乙型肝炎核心相关抗原（HBcrAg）：慢性乙型肝炎病毒感染的

StephenW

Alimentary Pharmacology & Therapeutics

Review Article
Hepatitis B Core-related Antigen (HBcrAg): An Emerging Marker for Chronic Hepatitis B Virus Infection

L.-Y. Mak; D. K.-H. Wong; K.-S. Cheung; W.-K. Seto; C.-L. Lai; M.-F. Yuen
Disclosures

Aliment Pharmacol Ther. 2018;47(1):43-54.

   Abstract and Introduction
Abstract

Background Chronic hepatitis B (CHB) cannot be completely eradicated due to the presence of covalently closed circular DNA (cccDNA) in the nuclei of infected hepatocytes. While quantification of intrahepatic cccDNA requires liver biopsies, serological markers can be non-invasive alternatives to reflect intrahepatic viral replicative activity. Recently, hepatitis B core-related antigen (HBcrAg) has been advocated as a novel serum marker for disease monitoring and prognostication of CHB.

Aim To examine the virological aspect and clinical application of HBcrAg with respect to the natural history and treatment of CHB.

Methods We reviewed all papers published in the PubMed journal list and abstracts from major international meetings that included the keyword "HBcrAg" or "hepatitis B core-related antigen" until March 2017. Selected studies were compared and summarised on the basis of existing theories, as well as the authors' experience.

Results HBcrAg exhibited good correlation with intrahepatic (ih) cccDNA, ih total hepatitis B virus (HBV) DNA, serum HBV DNA and to a lesser extent HBV surface antigen (HBsAg). In situations where serum HBV DNA levels become undetectable or HBsAg loss is achieved, HBcrAg can still be detectable. This marker is helpful in differentiation of HBeAg-negative chronic hepatitis from HBeAg-negative chronic infection, predicting spontaneous or treatment-induced HBeAg seroconversion, sustained response to nucleos(t)ide analogue (NA), risk of HBV reactivation in occult HBV infection under immunosuppressive therapies, and risk of hepatocellular carcinoma (HCC) development as well as post-operative HCC recurrence.

Conclusions HBcrAg is a potential surrogate marker of cccDNA. It may soon become a useful marker for disease monitoring, predicting treatment response and disease outcome of chronic hepatitis B.

StephenW

消化药理学和治疗学

评论文章
乙型肝炎核心相关抗原（HBcrAg）：慢性乙型肝炎病毒感染的新标志物

L.-Y.麦; D.K.-H.黄; K.-S.祥; W.-K.濑户; C.-L.赖; M.-F.玄
披露

Aliment Pharmacol Ther。 2018; 47（1）：43-54。

    已添加到电子邮件警报

摘要和介绍
抽象

背景慢性乙型肝炎（CHB）由于受感染的肝细胞核中存在共价闭合环状DNA（cccDNA），因此不能完全根除。虽然肝内cccDNA的定量需要肝活检，但血清学标志物可能是反映肝内病毒复制活性的非侵入性替代方法。最近，乙肝核心相关抗原（HBcrAg）被认为是CHB疾病监测和预测的新型血清标志物。

目的探讨HBcrAg在CHB自然病程和治疗方面的病毒学表现和临床应用。

方法我们回顾了PubMed杂志上发表的所有论文以及主要国际会议摘要，包括关键词“HBcrAg”或“乙型肝炎核心相关抗原”，截止到2017年3月。选择的研究在现有理论的基础上进行比较和总结，以及作者的经验。

结果HBcrAg与肝内（ih）cccDNA，ih总乙型肝炎病毒（HBV）DNA，血清HBV DNA以及较小程度的HBV表面抗原（HBsAg）具有良好的相关性。在血清HBV DNA水平不可检测或达到HBsAg消失的情况下，HBcrAg仍可检测到。该标志物有助于区分HBeAg阴性慢性肝炎与HBeAg阴性慢性感染，预测自发性或治疗性诱导的HBeAg血清学转换，对核苷（酸）类似物（NA）的持续反应，隐匿性HBV感染中HBV再激活的风险免疫抑制治疗以及肝细胞癌（HCC）发展的风险以及术后HCC复发。

