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
Young-Suk Lim1, Kwan Soo Byun2, Byung Chul Yoo3, So Young Kwon4, Yoon Jun Kim5, Jihyun An1, Han Chu Lee1, Yung Sang Lee1
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Author Affiliations
1Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
2Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
3Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
4Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Republic of Korea
5Department of Internal Medicine, Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
Correspondence to Professor Young-Suk Lim, Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Republic of Korea; [email protected] and Professor Kwan Soo Byun, Department of Internal Medicine, Korea University Guro Hospital, 148, Gurodong-ro, Guro-gu, Seoul 152-703, Republic of Korea; [email protected]
Received 31 August 2014
Revised 24 December 2014
Accepted 27 December 2014
Published Online First 16 January 2015
Abstract
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 log10 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.
Trial registration number ClinicalTrials.gov ID NCT01639092.
设计在这个多中心随机试验中，谁曾与HBV ETV耐药相关的突变和血清HBV DNA浓度> 60 IU / mL的患者被随机分配接受富马酸替诺福韦酯（TDF，300毫克/天）单药治疗（N = 45）或TDF和ETV（1毫克/天）的组合疗法（45）48周。
结果基线特征可比组之间，包括HBV DNA水平（中位数，4.02日志10 IU / mL）和乙型肝炎e抗原阳性（89％）。所有患者至少有一个ETV耐药突变：rtT184A / C / F / G / I / L / S（N = 49），rtS202G（N = 43）和rtM250L / V（N = 7），除了rtM204V / I（N = 90）。所有除一名患者的TDF集团在完成治疗48周。在48周时，患者的HBV DNA的比例<15 IU / mL时，主要疗效终点，不是TDF和TDF + ETV组（71％比73％; P之间显著不同> 0.99）。从基线HBV DNA水平的平均变化在两组之间显著的不同（-3.66 VS -3.74日志10 IU / mL的; P = 0.81）。病毒学突破发生在一名患者TDF，这是由于药物依从性差。在48周，6年和3例患者在TDF和TDF + ETV组，分别保留其基线耐药突变（P> 0.99）。没有开发的附加性的突变。安全配置文件是可比较的两组。
结论TDF单一疗法48周设置的病毒学应答媲美TDF和ETV联合治疗的患者感染ETV耐药HBV。
试用注册号ClinicalTrials.gov ID NCT01639092。
Cháng dào DOI:10.1136/ Gutjnl-2014-30