SWITCHING TENOFOVIR DISOPROXIL FUMARATE (TDF) PLUS ENTECAVIR COMBINATION THERAPY TO TDF MONOTHERAPY IS SAFE AND EFFICACIOUS IN PATIENTS WITH MULTIPLE DRUG-RESISTANT CHRONIC HEPATITIS B: RANDOMIZED TRIAL

초록

Background and Aims: Combination therapy with a nucleoside analogue and a nucleotide analogue has been generally recommended for the treatment of patients harboring multiple drug-resistant (MDR) hepatitis B virus (HBV). Little data are available regarding whether switching the combination therapy to tenofovir disoproxil fumarate (TDF) monotherapy is safe and efficacious in patients with MDR HBV. Methods: This integrated analysis combines results from two Phase 4 trials for 192 patients with HBV resistant to entecavir and adefovir, respectively. In both studies, patients with serum HBV DNA levels > 60 IU/mL were randomized to receive TDF (300 mg/day) monotherapy (n = 95) or TDF and entecavir (1 mg/day) combination therapy (TDF + ETV, n = 97) for 48 weeks. All who completed 48 weeks in either group received TDF monotherapy for 48 additional weeks. Results: Mean basal HBV DNA level was 4.08 log10 IU/mL without significant difference between TDF and TDF + ETV groups. All patients had HBV resistance mutations to entecavir and/or adefovir in addition to lamivudine; rtT184A/C/F/G/I/L/S (n = 73), rtS202G (n = 64), rtM250L/V (n = 17), rtA181V/T (n = 97), rtN236T (n = 39), rtL180M (n = 157), and rtM204V/I (n = 192). Sixty-eight and 34 patients, respectively, had single (rtA181V/T or rtN236T) and double (rtA181V/T and rtN236T) resistance mutations to adefovir at baseline. The proportion of patients with HBV DNA < 15 IU/mL was not significantly different between the TDF and TDF + ETV groups at week 48 (66.3% vs 68.0%; p = 0.80). At week 96, HBV DNA was detectable in 63 patients (32.8%), but the level was below 3 log10 IU/mL in all patients except one (1.88 [±0.46] log10 IU/mL). None developed additional resistance mutations. After switching TDF + ETV to TDF, virologic breakthrough occurred only in one patient at 96 weeks by poor drug adherence. Only higher HBV DNA level (OR, 0.46; p < 0.001) and harboring double adefovir-resistance mutations (OR, 0.16; p = 0.003) at baseline were significantly associated with lower rate of virologic response at 96 weeks by multivariable analysis. Conclusions: In patients with MDR HBV, TDF monotherapy provided a virologic response comparable to that of TDF + ETV combination therapy during 48 weeks of treatment. Switching TDF + ETV combination therapy to TDF monotherapy was safe and efficacious.