结论HBcrAg是cccDNA的潜在替代指标。它可能很快成为疾病监测，预测慢性乙型肝炎的治疗反应和疾病结局的有用指标。

StephenW

HBcrAg, which consists of 3 species of related proteins sharing an identical 149 amino acid sequence: HBcAg, hepatitis B e antigen (HBeAg), and a truncated 22 kDa precore protein (p22Cr). HBcAg is the structural component of the viral capsids, which can be found in mature virions. HBeAg, a nonstructural HBV protein, is the N-terminal processed product of the precore protein. Like HBeAg, p22cr is also a processed product of the precore protein, but with protein processing at both the N- and C-terminals.[17] The viral replication cycle and the origins of HBV DNA, HBsAg, HBeAg and HBcrAg are illustrated in Figure 1.
HBcrAg由3种相关蛋白组成，它们共享相同的149个氨基酸序列：HBcAg，乙型肝炎e抗原（HBeAg）和截短的22 kDa前核蛋白（p22Cr）。 HBcAg是病毒衣壳的结构成分，可以在成熟病毒体中找到。 HBeAg是一种非结构性HBV蛋白，是前C蛋白的N-末端加工产物。 与HBeAg一样，p22cr也是前核蛋白的加工产物，但是在N端和C端都有蛋白质加工[17]。 病毒复制周期和HBV DNA，HBsAg，HBeAg和HBcrAg的来源如图1所示。

StephenW

The serum HBcrAg concentration correlates strongly with the serum HBV DNA concentration in a positive and linear manner, regardless of the HBeAg status
无论HBeAg状态如何，血清HBcrAg浓度与血清HBV DNA浓度呈正相关且呈线性关系

HBcrAg has a much stronger correlation with intrahepatic cccDNA.
In comparison, serum HBV DNA also correlates equally well with intrahepatic cccDNA.
However, patients receiving anti-viral therapy often have undetectable serum HBV DNA, while 78% of these patients still have detectable serum HBcrAg.[22] Therefore, in the context of serum DNA undetectability, HBcrAg would be the preferred serum marker to estimate intrahepatic cccDNA quantity.
HBcrAg与肝内cccDNA的相关性更强。
相比之下，血清HBV DNA也与肝内cccDNA同样相关。
然而，接受抗病毒治疗的患者通常无法检测到血清HBV DNA，而这些患者中有78％仍然有可检测到的血清HBcrAg [22]。 因此，在血清DNA检测不到的情况下，HBcrAg将成为估计肝内cccDNA数量的首选血清标志物。

StephenW

Profile of HBcrAg in the Natural History of Chb

The profiles were well characterized by 2 landmark studies performed in treatment-naïve Asian (N = 404) and European (N = 249) CHB patients across genotypes AD. [16,26] In both studies, the HBcrAg levels differed significantly between HBeAg-positive and -negative patients. In general, HBeAg-positive patients have a higher HBcrAg level compared to HBeAg-negative patients (Figure 2). is related to the diminished production of HBeAg after HBeAg seroconversion. Specifically, in HBeAg-positive patients, the HBcrAg levels were 8.54 and 7.92 log U / mL in HBeAg-positive chronic infection (also known as immunotolerant phase) and HBeAg-positive chronic hepatitis (also known as immune clearance phase) respectively (P <.001). [16] It suggests that HBeAg-positive patients with lower HBcrAg levels are more likely to be under a more intense immune control. els can reflect immune clearance activity deserves more future studies to examine.
Click to zoom
(Enlarge Image)

Figure 2.


Median HBcrAg levels in natural history of CHB and correlation with other viral markers

For HBeAg-negative patients, the HBcrAg levels were significantly lower in HBeAg-negative chronic infection (also known as inactive carrier state) patients compared to HBeAg- negative chronic hepatitis (also known as HBeAg-negative active phase) patients (2.60 vs. 4.92 log (Figure 2). [16] A higher HBcrAg in HBeAg-negative chronic hepatitis compared to HBeAg-negative chronic infection was associated with more significant necroinflammatory activity and significant fibrosis. [27] D in HBeAg-positive phase, if HBeAg-negative patients (although with lower HBcrAg level compared with HBeAg-positive patients) still have relatively high HBcrAg levels after HBeAg seroconversion, the disease activities are in fact more advanced.

