Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
J Hepatol. 2019 Jul;71(1):35-44. doi: 10.1016/j.jhep.2019.02.021. Epub 2019 Mar 13.
BACKGROUND & AIMS: Tenofovir disoproxil fumarate (TDF) monotherapy has displayed non-inferior efficacy to TDF plus entecavir (ETV) combination therapy in patients with hepatitis B virus (HBV) resistant to ETV and/or adefovir (ADV). Nonetheless, the virologic response rate was suboptimal in patients receiving up to 144 weeks of TDF monotherapy. We aimed to assess the efficacy and safety of TDF monotherapy given for up to 240 weeks.
One trial enrolled patients with ETV resistance without ADV resistance (n = 90), and another trial included patients with ADV resistance (n = 102). Most patients (91.2%) also had lamivudine resistance. Patients were randomized 1:1 to receive TDF monotherapy or TDF + ETV combination therapy for 48 weeks, and then TDF monotherapy until week 240. We compared efficacy between the studies and safety in the pooled population at 240 weeks.
At week 240, the proportion of patients with serum HBV DNA <15 IU/ml was not significantly different between the ETV and ADV resistance groups in the full analysis set (84.4% vs. 73.5%; p = 0.07), which was significantly different by on-treatment analysis (92.7% vs. 79.8%; p = 0.02). Virologic blips associated with poor medication adherence occurred in 7 patients throughout the 240 weeks. None developed additional HBV resistance mutations. Among the 170 HBV e antigen (HBeAg)-positive patients at baseline, 12 (7.1%) achieved HBeAg seroconversion at week 240. None achieved HBV surface antigen seroclearance. Significant decreases from baseline were observed at week 240 in the estimated glomerular filtration rate (-3.21 ml/min/1.73 m by the CKD-EPI equation, p <0.001) and bone mineral density (g/cm) at the femur (-2.48%, p <0.001).
Up to 240 weeks of TDF monotherapy provided an increasing virologic response rate in heavily pretreated patients with HBV resistant to ETV and/or ADV. However, it was associated with poor serological responses and decreasing renal function and bone mineral density. (ClinicalTrials.gov No, NCT01639066 and NCT01639092).
In patients chronically infected with hepatitis B virus resistant to multiple drugs including lamivudine, entecavir, and/or adefovir, tenofovir disoproxil fumarate (TDF) monotherapy showed non-inferior efficacy compared with the combination therapy of TDF plus entecavir. Nonetheless, short-term TDF monotherapy was associated with suboptimal virologic response, and its long-term safety was uncertain. This study displayed that 240 weeks of TDF monotherapy provided a virologic response in most of those patients, but it was associated with poor serological responses and decreasing renal function and bone mineral density.
富马酸替诺福韦二吡呋酯（TDF）单药治疗在对恩替卡韦（ETV）和/或阿德福韦（ADV）耐药的乙型肝炎病毒（HBV）患者中显示出与 TDF 联合 ETV 治疗相当的疗效。然而，在接受长达 144 周 TDF 单药治疗的患者中，病毒学应答率并不理想。我们旨在评估长达 240 周 TDF 单药治疗的疗效和安全性。
一项试验纳入了对 ETV 耐药而无 ADV 耐药的患者（n=90），另一项试验纳入了对 ADV 耐药的患者（n=102）。大多数患者（91.2%）也有拉米夫定耐药。患者按 1:1 随机接受 TDF 单药治疗或 TDF+ETV 联合治疗 48 周，然后接受 TDF 单药治疗直至 240 周。我们比较了研究之间的疗效和 240 周时的汇总人群安全性。
在 240 周时，在全分析集（84.4% vs. 73.5%；p=0.07）和治疗分析（92.7% vs. 79.8%；p=0.02）中，血清 HBV DNA <15 IU/ml 的患者比例在 ETV 和 ADV 耐药组之间无显著差异。在 240 周的整个研究期间，有 7 名患者出现了与药物依从性差相关的病毒学突破。没有患者发生额外的 HBV 耐药突变。在基线时 170 名 HBV e 抗原（HBeAg）阳性患者中，12 名（7.1%）在 240 周时实现了 HBeAg 血清学转换。没有人实现 HBV 表面抗原血清学清除。在 240 周时，肾小球滤过率（CKD-EPI 方程估计的肾小球滤过率下降 3.21 ml/min/1.73 m，p<0.001）和股骨骨密度（g/cm）下降（下降 2.48%，p<0.001）有显著的下降。
长达 240 周的 TDF 单药治疗为对 ETV 和/或 ADV 耐药的 HBV 大量预先治疗的患者提供了越来越高的病毒学应答率。然而，它与较差的血清学应答以及肾功能和骨密度下降有关。（临床试验.gov 号，NCT01639066 和 NCT01639092）。
非医学专业人士请不要自行翻译，以免造成误解。
