自发表面抗原损失乙肝携带者终生较高的机会与C基因型感染

StephenW

Higher lifetime chance of spontaneous surface antigen loss in hepatitis B carriers with genotype C infection

    T.-C. Tseng1,2, C.-J. Liu3,4, C.-L. Chen4, W.-T. Yang5,6, H.-C. Yang3,7, T.-H. Su3,4, C.-C. Wang1,6, S. F.-T. Kuo8, C.-H. Liu3,4, P.-J. Chen3,4, D.-S. Chen3,4 andJ.-H. Kao3,4,5,9,*

Article first published online: 23 MAR 2015

DOI: 10.1111/apt.13170

© 2015 John Wiley & Sons Ltd

Issue
Alimentary Pharmacology & Therapeutics
Alimentary Pharmacology & Therapeutics

Volume 41, Issue 10, pages 949–960, May 2015
Article has an altmetric score of 3

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Tseng, T.-C., Liu, C.-J., Chen, C.-L., Yang, W.-T., Yang, H.-C., Su, T.-H., Wang, C.-C., Kuo, S. F.-T., Liu, C.-H., Chen, P.-J., Chen, D.-S. and Kao, J.-H. (2015), Higher lifetime chance of spontaneous surface antigen loss in hepatitis B carriers with genotype C infection. Alimentary Pharmacology & Therapeutics, 41: 949–960. doi: 10.1111/apt.13170
Author Information

    1    Division of Gastroenterology, Department of Internal Medicine, Taipei Tzuchi Hospital, The Buddhist Tzuchi Medical Foundation, Taipei, Taiwan
    2    School of Medicine, Tzu Chi University, Hualien, Taiwan
    3    Division of Gastroenterology, Department of Internal Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan
    4    Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan
    5    Hepatitis Research Center, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan
    6    Master of Public Health Degree Program, National Taiwan University, Taipei, Taiwan
    7    Department of Microbiology, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan
    8    St Vincent's Hospital, Melbourne, Vic., Australia
    9    Department of Medical Research, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan

* Correspondence to:
Dr J.-H. Kao, Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, 1 Chang-Te St., Taipei 10002, Taiwan.
E-mail: [email protected]

    This article was accepted for publication after full peer-review
Publication History

    Issue published online: 16 APR 2015
    Article first published online: 23 MAR 2015
    Manuscript Accepted: 2 MAR 2015
    Manuscript Revised: 20 FEB 2015
    Manuscript Revised: 13 JAN 2015
    Manuscript Revised: 18 NOV 2014
    Manuscript Received: 6 OCT 2014

Funded by

    Taipei Tzu-Chi Hospital. Grant Numbers: TCRD-TPE-101-12, TCRD-TPE-103-32, TCRD-TPE-NSC-102-02
    National Taiwan University Hospital. Grant Number: NTUH100-S1534
    Department of Health. Grant Numbers: DOH99-DC-1001, DOH100-DC-1019
    Ministry of Science and Techonology. Grant Numbers: NSC100-2314-B-303-012, NSC101-2314-B-303-00


Summary
Background

Clearance of hepatitis B surface antigen (HBsAg) indicates clinical control of hepatitis B virus (HBV) infection. However, little is known about the impact of viral genomic variations on HBsAg loss.
Methods

We explored the association between viral genomic factors and HBsAg loss in 2121HBeAg-negative patients. HBV pre-core stop codon (1896) and basal core promoter (BCP) (1762/1764) sequences were determined in patients with HBV DNA ≥200 IU/mL (N = 1693). The effect of HBV genotype on HBsAg loss was further validated in the whole cohort of 3445 HBsAg carriers.
Results

The cumulative lifetime (age 28–75 years) incidence of HBsAg loss was 50.4% in 2121 HBeAg-negative patients. We found that genotype C, but not pre-core stop codon or BCP mutants, was associated with HBsAg loss. Compared to genotype B patients, genotype C patients had higher lifetime chance of HBsAg loss, with hazard ratio of 1.8 (95% confidence interval: 1.4–2.4). Multivariable analysis showed that male sex, elevated ALT levels, lower serum HBV DNA and HBsAg levels, and genotype C infection were associated with higher chance of HBsAg loss independently. We then performed sensitivity analysis, which re-included HBeAg-positive, cirrhotic and treatment-experienced patients, and confirmed the robustness of our results in 3445 HBsAg carriers.
Conclusion

Genotype C infection, compared to genotype B, is associated with a higher lifetime chance of HBsAg loss in Asian HBV carriers.

