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 correspondencePress enter key for correspondence informationemailPress enter key to Email the author
Article has an altmetric score of 8
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.
Keywords:
Hepatitis B, HBsAg, Pegylated interferon, Entecavir, Tenofovir, Antiviral treatment

StephenW

定量乙型肝炎表面抗原的作用

Markus Cornberg
，文世伟伟
，Stephen Locarnini
，Maurizia Brunetto
，Harry L.A.Janssen
，Henry Lik-Yuen Chan通信按确认键进入通信信息邮件按Enter键发电子邮件给作者
文章的测量分数为8
DOI：http://dx.doi.org/10.1016/j.jhep.2016.08.009

概要

在过去的10年中，围绕使用血清乙型肝炎表面抗原（HBsAg）定量来预测疾病活动和监测慢性乙型肝炎的治疗反应已经有很多有利的.HBsAg水平的测量已经在IU / M1，并且现在由于针对HBsAg血清学清除（即乙型肝炎的功能性治愈）的新的抗病毒治疗的开发，几乎是一种强制性测量。近来，已经对HBsAg的分子病毒学，特别是相对共价闭合的环状DNA和整合的乙型肝炎病毒（HBV）DNA的作用。这揭示了在慢性乙型肝炎的不同阶段HBsAg水平的解释新的光线.HBsAg水平可以帮助乙型肝炎抗原（HBeAg）阳性患者的免疫耐受和免疫清除的分化，并且它可以预测无活性疾病和自发HBeAg阴性患者HBsAg血清清除。 HBsAg水平的测定对于个体化聚乙二醇化干扰素（PegIFN）治疗是关键的;它是决定早期终止PegIFN在非应答者之间的关键调查。在由核苷（t）ide类似物治疗的患者中，应答者倾向于将HBsAg急剧降低至低水平，其后可能是HBsAg血清清除。关于PegIFN和核（t）Ide类似物以及新出现的新抗病毒剂的组合治疗的更新数据，HBsAg定量预期对于监测和指导慢性乙型肝炎的抗病毒治疗越来越重要
关键词：
乙型肝炎，HBsAg，聚乙二醇化干扰素，恩替卡韦，替诺福韦，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.

附加型整合HBV DNA的作用

乙肝病毒（一种通过逆转录复制的DNA病毒）的生产性复制由其转录模板驱动，cccDNA在核中被发现作为病毒微染色体[10] [11]。从该微染色体的转录产生HBV复制所需的所有mRNA，包括SVP生产。 HBsAg也可以由整合入宿主基因组的HBV DNA产生（图2）。尽管病毒整合不是正常生产性复制所必需的，但通过使用作用于HBV的双链线性（DSL）DNA形式的宿主酶的重组机制，HBV DNA的整合非正式地发生[12]。 DSL DNA复制中间体是由于无法移位引发HBV基因组的正链DNA合成所需的RNA引物的结果[13]。病毒基因组的DR-1 / DR-2区域是整合的优选位点[14]，但是整合的序列不能提供用于生产性病毒复制的模板，因为完整的基因组不存在。然而，S基因与其调节元件的开放阅读框（ORF）通常仍以整合序列存在，是完整的，因此可以产生HBsAg。因此，可以鉴定两种HBsAg来源：cccDNA来源的和整合的DNA来源（图2）。这具有重要意义，不仅在定义治疗终点，如功能或完整[15]，而且在尝试将血清中的HBsAg水平与肝脏中特定的复制标记物相关联。

StephenW

Therapy with nucleos(t)ide analogues

The aim of NA treatment is maintained viral suppression during treatment [66]. The optimal endpoint and the only situation where NA treatment can be safely discontinued is HBsAg loss, which is a rare event [74]. In HBeAg-positive patients, discontinuation of NA treatment 12 months after HBeAg seroconversion can be recommended [66] but relapse is not infrequently observed [75]. HBsAg levels may help to predict who may achieve HBsAg loss in the long-term and HBsAg may also be an interesting marker to predict HBV rebound after stopping NA treatment.
General trend of HBsAg decline during nucleos(t)ide analogue therapy

