Switching From TDF to TAF vs. Maintaining TDF in Chronic Hepatitis B With Resistance to Adefovir or Entecavir.

Study objectives The objective of this study is to evaluate whether efficacy, safety, and tolerability (including bone and renal outcomes) were non-inferior in patients switched to a tenofovir alafenamide (TAF), compared with patients who remained on tenofovir disoproxil fumarate (TDF).

Study procedures This is a randomized, active-controlled, open-label, multicenter study to evaluate safety and non-inferior efficacy of switching from TDF 300 mg QD to TAF 25 mg QD for 48 weeks in chronic hepatitis B patients who have genotypic resistance to Adefovir/Entecavir.

174 subjects who complete the previous IN-US-174-0202/0205 studies will be randomized in a 1:1 ratio (A:B) to receive either TAF 25 mg QD or TDF 300 mg QD Case group: approximately 87 subjects administered TAF 25 mg QD Control group: approximately 87 subjects administered TDF 300 mg QD

The primary analysis will occur at Week 48 with the primary efficacy endpoint being newly achievement and maintenance of virologic response (HBV DNA <60 IU/mL at Week 48).

The duration of maintaining both arms is 48 weeks. All subjects who complete 48 weeks of treatment are eligible for participation in the open label TAF 25 mg extension period for an additional 48 weeks (through Week 96)

Inclusion criteria

All of below

• Patient must have the ability to understand and sign a written informed consent form; consent must be obtained prior to initiation of study procedures
• Male or female, 20 to 80 years of age
• Compensated liver disease (Child-Pugh score < 8)
• HBsAg positive at least 6 months or more
• HBeAg positive or negative
• Confirmation of ETV resistance mutation (rt184, rtS202, or rtM250) at the enrollment of IN-US-174-0202 study, or ADV resistance mutation (rtA181V, rtA181T or rtN236T) at the enrollment of IN-US-174-0205 study
• Completion of the week 240 visit in studies IN-US-174-0202 or 0205 study and maintained on TDF 300 mg QD
• Patient is willing and able to comply with all study requirements

Exclusion criteria

Any of below

• Co-infection with HCV, HDV, HIV
• Abusing alcohol (more than 40 g/day) or illicit drugs
• Abnormal hematological and biochemical parameters, including:

• serum bilirubin >3 mg/dL 2) prothrombin time (INR) >1.5 3) serum albumin <2.8 g/dL 4) ascites, encephalopathy or variceal hemorrhage 5) Child-Pugh score ≥8

• Received interferon or other immunomodulatory treatment for HBV infection in the 12 months before screening for this study

• Medical condition that requires concurrent use of systemic corticosteroid or other immunosuppressive agent

• Received solid organ or bone marrow transplant

• Known hypersensitivity to study drugs, metabolites, or formulation excipients

• Any other clinical condition or prior therapy that, in the opinion of the Investigator, would make the patient unsuitable for the study or unable to comply with dosing requirements

• Use of investigational agents within 3 months of screening, unless allowed by the Sponsor or Investigator

• A history of hepatocellular carcinoma (HCC) within 5 years of screening

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

• Participation in another investigational drug trial

• Pregnant or breastfeeding or willing to be pregnant