Tenofovir vs. Tenofovir Plus Entecavir in Entecavir-Resistant Chronic Hepatitis B (IN-US-0202)

• Changes in serum HBV DNA levels [ Time Frame: at week 48 of treatment ] [ Designated as safety issue: No ]
  Changes in serum HBV DNA levels during 48 weeks of treatment
• Proportion of patients with normal ALT [ Time Frame: at 48 weeks of treatment ] [ Designated as safety issue: No ]
• Proportion of patients with HBe-Ag loss or seroconversion [ Time Frame: at 48 weeks of treatment ] [ Designated as safety issue: No ]
• Proportion of patients with resistance mutations to Entecavir or Tenofovir [ Time Frame: at 48 weeks of treatment ] [ Designated as safety issue: No ]
  The proportion of patients with resistance mutations to Entecavir or Tenofovir at week 48
• Proportion of patients with virologic breakthrough [ Time Frame: at 48 weeks of treatment ] [ Designated as safety issue: No ]
  Virologic breakthrough is defined as the increase in serum HBV DNA by >1 log10 (10-fold) above nadir after achieving virologic response as determined by at least 2 consecutive measurements of at least 2 weeks apart, during continued treatment

With the availability of potent nucloes(t)ide analogues (NA), such as tenofovir disoproxil fumarate (TDF) and entecavir (ETV), suppression of serum HBV DNA to undetectable levels by polymerase chain reaction (PCR) assays became achievable in most NA treatment-naïve patients. Until recently, however, many patients commenced antiviral treatment with inferior NAs prior to the availability of TDF or ETV, such as lamivudine (LAM) which has a low genetic barrier to resistance.

ETV resistance increase up to 51% of patients after 5 years of ETV treatment in lamivudine-refractory patients. Resistance to ETV appears to occur through a two-hit mechanism with initial selection of M204V/I mutation followed by amino acid substitutions at rtT184, rtS202, or rtM250.

In vitro studies showed that ETV-resistant mutations are susceptible to TDF, but there are little clinical data on the efficacy of TDF monotherapy in patients with ETV-resistance.

On the other hand, there was a retrospective cohort study reporting that, with the combination of TDF and ETV, most of patients became HBV DNA undetectable after median 6 months of treatment. Probability of reaching complete HBV DNA suppression was not decreased in patients with ADV or ETV-resistance.

Thus, there is no consistent treatment recommendation for patients with ETV-resistance.

In this clinical trial, the investigators will clarify whether tenofovir monotherapy is as effective as tenofovir plus entecavir in inducing complete virologic response in CHB patients with genotypic resistance to ETV and partial virologic response to ongoing treatment.

A multi-center randomized active-controlled open-label trial

• Patients will be randomly assigned 1:1 to receive tenofovir (300 mg/day) or tenofovir (300 mg/day) plus entecavir (1 mg/day) for 48 weeks.
• Because over 98% of Korean patients with CHB have HBV genotype C, HBV genotype will not determined or be regarded as a stratification factor.
• Patients' treatment information before randomization will be retrospectively collected.(DNA change, HBeAg status, HBsAg titre, ALT, and treatment duration. etc)
• Patients will be screened within 4 weeks before randomization to determine study eligibility.

• Drug: Tenofovir
  Tenofovir 300mg Daily Oral
  Other Name: Viread
• Drug: Entecavir
  Entecavir 1 mg daily Oral
  Other Name: Baraclude

• Experimental: Tenofovir monotherapy
  Intervention: Drug: Tenofovir
• Active Comparator: Tenofovir plus Entecavir combination
  Interventions:

  • Drug: Tenofovir
  • Drug: Entecavir

Inclusion Criteria: All of below

• Compensated liver disease (Child-Pugh class A)
• HBsAg positive at least 6 months or more
• HBeAg positive or negative
• Confirmation of resistance mutations to Lamivudine (rtM204V/I and/or rtL180M) and ETV (rtT184 or rtS202 or rtM250) at any time before screening
• Serum HBV DNA ≥ 60 IU/mL despite continued preceding oral antiviral treatment (Serum HBV DNA should be determined by the PCR assay at the local laboratory at screening for this study)
• Patient is ambulatory.
• Patient is willing and able to comply with the study drug regimen and all other study requirements.
• The patient is willing and able to provide written informed consent to participate in the study.

Exclusion Criteria: Any of below

• Patient previously received TDF for more than 1 week
• Patient had documented resistance mutations to ADV at any time before or at screening
• Patient has a history of hepatocellular carcinoma (HCC) or findings suggestive of possible HCC, such as suspicious foci on imaging studies. In patients with such findings, HCC should be ruled-out prior to randomizing the patient for the present study.
• Patient has received interferon or other immunomodulatory treatment for HBV infection in the 12 months before screening for this study.
• Patient has concomitant other chronic viral infection (HCV or HIV)
• Patient has evidence of renal insufficiency defined as serum creatinine > 1.5 mg/dL
• Patient has medical condition that requires concurrent use of systemic prednisolone or other immunosuppressive agent (including chemotherapeutic agent)
• Patient is currently abusing alcohol (more than 40 g/day) or illicit drugs, or has a history of alcohol abuse or illicit substance abuse within the preceding two years.
• Patient is pregnant or breastfeeding or willing to be pregnant
• 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.).
• 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.

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

  1. serum bilirubin > 3 mg/dL
  2. prothrombin time > 6 seconds prolonged or INR >1.5
  3. serum albumin < 2.8 g/dL
  4. History of ascites, variceal hemorrhage, or hepatic encephalopathy
  5. Child-Pugh score ≥7

• Samsung Medical Center
• Konkuk University Medical Center
• Korea University Guro Hospital
• Seoul National University Hospital