Tenofovir vs. Tenofovir Plus Entecavir in Entecavir-Resistant Chronic Hepatitis B (IN-US-0202)
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.
|Chronic Viral Hepatitis B Without Delta-agent||Drug: Tenofovir Drug: Entecavir||Phase 4|
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Official Title:||A Multicenter Randomized Controlled Open-label Trial of Tenofovir vs. Tenofovir Plus Entecavir in Chronic Hepatitis B Patients With Genotypic Resistance to Entecavir and Partial Virologic Response to Ongoing Treatment|
- Proportion of patients with complete virologic response [ Time Frame: at week 48 of treatment ]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, 96, 144, and 240 of treatment ]Changes in serum HBV DNA levels during 48 weeks of treatment
- Proportion of patients with normal ALT [ Time Frame: at week 48, 96, 144, and 240 of treatment ]
- Proportion of patients with HBe-Ag loss or seroconversion [ Time Frame: at week 48, 96, 144, and 240 of treatment ]
- Proportion of patients with resistance mutations to Entecavir or Tenofovir [ Time Frame: at week 48, 96, 144, and 240 of treatment ]The proportion of patients with resistance mutations to Entecavir or Tenofovir at week 48
- Proportion of patients with virologic breakthrough [ Time Frame: at week 48, 96, 144, and 240 of treatment ]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
- Proportion of patients with complete virologic response [ Time Frame: at week 48, 96, 144, and 240 of treatment ]The proportion of patients who achieve complete virologic response (serum HBV DNA concentrations below 15 IU/mL)
|Study Start Date:||September 2012|
|Estimated Study Completion Date:||June 2018|
|Primary Completion Date:||June 2014 (Final data collection date for primary outcome measure)|
Experimental: Tenofovir monotherapy
Tenofovir 300 mg/day orally
Tenofovir 300mg Daily Oral
Other Name: Viread
Active Comparator: 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
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01639092
|Korea, Republic of|
|Asan Medical Center|
|Seoul, Korea, Republic of, 138-736|
|Principal Investigator:||Young-Suk Lim, M.D.,Ph.D.||Asan Medical Center|