AASLD2016[608]HBsAg水平随着CHB的自然史而变化 受HBV基因型和出现

StephenW

608
HBsAg levels vary across the natural history of CHB and
are influenced by HBV genotype and the emergence of
basal core promoter variants.
Alex J. Thompson2, Lilly Yuen1, Darren Wong2, Margaret Littlejohn1,
Julianne Bayliss1, Gillian Rosenberg1, Kathleen jackson1,
Anuj Gaggar3, Kathryn M. Kitrinos3, Mani Subramanian3, Patrick
Marcellin4, Edward J. Gane5, Henry Lik-Yuen Chan6, Harry L. Janssen7,
Maria Buti8, Scott Bowden1, Tina Sozzi1, Danni Colledge1,
Rachel Hammond1, Rosalind Edwards1, Stephen Locarnini1, Peter
A. Revill1; 1VIDRL, North Melbourne, VIC, Australia; 2St Vincents
Hospital, Melbourne, VIC, Australia; 3Gilead Sciences, Foster City,
CA; 4Hopital Beaujon University of Paris, Paris, France; 5New Zealand
Liver Transplant Unit Auckland CIty Hospital, Auckland, New
Zealand; 6Chinese University of Hong Kong, Hong Kong, Hong
Kong; 7Toronto Centre for Liver Diseases, Toronto, ON, Canada;
8LIver Unit Valle d’Hebron (Ciberehd) Univerisity Hospital, Barcelona,
Spain
Background. Quantitative HBsAg level is emerging as a clinically
relevant biomarker for natural history as well as treatment
response in CHB. However, virological determinants of
HBsAg levels, including disease phase and presence of clinically
important variants and sequence diversity remain poorly
described. We used deep sequencing and quantitative serology
to perform a detailed cross-sectional analysis of HBV virological
phenotypes comparing patients with immune tolerant
(IT), immune clearance (IC / HBeAg-positive) and immune
reactivation (IR / HBeAg-negative) CHB from three large randomised
controlled studies. Methods. GS-US-203-0101 evaluated
the treatment of tenofovir vs tenofovir plus emtricitabine
in IT persons ( HBeAg positive, HBV DNA >7.28log10IU/ml
and ALT<ULN). GS-US-174-0102 evaluated tenofovir in IR persons
(HBeAg negative, HBV DNA >5log10copies/ml and ALT
>1xULN but <10xULN). GS-US-174-0103 evaluated tenofovir
in IC persons (HBeAg positive, HBV DNA >6log10 copies/ml
and ALT >2x but <10xULN). Virological studies included HBV
full genome deep sequencing (NGS) and quantitative HBsAg
and HBeAg levels on 89 IT patients, 157 IC patients and 119
IR patients, genotypes (Gt) A to D. Frequency of mutations in
the basal core promoter (BCP) and precore (PC) regions was
compared to clinical outcomes by multivariate analysis (SAS
v9.2). Results. HBsAg levels significantly differed according to
the phase of disease (IT>IC>IR, P<0.0001, Table 1) and HBV
Gt in each phase of disease, being lower in Gt B/C vs. Gt A/D
(P<0.05Table 1). BCP and PC variants were detectable in all
phases of disease (IT<IC<IR, Table 1, P < 0.0001). The presence
of BCP variants was associated with lower HBsAg levels
in IT and IC but not IR patients (Table 1). Using linear regression
modelling, variables that were independently associated
with HBsAg level include disease phase, HBV Gt, the presence
of BCP variants, HBV DNA and ALT level. There was a significant
correlation between disease phase and the presence of
BCP variants. The presence of PC variants was not associated
with HBsAg level. Conclusions. HBsAg levels differ according
to phase of disease, HBV Gt and the presence of BCP variants.
Studies evaluating the utility of HBsAg levels as a clinical biomarker
should stratify analyses according to these variables.
Table 1. HBsAg levels
*Patients grouped by mutations detected by NGS
Disclosures:
Alex J. Thompson - Advisory Committees or Review Panels: Gilead, Abbvie,
BMS, Merck, Spring Bank Pharmaceuticals, Arrowhead, Roche; Grant/Research
Support: Gilead, Abbvie, BMS, Merck; Speaking and Teaching: Roche, Gilead,
Abbvie, BMS
Anuj Gaggar - Employment: Gilead Sciences, Inc.