StephenW

自发表面抗原损失乙肝携带者终生较高的机会与C基因型感染

    T.-C. Tseng1,2，C.-J. Liu3,4，C.-L. Chen4，W.-T. Yang5,6，H.-C. Yang3,7，T.-H. Su3,4，C.-C. Wang1,6，S. F.-T. Kuo8，C.-H. Liu3,4，P.-J. Chen3,4，D-S. Chen3,4 andJ.-H. Kao3,4,5,9，*

文章首次在网上公布：2015年3月23日

DOI：10.1111 / apt.13170

©2015年约翰·威利父子有限公司

问题
消化系统药理学与治疗学
消化系统药理学与治疗学

卷41，第10期，页949-960，2015年5月
第二十有altmetric比分3

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曾雅妮，T.-C.，刘C.-J.，陈C.-L.，杨，W.，T.，杨，H.-C.，苏，T.-H.，王， C.-C.，郭，SF-T，刘C.-H.，陈，P.-J.，陈，D-S.和花王，J.-H. （2015），较高的一生的机会自然表面抗原损失乙肝携带者与C基因型感染。消化系统药理学和治疗学，41：949-960。 DOI：10.1111 / apt.13170
作者信息

    消化内科，内科，台北Tzuchi医院，佛教Tzuchi医学基金会系，台北，台湾1部
    医药，慈济大学，花莲，台2学校
    消化内科，内科，医学国立台湾大学和国立台湾大学医院系，台北，台湾3部
    临床医学4研究所，医学国立台湾大学和国立台湾大学医院，台北，台湾
    5肝炎研究中心，医学国立台湾大学和国立台湾大学医院，台北，台湾
    6公共卫生硕士学位课程，国立台湾大学，台北，台湾
    微生物学系7，医学和台大医院，台北，台湾台大医学院
    8圣文森特医院，墨尔本，澳大利亚
    医学研究，医学国立台湾大学和国立台湾大学医院，台北，台湾的9处

*通讯作者：
医生J.-H.花王，临床医学研究所，医学国立台湾大学，1昌特街，台北10002，台湾。
电子邮件：[email protected]

    这篇文章是经过充分的同行审查同意出版
出版史

    发行网上公布：2015年4月16日
    文章首次在网上公布：2015年3月23日
    稿件接受：2015年3月2日
    手稿修订：2015年2月20日
    手稿修订：2015年1月13日
    手稿修订：2014年11月18日
    稿件收稿日期：2014年10月6日

受资助

    台北慈济医院。格兰特编号：TCRD-TPE-101-12，TCRD-TPE-103-32，TCRD-TPE-NSC-102-02
    台大医院。授权号：NTUH100-S1534
    卫生署。格兰特编号：DOH99-DC-1001，DOH100-DC-1019
    教育部理工科的。格兰特编号：NSC100-2314-B-303-012，NSC101-2314-B-303-00


总结
背景

乙肝表面抗原（HBsAg）的间隙表示临床控制乙肝病毒（HBV）感染。然而，鲜为人知的是，病毒基因组的变化对HBsAg损失的影响。
方法：

我们探讨病毒基因组的因素和HBsAg消失在2121HBeAg阴性患者之间的关联。 HBV前C终止密码子（1896年）和基础核心启动子（BCP）（一千七百六十四分之一千七百六十二）序列的患者HBV DNA≥200IU / mL的（N = 1693）来确定。 HBV基因型对HBsAg消失的影响，进一步验证在3445 HBsAg携带者整个队列。
结果

累积终身HBsAg消失（年龄28-75岁）发生率为50.4％在2121 HBeAg阴性患者。我们发现，C基因型，但没有预先核终止密码子或BCP突变，与乙肝表面抗原的损失有关。相较于B基因型患​​者，C基因型患者HBsAg消失的高一生的机会，1.8（95％置信区间：1.4-2.4）的风险比。多变量分析显示，男性，ALT水平升高，降低血清HBV DNA和HBsAg水平，和C基因型感染者有较高的机会HBsAg消失的独立相关。然后，我们进行敏感性分析，从而重新纳入HBeAg阳性，肝硬化和治疗经验的患者，并证实了我们在3445 HBsAg携带者结果的稳健性。
结论

