定量乙型肝炎表面抗原的作用

StephenW

The role of quantitative hepatitis B surface antigen revisited
Markus Cornberg
, Vincent Wai-Sun Wong
, Stephen Locarnini
, Maurizia Brunetto
, Harry L.A. Janssen
, Henry Lik-Yuen Chan'Correspondence information about the author Henry Lik-Yuen ChanEmail the author Henry Lik-Yuen Chan
Article has an altmetric score of 25
DOI: http://dx.doi.org/10.1016/j.jhep.2016.08.009

Summary

In the past 10 years, there has been a lot of enthusiasm surrounding the use of serum hepatitis B surface antigen (HBsAg) quantification to predict disease activity and monitor treatment response in chronic hepatitis B. The measurement of HBsAg levels have been standardized in IU/ml, and nowadays it is almost a mandatory measurement due to the development of new antiviral treatments aiming at HBsAg seroclearance, i.e., functional cure of hepatitis B. Recently, there has been an improved understanding of the molecular virology of HBsAg, and particularly the relative roles of covalently closed circular DNA and integrated hepatitis B virus (HBV) DNA. This has shed new light on the interpretation of HBsAg levels in different phases of chronic hepatitis B. HBsAg level can assist the differentiation of immune tolerance and immune clearance in hepatitis B e antigen (HBeAg)-positive patients, and it can predict inactive disease and spontaneous HBsAg seroclearance in HBeAg-negative patients. The determination of HBsAg level is pivotal to individualize pegylated interferon (PegIFN) treatment; it is the key investigation to decide early termination of PegIFN among non-responders. Among patients treated by nucleos(t)ide analogues, responders tend to have dramatic reduction of HBsAg to low levels, which may be followed by HBsAg seroclearance. With newer data on combination treatment of PegIFN and nucleos(t)ide analogues as well as emerging new antiviral agents, HBsAg quantification is expected to become increasingly important to monitor and guide antiviral therapy for chronic hepatitis B.

StephenW

定量乙型肝炎表面抗原的作用
马克斯·康贝尔
王文雄王永平
，Stephen Locarnini
，Maurizia Brunetto
，哈利L.A.扬森
，Henry Lik-Yuen Chan'Corator相关作者的信息Henry Lik-Yuen ChanEmail作者Henry Lik-Yuen Chan
文章的高分为25分
DOI：http://dx.doi.org/10.1016/j.jhep.2016.08.009

概要

在过去十年中，围绕使用血清乙型肝炎表面抗原（HBsAg）定量来预测慢性乙型肝炎的疾病活动和监测治疗反应有很大的热情.HBsAg水平的测量已经在IU / ml，而且现在几乎是强制性测量，因为针对HBsAg血清学，即乙型肝炎的功能治疗的新的抗病毒治疗的发展。最近，对HBsAg的分子病毒学的了解有所改善，特别是相对共同闭合的环状DNA和综合乙型肝炎病毒（HBV）DNA的作用。 HBsAg水平可以帮助乙型肝炎病毒抗原（HBeAg）阳性患者的免疫耐受和免疫清除作用的分化，并可预测无效的疾病和HBeAg阴性患者自发HBsAg血清清除率。 HBsAg水平的测定是聚乙二醇化干扰素（PegIFN）治疗个体化的关键。决定提前终止PegIFN的重要调查是不应答者。在用核酸（t）ide类似物治疗的患者中，应答者往往将HBsAg显着降低至低水平，其后可能是HBsAg血清白蛋白。随着PegIFN和核酸（t）ide类似物以及新出现的新型抗病毒药物联合治疗的较新数据，HBsAg量化预计将变得越来越重要，用于监测和指导慢性乙型肝炎的抗病毒治疗。

StephenW

Role of episomal integrated HBV DNA

Productive replication of HBV, a DNA virus that replicates via reverse transcription, is driven from its transcriptional template, the cccDNA, which is found in the nucleus as a viral minichromosome [[10], [11]]. Transcription from this minichromosome generates all the mRNAs needed for HBV replication including SVP production. HBsAg may also be produced from HBV DNA integrated into the host genome (Fig. 2). Although viral integration is not required for normal productive replication, integration of HBV DNA occurs illegitimately through recombination mechanisms using host enzymes acting on the double-stranded linear (DSL) DNA form of HBV [12]. The DSL DNA replicative intermediate is generated as a consequence of the failure to translocate the RNA primer needed to prime plus-stranded DNA synthesis of the HBV genome [13]. The DR-1/DR-2 regions of the viral genome are preferential sites for integration [14], but integrated sequences cannot provide a template for productive viral replication since the complete genome is not present. However, the open reading frame (ORF) of the S gene with its regulatory elements are often still present in integrated sequences, are intact and so, HBsAg can be produced. Thus, two sources of HBsAg can be identified: cccDNA derived and integrated DNA derived (Fig. 2). This has significance, not only in defining cure end-points such as functional or complete [15] but also in attempting to correlate HBsAg levels in serum to particular replicative markers in the liver.

