替诺福韦盐酸阿芬芬与替诺福韦地索普西富马酸盐治疗HBeAg阳

StephenW

Lancet Gastroenterol Hepatol. 2016 Nov;1(3):185-195. doi: 10.1016/S2468-1253(16)30024-3. Epub 2016 Sep 22.
Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of HBeAg-positive chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial.
Chan HL1, Fung S2, Seto WK3, Chuang WL4, Chen CY5, Kim HJ6, Hui AJ7, Janssen HL8, Chowdhury A9, Tsang TY10, Mehta R11, Gane E12, Flaherty JF13, Massetto B13, Gaggar A13, Kitrinos KM13, Lin L13, Subramanian GM13, McHutchison JG13, Lim YS14, Acharya SK15, Agarwal K16; GS-US-320-0110 Investigators.
Author information

1    The Chinese University of Hong Kong, Hong Kong. Electronic address: [email protected].
2    Toronto General Hospital, Toronto, ON, Canada.
3    Queen Mary Hospital, Hong Kong.
4    Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
5    Chiayi Christian Hospital, Chiayi, Taiwan.
6    Chung-Ang University Hospital, Seoul, South Korea.
7    Alice Ho Miu Ling Nethersole Hospital, Hong Kong.
8    Toronto Centre for Liver Disease, Toronto, ON, Canada.
9    Institute of Post Graduate Medical Education and Research, Kolkata, India.
10    Princess Margaret Hospital, Hong Kong.
11    Surat Institute of Medical Sciences, Surat, Gujarat, India.
12    Auckland Clinical Studies, Auckland, New Zealand.
13    Gilead Sciences, Foster City, CA, USA.
14    Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
15    All India Institute of Medical Sciences, New Delhi, Delhi, India.
16    Kings College Hospital, London, UK.

Abstract
BACKGROUND:

Tenofovir alafenamide is a novel prodrug formulated to deliver the active metabolite to target cells more efficiently than tenofovir disoproxil fumarate at a lower dose, thereby reducing systemic exposure. In patients with HIV, tenofovir alafenamide was as efficacious as tenofovir disoproxil fumarate, with reduced bone and renal toxic effects. We compared the efficacy and safety of the two drugs in patients with HBeAg-positive chronic hepatitis B virus (HBV) infection in a non-inferiority study.
METHODS:

We did this ongoing double-blind, non-inferiority study in 161 outpatient centres in 19 countries. Patients with chronic HBV infection who were positive for the hepatitis B e antigen (HBeAg) were randomly assigned (2:1) to receive either 25 mg tenofovir alafenamide or 300 mg tenofovir disoproxil fumarate with matching placebo. Randomisation was done by a computer-generated allocation sequence (block size six) stratified by plasma HBV DNA concentration and previous treatment experience. The primary efficacy endpoint was the proportion of patients with HBV DNA less than 29 IU/mL at week 48 in all patients who were randomly assigned and received at least one dose of study drug using a missing-equals-failed approach. The pre-specified non-inferiority margin was 10%. Key prespecified safety endpoints were bone and renal parameters at week 48. This study is registered with ClinicalTrials.gov, number NCT01940471.
FINDINGS:

Of the 1473 patients screened from Sept 11, 2013, to Dec 20, 2014, 875 eligible patients were randomly assigned and 873 received treatment (581 with tenofovir alafenamide and 292 with tenofovir disoproxil fumarate). 371 (64%) patients receiving tenofovir alafenamide had HBV DNA less than 29 IU/mL at week 48, which was non-inferior to the 195 (67%) of patients receiving tenofovir disoproxil fumarate who had HBV DNA less than 29 IU/mL (adjusted difference -3·6% [95% CI -9·8 to 2·6]; p=0·25). Patients given tenofovir alafenamide had a significantly smaller decrease in bone mineral density at hip (mean change -0·10% [95% CI -0·29 to 0·09] vs -1·72% [-2·02 to -1·41]; adjusted difference 1·62 [1·27 to 1·96]; p<0·0001) and at spine (mean change -0·42% [-0·66 to -0·17] vs -2·29% [-2·67 to -1·92]; adjusted difference 1·88 [1·44 to 2·31]; p<0·0001) as well as smaller mean increases in serum creatinine at week 48 (0·01 mg/dL [0·00-0·02] vs 0·03 mg/dL [0·02-0·04]; p=0·02). The most common adverse events overall were upper respiratory tract infection (51 [9%] of 581 patients receiving tenofovir alafenamide vs 22 [8%] of 292 patients receiving tenofovir disoproxil fumarate), nasopharyngitis (56 [10%] vs 16 [5%]), and headache (42 [7%] vs 22 [8%]). 22 (4%) patients receiving tenofovir alafenamide and 12 (4%) patients receiving tenofovir disoproxil fumarate experienced serious adverse events, none of which was deemed by the investigator to be related to study treatment. 187 (32%) of 581 patients in the tenofovir alafenamide group and 96 (33%) of 292 patients in the tenofovir disoproxil fumarate group had grade 3 or 4 laboratory abnormalities, the most common of which were elevations in ALT (62 [11%] of 577 patients receiving tenofovir alafenamide and 36 [13%] of 288 patients receiving tenofovir disoproxil fumarate) and AST (20 [3%] of 577 patients receiving tenofovir alafenamide and 19 [7%] of 288 patients receiving tenofovir disoproxil fumarate).
INTERPRETATION: In patients with HBeAg-positive HBV infection, tenofovir alafenamide was non-inferior to tenofovir disoproxil fumarate, and had improved bone and renal effects. Longer term follow-up is needed to better understand the clinical impact of these changes.
FUNDING: Gilead Sciences.