HBsAg decline during NA therapy is much slower and less pronounced compared to PegIFN treatment, although NA are much more potent on HBV DNA suppression [[69], [76], [77]]. NAs inhibit only the reverse transcription of the pgRNA but do not target the cccDNA directly. Thus, changes at transcriptional levels, particularly in the HBsAg secretory pathway, are not expected. On the other hand, IFN has both direct antiviral and immune mediated effects. It is likely that the immune modulation by IFN leads to a more dramatic decline in HBsAg production and secretion. Based on HBsAg kinetics, some authors estimated that the median time to HBsAg loss in NA treated patients could be far more than 30 years [[78], [79]]. The rate of HBsAg decline is higher in HBeAg-positive patients vs. HBeAg-negative patients [[79], [80], [81]]. The faster decline in HBeAg-positive patients, especially in the first year of NA therapy [[80], [82]], may be explained by the NA effect on HBV DNA containing virions. In addition, HBeAg-negative patients may have higher amounts of integrated HBV DNA, which can still lead to HBsAg production, as discussed above. Although HBsAg decline is very slow, there are individual differences [83]. Stronger HBsAg decline during NA therapy was associated with higher pre-treatment ALT [79] or IP-10 (CXCL-10) level [[83], [84]] confirming that immune responses are required for HBsAg decline and HBV clearance. So far there is no evidence that different NA or even combinations of NA have different effects on HBsAg kinetics [[81], [83]]. It may be more likely that inter-current events such as infections which may induce cytokines leading to HBsAg decline. Just recently, it has been shown that IFN gamma or tumor necrosis factor alfa can reduce cccDNA without cytolysis [85]

用核苷（t）ide类似物治疗

NA治疗的目的是维持治疗期间的病毒抑制[66]。最佳的终点和NA治疗可以安全停止的唯一情况是HBsAg丢失，这是一个罕见的事件[74]。在HBeAg阳性患者中，可以推荐HBeAg血清转换后12个月停止NA治疗[66]，但不常见的是复发[75]。 HBsAg水平可能有助于预测谁可能实现长期的HBsAg损失和HBsAg也可能是一个有趣的标志物，预测HBV反弹后停止NA治疗。
在核苷类似物治疗期间HBsAg下降的一般趋势

在NA治疗期间，HBsAg下降比PegIFN治疗慢得多，不太明显，尽管NA对HBV DNA抑制作用更强[[69]，[76]，[77]]。 NAs仅抑制pgRNA的逆转录，但不直接靶向cccDNA。因此，不期望在转录水平，特别是在HBsAg分泌途径中的变化。另一方面，IFN具有直接的抗病毒和免疫介导的作用。可能的是，IFN的免疫调节导致HBsAg产生和分泌的更显着的下降。基于HBsAg动力学，一些作者估计，在NA治疗的患者中HBsAg缺失的中值时间可以远远超过30年[[78]，[79]]。 HBeAg阳性患者与HBeAg阴性患者的HBsAg下降率较高[[79]，[80]，[81]。 HBeAg阳性患者，尤其是在NA治疗的第一年[[80]，[82]]，更快的下降可以通过NA对含有病毒颗粒的DNA的影响来解释。此外，如上所述，HBeAg阴性患者可能具有更高量的整合的HBV DNA，其仍然可以导致HBsAg产生。虽然HBsAg下降非常缓慢，但有个体差异[83]。 NA治疗期间更强的HBsAg下降与更高的治疗前ALT [79]或IP-10（CXCL-10）水平[[83]，[84]]相关，证实免疫应答是HBsAg下降和HBV清除所必需的。到目前为止，没有证据表明不同的NA或甚至NA的组合对HBsAg动力学有不同的影响[[81]，[83]]。可能更可能的是间流事件，例如可诱导导致HBsAg的细胞因子的感染降低。最近，已经表明干扰素γ或肿瘤坏死因子α可以减少cccDNA没有细胞溶解[85]

StephenW

HBeAg-positive patients

In HBeAg-positive patients it would be interesting if HBsAg level could predict HBsAg loss or sustained immune control after HBeAg seroconversion. Wursthorn et al. showed that a rapid HBsAg decline of more than 1 log after 1 year of treatment with telbivudine was predictive for HBsAg loss [86]. Supporting the aforementioned hypothesis, HBsAg decline was associated with markedly enhanced antiviral T cell reactivity. Similar data have been documented in patients treated with tenofovir or entecavir. In patients treated with tenofovir, a reduction in HBsAg level of at least 1 log by week 12 or 24 were predictive for HBsAg loss with a positive predictive value of up to 45% and a NPV of up to 97% [87]. It appears that HBeAg-positive patients with stronger HBsAg decline are more likely to achieve HBeAg seroconversion [[81], [88]] but this was not observed in all studies [[89], [90]]. There is less data if HBsAg level can predict off-treatment response after HBeAg seroconversion. For example, in a small study with 11 HBeAg-positive patients who were treated with telbivudine for 2 years, HBsAg <100 IU/ml at the end of treatment predicted for sustained response (defined as undetectable HBV DNA, normal ALT and HBeAg seroconversion) for 2 years after stopping treatment [91].

