评论:在临床实践中定量B肝表面抗原和病毒DNA的运用

StephenW

Review
Use of quantitative hepatitis B surface antigen with hepatitis B virus DNA in clinical practice†

Grace Lai-Hung Wong1,2,
Henry Lik-Yuen Chan1,2,*
    1    Institute of Digestive Disease and the Chinese University of Hong Kong, Hong Kong SAR, China
    2    Department of Medicine and Therapeutics, the Chinese University of Hong Kong, Hong Kong SAR, China

Email: Henry Lik-Yuen Chan ([email protected].)

*Department of Medicine and Therapeutics, 9/F Prince of Wales Hospital, 30-32 Ngan Shing Street, Shatin, Hong Kong
Article first published online: 1 MAR 2013

DOI: 10.1002/cld.165

Hepatitis B virus (HBV) DNA is the key prognostic factor determining both disease activity and risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B viral infection. It is also the key viral factor in deciding when to start antiviral therapy and to monitor the response to therapy. Quantitative hepatitis B surface antigen (HBsAg) reflects the amount and the transcriptional activity of covalently closed circular DNA inside hepatocytes.1 Therefore, quantitative HBsAg provides information concerning disease activity over and above an estimation of viral replication.

The enzyme immunoassays of HBsAg that are in widespread use do not quantify total circulating protein, nor do they distinguish between the different HBsAg proteins. HBsAg quantification detects all three forms of circulating HBsAg, namely the virion-associated HBsAg, subviral particles and HBsAg produced from integrated sequence. The two commercially available HBsAg quantification assays, the Architect QT assay (Abbott Laboratories, Wiesbaden, Germany) and the Elecsys HBsAg II Quant assay (Roche Diagnostic, Indianapolis, IN), give a measure of total HBsAg and have good correlation with each other.2 The clinical use of measuring quantitative HBsAg can be summarized below.


在临床实践中定量B肝表面抗原和病毒DNA的运用

格雷斯赖红Wong1，2，
亨利力源CHAN1，2，*
    1消化疾病研究所和中国香港大学，香港特区，中国
    内科及药物治疗学系，中国香港大学，香港特区，中国

电子邮件：力源陈亨利（[email protected]。）

内科及药物治疗学系，9 / F威尔斯亲王医院，沙田银城街30-32号，沙田，香港
在网上公布：2013年3月1日

DOI：10.1002/cld.165

乙型肝炎病毒（HBV）DNA是影响患者预后的关键因素，确定疾病的活动性和慢性乙肝病毒感染患者的肝细胞肝癌（HCC）的风险。这也是病毒的关键因素，决定何时开始抗病毒治疗和监测对治疗的反应。定量B型肝炎表面抗原（HBsAg）反映的量和hepatocytes.1因此内共价闭合环状DNA的转录活性，HBsAg定量提供有关疾病活动性病毒复制的估计之上。

的HBsAg的酶免疫测定法，是广泛使用的不量化总循环蛋白，他们也不区分不同HBsAg蛋白。乙肝表面抗原定量检测这三种形式的循环乙肝表面抗原，即病毒体相关的乙肝表面抗原，亚病毒颗粒和HBsAg产生的综合顺序。两种市售乙肝表面抗原定量检测，建筑师QT检测（雅培，威斯巴登，德国）和Elecsys2010的乙肝表面抗原定量检测（罗氏诊断，印第安纳波利斯，IN）II，就可以算出总的HBsAg，彼此有很好的相关性。 2 HBsAg定量测量中的临床应用可以概括如下。

