AASLD2016[108]乙型肝炎核心相关抗原与肝内相关 共价闭合环状DN

StephenW

108
Hepatitis B core-related antigen correlates with intrahepatic
covalently closed circular DNA (cccDNA) levels and
activity in untreated chronic hepatitis B (CHB) patients
Barbara Testoni1,3, Françoise Berby1, Clothilde Miaglia1,2,
Fanny Lebossé1,2, Pietro Lampertico4, massimo levrero1,5, Fabien
Zoulim1,2; 1INSERM U1052- Cancer Research Center of Lyon
(CRCL), Lyon, France; 2Department of Hepatology, Croix Rousse
hospital, Hospices Civils de Lyon, Lyon, France; 3University of
Lyon, UMR_S1052, CRCL, Lyon, France; 4Division of Gastroenterology
and Hepatology, Fondazione IRCCS Ca’ Granda Ospedale
Maggiore Policlinico, Milan, Italy; 5Department of Internal Medicine,
Sapienza University, Rome, Rome, Italy
Serum Hepatitis B core-related antigen (HBcrAg) has been
linked to intrahepatic cccDNA levels, but a comprehensive
investigation of its correlation with serum and intrahepatic viral
marker and liver histology in a large number of patients is still
lacking. To this purpose, 101 CHB patients, 21 HBeAg+ and
80 HBeAg-, not treated at the time of liver biopsy were analyzed
for serum HBV DNA, quantitative (q)HBsAg and alanine
aminotransferase (ALT) levels. Intrahepatic total (t)HBV-DNA
and cccDNA were assessed by qPCR. cccDNA productivity,
defined as the tHBV-DNA/cccDNA ratio, was calculated as a
surrogate marker of cccDNA activity. HBcrAg was measured
by chemiluminescence enzyme immunoassay Lumipulse® G
HBcrAg assay (Fujirebio Europe, Gent, Belgium). Fibrosis and
necroinflammatory activity scores were also available for the
patients. HBcrAg levels were higher in HBeAg+ vs HBeAgpatients
(median of 8.3 vs 3.4 LogU/mL, p <0.0001), in
patients with fibrosis (4.55 vs 3.5 LogU/mL, p=0.009) and
necroinflammatory activity (4.9 vs 3.5 LogU/mL, p<0.0001)
scores >2 and in those with ALT>2N (5.6 vs 3.4 LogU/mL,
p<0.001). HBcrAg significantly correlated with serum HBV
DNA (R=0.66, p<0.0001), intrahepatic tHBV-DNA (R=0.77,
p<0.0001) and cccDNA levels (R=0.69, p<0.0001). Notably,
qHBsAg showed a low correlation with HBcrAg (R=0.32,
p=0.001) and intrahepatic tHBV-DNA (R=0.43, p<0.001)
and no correlation with cccDNA levels (R=0.2, p=0.053). The
30 patients that scored negative for HBcrAg (quantification <
2 LogU/mL) had lower levels of liver cccDNA as compared
to the HBcrAg+ group (median 0.061 vs 0.233 copies/cell,
p<0.0001). Interestingly, HBcrAg+ patients showed also a
higher cccDNA productivity compared to HBcrAg-negative
ones (median of 85.9 vs 24.3, p=0.002). HBcrAg levels
were significantly correlated with cccDNA productivity both
in HBeAg+ (R=0.51, p=0.025) and in HBeAg- (R=0.47,
p<0.0001) patients. To better investigate the possible correlation
between HBcrAg levels and cccDNA transcriptional
activity, we selected a subgroup of 33 patients, including 5
HBeAg+ and 28 HBeAg-, with cccDNA levels ranging between
0.1-1.0 copies/cell and we found that HBcrAg+ patients had
higher tHBV-DNA (median 10.5 vs 4.4 copies/cell, p=0.005)
and, consequently DNA productivity levels (37.9 vs 25.6,
p=0.03) compared to HBcrAg- ones (Figure 1). Our results
confirm, in large group of CHB patients with available liver
biopsy samples, the correlation between HBcrAg and intrahepatic
cccDNA levels and indicate that HBcrAg may represent
a useful surrogate marker not only for intrahepatic cccDNA
amount, but also for its transcriptional and replicative activity.
Disclosures:
Pietro Lampertico - Advisory Committees or Review Panels: BMS, BMS, Roche,
Gilead, GSK, MSD; Speaking and Teaching: Roche, Gilead, GSK, MSD
massimo levrero - Advisory Committees or Review Panels: Merck, BMS, Gilead,
Jansen, Arbutus, Galapagos, Medimmune, Assembly; Grant/Research Support:
BMS; Speaking and Teaching: Roche
Fabien Zoulim - Advisory Committees or Review Panels: Janssen, Gilead, Novira,
Abbvie, Arbutus, Transgene; Consulting: Roche; Grant/Research Support:
Novartis, Gilead, Scynexis, Roche, Novira, Assemblypharm, Janssen; Speaking
and Teaching: Bristol Myers Squibb, Gilead
The following people have nothing to disclose: Barbara Testoni, Françoise Berby,
Clothilde Miaglia, Fanny Lebossé

