AASLD2016[1843]没有检测到替诺福韦苯甲酰胺的耐药性 通过48周

StephenW

1843
No Resistance to Tenofovir Alafenamide Detected
Through 48 Weeks of Treatment in Patients with Chronic
Hepatitis B
Henry Lik-Yuen Chan1, Scott Fung2, Andrea L. Cathcart3, Yang
Liu3, Karin S. Ku3, John F. Flaherty3, Michael D. Miller3, Anuj
Gaggar3, Kathryn M. Kitrinos3, Young-Suk Lim4, Maria Buti5; 1The
Chinese University of Hong Kong, Hong Kong, China; 2Department
of Medicine, University of Toronto, Toronto, ON, Canada;
3Gilead Sciences, Foster City, CA; 4Asan Medical Center, University
of Ulsan College of Medicine, Seoul, Korea (the Republic
of); 5Hospital Vall Hebron and Ciberehd del Instituto Carlos III,
Barcelona, Spain
Aim: Presented herein are the Week 48 resistance analyses for
2 Phase 3 studies (GS-US-320-0108 and GS-US-320-0110)
evaluating tenofovir alafenamide (TAF) versus tenofovir disoproxil
fumarate (TDF) for the treatment of chronic hepatitis B
(CHB) in HBeAg+ and HBeAg- treatment-naïve or treatment-experienced
adults. Methods: Patients were randomized 2:1 and
stratified by HBV DNA and treatment status to receive TAF or
TDF. Baseline (BL) resistance substitutions in HBV pol/RT were
assessed using INNO-LiPA Multi-DR v2/3 assay. HBV pol/RT
population sequencing was conducted for patients with ≥24
weeks of treatment who experienced virologic breakthrough
(VB) at Week 48 or discontinued with viremia (HBV DNA ≥69
IU/mL). VB was defined as HBV DNA ≥69 IU/mL after achieving
<69 IU/mL or a ≥1.0-log10 increase from nadir. Deep
sequencing was conducted for VB patients with HBV DNA
≥159 IU/mL. Phenotypic analysis using recombinant HBV in
HepG2 cells was performed for VB patients who were adherent
to study drug (plasma drug levels). Results: 1298 patients
were randomized and treated (TAF: n=866; TDF: n=432). At
BL, the majority of patients harbored wild type pol/RT (89.2%).
Of the patients with resistance substitutions (10.8%), a higher
percentage was seen in treatment-experienced patients
(21.6%) compared to treatment-naive patients (7.6%). After
up to 48 weeks of treatment, a small and similar percentage
of patients qualified for sequence analysis (TAF, 2.8%; TDF,
3.2%). In the TAF arm, 24 patients qualified: 15 patients had
no change from BL, 4 were unable to be sequenced (UTS),
and 5 had polymorphic site substitutions. In the TDF arm, 14
subjects qualified: 6 patients had no change, 4 were UTS,
2 had polymorphic site substitutions, and 2 had conserved
site substitutions (rtQ67Q/H, rtQ288Q/stop). VB was often
associated with study drug nonadherence (TAF, 44%; TDF,
62%). Of the 16 patients who qualified for deep sequencing;
2 polymorphic substitutions were detected in 2 patients
each (rtN123D, TAF n=1, TDF n=1; rtH124D, TAF n=2) and
1 adefovir resistance-associated substitution was detected in 1
patient (rtN236T, TDF n=1). rtN236T was detected at a level
of 14.7% at Week 48; however, rtN236T was not observed at
BL nor in visits preceding/following Week 48 and the patient
resuppressed HBV DNA with continued treatment. No deep
sequencing substitutions were associated with sustained VB,
and 4 of 4 patients remaining on study achieved HBV DNA
<69 IU/mL with continued treatment. Phenotypic analysis of
10 patients (TAF n=6, TDF n=4) showed no reduction in susceptibility
to TAF or tenofovir, respectively. Conclusion: No
resistance to TAF was detected through Week 48.
Disclosures:
Henry Lik-Yuen Chan - Advisory Committees or Review Panels: Gilead, Janssen,
Bristol-Myers Squibb, Roche, Novartis Pharmaceutical, Abbvie; Speaking and
Teaching: Echosens
Scott Fung - Advisory Committees or Review Panels: Gilead Sciences, Merck,
Abbvie; Speaking and Teaching: BMS, Gilead, AbbVie, Merck
Yang Liu - Employment: Gilead Sciences
Karin S. Ku - Employment: Gilead Sciences, Inc.; Stock Shareholder: Gilead
Sciences, Inc.
John F. Flaherty - Employment: Gilead Sciences; Stock Shareholder: Gilead Sciences
Michael D. Miller - Employment: Gilead Sciences; Stock Shareholder: Gilead
Sciences
Anuj Gaggar - Employment: Gilead Sciences, Inc.
Kathryn M. Kitrinos - Employment: Gilead Sciences; Stock Shareholder: Gilead
Sciences
Young-Suk Lim - Advisory Committees or Review Panels: Bayer Healthcare, Gilead
Sciences; Grant/Research Support: Bayer Healthcare, BMS, Gilead Sciences,
Novartis
Maria Buti - Advisory Committees or Review Panels: Gilead, Janssen, MSD;
Grant/Research Support: Gilead, Janssen; Speaking and Teaching: Gilead,
Janssen, BMS
The following people have nothing to disclose: Andrea L. Cathcart

