EASL2020[AS005] 配对肝活检的转录组分析可鉴定 安慰剂和TDF治疗

StephenW

AS005
Transcriptome analysis of paired liver biopsies identifies
correlates of HBsAg response in placebo and TDF treated CHB
patients
Yao-Chun Hsu1, Diana Chen2, Vithika Suri2, Jeffrey Wallin2,
Jing Zhu Zhou2, Cheng-Hao Tseng3, Yen-Tsung Huang4,
Mani Subramanian2, Anuj Gaggar2, Ondrej Podlaha2. 1Center for Liver
Diseases; 2Gilead Sciences, Inc., Foster City, United States; 3Division of
Gastroenterology and Hepatology; 4Institute of Statistical Science
Email: [url=mailto[email protected]][email protected][/url]
Background and Aims: Intrahepatic evaluation of host immunity can
provide insight into events leading to important clinical events in
patients with chronic hepatitis B (CHB) infection. Herewe investigate
baseline and year 3 liver biopsies from a randomized placebocontrolled
trial of Tenofovir Disoproxil Fumarate (TDF) in CHB
patients (IN-US-174-0178) with minimally elevated aminotransferase
for gene expression signatures associated with clinical response.
Method: CHB patients (N = 130) with serum ALT 1-2x upper limit of
normal (ULN) with no clinical liver cirrhosis or decompensationwere
randomized into TDF and Placebo 3-year treatment arms. Liver
biopsieswere taken at baseline and year 3. Gene expression fromliver
biopsies was quantified with salmon software and gene set
enrichment was interrogated using GSEA software package (Broad
Institute) and pathway gene signatures from MSigDB database.
Results: Overall, at year 3 patients treated with TDF displayed
significantly reduced inflammatory response (False Discovery Rate,
FDR = 0.001), while gene signatures for fatty and bile acid metabolism
and adipogenesis were significantly upregulated (FDR < 0.001),
suggesting improved liver function. Nine and 16 patients in the
placebo and TDF arms, respectively, experienced HBsAg reduction
greater than 0.5 Log10 IU at year 3. Compared to HBsAg nonresponders,
these HBsAg responders at baseline demonstrated
upregulation of B cell activation (FDR = 0.006) as well as IFN alpha
(FDR = 0.008) and IFN gamma response (FDR = 0.081). In addition,
placebo responders exhibited elevation of innate immune response
(FDR = 0.022) and TNF alpha signaling (FDR < 0.001) compared to
placebo non-responders, whereas TDF responders demonstrated
enrichment B cell activation signatures (FDR = 0.021) and B cell
proliferation (FDR = 0.061) compared to TDF non-responders.
Comparison between placebo and TDF HBsAg responders revealed
that placebo responders (NPlacebo = 9; NTDF = 16) again exhibited
stronger upregulated IFN-alpha (FDR < 0.001) and IFN-gamma (FDR
< 0.001) signaling pathways at baseline (Figure 1), suggesting
different pathways for HBsAg reduction by natural history and
antiviral treatment.
Conclusion: Our results demonstrate that HBV control is linked to
interferon and humoral immune response and suggest that immunotherapies
aimed to boost these immune responses may act
synergistically with nucleotide analogue therapy to achieve sustained
control of HBV.

StephenW

AS005
配对肝活检的转录组分析可鉴定
安慰剂和TDF治疗的CHB中HBsAg反应的相关性
耐心
许耀春1，戴安娜·陈2，维西卡·苏里2，杰弗里·沃林2，
荆竹洲2，曾成浩3，黄炎聪4，
Mani Subramanian2，Anuj Gaggar2，Ondrej Podlaha2。 1肝中心
疾病； 2Gilead Sciences，Inc.，美国福斯特城； 3部门
胃肠病学和肝病学； 4统计研究所
电子邮件：[email protected]
背景与目的：肝内评估宿主免疫力可以
提供对导致重要临床事件的事件的洞察
慢性乙型肝炎（CHB）感染的患者。我们在这里调查
随机安慰剂对照的基线和第3年肝活检
替诺福韦富马酸替索罗非酯（TDF）的临床试验
氨基转移酶升高极少的患者（IN-US-174-0178）
用于与临床反应相关的基因表达签名。
方法：CHB患者（N = 130）的血清ALT 1-2倍上限
正常（ULN），无临床肝硬化或代偿失调
随机分为TDF和安慰剂3年治疗组。肝
在基线和第3年进行活检。
用鲑鱼软件和基因组对活组织检查进行定量
使用GSEA软件包（广泛
研究所）和来自MSigDB数据库的途径基因签名。
结果：总体上，第3年接受TDF治疗的患者显示
大大降低了炎症反应（错误发现率，
FDR = 0.001），而脂肪和胆汁酸代谢的基因特征
和脂肪形成明显上调（FDR <0.001），
提示肝功能改善。 9例和16例患者
安慰剂和TDF臂分别降低了HBsAg
在第3年时大于0.5 Log10 IU。与HBsAg无反应者相比，
基线时这些HBsAg反应者表现出
B细胞激活（FDR = 0.006）以及IFNα的上调
（FDR = 0.008）和IFNγ反应（FDR = 0.081）。此外，
安慰剂反应者表现出先天免疫反应的升高
（FDR = 0.022）和TNFα信号转导（FDR <0.001）
安慰剂无反应者，而TDF反应者表现出
富集B细胞激活特征（FDR = 0.021）和B细胞
与TDF无反应者相比（FDR = 0.061）。
比较安慰剂和TDF HBsAg应答者
安慰剂反应者（NPlacebo = 9； NTDF = 16）再次出现
较强的上调IFN-α（FDR <0.001）和IFN-γ（FDR
<0.001）基线时的信号通路（图1），表明
自然病史和不同方式减少HBsAg的不同途径
抗病毒治疗。
结论：我们的结果表明，HBV控制与
干扰素和体液免疫反应，并提出免疫疗法
旨在增强这些免疫反应的行为
与核苷酸类似物疗法协同作用以实现持续
控制乙肝病毒。