AASLD2018[2106]乙型肝炎病毒抗原（HBeAg）的丢失 Nucleos（t）Ide（

StephenW

2106
Loss of Hepatitis B e Antigen (HBeAg) during
Nucleos(t)Ide (NUC) Therapy Is Associated
with Greater Improvement in Liver Fibrosis
Maria Buti1, Scott K. Fung2, Sang Hoon Ahn3, Graham R.
Foster4, Jenny C Yang5, Hongyuan Wang6, John F. Flaherty5,
Anuj Gaggar6, Mani Subramanian5, Kwan Soo Byun7, Cheng-
Yuan Peng8 and Patrick Marcellin9, (1)Hospital General
Universitari Vall d’Hebron and Ciberehd, Barcelona, Spain, (2)
Toronto General Hospital, Department of Medicine, University
of Toronto, Toronto, on, Canada, (3)Yonsei University College
of Medicine, Severance Hospital, Seoul, Republic of Korea,
(4)Queen Mary University of London, Barts Health NHS Trust,
London, England, UK, (5)Gilead Sciences, Inc, Foster City,
CA USA, (6)Gilead Sciences, Inc, Foster City, California, USA,
(7)Korea University, Guro Hospital, Seoul, Republic of Korea,
(8)China Medical University Hospital, Taichung, Taiwan, (9)
Service D’hépatologie, Hôpital Beaujon, Aphp and Inserm,
University Paris-Diderot, France
Background: The role of HBeAg in hepatic inflammation and
fibrosis is not well understood. The intrahepatic production
of HBeAg may contribute to inflammation in NUC-treated
patients and it follows that conversion to HBeAg negative
status may reduce intrahepatic inflammation and potentially
a reduction in fibrosis. The aim of this investigation was to
evaluate the effects of HBeAg loss during long-term NUC
therapy on liver fibrosis regression in a well characterized
study population. Methods: Viremic HBeAg+ CHB patients
randomized in an ongoing Phase 3 study (GS-US-320-0110)
to TAF or TDF once daily for up to 8 years. Available data
through Week (WK) 144 was pooled across treatment arms.
Serum HBeAg was evaluated qualitatively at Baseline (BSL)
and every 12 WKs. FibroTest scores (FT) were generated
at BSL and every 48 WKs by central laboratory. Descriptive
statistics of absolute and change from BSL at WKs 48, 96,
and 144 in FT scores and categorical changes in FT were
compared between patients with and without HBeAg loss by
WK 96. FT categories (Metavir fibrosis scores) were: <0.49
(F0-F1), 0.49 to <0.75 (F2-F3), and ≥0.75 (F4). ALT normal
levels defined as <19 U/L female and <30 U/L male. Results:
770 HBeAg+ patients had HBeAg results at WK 96: 517 were
randomized to TAF and 253 to TDF. Rates of HBeAg loss at
WKs 48, 96 and 144 were: 106 (14%), 174 (23%), and 193
(27%), respectively. The rate of HBeAg loss by WK 96 was
similar by treatment (24% TAF vs 20% TDF). A higher rate of
ALT normalization by WK 96 was observed in patients with vs
without HBeAg loss: 121 (70%) vs 295 (50%). In patients with
HBeAg loss by WK 96, a higher rate of ALT normalization was
observed in TAF vs TDF treated patients (75% TAF vs 57%
TDF). Key BSL characteristics and change from BSL in FT are
presented by HBeAg status at WK 96 in the Table. Majority
of patients were Asian (82%), male (65%), non-cirrhotic by
medical history (90%), GT C (54%), and NUC-naïve (74%).
Patients with HBeAg loss by WK 96 were older, non-obese,
had lower HBV DNA and higher ALT levels, and were more
likely to have FT ≥0.75 (13% vs 6% in HBeAg+) at BSL. Mean
decline from BSL in FT was observed in patients with and
without HBeAg loss; however, HBeAg loss patients had a
greater decline at WK 144 (Table). The difference observed
in the mean (SD) decline from BSL in FT between patients
with and without HBeAg loss remained when viremic patients
(HBV DNA ≥29 IU/mL at Week 96) were excluded from the
analysis (WK 144 of -0.08 [0.17] HBeAg loss vs -0.05 [0.14]
HBeAg+). A higher proportion of patients with vs without
HBeAg loss had ≥1 categorical improvement in FT: 21% vs
10%, 17% vs 10%, and 16% vs 9%, at WKs 48, 96, and 144,
respectively. Conclusion: By serum FT, improvement in liver
fibrosis was observed in CHB patients during NUC therapy
regardless of HBeAg status. However, patients with HBeAg
loss by Week 96 had a greater improvement in FT scores then
those that remained HBeAg+ suggesting a possible role for
HBeAg loss in reducing fibrogenesis.

