从替诺福韦二富马酸富马酸盐改为替诺福韦阿拉芬酰胺：一

StephenW

Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in virologically suppressed patients with chronic hepatitis B: a randomised, double-blind, phase 3, multicentre non-inferiority study


Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in virologically suppressed patients with chronic hepatitis B: a randomised, double-blind, phase 3, multicentre non-inferiority study

    Prof Pietro Lampertico, MD †
    Maria Buti, MD
    Scott Fung, MD
    Prof Sang Hoon Ahn, MD
    Prof Wan-Long Chuang, MD
    Prof Won Young Tak, PhD
    et al.
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Published:February 20, 2020DOI:https://doi.org/10.1016/S2468-1253(19)30421-2

Summary
Background
Treatment with tenofovir disoproxil fumarate has been associated with renal toxicity or reductions in bone mineral density, or both, in some patients with chronic hepatitis B virus (HBV) infection. Tenofovir alafenamide is a tenofovir prodrug with high intrahepatic concentrations of active drug and reduced systemic tenofovir exposures compared with tenofovir disoproxil fumarate. In patients with chronic HBV, tenofovir alafenamide has shown efficacy non-inferior to that of tenofovir disoproxil fumarate with improved renal and bone safety. With this non-inferiority study, we aimed to evaluate the efficacy and safety of tenofovir alafenamide in patients with HBV infection switching from tenofovir disoproxil fumarate who are virally suppressed.
Methods
Patients with chronic HBV infection who had been receiving tenofovir disoproxil fumarate for 48 weeks or more and who had HBV DNA less than the lower limit of quantification (LLOQ) for at least 12 weeks were recruited to this randomised, multicentre, double-blind, phase 3 non-inferiority study. Patients were randomly assigned in a 1:1 ratio to receive tenofovir alafenamide 25 mg once a day or to continue tenofovir disoproxil fumarate 300 mg once a day. The primary efficacy endpoint was loss of virological control, defined as the proportion of patients who received at least one dose of study drug who had HBV DNA of at least 20 IU/mL at week 48 by the modified US Food and Drug Administration (FDA) snapshot algorithm. Key safety endpoints were changes in hip and spine bone mineral density, estimated creatinine clearance by Cockcroft-Gault, and markers of bone turnover and renal tubular function. The study was powered for non-inferiority in efficacy of tenofovir alafenamide versus tenofovir disoproxil fumarate with a 4% margin. Investigators and patients were unaware of treatment allocation and on-treatment results. This trial is ongoing and is registered with ClinicalTrials.gov, number NCT02979613.
Findings
Participants in this study were enrolled between Dec 29, 2016, and Oct 20, 2017. 541 patients were screened and 490 patients were randomly assigned to switch to tenofovir alafenamide or to stay on tenofovir disoproxil fumarate. Two patients assigned to receive tenofovir alafenamide did not receive treatment; thus the full analysis set for efficacy and safety analyses consisted of 243 patients in the tenofovir alafenamide group and 245 in the tenofovir disoproxil fumarate group. At week 48, one patient from each treatment group (both <1%) had HBV DNA of at least 20 IU/mL (difference in proportion 0·0%, 95% CI −1·9 to 2·0), thereby showing non-inferior efficacy of tenofovir alafenamide to tenofovir disoproxil fumarate. Patients who received tenofovir alafenamide had significantly increased bone mineral density at hip (mean change 0·66% [SD 2·08] vs −0·51% [SD 1·91]; difference in least square means 1·17% [95% CI 0·80 to 1·54; p<0·0001]) and at spine (mean change 1·74% [3·46] vs −0·11% [3·13]; difference in least square means 1·85% [1·24 to 2·46; p<0·0001]), creatinine clearance by Cockcroft-Gault relative to tenofovir disoproxil fumarate (median change 0·94 mL/min [IQR −4·47 to 6·24] vs −2·74 mL/min [−7·89 to 1·88]; p <0·0001), and improved markers of bone turnover and tubular function at week 48. The most common treatment-emergent adverse events were upper respiratory tract infection (18 [7%] of 243 patients in the tenofovir alafenamide group and 16 [7%] of 245 patients in the tenofovir disoproxil fumarate group) and nasopharyngitis (13 [5%] of 243 patients in the tenofovir alafenamide group and 12 [5%] of 245 patients in the tenofovir disoproxil fumarate group). The incidence of grade 3 and above adverse events and serious adverse events was low and similar between groups. No viral resistance was observed in patients who qualified for viral sequencing.
Interpretation
These findings suggest that tenofovir alafenamide can be substituted for tenofovir disoproxil fumarate in patients with HBV infection for improved safety without a loss of efficacy.
Funding
Gilead Sciences.