C基因型感染，相较于B型，与HBsAg消失在亚洲乙肝病毒携带者的高一生的机会有关。

StephenW

DISCUSSION
In the daily practice, it is well recognised that HBsAg
loss is the best measurable indicator for functional cure
of HBV infection. In this study, we first showed that
HBV genotype C infection, but not PC or BCP mutants,
were associated with higher chance of HBsAg loss in
HBeAg-negative patients. In addition, we found the key
leading to a higher likelihood of HBsAg loss may be a
faster decline of HBsAg levels. Finally, we used a sensitivity
analysis to confirm our finding in the overall
cohort of HBV carriers without any selection.
The impact of genotype C infection on HBsAg loss
has not been well addressed. The case numbers of previous
reports were too small to draw definite conclusion.
7, 28 This is because the incidence rate of HBsAg
loss is low and serum viral load is usually undetectable
before HBsAg is cleared,3 which leads to unavailable
HBV genotype data. For example, the REVEAL-HBV
cohort study, which is a large prospective cohort study
that included 2491 HBV carriers, showed that the HR of
genotype C (vs. B) for HBsAg loss is 1.22 (95% CI:
0.92–1.63).29 However, HBV genotype was not determined
in 973 participants (39.1%) at enrolment and in
360 participants (68.8%) achieving HBsAg loss. In an
attempt to address this issue, we characterised the HBV
genotype using an ELISA assay. This more sensitive
assay reduced the undetermined rate to 5.6%. With the
reasonable study design and proper methodologies, we
believed that that our cohort provides a high statistical
power to address this interesting and important issue.
It is known that HBV genotype C infection, compared
to genotype B, is associated with delayed HBeAg seroconversion
and disease progression, such as hepatitis, cirrhosis
and HCC.6, 10, 12, 21, 30, 31 In this study, we have
shown that genotype C infection is associated with not
only higher risks of cirrhosis and HCC but also higher
chance of HBsAg loss. Although the mechanism underpinning
the paradox remains unclear, an in vitro study
has indicated that both genotype B and C have similar
replication characteristics.32 We thus postulated that
virus itself could not explain this paradox.
Interestingly, we also found another paradox regarding
male sex, which has been known as a risk factor for hepatitis,
cirrhosis and HCC.6, 9, 14, 21 In this study, we showed
that male HBV carriers had a higher chance of HBsAg
loss, which is consistent with what has been reported from
a large cohort study including 1965 HBV carriers.5
To address these two paradoxes, we made a hypothesis
based on the following observations: First, we found a
higher chance of HBsAg loss in patients with high-normal
and elevated ALT levels compared to those with
low-normal ALT levels. Second, previous studies have
shown that genotype C and male sex are associated with
more hepatitis activity.21, 33 Third, since elevated ALT
levels in chronic hepatitis B is attributed to a T-cell mediated
hepatocytolysis,34 this marker of liver damage
severity may also serve as a surrogate biomarker for
which leads to repeated necroinflammation of liver with
subsequent development of cirrhosis and HCC (Figure
3b). This hypothesis has been supported by the findings
that certain HLA-DP single nucleotide
polymorphisms are associated with HBsAg clearance and
disease control.35–38 Nevertheless, more studies are
needed to confirm the crucial interactions between host
and viral genomic factors, which should fully reveal how
the disease is controlled or progresses to HCC.
We also noted another paradox: the same genotype
may confer different prognosis in HBeAg-positive and -
negative stages. For example, it has been shown that
genotype B is associated with a better treatment response
to interferon in HBeAg-positive patients but not in
HBeAg-negative patients.39, 40 Our study and another
Taiwanese paediatric study found that genotype C was
associated with more HBsAg loss in HBeAg-negative
patients but not in HBeAg-positive patients.20 This may
be attributed to the evolution of viral populations from
HBeAg-positive to -negative stages. It has been shown
that most of the viruses are wild-type viruses in immune
tolerant phase, while mutants start to emerge in immune
clearance phase.41, 42 Variations of HBV genome
intensity of host immune responses. Taking into account
all these observations, we propose that genotype C virus
and male sex, compared to genotype B and female sex,
augments the host immune response. This effect of the
double-edged sword leads to not only a higher incidence
of HBsAg loss (favourable outcome) but also higher incidence
of cirrhosis and HCC development (adverse outcome)
(Figure 3a). Whether the disease progresses
towards HBsAg loss or HCC may depend upon the variations
of host genetic factors. For example, certain
HLA-alleles may lead to more ‘effective immune
response’, thus clear the virus with mild liver damage. In
contrast, others mount an ‘ineffective immune response
increase dramatically during HBeAg seroconversion and
persist in HBeAg-negative phase.43 Since certain
mutations, such as pre-S deletion, are more common in
genotype C than genotype B,44 the accumulation of these
viral mutants may lead to shift in the dominant viral
strain and therefore difference of clinical outcomes
between HBeAg-positive and HBeAg-negative phases.
This viral evolution may also explain why genotype C is
associated with a lower incidence of HBeAg loss but a
higher chance of HBsAg loss.30, 45, 46
Our study has a few limitations. First, we excluded
patients with liver cirrhosis at baseline, receiving anti-viral
treatment during the follow-up, or with positive HBeAg initially.
This is because most of them had received or were recommended
to receive anti-viral treatment, and treatment
itself alters the prognosis thus may confound the analysis.
19, 47 However, these excluded patients had a higher proportion
of genotype C infection but were less likely to clear
HBsAg, which may exaggerate our finding. To address this
issue, we re-included these patients and re-analysed the relationship
between HBsAg loss and HBV genotype. We found
that genotype C was consistently associated with a higher
lifetime chance of HBsAg loss. This sensitivity analysis partly
confirmed the robust of our findings and can fully address
the issue of possible selection bias.
Second, for patients with extremely low HBV DNA
and HBsAg levels, HBV genotype could not be determined
by either PCR-based or ELISA methods. In other
words, patients who failed to be genotyped generally had
low HBV DNA and HBsAg levels, which happen to be
important predictors for HBsAg loss. The association
between undetermined genotype and higher chance of
HBsAg loss could be attributed to low viral load and low
HBsAg level, which should be cautiously interpreted.
In summary, in Asian carriers with genotype B or C
infection, genotype C infection is found to be associated
with higher chance of HBsAg loss and HCC development.
Since genotype C infection is associated with both
disease progression and remission, this paradoxical finding
further highlights the importance of virus and host
interactions in the pathogenesis of HBV infection