For patients who underwent spontaneous HBsAg seroclearance, most of them (79%) had undetectable HBcrAg levels signifying a more quiescent disease state. Of the 21% still having detectable HBcrAg in the serum, the median HBcrAg was 2.7 log U / mL. [16 , 28]

All of the above findings offer a potential role for HBcrAg to further define the phases of CHB infection, although the optimal cut-offs remain determined. The latest EASL guideline acknowledged the potential of HBcrAg to help define the phase of chronic HBV infection, especially in HBeAg-negative patients. [7]

In addition, HBcrAg may be useful in predicting important milestones in natural history of CHB infection such as HBeAg seroconversion. A number of host and virological factors are found to be favorarable for spontaneous HBeAg seroconversion, including alanine aminotransferase (ALT)> 2 times the upper limit of normal (ULN), low HBV DNA, low HBsAg titre, non-C genotype and low serum interleukin-27 levels. [29-33] More recently, HBcrAg has been shown to be predictive of early spontaneous HBeAg seroconversion at 12 months in a Japanese study (N = 234) with an area under receiver-operating-characteristic (ROC) curve (AUROC) of 0.708. [34] In another Chinese study of 113 patients, the HBcrAg levels at week 28 of follow-up were significantly lower for patients in the HBeAg-positive chronic hepatitis phase who underwent spontaneous HBeAg seroconversion compared to those who did not (4.32 vs. 5.16 log U / mL, respectively; P = .004). To predict spontaneous HBeAg seroconversion, baseline HBcrAg lev The results were as follows: el below 4.9 log U / mL or a decline of HBcrAg by ≥ 2 logs at week 28 would confer positive predictive values ​​(PPV) of 73.9% and 76.2% respectively, and negative predictive values ​​(NPV) of 96.7% and 93.8% respectively. [35] Whether HBcrAg levels can be predictive of spontaneous HBsAg seroclearance remains to be determined.

StephenW

HBcrAg在自然史中的概况

这些资料的特点是在亚洲人群（N = 404）和欧洲人（N = 249）的不同基因型AD患者中进行了2项具有里程碑意义的研究。在这两项研究中，HBeAg阳性和阴性患者的HBcrAg水平均有显着差异[16,26]。一般来说，与HBeAg阴性患者相比，HBeAg阳性患者的HBcrAg水平更高（图2）。与HBeAg血清转换后HBeAg产生减少有关。具体而言，在HBeAg阳性患者中，HBeAg阳性慢性感染（也称为免疫耐受期）和HBeAg阳性慢性肝炎（也称为免疫清除期）中HBcrAg水平分别为8.54和7.92log U / mL（P < .001）。 [16]这表明HBeAg阳性的HBcrAg水平较低的患者更有可能处于更强烈的免疫控制下。埃尔斯可以反映免疫清除活动值得更多的未来研究审查。
点击放大
（放大图片）

图2。

CHB自然史中HBcrAg水平中位数与其他病毒标志物相关性

对于HBeAg阴性患者，与HBeAg阴性慢性肝炎（也称为HBeAg阴性活动期）患者相比，HBeAg阴性慢性感染（也称为无活性携带者状态）患者的HBcrAg水平显着降低（2.60比4.92 （图2）[16] HBeAg阴性慢性肝炎患者的HBcrAg较HBeAg阴性慢性感染者高，与更显着的坏死性炎症活动和显着的纤维化相关[27]。在HBeAg阳性期，如果HBeAg阴性HBeAg血清学转换后患者（尽管HBcrAg水平低于HBeAg阳性患者）仍然具有相对较高的HBcrAg水平，但实际上疾病活动更为先进。

对于接受自发性HBsAg血清学清除的患者，其中大多数（79％）HBcrAg水平检测不到，表明疾病状态更加缓和。在血清中仍然有可检测的HBcrAg的21％中，HBcrAg中位数为2.7log U / mL。 [16,28]