StephenW

Diagnosis of the True Inactive HBV Carrier

Patients in the inactive HBV carrier state do not need frequent follow-up or medical treatment. Therefore, the recognition of the inactive HBV carrier state is important. Based on natural history cohorts with long-term follow-up, the inactive HBV carrier state is often defined by persistently normal alanine aminotransferase levels,a low HBV DNA level (<2,000 IU/mL) in a hepatitis B e antigen (HBeAg)-negative patient with no or minimal liver injury.3 Recent data show that HBeAg-negative patients with HBV DNA between 2,000 and 20,000 IU/mL with persistently normal alanine aminotransferase levels can also have a very good prognosis without the need of antiviral therapy.4 However, HBV DNA may fluctuate with time; some patients who have low HBV DNA levels at one time may have viral and biochemical reactivation at a later time. The serum HBsAg level, which tends to change very slowly with time and remain at a low level among inactive carriers, is a useful adjunct to HBV DNA, thereby assisting the identification of true inactive HBV carriers.5 Numerous studies have shown that inactive HBV carriers usually have serum HBsAg levels <1,000 IU/mL.1 In European HBeAg-negative patients with HBV DNA levels <2,000 IU/mL, HBsAg levels <1,000 IU/mL can predict inactive disease in the subsequent year of follow-up.6 In Asian patients, HBsAg <100 IU/mL has been shown to increase the chance of subsequent spontaneous seroclearance of HBsAg.7

While we would expect that the true inactive HBV carrier state would also indicate a low HCC risk, this remains to be confirmed. Based on long-term follow-up studies in Taiwan, HBV DNA <2,000 IU/mL is associated with a lower HCC risk than higher HBV DNA levels. However, HBV DNA levels <2,000 IU/mL did not correlate with the risk of HCC risk.8 The exact reason is uncertain but may be related to fluctuating HBV DNA during follow-up. On the other hand, among patients with HBV DNA <2,000 IU/mL, those who have HBsAg <1,000 IU/mL have a significantly lower HCC risk (<100 per 100,000 person-years) than those with HBsAg >1,000 IU/mL. Hence the definition of a true inactive carrier probably needs a low HBV DNA (<2,000 IU/mL) plus a low HBsAg level (<1,000 IU/mL) (Table 1).
Table 1. HBV DNA and HBsAg Levels in Different Settings1
Response                                  HBV DNA                          HBsAg                                          References
Natural history               
Inactive hepatitis                      <2,000 IU/mL                     <1,000 IU/mL                                    6
Low risk of HCC                        <2,000 IU/mL                     <1,000 IU/mL                                    8
Treatment response to PEG-IFN               
HBeAg-positive               
  Good                                     <20,000 IU/mL at week 24    <1,500 IU/mL at week 24                     9
  Poor                                       High, no clear cutoff            >20,000 IU/mL at week 24                  10, 11
                                               High, no clear cutoff            No decline at week 12 or 24                 12
HBeAg-negative               
  Good                                      Unclear                              >1 log decline at week 48                     13
                                               Unclear                              >10% decline at week 24                      14
  Poor                                      ≤2 log decline at week 12     No decline at week 12                           15


真不活跃的乙肝病毒携带者的诊断

在非活动性HBV携带者状态的患者不需要频繁的随访或药物治疗。因此，非活动性HBV携带者状态的确认是非常重要的。基于长期后续的自然历史同伙，非活动性HBV携带者状态的谷丙转氨酶水平持续正常，HBV DNA水平低（<2,000 IU / mL）的B型肝炎e抗原（HBeAg）通常被定义 - 没有或很少肝损伤的最新数据显示阴性的患者与HBV DNA之间的2,000元及20,000 IU / mL的谷丙转氨酶水平持续正常的HBeAg阴性患者也有很好的预后，而不需要抗病毒治疗，但，HBV DNA可能出现波动，随着时间的推移，一些病人谁低HBV DNA水平在同一时间可能有病毒和生化重新在稍后的时间。血清HBsAg水平，会随着时间的变化非常缓慢，并保持在一个较低水平非活动性携带者，HBV DNA是一个有用的辅助，从而帮助识别真正的非活动性HBV carriers.5大量的研究表明，非活动性HBV携带者通常有血清HBsAg水平<1000 IU/mL.1在欧洲HBeAg阴性患者HBV DNA水平<2000 IU /毫升，HBsAg水平<1000 IU / mL的可预测疾病的后续up.6在随后的一年中不活动<100 IU / mL的亚洲患者，乙肝表面抗原已被证明能增加随后自发转阴的HBsAg.7的机会

