Tenofovir Plus Entecavir vs. Tenofovir in Adefovir-Resistant Chronic Hepatitis B (IN-US-0205)
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) or adefovir (ADV) which has a low genetic barrier to resistance.
For patients who developed genotypic resistance against ADV, the efficacy of TDF monotherapy is controversial. In recent studies, TDF monotherapy produced significant suppression of HBV replication. However, only half of patients with initial ADV resistance achieved an undetectable viral load (<15 IU/ml) with 48 weeks of therapy.
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.
Together, these observations indicate that there is a controversy about the efficacy of TDF monotherapy in patients with genotypic resistance to ADV.
Thus, in this clinical trial, the investigators will clarify whether tenofovir monotherapy is effective in inducing complete virologic response compared with tenofovir plus entecavir in CHB patients with genotypic resistance to ADV and partial virologic response to ongoing treatment.
Chronic Viral Hepatitis B Without Delta-agent
|Study Design:||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Multicenter Randomized Controlled Open-label Trial of Tenofovir Plus Entecavir Combination vs. Tenofovir Monotherapy in Chronic Hepatitis B Patients With Genotypic Resistance to Adefovir and Partial Virologic Response to Ongoing Treatment|
- Proportion of patients with complete virologic response [ Time Frame: at week 48 of treatment ] [ Designated as safety issue: No ]The proportion of patients who achieve complete virologic response (serum HBV DNA concentrations below 15 IU/mL)
- 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 Adefovir, Entecavir, or Tenofovir [ Time Frame: at 48 weeks of treatment ] [ Designated as safety issue: No ]The proportion of patients with resistance mutations to Adefovir, 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
|Study Start Date:||September 2012|
|Estimated Study Completion Date:||June 2014|
|Estimated Primary Completion Date:||June 2014 (Final data collection date for primary outcome measure)|
Experimental: Tenofovir plus Entecavir combination
Tenofovir 300 mg/day orally and Entecavir 1 mg/day orally
Tenofovir 300mg daily Oral
Other Name: VireadDrug: Entecavir
Entecavir 1 mg daily Oral
Other Name: Baraclude
Active Comparator: Tenofovir monotherapy
Tenofovir 300 mg/day orally
Tenofovir 300mg daily Oral
Other Name: Viread
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 be 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.
|Korea, Republic of|
|Asan Medical Center|
|Seoul, Korea, Republic of, 138-736|
|Principal Investigator:||Young-Suk Lim, M.D., Ph.D.||Asan Medical Center|