HBeAg阳性患者

在HBeAg阳性患者中，如果HBsAg水平可以预测HBeAg血清学转换后HBsAg丢失或持续的免疫控制，将是有趣的。 Wursthorn et al。显示在使用替比夫定1年的治疗后，HBsAg的快速下降超过1 log是HBsAg缺失的预测[86]。支持上述假说，HBsAg下降与显着增强的抗病毒T细胞反应性相关。已经在用替诺福韦或恩替卡韦治疗的患者中记录了类似的数据。在用替诺福韦治疗的患者中，在第12或24周时HBsAg水平降低至少1个log是HBsAg丧失的预测，阳性预测值高达45％，NPV高达97％[87]。似乎HBeAg阴性的HBeAg阳性患者更有可能实现HBeAg血清学转换[[81]，[88]但这没有在所有的研究中观察到[[89]，[90]]。如果HBsAg水平可以预测HBeAg血清转化后的治疗反应，则有较少的数据。例如，在11名HBeAg阳性患者接受telbivudine治疗2年的小型研究中，治疗结束时HBsAg <100 IU / ml，预测持续反应（定义为不可检测的HBV DNA，正常ALT和HBeAg血清转换）停止治疗后2年[91]。

StephenW

HBeAg-negative patients

The predictive value of HBsAg levels and interpretation of HBsAg kinetics is more difficult in HBeAg-negative patients [[88], [92]]. HBsAg negative patients may have higher amounts of integrated HBV DNA, which can be a source of HBsAg as discussed above. Thus, the relative effect of NA on the replenishment of cccDNA is lower. In addition, non-cytolytic immune responses may have effect on cccDNA degradation [85] but not on the cell and integrated DNA. Thus, HBeAg-negative patients may have different HBsAg kinetics to cytokines (i.e., IFN treatment) or non-cytolytic immune responses during the natural course of HBV infection or NA therapy compared with HBeAg-positive patients.

Another important fact for the interpretation of HBsAg levels is that some HBeAg-negative patients with early HBsAg decline during NA therapy might have just changed the phase of HBV infection (i.e., transition from immune clearance phase to HBeAg-negative hepatitis) [83], which is associated with lower HBsAg levels [[34], [35]]. Thus, it may represent an already ongoing natural HBsAg decline in some patients.

HBsAg levels in HBeAg-negative patients may be useful for the decision if treatment cessation is an option. Because of the aforementioned long-term treatment with NAs, efforts have been made to identify possible stop points for NA treatment. Hadziyannis et al. showed in HBeAg-negative infection with normalized ALT and suppressed HBV DNA after treatment with adefovir for 4–5 years, the withdrawal of antiviral therapy led to a sustained off-treatment HBV DNA suppression in 55% of patients and even subsequent HBsAg loss in 39%. Lower HBsAg levels at end of treatment were predictive for later HBsAg loss [93]. Again, this supports the idea that immune responses are important for the long-term control of HBV infection. A systematic review of several studies, most retrospective suggest that some patients with decreasing HBsAg levels or lower HBsAg levels (<100 IU/ml) are able to maintain control of HBV after discontinuation of long-term NA therapy [94]. In addition, a consolidation therapy of >3 years before stopping NA seem to be important as well [94]. However, stopping NA might be more complex than anticipated. Some studies suggest that HBV DNA rebounds shortly after NA cessation in most cases [[93], [95]]. This may induce ALT flares [[93], [95]] indicating immune responses, which may be the key for subsequent immune control and HBsAg loss [96]. Therefore, stopping NA is not at all recommended in patients with cirrhosis.