StephenW

在病毒学上抑制的慢性乙型肝炎患者中，从替诺福韦二富马酸富马酸盐改为替诺福韦阿拉芬酰胺：一项随机，双盲，3期，多中心非劣效性研究


在病毒学上抑制的慢性乙型肝炎患者中，从替诺福韦二富马酸富马酸盐改为替诺福韦阿拉芬酰胺：一项随机，双盲，3期，多中心非劣效性研究

    彼得罗·兰佩蒂科教授（医学博士†
    玛丽亚·布蒂（Maria Buti），医学博士
    冯志伟医学博士
    医学博士Sang Hoon Ahn教授
    庄万龙教授
    元永德教授
    等。
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发布时间：2020年2月20日DOI：https：//doi.org/10.1016/S2468-1253（19）30421-2

摘要
背景
在患有慢性乙型肝炎病毒（HBV）的某些患者中，替诺福韦酯富马酸二甲氧吡啶治疗与肾脏毒性或骨矿物质密度降低或两者均相关。替诺福韦alafenamide是替诺福韦的前药，与替诺福韦二富马酸富马酸酯相比，其肝内活性药物浓度高，全身替诺福韦暴露量降低。在患有慢性HBV的患者中，替诺福韦alafenamide的疗效不逊于富马酸替诺福韦二氢吡咯酯，并且改善了肾脏和骨骼的安全性。通过这项非劣效性研究，我们旨在评估替诺福韦阿拉芬酰胺从被病毒抑制的替诺福韦二富马酸富马酸酯转换为HBV感染的患者的疗效和安全性。
方法
将接受替诺福韦富马酸替诺福韦酯治疗48周或更长时间且HBV DNA低于定量下限（LLOQ）至少12周的慢性HBV感染患者纳入该随机，多中心，双盲，阶段3非自卑感研究。患者以1：1的比例随机分配，以每天一次接受替诺福韦阿拉芬酰胺25 mg或继续每天一次继续接受替诺福韦富马酸替索罗非300 mg。主要功效终点为病毒学控制丧失，定义为经过修改的美国食品药品监督管理局（FDA）在第48周接受至少一剂研究药物且HBV DNA至少为20 IU / mL的患者比例快照算法。重要的安全性终点指标是髋和脊柱骨矿物质密度的变化，Cockcroft-Gault估计的肌酐清除率以及骨转换和肾小管功能的标志物。这项研究证明了替诺福韦阿拉芬酰胺与替诺福韦富马酸替诺福韦地索非尔的疗效不逊色，为4％。研究者和患者不了解治疗分配和治疗结果。该试验正在进行中，并已在ClinicalTrials.gov上注册，编号为NCT02979613。
发现
这项研究的参与者于2016年12月29日至2017年10月20日期间进行了筛查。对541例患者进行了筛查，并随机分配了490例患者改用替诺福韦alafenamide或继续使用替诺福韦二吡呋酯富马酸酯。两名接受替诺福韦阿拉芬酰胺治疗的患者未接受治疗；因此，用于有效性和安全性分析的完整分析集包括tenofovir alafenamide组的243例患者和tenofovir disoproxil fumarate组的245例患者。在第48周，每个治疗组的一名患者（均<1％）的HBV DNA至少为20 IU / mL（比例差异为0·0％，95％CI -1·9至2·0），从而显示替诺福韦阿拉芬酰胺对替诺福韦二富马酸富马酸酯的非劣效疗效。接受替诺福韦阿拉芬酰胺治疗的患者髋部骨矿物质密度显着增加（平均变化0·66％[SD 2·08] vs −0·51％[SD 1·91]；最小二乘方差为1·17％[95] ％CI 0·80到1·54； p <0·0001]和脊柱处（平均变化1·74％[3·46] vs -0·11％[3·13]；最小二乘均值1 ·85％[1·24至2·46； p <0·0001]），相对于富马酸替诺福韦酯（中位数变化0·94 mL / min [IQR -4·47至6·24]，Cockcroft-Gault进行的肌酐清除率] vs -2·74 mL / min [−7·89至1·88]； p <0·0001），并在第48周时改善了骨转换和肾小管功能的标志物。呼吸道感染（替诺福韦阿拉芬酰胺组243例患者中有18例[7％]，富马酸替诺福韦二甲酚苄酯组中245例患者中有16例[7％]）和鼻咽炎（替诺福韦阿拉芬胺组243例中有13例[5％]），替诺福韦酯富马酸酯组245例患者中有12例（5％）。两组之间的3级及以上不良事件和严重不良事件的发生率较低且相似。在符合病毒测序条件的患者中未观察到病毒抗性。
解释
这些发现表明，乙型肝炎病毒感染患者可以用替诺福韦阿拉芬酰胺代替富马酸替诺福韦地索非尔，以提高安全性而又不损失疗效。
资金
吉利德科学。