Kathryn M. Kitrinos - Employment: Gilead Sciences; Stock Shareholder: Gilead
Sciences
Patrick Marcellin - Consulting: Roche, Gilead, BMS, Vertex, Novartis, Janssen,
MSD, Abbvie, Alios BioPharma, Idenix, Akron; Grant/Research Support: Roche,
Gilead, BMS, Novartis, Janssen, MSD, Alios BioPharma; Speaking and Teaching:
Roche, Gilead, BMS, Vertex, Novartis, Janssen, MSD, Boehringer, Pfizer,
Abbvie
Edward J. Gane - Advisory Committees or Review Panels: AbbVie, Janssen,
Gilead Sciences, Achillion, Merck; Speaking and Teaching: AbbVie, Gilead
Sciences, Merck, Alnylam
Henry Lik-Yuen Chan - Advisory Committees or Review Panels: Gilead, Janssen,
Bristol-Myers Squibb, Roche, Novartis Pharmaceutical, Abbvie; Speaking and
Teaching: Echosens
Harry L. Janssen - Consulting: AbbVie, Bristol Myers Squibb, GSK, Gilead Sciences,
Innogenetics, Merck, Medtronic, Novartis, Roche, Janssen, Medimmune,
ISIS Pharmaceuticals, Tekmira; Grant/Research Support: AbbVie, Bristol Myers
Squibb, Gilead Sciences, Innogenetics, Merck, Medtronic, Novartis, Roche,
Janssen, Medimmune
Maria Buti - Advisory Committees or Review Panels: Gilead, Janssen, MSD;
Grant/Research Support: Gilead, Janssen; Speaking and Teaching: Gilead,
Janssen, BMS
Stephen Locarnini - Consulting: Gilead Sciences Inc, Arrowhead Research Corp,
Spring Bank Pharmaceuticals, Inc.; Employment: Melbourne Health
Peter A. Revill - Grant/Research Support: Gilead Sciences
The following people have nothing to disclose: Lilly Yuen, Darren Wong, Margaret
Littlejohn, Julianne Bayliss, Gillian Rosenberg, Kathleen jackson, Mani
Subramanian, Scott Bowden, Tina Sozzi, Danni Colledge, Rachel Hammond,
Rosalind Edwards

StephenW

AASLD2016 [608] HBsAg水平随着CHB的自然史而变化
受HBV基因型和出现的影响
基础核心启动子变体。
HBsAg水平随着CHB的自然史而变化
受HBV基因型和出现的影响
基础核心启动子变体。
Alex J.Thompson2，Lilly Yuen1，Darren Wong2，Margaret Littlejohn1，
Julianne Bayliss1，Gillian Rosenberg1，Kathleen jackson1，
Anuj Gaggar3，Kathryn M. Kitrinos3，Mani Subramanian3，Patrick
Marcellin4，Edward J.Gane5，Henry Lik-Yuen Chan6，Harry L.Janssen7，
Maria Buti8，Scott Bowden1，Tina Sozzi1，Danni Colledge1，
Rachel Hammond1，Rosalind Edwards1，Stephen Locarnini1，Peter
A. Revill1; 1VIDRL，North Melbourne，VIC，Australia; 2St Vincents
医院，墨尔本，维多利亚州，澳大利亚; 3Gilead科学，福斯特城，
CA;巴黎，巴黎，法国; 5新西兰
肝移植单位奥克兰市医院，奥克兰，新
西兰; 6香港中文大学，香港，Hong
孔; 7多伦多肝脏疾病中心，多伦多，安大略，加拿大;
8LIver Unit Valle d'Hebron（Ciberehd）大学医院，巴塞罗那，
西班牙
背景。定量HBsAg水平作为临床出现
自然史的相关生物标志物以及治疗
反应在CHB。然而，病毒学决定因素
HBsAg水平，包括疾病期和临床存在
重要变异和序列多样性仍然很差
描述。我们使用深度测序和定量血清学
以进行HBV病毒学的详细横断面分析
表型比较患者免疫耐受
（IT），免疫清除（IC / HBeAg阳性）和免疫
再激活（IR / HBeAg阴性）CHB从三大随机
控制研究。方法。 GS-US-203-0101评估
替诺福韦对替诺福韦加恩曲他滨的治疗
在IT人（HBeAg阳性，HBV DNA> 7.28log10IU / ml
和ALT <ULN）。 GS-US-174-0102评估IR患者的替诺福韦
（HBeAg阴性，HBV DNA> 5log10copies / ml和ALT
> 1xULN，但<10xULN）。 GS-US-174-0103评价替诺福韦
在IC人（HBeAg阳性，HBV DNA> 6log10拷贝/ ml
和ALT> 2x但<10xULN）。病毒学研究包括HBV
全基因组深度测序（NGS）和定量HBsAg
和HBeAg水平对89位IT患者，157位IC患者和119位
IR患者，基因型（Gt）A至D.