StephenW

Lancet Gastroenterol Hepatol。 2016年11月; 1（3）：185-195。 doi：10.1016 / S2468-1253（16）30024-3。 Epub 2016 Sep 22。
替诺福韦盐酸阿芬芬与替诺福韦地索普西富马酸盐治疗HBeAg阳性慢性乙型肝炎病毒感染：一项随机，双盲，3期非劣效性试验。
Chan HL1，Fung S2，Seto WK3，Chuang WL4，Chen CY5，Kim HJ6，Hui AJ7，Janssen HL8，Chowdhury A9，Tsang TY10，Mehta R11，Gane E12，Flaherty JF13，Massetto B13，Gaggar A13，Kitrinos KM13，Lin L13 ，Subramanian GM13，McHutchison JG13，Lim YS14，Acharya SK15，Agarwal K16; GS-US-320-0110调查员。
作者信息

1香港中文大学香港。电子邮件地址：[email protected]。
2 Toronto General Hospital，Toronto，ON，Canada。
3玛丽医院，香港。
高雄医科大学高雄医院，高雄，台湾。
台湾嘉义嘉义基督教医院5号
6中央大学医院，首尔，韩国。
7香港爱丽丝何妙龄那打素医院
多伦多，加拿大多伦多肝病中心8号。
9印度加尔各答研究生医学教育与研究所。
十号香港玛嘉烈医院。
11苏拉特医学科学研究所，苏拉特，古吉拉来邦，印度。
12奥克兰临床研究，新西兰奥克兰。
美国加州福斯特市吉利德科学13。
蔚山医科大学Asan医学中心，韩国首尔。
15印度所有印度医学科学院，新德里，印度德里。
16国王学院医院，伦敦，英国。

抽象
背景：

替诺福韦盐酸阿芬芬是一种新药前体药物，配制成能够以比较低剂量的替诺福韦地索普伐他富马酸盐递送活性代谢物以更有效地靶向细胞，从而减少全身暴露。在艾滋病毒患者中，替诺福韦甲酰胺与替诺福韦地索普利富马酸一样有效，具有降低的骨和肾毒性作用。在非劣效性研究中，我们比较了两种药物在HBeAg阳性慢性乙型肝炎病毒（HBV）感染患者中的疗效和安全性。
方法：

我们在19个国家的161个门诊中心进行了双盲，非劣性研究。患有乙型肝炎病毒抗原（HBeAg）阳性的慢性HBV感染患者被随机分配（2：1）接受25 mg替诺福韦甲酰胺或300 mg替诺福韦富马酸替夫洛尔与匹配的安慰剂。随机化是通过计算机生成的分配序列（块大小六）进行的，其由血浆HBV DNA浓度和先前的治疗经验分层。主要疗效终点是在所有随机分配的患者和接受至少一剂剂量的研究药物使用失踪等效失败方法的第48周HBV DNA小于29 IU / mL的患者比例。预先确定的非劣效保证金为10％。关键的预先指定的安全终点是第48周的骨和肾参数。本研究用ClinicalTrials.gov登记，编号NCT01940471。
发现：

在2013年9月11日至2014年12月20日筛查的1473例患者中，随机分配了875名符合条件的患者，接受治疗873例（替诺福韦甲酰胺组为581例，富马酸替莫福韦为292例）。接受替诺福韦甲醛酰胺治疗的371例（64％）患者在第48周HBV DNA低于29 IU / mL，与接受替诺福韦地塞米芬富马酸替诺福昔组患者的195（67％）低于29 IU / （调整差值-3.6％[95％CI -9.8〜2.6]; p = 0·25）。给予替诺福韦甲酰胺的患者臀部骨矿物质密度降低显着降低（平均变化-0.10％[95％CI -0.29〜0。09] vs -1·72％[-2·02〜-1 ·41];调整差异1·62 [1·27〜1·96]; p <0·0001）和脊柱（平均变化-0·42％[-0·66〜-0·17] vs -2 ·29％[-2·67〜-1·92];调整差异1·88 [1·44〜2·31]; p <0·0001）以及第48周血清肌酸酐平均增加·01mg / dL [0·00-0·02] vs0·03mg / dL [0·02-0·04]; p = 0·02）。总体上最常见的不良事件是上呼吸道感染（581例接受替诺福韦甲酰胺酰胺治疗的患者中有51例[9％]，接受替诺福韦富马酸替诺泊芬治疗的292例患者中有22例[8％]），鼻咽炎（56 [10％] vs 16 [5％ ]）和头痛（42 [7％] vs 22 [8％]）。 22例（4％）接受替诺福韦甲酰胺的患者和12例（4％）接受替诺福韦地索他芬富马酸盐的患者出现严重不良事件，研究者认为其中没有一项与研究治疗相关。替诺福韦甲酰胺组581例患者中有187例（32％），替诺福韦富马酸酯组的292例患者中有96例（33％）有三级或四级实验室异常，其中最常见的是ALT升高（62％[11％ ] 577例接受替诺福韦甲酰胺的患者中，36例[占13％] 288例接受替诺福韦地索他芬富马酸盐治疗的患者）和AST（20例[3％] 577例接受替诺福韦甲酰胺和19 [7％] 288例患者接受替诺福韦地索他芬富马酸盐）。
解释：

Inna与HBeAg阳性HBV感染，替诺福韦甲酰胺不逊于替诺福韦地索普利富马酸，具有改善的骨和肾功能。 需要更长期的后续行动来更好地了解这些变化的临床影响。
资金：

吉利德科学。