Disoproxil Fumarate (TDF) Therapy in Chinese Chronic Hepatitis B (CHB) Subjects With Advanced Fibrosis & Compensated Cirrhosis

Chronic Hepatitis B infection (CHB) is known as the most frequently identified cause of liver disease that predisposes patients to the development of hepatocellular carcinoma (HCC). Active hepatitis B virus (HBV) replication is the key driver of liver injury and disease progression. Majority of Chinese patients are infected with genotype B and C HBV, which is different from Caucasian counterparts. This prospective multi-center cohort open-label study is designed to investigate the long-term effect of TDF on prevention of HCC and disease progression as well as to evaluate the efficacy and safety of long-term TDF in Chinese CHB subjects with advanced liver diseases. The study will enrol 240 subjects.

Inclusion Criteria:

• Age 18-60 years(inclusive);
• Presence of HBsAg in serum at screening and for at least 6 months before screening assessment;
• Serum HBV DNA>=2000 IU/mL if HBeAg positive at screening (with or without ALT elevation); or serum HBV DNA>=200IU/mL if HBeAg negative at screening (with or without ALT elevation);
• Clinically diagnosed as advanced fibrosis or compensated cirrhosis defined as both of following : liver stiffness measure (LSM) >12.4 kiloPascals (kpa) (ALT> Upper limit of normal [ULN]) or LSM>9.0 kpa (ALT<=ULN); One of following: Liver biopsy showing advanced fibrosis or cirrhosis (Ishak score >=4, within the previous 6 months before screening and provided that no treatment likely to improve liver histology has been taken since). The slides must be available for review by an independent histopathologist; Endoscopy-proven gastroesophageal or gastric varices, non-cirrhotic portal hypertension excluded; Abdominal ultrasound or CT found changes indicating cirrhosis, irregular liver surface or nodularity, with/without splenomegaly (depth of spleen>4.0cm or spleen length>13cm); Blood platelets <100 x10^9/L (and other causes of thrombocytopenia excluded);
• Ability to give written informed consent;
• A female is eligible to enter and participate in this study if she is of: non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is post-menopausal), or Child-bearing potential, has a negative urine pregnancy test at screening, and agrees to one of the following methods for avoidance of pregnancy during the period of the study and until 30 days after last dose of study medication: Oral contraceptive, either combined or progestogen alone; Injectable progestogen; Implants of levonorgestrel; Oestrogenic vaginal ring; Percutaneous contraceptive patches; Intrauterine device (IUD) or intrauterine system (IUS) showing that the expected failure rate is less than 1% per year as stated in the IUD or IUS product label; Has a male partner who is sterilised; Double barrier method: condom and an occlusive cap (diaphragm orcervical/vault caps) with a vaginal spermicidal agent (foam/gel/film /cream/suppository).
• Agreement not to participate in any other investigational trials or to undertake other HBV systemic antiviral or interferon (IFN) regimens during participation in this study.

Exclusion Criteria:

• Hepatocellular carcinoma as evidenced by one of the following: Suspicious foci on ultrasound or radiological examination; Normal ultrasound serum alpha-fetoprotein >50 nanograms (ng)/mL at screening.
• Serum ALT >10 times ULN at screening or history of acute exacerbation leading to transient decompensation;
• Documented co-infection with hepatitis A (HAV), hepatitis C (HCV), hepatitis delta virus (HDV), hepatitis E virus (HEV) or human immunodeficiency virus (HIV). For HCV co-infection, subjects who are anti-HCV positive and in whom HCV ribonucleic acid (RNA) is undetectable are considered to be not eligible for enrolment.
• Evidence of active liver disease due to autoimmune hepatitis (antinuclear antibody (ANA) titre >1:160).
• Decompensated liver disease as indicated by any of the following: serum bilirubin >1.5 xULN prothrombin time activity <60% or International normalized ratio (INR)>1.5; serum albumin <32 grams per liter (g/L); history of previous clinical hepatic decompensation (e.g., ascites, variceal bleeding, or encephalopathy);
• Planned for liver transplantation or previous liver transplantation;
• Creatinine clearance less than 70 mL/minute (min);
• Haemoglobin <10 g/deciliter (dL), white blood cell (WBC) count <1.5 x 10^9/liter (L), platelets <=50 x 10^9/L;
• Any serious or active medical or psychiatric illnesses other than hepatitis B which, in the opinion of the Investigator, would interfere with subject treatment, assessment or compliance with the protocol. This would include any uncontrolled clinically significant renal, cardiac, pulmonary, vascular, neurogenic, digestive, metabolic (diabetes, thyroid disorders, adrenal disease), immunodeficiency disorders, pathological fractures or cancer;
• Active alcohol or drug abuse or history of alcohol or drug abuse considered by the Investigator to be sufficient to hinder compliance with treatment, participation in the study or interpretation of results;
• A female who is breastfeeding or plan to breastfeed;
• Use of immunosuppressive therapy, immunomodulatory therapy (including IFN or thymosin alpha), systemic cytotoxic agents, chronic antiviral agents including Chinese herbal medicines known to have activity against HBV (e.g., lamivudine (LAM), adefovir, entecavir (ETV), telbivudine (LdT) or hepatitis B immunoglobulin (HBIg)) within the previous 6 months prior to screening into this study;
• Have ever received TDF or any medicinal products containing the above mentioned antiviral agents or any investigative anti-HBV treatments (e.g., emtricitabine (FTC), (2R,4R)-4-(2,6-Diaminopurin-9-yl)-1,3-dioxolan-2-yl]methanol (DAPD) and 1-(2-fluoro-5-methyl-beta, Larabinofuranosyl) uracil (L-FMAU));
• History of hypersensitivity to nucleoside and/or nucleotide analogues and/or any component of study medication;
• Therapy with nephrotoxic drugs (e.g., aminoglycosides, amphotercin B, vancomycin, cidofovir, foscarnet, cis-platinum, pentamidine etc.) or competitors of renal excretion (e.g., probenecid) within 2 months prior to study screening or the expectation that subject will receive any of these during the course of the study;
• Inability to comply with study requirements as determined by the study Investigator