Tenofovir Disoproxil Fumarate Alone or in Combination With Entecavir in Patients With Entecavir-Resistant Chronic Hepatitis B: Multicenter Randomized Trial

Abstract

Background/Aims: It is not clear whether tenofovir disoproxil fumarate (TDF) and entecavir (ETV) combination therapy shows superior antiviral efficacy over tenofovir monotherapy in patients who harbor ETV-resistant hepatitis B virus (HBV).

Methods: In this multicenter open-label trial, patients who had HBV with genotypic resistance mutations to ETV and serum HBV DNA concentration >60 IU/mL were randomized to TDF (300 mg/day) monotherapy (TDF group, n = 45) or to TDF and ETV (1 mg/day) combination therapy (TDF+ETV group, n = 45), and were included in the intention-to-treat analyses. Patients who had adefovir-resistant HBV (rtA181V/T and/or rtN236T) were excluded.

Results: At baseline, mean HBV DNA level was 4.28 +/- 1.60 log10 IU/mL. All 90 patients had at least one ETV-resistance mutations; rtT184 (n = 49), rtS202 (n = 43), or rtM250 (n = 7). All also had rtM204V/I +/- rtL180M mutations. One patient in the TDF group withdrew the consent at week 2. At week 48, the number of patients with HBV DNA <15 IU/mL, the primary efficacy endpoint, was 32 (71%) and 33 (73%) in the TDF and TDF+ETV groups, respectively (P=0.81). Mean reduction in HBV DNA levels from baseline was -3.65 +/- 1.64 log10 IU/mL and -3.77 +/- 1.30 log10 IU/mL in the TDF and TDF+ETV groups, respectively (P=0.69). Virological breakthrough was observed in a patient in the TDF group at 48 weeks, which was attributed to documented non-adherence to study drug. Only 7 and 5 patients in the TDF and TDF+ETV groups, respectively, had HBV DNA >60 IU/mL at 48 weeks, and were qualified for HBV resistance tests. Resistance mutations to lamivudine and/or ETV was detected only in 3 and 2 patients in the TDF and TDF+ETV groups, respectively, at 48 weeks. None developed additional resistance mutations. None in the TDF group required protocol-defined switch over of treatment. Both treatments were well tolerated, and safety and adverse event profiles were similar in the two groups.

Conclusions: TDF monotherapy showed similarly high antiviral efficacy and safety as TDF and ETV combination therapy during 48 weeks of treatment in patients with ETV-resistant HBV. None developed additional resistance mutations.