StephenW

2106
乙型肝炎病毒抗原（HBeAg）的丢失
Nucleos（t）Ide（NUC）疗法是相关的
肝纤维化的改善
Maria Buti1，Scott K. Fung2，Sang Hoon Ahn3，Graham R.
Foster4，Jenny C Yang5，Hongyuan Wang6，John F. Flaherty5，
Anuj Gaggar6，Mani Subramanian5，Kwan Soo Byun7，Cheng-
袁鹏8和帕特里克马塞林9，（1）医院院长
Universitari Vall d'Hebron和Ciberehd，西班牙巴塞罗那，（2）
多伦多综合医院，大学医学系
多伦多，多伦多，加拿大，（3）延世大学学院
医学，Severance医院，首尔，大韩民国，
（4）伦敦玛丽皇后学院，Barts Health NHS Trust，
伦敦，英国，英国，（5）Gilead Sciences，Inc，Foster City，
CA USA，（6）Gilead Sciences，Inc，Foster City，California，USA，
（7）韩国大学，首尔，韩国九老医院，
（8）台湾台中医科大学附属医院（9）
服务D'hépatologie，HôpitalBeaujon，Aphp和Inserm，
法国巴黎 - 狄德罗大学
背景：HBeAg在肝脏炎症和肝细胞癌中的作用
纤维化尚不清楚。肝内生产
HBeAg可能导致NUC治疗的炎症
患者及其随后转为HBeAg阴性
状态可能会减少肝内炎症和潜在的炎症
减少纤维化。这项调查的目的是为了
评估长期NUC期间HBeAg消失的影响
治疗对肝纤维化的消退有良好的特征性
研究人口。方法：病毒血症HBeAg + CHB患者
在正在进行的第3阶段研究中随机化（GS-US-320-0110）
TAF或TDF每天一次，最长可达8年。可用数据
通过周（WK）144汇集治疗组。
血清HBeAg在基线（BSL）定性评估
每12个WK。生成FibroTest分数（FT）
在BSL和中心实验室每48 WK。描述的
来自BSL的绝对值和变化统计数据为48,96 WK，
FT评分为144分，FT分类变化为144分
比较有和没有HBeAg损失的患者
WK 96. FT类别（Metavir纤维化评分）：<0.49
（F0-F1），0.49至<0.75（F2-F3），和≥0.75（F4）。 ALT正常
水平定义为<19 U / L女性和<30 U / L男性。结果：
770名HBeAg +患者的HBeAg结果为WK 96：517
随机分配到TAF和253分到TDF。 HBeAg丢失率
WK 48,96和144分别是：106（14％），174（23％）和193
（27％），分别。 WK 96的HBeAg丢失率为
治疗相似（24％TAF vs 20％TDF）。更高的比率
在患者中观察到WK 96的ALT正常化
没有HBeAg损失：121（70％）vs 295（50％）。在患者中
WK 96引起HBeAg丢失，ALT正常化率更高
在TAF和TDF治疗的患者中观察到（75％TAF对57％
TDF）。关键BSL特征和FT中BSL的变化是
由HBeAg在表中的WK 96表示。多数
患者为亚洲人（82％），男性（65％），非肝硬化患者
病史（90％），GT C（54％）和NUC-naïve（74％）。
WK 96失去HBeAg的患者年龄较大，非肥胖，
HBV DNA较低，ALT水平较高，且更多
BSL可能有FT≥0.75（HBeAg +为13％vs 6％）。意思
在患有和的患者中观察到FT中的BSL下降
没有HBeAg损失;然而，HBeAg丢失患者有一个
在WK 144下跌幅度更大（表）。观察到的差异
患者中FT与BSL的平均值（SD）下降
当病毒血症患者时，有和没有HBeAg丢失
（第96周的HBVDNA≥29IU/ mL）被排除在外
分析（WK 144为-0.08 [0.17] HBeAg损失vs -0.05 [0.14]
大三阳+）。更高比例的患者与无
英国“金融时报”的HBeAg损失≥1分类：21％vs
WKs 48,96和144分别为10％，17％vs 10％，16％vs 9％，
分别。结论：通过血清FT，改善肝脏
在NUC治疗期间在CHB患者中观察到纤维化
无论HBeAg状态如何。但是，HBeAg患者
第96周的损失使得FT分数有了更大的改善
那些仍然存在HBeAg +的人建议可能发挥作用
HBeAg在减少纤维发生方面的损失。

