Monotherapy with Tenofovir Disoproxil Fumarate for Multiple Drug-Resistant Chronic Hepatitis B: Results of 5-Year Clinical Trial

초록

Background: We recently demonstrated by randomized trials that monotherapy with tenofovir disoproxil fumarate (TDF) for 48 weeks displayed non-inferior efficacy to TDF plus entecavir (ETV) combination therapy in patients with hepatitis B virus (HBV) resistant to multiple drugs, including ETV and/or adefovir. Nonetheless, whether prolonged TDF monotherapy would be safe and increase the virologic response rate in these patients is unclear. Methods: Among 192 patients with HBV resistance mutations to ETV and/or adefovir, who were randomized to receive TDF monotherapy (n=95) or TDF+ETV combination therapy (n=97) for 48 weeks, 189 agreed to continue TDF monotherapy (TDF-TDF group) or to switch to TDF monotherapy (TDF+ETV-TDF group), and 176 (91.7%) completed the 240-week study. Results: By intention-to-treat analysis, serum HBV DNA <15 IU/mL at week 48, the primary efficacy endpoint, was achieved in 66.3% in TDF-TDF group and 68.0% in TDF+ETV-TDF group (P=0.80). At week 240, the overall proportion with HBV DNA <15 IU/mL increased to 78.6%, which was significantly higher compared with that at week 48 (P=0.003), without significant difference between groups (P=0.92). By on-treatment analysis, 85.8% of the patients had HBV DNA <15 IU/mL at week 240. Transient virologic blip occurred in 7 patients throughout 240 weeks of the study period, all of which was associated with poor drug adherence. At week 240, 9 patients had HBV DNA levels >60 IU/mL. A total of 29 patients had HBV DNA levels >15 IU/mL at discontinuation or completion of the study with median HBV DNA levels of 42 IU/mL (range, 16 – 690 IU/mL). None developed additional resistance mutations throughout the study period. Among 170 HBeAg-positive patients at baseline, HBeAg seroclearance was achieved in 46 (27.1%) patients, and HBeAg seroconversion in 12 (7.1%) at week 240. None achieved HBsAg seroclearance. Changes in estimated GFR at week 240 from baseline was not significant (–0.43 mL/min/1.73 m2, P=0.69). Among 187 patients with baseline eGFR > 60 mL/min/1.73 m2, 3 patients had eGFR < 60 mL/min/1.73 m2 at week 240. The mean change in bone mineral density from baseline at week 240 was −0.64% and −2.47% at the spine (P=0.22) and femur (P<0.001), respectively. At week 240, 34.5% and 43.2% of the patients had >3% decline in bone mineral density at spine and femur, respectively, from baseline. Conclusion: TDF monotherapy was efficacious for up to 240 weeks, providing an increasing rate of virologic response in heavily pretreated patients with multidrug-resistant HBV.