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

Treatment of CHB patients with genotypic resistance to NUCs has been problematic due to the lack of data from randomized trials. Recently, two randomized trials comparing the efficacy of TDF monotherapy versus TDF and ETV combination therapy in CHB patients with documented genotypic resistance to adefovir (ADV) or ETV demonstrated TDF monotherapy was not statistically different in viral suppression at week 48 of treatment.1,2 The extension study based on the above two trials merged study subjects from these trials with changing from TDF and ETV combination group to TDF monotherapy to evaluate long-term efficacy and safety of TDF monotherapy for multidrug-resistant patients. At the time of merging of 192 subjects, by intention-to-treat analysis, 66.3% of TDF group and 68.0% of TDF-ETV group had virological response as determined by serum HBV DNA \<15 IU/mL. (in press) Three year long-term follow up study showed that the proportion of virologic suppression increased to 76.8% and 72.2% in TDF-TDF and TDF/TDF-ETV groups, respectively( P=0.46). (in press)

TAF, a novel prodrug of tenofovir was developed to have greater stability in plasma than TDF, thereby enabling more efficient delivery of the active metabolite to target cells at a substantially lower dose. The reduced systemic exposure of tenofovir offers the potential for an improved safety profile compared to TDF a benefit that demonstrated in a recent clinical trial in patients with HIV infection. In a recent double-blind randomized phase 3 noninferiority trial with 873 treatment naive patients who were positive for HBeAg, the proportion of patients receiving TAF who had HBV DNA \<29 IU/mL at week 48 was 64%, which was non-inferior to the rate of 67% in patients receiving TDF (P=0.25).3 In the safety profile, TAF group had significantly smaller decrease in BMD than TDF group in the hip and spine, as well as significantly smaller increases in serum creatinine at week 48.3 For treatment naive HBeAg negative patients, a recent study with 425 subjects applied the same methodology and showed noninferiority in efficacy of TAF compared to TDF at week 48.4 Considering noninferiority in efficacy and superior bone and renal safety from TAF, TAF might be considered preferred choice of NUC instead of TDF. However, it is still unknown whether TAF would show similar efficacy and safety profile in patients with multidrug-resistant CHB.

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)

Eligibility Criteria:
Inclusion Criteria:All of below

1. Patient must have the ability to understand and sign a written informed consent form; consent must be obtained prior to initiation of study procedures
2. Male or female, 20 to 80 years of age
3. Compensated liver disease (Child-Pugh score \< 8)
4. HBsAg positive at least 6 months or more
5. HBeAg positive or negative
6. 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
7. Completion of the week 240 visit in studies IN-US-174-0202 or 0205 study and maintained on TDF 300 mg QD
8. Patient is willing and able to comply with all study requirements

Exclusion Criteria: Any of below

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

1) 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

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

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

6. Received solid organ or bone marrow transplant

7. Known hypersensitivity to study drugs, metabolites, or formulation excipients

8. 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

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

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

11. 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

12. Participation in another investigational drug trial

13. Pregnant or breastfeeding or willing to be pregnant