附加型综合HBV DNA的作用

通过逆转录复制的DNA病毒的生物复制由其转录模板驱动，cccDNA作为病毒微染色体在细胞核中发现[[10]，[11]]。来自该微染色体的转录产生HBV复制所需的所有mRNA，包括SVP产生。 HBsAg也可以从整合到宿主基因组中的HBV DNA产生（图2）。虽然病毒整合对于正常的生产复制来说不是必需的，但HBV DNA的整合通过使用作用于HBV双链线性（DSL）DNA形式的宿主酶的重组机制而非法发生[12]。 DSL DNA复制中间体是由于未能转移引入HBV基因组的正链DNA合成所需的RNA引物而产生的[13]。病毒基因组的DR-1 / DR-2区域是整合的优先位点[14]，但是由于完整的基因组不存在，整合序列不能为生产性病毒复制提供模板。然而，S基因及其调节元件的开放阅读框（ORF）通常仍然以整合序列存在，是完整的，因此可以产生HBsAg。因此，可以鉴定出两种来源的HBsAg：来源于cccDNA和整合的DNA（图2）。这具有重要意义，不仅在确定治疗终点如功能或完全[15]，而且还试图将血清中的HBsAg水平与肝脏中的特定复制标记物相关联。

StephenW

Table 1Quantitative HBsAg in the management of different settings of chronic HBV-infections.Natural course
HBeAg positive
 HBsAg >100,000 IU/ml associated with high replicative HBsAg carrier (“immune tolerance”)
 HBsAg >25,000 IU/ml >90% PPV for minimal liver fibrosis <F1
HBeAg negative
 HBsAg <1000 IU/ml and HBV-DNA <2000 IU/ml is associated with lower risk for HCC
 HBsAg <1000 IU/ml and HBV DNA <2000 IU/ml corresponds to 90% PPV for inactive carrier phase (genotype D)
 HBsAg <100 IU/ml is probably associated with spontaneous HBsAg clearance
Treatment with PegIFN
HBeAg positive
 HBsAg <1500 IU/ml at week 12 corresponds to 57% PPV for HBeAg seroconversion and 17.6% HBsAg clearance
 No decline (any decline) of HBsAg at week 12 has a high NP for response (HBeAg loss and HBV DNA <2000 IU/ml at 24 weeks post-treatment). Response <5% (genotypes A and D)
 HBsAg >20,000 IU/ml at week 12 and 24 associated with 100% NPV for response (HBeAg loss and HBV DNA <2000 IU/ml at 24 weeks post-treatment) (genotypes B and C)
HBeAg negative
 No HBsAg decline (any decline) and <2 log decline of HBV DNA showed a NPV of 100% for non-response in genotype D patients
Treatment with NA
HBeAg positive
 HBsAg decline >1 log after 12–48 weeks has been associated with HBsAg loss
HBeAg negative
 Very slow decline of HBsAg.
 Low HBsAg levels (<100 IU/ml) may predict off-treatment response after cessation of NA (after consolidation therapy ⩾3 years)
Treatment with PegIFN and NA
HBsAg decline of <1 log from baseline to week 12 is associated with high NPV for HBsAg loss
Co-infections
HBV/HCV: Lower HBsAg in HCV dominant patients
HBV/HIV: Higher HBsAg levels compared to monoinfection. Association with CD4 T-cell count. HBsAg decline during ART is associated with CD4 T-cell count
HBV/HDV: Relative high HBsAg level. HBsAg level may be useful to guide IFN therapy

表1 HBsAg定量治疗慢性HBV感染的不同环境
HBeAg阳性
与高复制HBsAg载体相关的HBsAg> 100,000 IU / ml（“免疫耐受”）
HBsAg> 25,000 IU / ml> 90％PPV，用于肝纤维化最小<F1
HBeAg阴性
HBsAg <1000 IU / ml，HBV-DNA <2000 IU / ml与HCC风险降低有关
HBsAg <1000IU / ml，HBV DNA <2000IU / ml对应于无活性载体相（基因型D）的90％PPV
HBsAg <100 IU / ml可能与自发的HBsAg清除有关
用PegIFN处​​理
HBeAg阳性
HBsAg在第12周时<1500IU / ml对应于HBeAg血清学转换的57％PPV和17.6％HBsAg清除率
HBsAg在第12周没有下降（任何下降），具有高反应性（HBeAg损失和HBV DNA <2000IU / ml，在治疗后24周）。反应<5％（基因型A和D）
HBsAg> 20,000 IU / ml在第12周和第24天与100％NPV相关（HBeAg损失和HBV DNA <2000 IU / ml在治疗后24周）（基因型B和C）
HBeAg阴性
HBV DNA无HBsAg下降（任何下降）和<2 log下降显示基因型D患者无反应的NPV为100％
用NA治疗
HBeAg阳性
HBsAg下降> 1〜12周后与HBsAg相关
HBeAg阴性
HBsAg非常缓慢的下降。
低HBsAg水平（<100 IU / ml）可能会预测NA停止后的治疗反应（巩固治疗3年后）
用PegIFN和NA处理
从基线到第12周HBsAg下降<1 log与HBsAg损失的高NPV相关
共感染
HBV / HCV：HCV优势患者HBsAg较低
HBV / HIV：与单感染相比，HBsAg水平较高。与CD4 T细胞计数相关。抗病毒治疗中HBsAg的下降与CD4 T细胞计数有关
HBV / HDV：相对高的HBsAg水平。 HBsAg水平可能有助于指导IFN治疗

StephenW

http://www.journal-of-hepatology ... 16)30441-X/fulltext