Hepbest

2106 Loss of Hepatitis B e Antigen (HBeAg) during Nucleos(t)Ide (NUC) Therapy Is Associated with Greater Improvement in Liver Fibrosis Maria Buti1, Scott K. Fung2, Sang Hoon Ahn3, Graham R. Foster4, Jenny C Yang5, Hongyuan Wang6, John F. Flaherty5, Anuj Gaggar6, Mani Subramanian5, Kwan Soo Byun7, Cheng- Yuan Peng8 and Patrick Marcellin9, (1)Hospital General Universitari Vall d’Hebron and Ciberehd, Barcelona, Spain, (2) Toronto General Hospital, Department of Medicine, University of Toronto, Toronto, on, Canada, (3)Yonsei University College of Medicine, Severance Hospital, Seoul, Republic of Korea, (4)Queen Mary University of London, Barts Health NHS Trust, London, England, UK, (5)Gilead Sciences, Inc, Foster City, CA USA, (6)Gilead Sciences, Inc, Foster City, California, USA, (7)Korea University, Guro Hospital, Seoul, Republic of Korea, (8)China Medical University Hospital, Taichung, Taiwan, (9) Service D’hépatologie, Hôpital Beaujon, Aphp and Inserm, University Paris-Diderot, France
Background:
The role of HBeAg in hepatic inflammation and fibrosis is not well understood. The intrahepatic production of HBeAg may contribute to inflammation in NUC-treated patients and it follows that conversion to HBeAg negative status may reduce intrahepatic inflammation and potentially a reduction in fibrosis. The aim of this investigation was to evaluate the effects of HBeAg loss during long-term NUC therapy on liver fibrosis regression in a well characterized study population.

Methods:
Viremic HBeAg+ CHB patients randomized in an ongoing Phase 3 study (GS-US-320-0110) to TAF or TDF once daily for up to 8 years. Available data through Week (WK) 144 was pooled across treatment arms. Serum HBeAg was evaluated qualitatively at Baseline (BSL) and every 12 WKs. FibroTest scores (FT) were generated at BSL and every 48 WKs by central laboratory. Descriptive statistics of absolute and change from BSL at WKs 48, 96, and 144 in FT scores and categorical changes in FT were compared between patients with and without HBeAg loss by WK 96. FT categories (Metavir fibrosis scores) were: <0.49 (F0-F1), 0.49 to <0.75 (F2-F3), and ≥0.75 (F4). ALT normal levels defined as <19 U/L female and <30 U/L male.
Results:
770 HBeAg+ patients had HBeAg results at WK 96: 517 were randomized to TAF and 253 to TDF. Rates of HBeAg loss at WKs 48, 96 and 144 were: 106 (14%), 174 (23%), and 193 (27%), respectively. The rate of HBeAg loss by WK 96 was similar by treatment (24% TAF vs 20% TDF). A higher rate of ALT normalization by WK 96 was observed in patients with vs without HBeAg loss: 121 (70%) vs 295 (50%). In patients with HBeAg loss by WK 96, a higher rate of ALT normalization was observed in TAF vs TDF treated patients (75% TAF vs 57% TDF). Key BSL characteristics and change from BSL in FT are presented by HBeAg status at WK 96 in the Table. Majority of patients were Asian (82%), male (65%), non-cirrhotic by medical history (90%), GT C (54%), and NUC-naïve (74%). Patients with HBeAg loss by WK 96 were older, non-obese, had lower HBV DNA and higher ALT levels, and were more likely to have FT ≥0.75 (13% vs 6% in HBeAg+) at BSL. Mean decline from BSL in FT was observed in patients with and without HBeAg loss; however, HBeAg loss patients had a greater decline at WK 144 (Table). The difference observed in the mean (SD) decline from BSL in FT between patients with and without HBeAg loss remained when viremic patients (HBV DNA ≥29 IU/mL at Week 96) were excluded from the analysis (WK 144 of -0.08 [0.17] HBeAg loss vs -0.05 [0.14] HBeAg+). A higher proportion of patients with vs without HBeAg loss had ≥1 categorical improvement in FT: 21% vs 10%, 17% vs 10%, and 16% vs 9%, at WKs 48, 96, and 144, respectively.