StephenW

108
AASLD2016 [108]乙型肝炎核心相关抗原与肝内相关
共价闭合环状DNA（cccDNA的的）水平
乙型肝炎核心相关抗原与肝内相关
共价闭合环状DNA（cccDNA的）水平，
在未经治疗的慢性乙型肝炎（CHB）患者活动
芭芭拉Testoni1,3，弗朗索瓦Berby1，克洛蒂尔德Miaglia1,2，
范妮Lebossé1,2，彼得Lampertico4，马西莫levrero1,5，法比安斯基
Zoulim1,2;里昂1INSERM U1052-癌症研究中心
（CRCL），法国里昂;肝病十字鲁塞教研室
医院，收容所Civils里昂，里昂，法国;的3University
里昂，UMR_S1052，CRCL，法国里昂;胃肠病学4Division
和肝病，基金会IRCCS钙'格兰达Ospedale
教堂位于Policlinico，意大利米兰;内科5Department，
Sapienza大学，罗马，罗马，意大利
血清乙型肝炎核心相关抗原（HBcrAg）一直
联系到肝内cccDNA的水平，而是一个综合
与血清及肝内病毒相关性研究
标记和肝脏组织学在大量的病人仍是
不足。为了这个目的，101 CHB患者，21大三阳+和
80个HBeAg-，在肝活检不及时治疗进行了分析
血清HBV DNA定量（Q）HBsAg和丙氨酸
转氨酶（ALT）的水平。肝内总（T）HBV-DNA
和的cccDNA通过qPCR评估。 cccDNA的生产力，
定义为tHBV-DNA / cccDNA的比率，计算为一个
cccDNA的活动的替代指标。 HBcrAg测量
化学发光酶免疫Lumipulse®摹
HBcrAg法（Fujirebio公司欧洲，比利时根特）。纤维化和
坏死性炎症评分也可用于
耐心。 HBcrAg水平在大三阳+高VS HBeAgpatients
，在（8.3 VS 3.4 LogU /毫升，P <0.0001中值）
患者纤维化（4.55 VS 3.5 LogU /毫升，p值= 0.009）和
坏死性炎症（4.9和3.5 LogU /毫升，P <0.0001）
分数> 2和在那些与ALT> N（5.6 VS 3.4 LogU /毫升，
P <0.001）。 HBcrAg的血清HBV显著相关
脱氧核糖核酸（R = 0.66，P <0.0001），肝内tHBV -DNA（R = 0.77，
P <0.0001）和水平的cccDNA（R = 0.69，P <0.0001）。值得注意的是，
qHBsAg表现出与HBcrAg（R = 0.32的相关性较低，
p值= 0.001）和肝内tHBV -DNA（R = 0.43，P <0.001）
并用的cccDNA水平没有相关（R = 0.2，p值= 0.053）。该
30例患者，对于HBcrAg（量化计分的负<
相比2 LogU /毫升）有肝脏的cccDNA水平较低
到HBcrAg +组（中位数0.061 VS 0.233拷贝/细胞，
P <0.0001）。有趣的是，HBcrAg +患者也表现出一
相比HBcrAg阴性更高生产率的cccDNA
那些（85.9 VS 24.3位数，P = 0.002）。 HBcrAg水平
均显著与cccDNA的生产力之间既有联系
在e抗原+（R = 0.51，P = 0.025）和在个HBeAg-（R = 0.47，
P <0.0001）的患者。为了更好地调查可能存在的关联
HBcrAg水平和转录的cccDNA之间
活动中，我们选择了33例患者亚组，其中5
大三阳+和28个HBeAg-，与cccDNA的水平之间不等
0.1-1.0拷贝/细胞，我们发现，HBcrAg +患者
更高tHBV -DNA（中位数10.5 VS 4.4拷贝/细胞，p值= 0.005）
，因此DNA生产力水平（37.9 VS 25.6，
p值= 0.03）相比HBcrAg-那些（图1）。我们的研究结果
确认后，在大集团CHB患者可用肝
活检样本，HBcrAg和肝内之间的相关性
的cccDNA水平和指示HBcrAg可表示
不仅为肝内cccDNA的一个有用的替代指标
量，也为它的转录和复制活性。
披露：
彼得Lampertico - 咨询委员会或审查小组：BMS，BMS，罗氏，
Gilead公司，葛兰素史克，MSD;口语和教学领域：罗氏公司，Gilead公司，葛兰素史克，MSD
马西莫levrero - 咨询委员会或审查小组：默克，拜耳，Gilead公司，
扬森，杨梅，加拉帕戈斯群岛，MedImmune公司，组装;格兰特/研究支持：
BMS;口语和教学：罗氏
法比安斯基Zoulim - 咨询委员会或审查小组：扬森，Gilead公司，Novira，
艾伯维，杨梅，转基因;咨询：罗氏;格兰特/研究支持：
诺华公司，Gilead公司，Scynexis，罗氏，Novira，Assemblypharm，扬森;请讲
教学：百时美施贵宝，吉利德
下面的人都没有透露：铁狮东尼芭芭拉，弗朗索瓦Berby，
克洛西德Miaglia，范妮Lebossé
108

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希望CFDA会批

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2017年2月26日才可以再申请…