EASL2020[LBP27]新型標誌物可預測病毒學和臨床復發發作 慢性肝

StephenW

LBP27
Novel markers to predict virological and clinical relapse onset
following antiviral treatment discontinuation in chronic hepatitis
B patients
Marianne Tuefferd1, Marjolein Crabbe2, Tsung-Hui Hu3, Chi-Yi Chen4,
Rong-Nan Chien5, Wei Kuo-Liang6,7, Cheng-Yuan Peng8,
Wan-Long Chuang9, Wei-Wen Su10, Liang Kung-Hao11,12,
Anna Shen13, Lin Yu-Shuang13, Alessandro Di Cara14,
Jacques Bollekens15, Chau-Ting Yeh16, Kurt Spittaels15,
Jeroen Aerssens1. 1Janssen Pharmaceutica N.V., Infectious Diseases,
Translational Biomarker, Beerse, Belgium; 2Janssen Pharmaceutica N.V.,
Quantitative Sciences, Beerse, Belgium; 3Kaohsiung Chang Gung
Memorial Hospital, Kaohsiung, Taiwan; 4Chia-Yi Christian Hospital,
Chia-Yi, Taiwan; 5Linkou Chang Gung Memorial Hospital and University,
Taoyuan, Taiwan; 6Chiayi Chang-Gung Memorial Hospital, Chiayi,
Taiwan; 7Taipei Veterans General Hospital, Medical Research
Department, Taipei, Taiwan; 8China Medical University Hospital,
Taichung, Taiwan; 9Kaohsiung Medical University Hospital, Kaohsiung,
Taiwan; 10Chang-Hua Christian Hospital, Chang-Hua, Taiwan; 11Taipei
Veterans General Hospital, Medical Research Department, Taipei,
Taiwan; 12Chang Gung Memorial Hospital, Liver Research Center, Linkou,
Taiwan; 13Janssen Pharmaceutica, GCO, Taipei, Taiwan; 14Precision for
Medicine, Geneva, Switzerland; 15Janssen Pharmaceutica N.V, Infectious
Diseases, Translational Medicine, Beerse, Belgium; 16Chang Gung
Memorial Hospital, Liver Research Center, Linkou, Taiwan
Email: [email protected].
Background and aims: This observational study aims to identify
virological and host genetic predictive markers for relapse onset in
chronic hepatitis B (CHB) patients discontinuing direct antiviral
treatment.
Method: This multi-center, prospective study in Taiwan enrolled 186
CHB patients in their last year of a minimum 3-year treatmentregimen with direct antivirals. Patients were followed for up to 2
years after treatment discontinuation. Virological relapse (VR) was
defined as HBV DNA >2000 IU/mL. Clinical relapse (CR) was defined
as ALT level >2× the upper limit of normal in addition to VR.
Blood samples were collected for DNA profiling by whole genome
genotyping (Affymetrix Axiom™ Asia Precision Medicine Research
Array).
Results: Of the cohort, 161 (86.6%) patients experienced VR of whom
110 (59.2%) also had a CR. HBeAg negativity prior to the start of
treatment was associated with earlier VR. High HBsAg levels
(≥100 IU/mL) at the end of the treatment (EoT) periodwas associated
with earlier onset of VR and CR. Entecavir treatment was associated
with delayed VR and CR compared to tenofovir.
A genome-wide association study revealed 33 independent genetic
markers significantly associated with onset of VR and 9 markers
significantly associated with onset of CR. Amongst those markers,
SNPs in CTLA4, HLA-DPB1 and RBFOX1 (reported earlier as a recurrent
site for HBV integration)were found to be associated with onset of CR,
and SNPs in SLC10A1 (encoding HBV receptor NTCP), FUT8 (regulating
NTCP expression) and several SNPs in the HLA-C region with onset of
VR after treatment discontinuation.
Clearly improved sensitivity and specificity of the Cox proportional
hazard regression models was observed when adding genetic
markers to HBsAg level at EoT, antiviral treatment regimen, and
HBeAg status at the beginning of the last treatment regimen. The
Receiver Operating Characteristic (ROC) AUC increased from 0.67 to
0.86 to predict CR within 6 months after EoT, and from 0.82 to 0.95 to
predict VR within 3 months after EoT.
Conclusion: The study revealed novel genetic markers predictive of
relapse onset after treatment discontinuation. Several identified
genes have previously been described already as key player in HBV
replication but are now for the first time also shown to be associated
with time to relapse in CHB. Host genetic markers can be useful
contributors in predicting patient outcome when considering
stopping suppressive treatment.