基底核启动子（BCP）和前核（PC）区
与多变量分析的临床结果相比（SAS
v9.2）。结果。 HBsAg水平显着不同
疾病的阶段（IT> IC> IR，P <0.0001，表1）和HBV
Gt在疾病的每个阶段，GtB / C相对于Gt A / D较低
（P <0.05，表1）。 BCP和PC变体都可检测
疾病阶段（IT <IC <IR，表1，P <0.0001）。存在
的BCP变体与较低的HBsAg水平相关
在IT和IC，但不是IR患者（表1）。使用线性回归
建模，独立相关的变量
与HBsAg水平包括疾病期，HBV Gt，存在
的BCP变体，HBV DNA和ALT水平。有一个显着
疾病相和存在的相关性
BCP变体。 PC变体的存在没有关联
与HBsAg水平。结论。 HBsAg水平根据不同
到疾病阶段，HBV Gt和BCP变体的存在。
评价HBsAg水平作为临床生物标志物的效用的研究
应根据这些变量分层分析。
表1. HBsAg水平
*根据NGS检测的突变分组的患者
披露：
Alex J. Thompson - 咨询委员会或审查小组：G​​ilead，Abbvie，
BMS，Merck，Spring Bank Pharmaceuticals，Arrowhead，Roche;资助/研究
支持：Gilead，Abbvie，BMS，Merck;讲座和教学：罗氏，吉利德，
Abbvie，BMS
Anuj Gaggar - 就业：Gilead Sciences，Inc.
就业：吉利德科学;股票股东：Gilead
科学
Patrick Marcellin - 咨询：Roche，Gilead，BMS，Vertex，Novartis，Janssen，
MSD，Abbvie，Alios BioPharma，Idenix，Akron;资助/研究支持：罗氏，
Gilead，BMS，Novartis，Janssen，MSD，Alios BioPharma;口语和教学：
Roche，Gilead，BMS，Vertex，Novartis，Janssen，MSD，Boehringer，Pfizer，
Abbvie
Edward J. Gane - 咨询委员会或审核小组：AbbVie，Janssen，
吉利德科学，Achillion，默克;口语和教学：AbbVie，Gilead
科学，默克，Alnylam
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
Harry L. Janssen - 咨询：AbbVie，Bristol Myers Squibb，GSK，吉利德科学，
Innogenetics，Merck，Medtronic，Novartis，Roche，Janssen，Medimmune，
ISIS制药，Tekmira;资助/研究支持：AbbVie，Bristol Myers
Squibb，Gilead Sciences，Innogenetics，Merck，Medtronic，Novartis，Roche，
Janssen，Medimmune
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
Stephen Locarnini - 咨询：吉利德科学公司，Arrowhead研究公司，
春天药业有限公司就业：墨尔本健康
Peter A. Revill - 资助/研究支持：吉利德科学
以下人士没有透露：莉莉苑，王永平，玛格丽特
Littlejohn，Julianne Bayliss，Gillian Rosenberg，Kathleen jackson，Mani
Subramanian，Scott Bowden，Tina Sozzi，Danni Colledge，Rachel Hammond，
Rosalind爱德华兹