StephenW

讨论
在日常实践中，众所周知，乙肝表面抗原
损失是功能性治愈的最佳衡量指标
乙肝病毒感染。在这项研究中，我们首次表明
HBV C基因型感染，但没有PC或BCP突变体，
与HBsAg消失的几率较高有关联
HBeAg阴性患者。此外，我们发现的关键
导致HBsAg消失的较高可能性可以是
更快下降的HBsAg水平。最后，我们使用了一个灵敏度
分析证实了我们的整体结果
乙肝病毒携带者的人群没有任何选择。
对C基因型感染对HBsAg消失的影响
没有得到很好的解决。以前的病例数
报告是太小，无法得出明确的结论。
7，28，这是因为HBsAg的发病率
损耗低和血清病毒载量通常是检测不到的
的HBsAg被清除，3这导致不可用之前
HBV基因型数据。例如，REVEAL-HBV
队列研究，这是一个大的前瞻性队列研究
其中包括2491年乙肝病毒携带者，显示的HR
C基因型（对B）为HBsAg消失是1.22（95％CI：
0.92-1.63）0.29然而，HBV基因型没有确定
在973参与者（39.1％）的入学率和在
360人（68.8％）实现HBsAg消失。在一个
试图解决这个问题，我们的特点HBV
基因型使用ELISA测定。这更敏感
测定中未确定速率降低到5.6％。随着
合理的研究设计和适当的方法，我们
相信我们的队列提供了一种高统计
电源解决这个有趣和重要的问题。
已知的是HBV基因型肝炎感染，相比
基因型B，与延迟HBeAg血清转换有关
和疾病的进展，如肝炎，肝硬化
和HCC.6，10，12，21，30，31在这项研究中，我们有
表明C基因型感染与没有关联
肝硬化和肝癌，但也较高，只有高风险
机会HBsAg消失的。虽然托底机制
悖论尚不清楚，体外研究
已表明，这两个基因型B和C具有相似的
复制characteristics.32因此，我们推测，
病毒本身不能解释这个悖论。
有趣的是，我们还发现了另外一个方面悖论
男性性，这已被认为是一个危险因素，肝炎，
肝硬化和HCC.6，9，14，21在这项研究中，我们发现
男性乙肝病毒携带者乙肝表面抗原的机会较高
损失，这是与已报告从一致
一个大型队列研究，包括1965年HBV carriers.5
为了解决这两个矛盾，我们做了一个假设，
基于以下意见：一，我们发现了一个
HBsAg消失患者正常高值较高的机会
和升高的ALT水平相比，这些与
低ALT水平正常。其次，以往的研究
表明C基因型和男性的关联
更肝炎activity.21，33第三，由于ALT升高
在慢性乙型肝炎水平归因于T细胞介导
hepatocytolysis，34这个标记的肝损害
严重性也可以作为一个替代的生物标志物
这导致肝脏反复坏死性炎症
肝硬化和HCC（图后续发展
图3b）。该假说已支撑的结果
某些HLA-DP单核苷酸
多态性与HBsAg清除相关，
疾病control.35-38然而，更多的研究是
确认主机之间的重要互动需要
和病毒基因组的因素，应该充分揭示如何
该疾病被控制或前进到肝癌。
我们也注意到另外一个悖论：同一基因型
可以赋予不同的预后HBeAg阳性和 -
消极的阶段。例如，已经表明
B基因型与更好的治疗反应相关
干扰素治疗HBeAg阳性患者，但不
HBeAg阴性patients.39，40我们的研究，另一个
