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.
Name: Tenofovir
Description: Tenofovir 300mg Daily OralType: DrugTenofovir monotherapy
Name: Tenofovir
Description: Tenofovir 300mg Daily OralType: DrugTenofovir plus Entecavir combination
Name: Entecavir
Description: Entecavir 1 mg daily OralType: DrugTenofovir plus Entecavir combination
Description: The proportion of patients who achieve complete virologic response (serum HBV DNA concentrations below 15 IU/mL)
Measure: Proportion of patients with complete virologic response Time: at week 48 of treatmentDescription: Changes in serum HBV DNA levels during 48 weeks of treatment
Measure: Changes in serum HBV DNA levels Time: at week 48, 96, 144, and 240 of treatmentDescription: The proportion of patients with resistance mutations to Entecavir or Tenofovir at week 48
Measure: Proportion of patients with resistance mutations to Entecavir or Tenofovir Time: at week 48, 96, 144, and 240 of treatmentDescription: 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
Measure: Proportion of patients with virologic breakthrough Time: at week 48, 96, 144, and 240 of treatmentDescription: The proportion of patients who achieve complete virologic response (serum HBV DNA concentrations below 15 IU/mL)
Measure: Proportion of patients with complete virologic response Time: at week 48, 96, 144, and 240 of treatmentAllocation: Randomized
Parallel Assignment
There is one SNP
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. --- M204V ---