Conclusion:
By serum FT, improvement in liver fibrosis was observed in CHB patients during NUC therapy regardless of HBeAg status. However, patients with HBeAg loss by Week 96 had a greater improvement in FT scores then those that remained HBeAg+ suggesting a possible role for HBeAg loss in reducing fibrogenesis.

Hepbest

2106 Nucleos（t）Ide（NUC）疗法中肝炎和抗原（HBeAg）的丢失与肝纤维化的改善有关Maria Buti1，Scott K. Fung2，Sang Hoon Ahn3，Graham R. Foster4，Jenny C Yang5，Hongyuan Wang6，John F. Flaherty5，Anuj Gaggar6，Mani Subramanian5，Kwan Soo Byun7，Cheng-Yuan Peng 8和Patrick Marcellin9，（1）西班牙巴塞罗那Vall d'Hebron大学和Ciberehd医院，（2）多伦多综合医院，系多伦多大学医学院，加拿大多伦多，（3）延世大学医学院，Severance医院，韩国首尔，（4）伦敦大学玛丽皇后学院，Barts Health NHS Trust，英国伦敦，英国，（5）Gilead Sciences，Inc，Foster City，CA USA，（6）Gilead Sciences，Inc，Foster City，California，USA，（7）Korea University，Guro Hospital，Seoul，Korea，（8）China Medical台湾台中大学医院，（9）巴黎Diderot大学医院，HôpitalBeaujon，Aphp和Inserm，Fr ANCE
 背景：
 HBeAg在肝脏炎症和纤维化中的作用尚不清楚。 HBeAg的肝内产生可能导致NUC治疗的患者的炎症，并且随后转变为HBeAg阴性状态可以减少肝内炎症并且可能减少纤维化。这项研究的目的是评估在长期NUC治疗期间HBeAg在特征良好的研究人群中对肝纤维化消退的影响。
 
 方法：
 病毒血症HBeAg + CHB患者在正在进行的3期研究（GS-US-320-0110）中随机分配至TAF或TDF，每日一次，持续长达8年。通过周（WK）144的可用数据汇集在治疗组中。血清HBeAg在基线（BSL）和每12 WK定性评估。 FibroTest评分（FT）由BSL生成，中心实验室每48 WK生成一次。在WK 96中，有和没有HBeAg丢失的患者之间比较了FT评分为48分，96分和144分的FTL的绝对值和变化以及FT的分类变化的描述性统计.FT类别（Metavir纤维化评分）为：<0.49（F0） -F1），0.49至<0.75（F2-F3），和≥0.75（F4）。 ALT正常水平定义为<19 U / L女性和<30 U / L男性。
 结果：
 770例HBeAg +患者在WK 96：517时HBeAg结果被随机分配至TAF，253例随机分配至TDF。 WKs 48,96和144的HBeAg丢失率分别为：106（14％），174（23％）和193（27％）。通过治疗，WK 96的HBeAg消失率相似（24％TAF对20％TDF）。在没有HBeAg消失的患者中观察到WK 96的ALT正常化率更高：121（70％）对295（50％）。在WK 96引起HBeAg丢失的患者中，TAF与TDF治疗患者的ALT正常化率较高（75％TAF与57％TDF）。 BSL的关键BSL特征和变化由表中的WK 96的HBeAg状态表示。大多数患者为亚洲人（82％），男性（65％），非肝硬化病史（90％），GT C（54％）和NUC-naïve（74％）。 WK 96引起HBeAg丢失的患者年龄较大，非肥胖，HBV DNA较低，ALT水平较高，BSL患者更可能有FT≥0.75（HBeAg +为13％vs 6％）。在有和没有HBeAg丢失的患者中观察到FT中BSL的平均下降;然而，HBeAg丢失患者的WK 144下降幅度更大（表）。当病毒血症患者（第96周时HBVDNA≥29IU/ mL）被排除在分析之外时，观察到有和无HBeAg消失的患者BS中FTL平均值（SD）下降的差异（WK 144为-0.08 [0.17] ] HBeAg损失vs -0.05 [0.14] HBeAg +）。在没有HBeAg损失的患者中，FT的分类改善≥1％，分别为21％和10％，17％对10％，16％对9％，WK分别为48,96和144。
 
 结论：
 通过血清FT，无论HBeAg状态如何，在NUC治疗期间在CHB患者中观察到肝纤维化的改善。然而，第96周HBeAg丢失的患者FT评分的改善程度大于HBeAg +，这表明HBeAg缺失可能在减少纤维发生中起作用。