HBeAg阴性患者

HBsAg水平的预测值和HBsAg动力学的解释在HBeAg阴性患者中更加困难[[88]，[92]]。 HBsAg阴性患者可以具有更高量的整合的HBV DNA，其可以是如上所讨论的HBsAg的来源。因此，NA对cccDNA补充的相对效应较低。此外，非溶细胞免疫应答可能对cccDNA降解有影响，但不影响细胞和整合的DNA。因此，与HBeAg阳性患者相比，HBeAg阴性患者在HBV感染或NA治疗的自然过程期间可具有与细胞因子（即IFN治疗）或非溶细胞免疫应答不同的HBsAg动力学。

另一个解释HBsAg水平的重要事实是，一些HBeAg阴性患者在NA治疗期间早期HBsAg下降可能只是改变了HBV感染的阶段（即从免疫清除阶段过渡到HBeAg阴性肝炎）[83]这与较低的HBsAg水平相关[[34]，[35]]。因此，它可能代表一些患者已经持续的天然HBsAg下降。

HBeAg阴性患者中的HBsAg水平可能有助于决定是否可以选择治疗。由于上述用NA的长期治疗，已经做出努力来鉴定NA治疗的可能停止点。 Hadziyannis et al。在用阿德福韦治疗4-5年后的HBeAg阴性感染中显示出标准化的ALT和抑制的HBV DNA，在55％的患者中撤出抗病毒治疗导致持续的脱离HBV DNA抑制，甚至在39天后的HBsAg消失％。在治疗结束时较低的HBsAg水平预示着后来的HBsAg缺失[93]。同样，这支持免疫反应对于HBV感染的长期控制很重要的观点。几项研究的系统综述，大多数回顾性研究表明，一些具有降低的HBsAg水平或更低的HBsAg水平（<100 IU / ml）的患者能够在停止长期NA治疗后维持对HBV的控制[94]。此外，在停止NA之前≥3年的巩固治疗同样重要[94]。然而，停止NA可能比预期更复杂。一些研究表明，HBV DNA在大多数情况下在NA停止后不久就会反弹[[93]，[95]]。这可能诱导ALT耀斑[[93]，[95]]表明免疫反应，这可能是后续免疫控制和HBsAg消失的关键[96]。因此，在肝硬化患者中完全不推荐停止NA。

StephenW

Table 1
Quantitative 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

表格1
定量HBsAg在管理不同设置的慢性HBV感染。

自然过程
HBeAg阳性
HBsAg> 100,000IU / ml与高复制性HBsAg载体相关（“免疫耐受性”）
HBsAg> 25,000IU / ml> 90％PPV，用于最小肝纤维化<F1
HBeAg阴性
HBsAg <1000 IU / ml和HBV-DNA <2000 IU / ml与较低的HCC风险相关
HBsAg <1000IU / ml和HBV DNA <2000IU / ml对应于非活性载体相（基因型D）的90％PPV，
HBsAg <100 IU / ml可能与自发HBsAg清除有关
用PegIFN治疗
HBeAg阳性
在第12周时HBsAg <1500IU / ml对应于HBeAg血清转化的57％PPV和17.6％HBsAg清除率
在第12周HBsAg没有下降（任何下降）具有高的响应NP（HBeAg丢失和HBV DNA <2000IU / ml，在治疗后24周）。反应<5％（基因型A和D）
在第12周和24周时HBsAg> 20,000IU / ml，与100％NPV相关（HBeAg丢失和HBV DNA <2000IU / ml，在治疗后24周）（基因型B和C）
HBeAg阴性
在基因型D患者中，没有HBsAg下降（任何下降）和HBV DNA的<2log下降显示100％的NPV为无反应
用NA治疗
HBeAg阳性
在12-48周后HBsAg下降> 1个对数与HBsAg消失相关
HBeAg阴性
HBsAg的缓慢下降。
低HBsAg水平（<100IU / ml）可以预测NA停止后的治疗反应（巩固治疗后3年）
用PegIFN和NA治疗
从基线到第12周的HBsAg下降<1log与HBsAg缺失的高NPV相关
共感染
HBV / HCV：HCV显性患者中HBsAg降低
HBV / HIV：与单一感染相比，HBsAg水平更高。与CD4 T细胞计数的关联。 ART期间HBsAg下降与CD4 T细胞计数相关
HBV / HDV：相对高Goog的HBsAg水平。 HBsAg水平可用于指导IFN治疗

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