Tenofovir monotherapy versus tenofovir and entecavir combination therapy in patients with entecavir-resistant chronic hepatitis B with multiple drug failure: results of a randomised trial

Objective Little clinical data are available regarding the optimal treatment of patients who harbour entecavir (ETV)-resistant HBV. Design In this multicentre randomised trial, patients who had HBV with ETV resistance-associated mutations and serum HBV DNA concentrations > 60 IU/mL were randomised to receive tenofovir disoproxil fumarate (TDF, 300 mg/day) monotherapy (n= 45) or TDF and ETV (1 mg/day) combination therapy (n= 45) for 48 weeks. Results Baseline characteristics were comparable between groups, including HBV DNA levels (median, 4.02 log(10) IU/mL) and hepatitis B e antigen-positivity (89%). All patients had at least one ETV-resistance mutation: rtT184A/C/F/G/I/L/S (n= 49), rtS202G (n= 43) and rtM250L/V (n= 7), in addition to rtM204V/I (n= 90). All except one patient in the TDF group completed 48 weeks of treatment. At week 48, the proportion of patients with HBV DNA < 15 IU/mL, the primary efficacy endpoint, was not significantly different between the TDF and TDF+ ETV groups (71% vs 73%; p> 0.99). The mean change in HBV DNA levels from baseline was not significantly different between groups (-3.66 vs -3.74 log10 IU/mL; p= 0.81). Virological breakthrough occurred in one patient on TDF, which was attributed to poor drug adherence. At week 48, six and three patients in the TDF and TDF+ ETV groups, respectively, retained their baseline resistance mutations (p> 0.99). None developed additional resistance mutations. Safety profiles were comparable in the two groups. Conclusions TDF monotherapy for 48 weeks provided a virological response comparable to that of TDF and ETV combination therapy in patients infected with ETV-resistant HBV.