所有上述发现为HBcrAg进一步确定慢性乙型肝炎感染的阶段提供了潜在的作用，尽管仍然确定了最佳临界值。最新的EASL指南承认HBcrAg有助于确定慢性HBV感染阶段的潜力，特别是在HBeAg阴性患者中。 [7]

此外，HBcrAg可能有助于预测CHB感染自然史中的重要里程碑，如HBeAg血清学转换。发现一些宿主和病毒学因素对于自发性HBeAg血清转化是有利的，包括丙氨酸转氨酶（ALT）>正常上限（ULN）的2倍，低HBV DNA，低HBsAg滴度，非C基因型和低血清白介素-27水平。最近，在日本的一项研究（N = 234）中，HBcrAg可以预测12个月时早期自发性HBeAg血清学转换，受试者工作特征曲线（AOCOC）曲线下面积（AUROC）为0.708 。在另一项113例患者的研究中，HBeAg阳性慢性肝炎阶段接受自发HBeAg血清学转换的患者随访28周HBcrAg水平显着低于未接受HBeAg血清学转换的患者（4.32 vs. 5.16日志U /毫升，分别; P = .004）。为了预测自发性HBeAg血清转化，基线HBcrAg水平结果如下：el低于4.9log U / mL或在28周时HBcrAg下降≥2log将赋予阳性预测值（PPV）73.9％和76.2％ ，阴性预测值（NPV）分别为96.7％和93.8％。 HBcrAg水平是否可以预测自发性HBsAg血清学清除仍有待确定[35]。

StephenW

The Japanese Society of Hepatology guidelines have recently incorporated the use of HBcrAg levels in identifying patients at low risk of relapse using the cut-offs <1.9 log U/mL or <3.0 log U/mL for HBsAg and HBcrAg respectively.[53] Validation studies using these criteria for selecting patients to stop NA should be performed in different populations.
日本肝脏病学会指南最近纳入了HBcrAg水平用于鉴别复发风险低的患者，分别使用HBsAg和HBcrAg分别<1.9 log U / mL或<3.0 log U / mL [53]。 使用这些标准选择停止NA的患者的验证研究应该在不同的人群中进行。

StephenW

More recently, HBcrAg has been shown to be associated with HCC development.[62–64] For treatment-naïve patients, the time-dependent AUROCs of HBcrAg for predicting HCC incidence were superior to HBV DNA levels for up to 10 years of follow-up.[64] For treatment-experienced patients, NA can only reduce but cannot eliminate the risk of HCC,[65] and HBcrAg positivity after NA for at least 2-year duration was an independent risk factor for HCC.[62] In 76 CHB patients treated with NA with undetectable serum HBV DNA, the pre-treatment HBcrAg levels were significantly higher in the HCC group compared to the matched control group (279.0 vs 35.4 kU/mL, ie 5.45 log U/mL vs 4.55 log U/mL respectively; P = .005) and a pre-treatment cut-off of 47.1 kU/mL (ie 4.67 log U/mL) independently predicted HCC. Furthermore, a post-treatment HBcrAg >7.8 kU/mL (ie 3.89 log U/mL) predicted HCC with an odds ratio of 3.27. When only noncirrhotic patients were considered, a cut-off of >7.9 kU/mL (ie 3.90 log U/mL) predicted HCC with an odds ratio of 5.95.[66] These findings highlight the importance of conducting further studies to examine the predictive capacity of using HBcrAg for the development of HCC in patients who are already on anti-viral treatment.
最近，HBcrAg已被证实与HCC发生有关[62-64]。对于未经治疗的患者，HBcrAg预测HCC发病率的时间依赖性AUROCs在随访10年后优于HBV DNA水平，起来。[64]对于经历过治疗的患者，NA只能降低但不能消除HCC的危险[65]，且NA后至少2年的HBcrAg阳性是HCC的独立危险因素[62]。在76例乙型肝炎患者血清HBV DNA检测不到的情况下，HCC组的HBcrAg水平显着高于匹配的对照组（279.0 vs 35.4 kU / mL，即5.45 log U / mL vs 4.55 log U / mL; P = .005）和47.1kU / mL（即4.67log U / mL）的预处理截止值独立预测HCC。此外，治疗后HBcrAg> 7.8 kU / mL（即3.89 log U / mL）预测HCC的比值比为3.27。当仅考虑非肝硬化患者时，截断值> 7.9 kU / mL（即3.90 log U / mL）预测HCC的比值比为5.95 [66]。这些发现强调了进行进一步研究以检查HBcrAg在已经接受抗病毒治疗的患者中发展为HCC的预测能力的重要性。