台湾儿科研究发现，C基因型是
更多HBsAg消失在相关HBe​​Ag阴性
病人而不是在HBeAg阳性patients.20这可能
归因于病毒种群从进化
HBeAg阳性阴性到阶段。它已被证明
大多数的病毒是在免疫的野生型病毒的
耐受期，而突变体启动免疫涌现
间隙phase.41，42 HBV变异基因组
宿主免疫反应强度。考虑到
所有这些意见，我们建议C型病毒
和男性相比，B型和女性，
增强宿主的免疫反应。的这种效应
双刃剑导致不仅有较高的发病率
HBsAg消失（有利的结果），而且发病率较高的
肝硬化和肝癌发展（不良转归）的
（图3a）。是否疾病的进展
朝HBsAg消失或肝癌可以取决于变化
主机的遗传因素。例如，某些
HLA等位基因可能会导致更多的“有效的免疫
回应“，可见轻度肝损害的病毒。在
相比之下，其他安装一个“无效的免疫反应
在HBeAg血清转换显着增加，并
坚持HBeAg阴性phase.43由于某些
突变，如前S缺失，在更常见
C基因型比B基因型，其中44积聚
病毒变异可能导致的主导病毒转移
应变，因此临床结果的差异
HBeAg阳性和HBeAg阴性阶段之间。
该病毒的演变也可以解释为什么C基因型是
与HBeAg阴转但发病率较低有关
机会较高的HBsAg loss.30，45，46
我们的研究有一些限制。首先，我们排除
肝硬化患者在基线，接受抗病毒
在后续处理，或用HBeAg阳性最初。
这是因为他们大多接受过或正在推荐
接受了抗病毒治疗，以及治疗
本身改变预后从而可能混淆了分析。
19日，47但是，这些排除患者比例较高
对C基因型感染，但不太可能清除
乙肝表面抗原，这可能夸大我们的发现。为了解决这个
问题，我们重新包括这类患者并重新分析的关系
与HBsAg消失和HBV基因型。我们发现
即C基因型是始终有较高的关联
一生的机会HBsAg消失的。此敏感性分析部分
证实了我们的研究结果的稳健并能完全解决
可能的选择偏差的问题。
第二，对于患者的极低的HBV DNA
和HBsAg水平，HBV基因型无法确定
由任一基于PCR或ELISA法。在其他
也就是说，谁没有进行基因分型患者一般有
低HBV DNA和HBsAg水平，这正好是
重要的预测为HBsAg消失。该协会
未确定基因型和更高的几率之间
HBsAg的损耗可以归因于低病毒载量和低
HBsAg的水平，应谨慎解释。
综上所述，在亚洲航空公司与B型或C
感染，C基因型感染被发现关联
与HBsAg消失和HCC更高的发展机会。
由于C基因型感染与两者相关
疾病进展和缓解这种矛盾的结果
进一步凸显病毒与宿主的重要性
在HBV感染的发病机理的相互作用

疯一点好

C基因型感染被发现关联
与HBsAg消失和HCC更高的发展机会


此文对于已经转阴的人来说，又增加了无限的担忧，难怪癌版那边确实有不少人就是转阴的同时就癌变了，转阴有风险啊。

咬牙硬挺

如何区分ABCD各种型号？

StephenW

回复 疯一点好 的帖子

不是转阴有癌变风险, C基因型感染关联HCC更高(相比于其他基因型)风险.

newchinabok

回复 疯一点好 的帖子

hbsag有的是痊愈，有的是变异，不表达hbsag，影响基因，癌变

疯一点好

转阴者以c基因型居多，而c基因型癌变的风险也高。

zgct

怎样测C基因？