StephenW

AASLD2016 [1843]没有检测到替诺福韦苯甲酰胺的耐药性
通过48周治疗
没有检测到替诺福韦苯甲酰胺的耐药性
通过48周治疗慢性病人
乙型肝炎
Henry Lik-Yuen Chan1，Scott Fung2，Andrea L.Cathcart3，Yang
Liu3，Karin S.Ku3，John F.Faherty3，Michael D.Miller3，Anuj
Gaggar3，Kathryn M. Kitrinos3，Young-Suk Lim4，Maria Buti5; 1，
中国香港中文大学; 2
of Toronto，Toronto，ON，Canada;
3Gilead Sciences，Foster City，CA; 4亚萨医疗中心，大学
蔚山医学院，韩国首尔（共和国
的）; 5Hospital Vall Hebron和Ciberehd del Instituto Carlos III，
西班牙巴塞罗那
目的：本文提供的是第48周抵抗分析
2 3期研究（GS-US-320-0108和GS-US-320-0110）
评估替诺福韦艾拉酚胺（TAF）与替诺福韦地索普西
富马酸盐（TDF）用于治疗慢性乙型肝炎
（CHB）在HBeAg +和HBeAg-治疗首次或治疗经历
成人。方法：患者随机分为2：1和
分层的HBV DNA和治疗状态接受TAF或
TDF。 HBV pol / RT中的基线（BL）电阻置换
使用INNO-LiPA Multi-DR v2 / 3测定法评估。 HBV pol / RT
对≥24岁的患者进行群体测序
周的治疗经历病毒学突破
（VB）或以病毒血症（HBV DNA≥69）终止
IU / mL）。 VB定义为达到后HBV DNA≥69IU / mL
<69 IU / mL或从最低点增加≥1.0-log10。深
对具有HBV DNA的VB患者进行测序
≥159IU / mL。使用重组HBV的表型分析
对粘附的VB患者进行HepG2细胞
研究药物（血浆药物水平）。结果：1298例患者
随机化并进行治疗（TAF：n = 866; TDF：n = 432）。在
BL，大多数患者携带野生型pol / RT（89.2％）。
在具有抗性替代（10.8％）的患者中，更高
在经历过治疗的患者中观察到百分比
（21.6％）相比，未接受治疗的患者（7.6％）。后
可达48周的治疗，小而类似的百分比
的符合序列分析资格的患者（TAF，2.8％; TDF，
3.2％）。在TAF组，24名合格：15名患者
与BL无变化，4例无法测序（UTS）
和5个具有多态性位点替换。在TDF臂中，14
受试者资格：6例无变化，4例为UTS，
2具有多态位点置换，2个具有保守性
位点置换（rtQ67Q / H，rtQ288Q / stop）。 VB经常
与研究药物不粘附有关（TAF，44％; TDF，
62％）。在符合深度测序的16名患者中;
2例患者检测到2个多态性替换
每个（rtN123D，TAF n = 1，TDF n = 1; rtH124D，TAF n = 2）和
在1中检测到1个阿德福韦抗性相关的替代
患者（rtN236T，TDF n = 1）。检测到rtN236T水平
在第48周时为14.7％然而，未观察到rtN236T
BL或在第48周和患者之前/之后的访视
重复抑制HBV DNA并继续治疗。没有深
测序取代与持续性VB相关，
剩余4名患者中有4名患者获得HBV DNA
<69 IU / mL，持续治疗。表型分析
10例（TAF n = 6，TDF n = 4）未显示敏感性降低
分别与TAF或替诺福韦。结论：不
通过第48周检测对TAF的抗性。
披露：
Henry Lik-Yuen陈 - 咨询委员会或审核小组：Gilead，Janssen，
Bristol-Myers Squibb，Roche，Novartis Pharmaceutical，Abbvie;说话和
教学：Echosens
Scott Fung - 咨询委员会或审查小组：G​​ilead Sciences，Merck，
Abbvie;口语和教学：BMS，Gilead，AbbVie，Merck
杨柳 - 就业：吉利德科学
就业：吉利德科学公司。股票股东：Gilead
科学公司
约翰·弗莱厄蒂 - 就业：吉利德科学;股票股东：Gilead Sciences
Michael D. Miller - 就业：吉利德科学;股票股东：Gilead
科学
Anuj Gaggar - 就业：Gilead Sciences，Inc.
就业：吉利德科学;股票股东：Gilead
科学
Young-Suk Lim - 咨询委员会或审查小组：Bayer Healthcare，Gilead
科学;资助/研究支持：拜耳医疗保健，BMS，吉利德科学，
诺华
Maria Buti - 咨询委员会或审查小组：G​​ilead，Janssen，MSD;
资助/研究支持：Gilead，Janssen;口语和教学：Gilead，
Janssen，BMS
以下人没有什么可披露：Andrea L. Cathcart