StephenW

LBP27
新型標誌物可預測病毒學和臨床復發發作
慢性肝炎停用抗病毒藥物後
B病人
瑪麗安（Marianne Tuefferd）1，瑪喬琳·克拉布（Marjolein Crabbe）2，胡宗輝3，陳志怡4，
錢榮南5，魏國良6,7，彭成元8，
莊萬龍9，蘇維文10，梁功浩11,12，
沉安娜（Anna Shen），林玉雙（13），亞歷山德羅（Alessandro Di Cara）14，
Jacques Bollekens15，Chau-Ting Yeh16，Kurt Spittaels15，
耶隆·埃森斯（Jeroen Aerssens）1。 1Janssen Pharmaceutica N.V.，傳染病，
轉化生物標誌物，比利時比爾； 2 Janssen Pharmaceutica N.V.，
定量科學，比利時比爾； 3高雄長庚
台灣高雄紀念醫院； 4嘉義基督教醫院，
台灣嘉義； 5林口長庚紀念醫院和大學
台灣桃園; 6嘉義長庚紀念醫院
台灣; 7台北榮民總醫院醫學研究
台灣台北市8中國醫科大學附屬醫院
台中，台灣; 9高雄市高雄醫科大學附屬醫院
台灣; 10台灣彰化市彰化基督教醫院； 11台北
台北市醫學研究部退伍軍人總醫院
台灣; 12林口肝臟研究中心長庚紀念醫院
台灣; 13台灣台北市GCO詹森藥業； 14精度
醫藥，瑞士日內瓦； 15 Janssen Pharmaceutica N.V，傳染性
疾病，轉化醫學，比利時比爾； 16長庚
台灣林口市肝臟研究中心紀念醫院
電子郵件：[email protected]。
背景和目的：本觀察研究旨在確定
復發的病毒學和宿主遺傳預測標誌物
停用直接抗病毒藥的慢性乙型肝炎（CHB）患者
治療。
方法：這項台灣多中心前瞻性研究共納入186個
CHB患者在最近3年中至少接受了直接抗病毒藥物治療。對患者進行了最多2次隨訪
停藥多年後。病毒學復發（VR）原為
定義為HBV DNA> 2000 IU / mL。定義了臨床復發（CR）
除了VR以外，ALT水平> 2倍於正常上限。
收集血液樣本以進行全基因組DNA分析
基因分型（Affymetrix Axiom™亞洲精密醫學研究
數組）。
結果：在該隊列中，有161名患者（86.6％）經歷了VR，其中
110（59.2％）也有CR。開始之前HBeAg陰性
治療與早期VR相關。高HBsAg水平
在治療（EoT）期結束時（≥100 IU / mL）相關
隨著VR和CR的出現較早。恩替卡韋治療與
與替諾福韋相比，VR和CR延遲。
全基因組關聯研究揭示了33個獨立的遺傳
與VR發病顯著相關的9種標誌物
與CR的發生顯著相關。在這些標記中，
CTLA4，HLA-DPB1和RBFOX1中的SNP（較早報告為複發
HBV整合位點）被發現與CR的發作有關，
SLC10A1（編碼HBV受體NTCP），FUT8（調節
NTCP表達）和HLA-C區域中幾個SNP的發作
停藥後VR。
明顯提高了Cox比例的靈敏度和特異性
添加遺傳基因時，觀察到危害回歸模型
EoT，抗病毒治療方案和
最後一次治療方案開始時的HBeAg狀態。的
接收器工作特性（ROC）AUC從0.67增加到
0.86可以預測EoT後6個月內的CR，從0.82到0.95至
在EoT之後的3個月內預測VR。
結論：該研究揭示了可預測糖尿病的新遺傳標記。
停藥後復發發作。幾個確定
基因先前已被描述為HBV的關鍵角色
複製，但現在也首次顯示出關聯
隨著時間的推移，CHB復發。宿主遺傳標記可能有用
在考慮患者預後時做出貢獻
停止抑制性治療。