StephenW

Conclusions

In summary, HBcrAg is a good surrogate marker of intrahepatic cccDNA. It correlates with HBV DNA in all disease states. HBcrAg is helpful in differentiation of HBeAg-negative chronic hepatitis from inactive carrier state as shown by 2 large-scale studies. These 2 disease states carry entirely different clinical implications and prognosis, and the role of HBcrAg in here should be further elaborated in particular for HBeAg-negative patients with apparently normal ALT. In patients with undetectable serum HBV DNA and HBsAg, ie achieving "functional cure," complications would still occur. Certain proportion of patients achieving "functional cure" still have detectable HBcrAg and this warrants prospective studies comparing the long-term outcome between HBcrAg-positive and HBcrAg-negative patients. HBcrAg, similar to HBsAg titre, is potentially useful in predicting HBsAg loss under NA therapy, although the cumulative rates of HBsAg loss is still disappointing. On the other hand, sustained off-therapy response to NA is a more attractive outcome to investigate, as most NA is continued indefinitely and the role of HBcrAg in selecting low-risk patients for NA cessation should be further explored.

Finally, use of HBcrAg needs further exploration in 2 special populations. First, as HBcrAg demonstrated good predictive value for risk of HBV reactivation in occult HBV, and more studies should be performed on moderate-risk and low-risk group for risk stratification, as well as for determining the optimal duration of NA after cessation of rituximab or immunosuppressive therapy for HSCT. Second, predicting HCC by HBcrAg for both treatment-naïve and treatment-experienced group is an exciting area.

However, as remarked in the EASL guideline, most studies were performed in Japan and other Asia countries and large correlation studies derived from Caucasian patients are lacking. As such, in spite of being a very promising new viral marker, more extensive clinical validation is needed before routine use in clinical practice.
结论

总之，HBcrAg是肝内cccDNA的良好替代指标。它与所有疾病状态下的HBV DNA相关。 HBcrAg有助于区分HBeAg阴性慢性肝炎和非活动性携带者状态，如2项大规模研究所示。这2种疾病状态具有完全不同的临床意义和预后，HBcrAg在这里的作用应该进一步阐述，特别是对于ALT正常的HBeAg阴性患者。在血清HBV DNA和HBsAg检测不到的患者中，即达到“功能性治愈”，并发症仍会发生。实现“功能性治愈”的患者的某些比例仍然具有可检测的HBcrAg，并且这保证了前瞻性研究比较HBcrAg阳性和HBcrAg阴性患者之间的长期结果。与HBsAg滴度类似，HBcrAg可能有助于预测NA治疗下的HBsAg消失，但HBsAg的累积丢失率仍然令人失望。另一方面，由于大多数NA无限期地持续存在，并且HBcrAg在选择低风险患者停止NA时的作用应该进一步探索，所以对NA进行的持续不治疗反应是更有吸引力的研究结果。

最后，使用HBcrAg需要在2个特殊人群中进一步探索。首先，由于HBcrAg对隐匿性HBV的HBV再激活风险具有良好的预测价值，因此应对中危和低危组进行危险分层以及确定停用利妥昔单抗后NA的最佳持续时间或免疫抑制治疗HSCT。其次，HBcrAg预测HCC治疗初治和治疗经验组是一个令人兴奋的领域。

然而，正如EASL指南所指出的，大多数研究在日本和其他亚洲国家进行，缺乏来自高加索患者的大量相关性研究。因此，尽管是一种非常有前途的新型病毒标志物，但在临床实践中常规使用之前需要进行更广泛的临床验证。

StephenW

https://www.medscape.com/viewarticle/890298_1