虽然我们所期望的，也表明了真正的非活动性HBV携带者状态的HCC风险低，这还有待证实。基于长期在台湾的后续研究，HBV DNA <2000 IU / ml是与较高的HBV DNA水平较低的HCC危险性比。然而，HBV DNA水平<2000 IU / mL的不相关的的HCC risk.8风险的确切原因是不确定的，但可能会在后续的波动HBV DNA。另一方面，在患者HBV DNA <2000 IU / mL时，有乙肝表面抗原<1000 IU / mL的有显着降低肝癌风险比与HBsAg（<100每10万人年）> 1000 IU /毫升。因此，一个真正的惰性载体的定义可能需要低HBV DNA（<2000 IU / mL）的加一个HBsAg水平低（<1,000 IU /毫升）（表1）。
表1中。 HBV DNA和HBsAg水平在不同的设定1
Response                     HBV DNA                                   HBsAg                           参考文献
自然史
非活动性肝炎              <2000 IU / mL                           <1000 IU / mL                    6
低风险的HCC              <2,000 IU / mL                           <1000 IU / mL                    8
PEG-IFN治疗反应
HBeAg阳性

好                           <20000 IU / mL 24周                 <1500 IU / mL 周24              9  
  
差                           高，没有明确的截止                   > 20,000 IU / mL 周24          10 11
                                高，没有明确的截止                   没有下降 周12或24                12
HBeAg阴性
  好                          不清楚                                       > 1的log下降 在48周             13
                               不清楚                                       > 10％的跌幅 在24周             14
  差                          ≤ 2log下降 在12周                      没有下降  12周                      15

StephenW

Treatment Response to Pegylated Interferon聚乙二醇干扰素的治疗反应

Pegylated interferon (PEG-IFN) is a recommended first-line therapy for chronic hepatitis B. However, the use of PEG-IFN is limited by its relatively low efficacy (∼30%-40% sustained response), side effects, and high cost. It is therefore desirable to predict which patients will fail therapy so that PEG-IFN can be stopped. Several studies have evaluated the use of serum HBV DNA to predict response to PEG-IFN. In general, a high serum HBV DNA during treatment predicts nonresponse, although the exact cutoff HBV DNA level and the timing of evaluation to be used as a stopping rule are controversial.17 In contrast, the absolute levels as well as the kinetics of serum HBsAg are predictive of treatment response to PEG-IFN.
聚乙二醇化干扰素（PEG-IFN）是推荐的第一线治疗慢性乙型肝炎然而，使用PEG-IFN是有限的（约30％-40％的持续应答），其相对较低的疗效副作用，和高成本。因此，这是可取的预测哪些患者将失败的PEG-IFN治疗，这样可以停止。一些研究探讨了使用的血清HBV DNA来预测PEG-IFN。在一般情况下，高的血清HBV DNA在治疗过程中预测不应答，虽然确切的截止HBV DNA水平和要用作停止规则的定时评价controversial.17相反的绝对水平，以及血清HBsAg动力学预测PEG-IFN治疗反应。

HBeAg-Positive PatientsHBeAg阳性患者

Based on the phase 3 studies of peginterferon alfa-2a (with or without lamivudine in combination) in HBeAg-positive patients, HBsAg >20,000 IU/mL at week 12 or 24 predicts treatment failure.10, 11, 16 Among patients on PEG-IFN monotherapy, HBsAg >20,000 IU/mL together with HBV DNA >100,000 copies/mL (∼20,000 IU/mL) can further increase the negative predictive value for HBeAg seroconversion (i.e., failure to seroconvert) to 91% and predicts failure to achieve a combined response (HBeAg seroconversion and HBV DNA <10,000 copies/mL) in 98% of patients.3 A more vigorous early decline in HBsAg level starting at week 4 of peginterferon alfa-2b treatment was observed in sustained responders (those with HBeAg loss and HBV DNA <2,000 IU/mL at 6 months posttreatment), whereas absence of such an HBsAg decline at weeks 12 and 24 had negative predictive values of 97% and 92%, respectively.4
基于相研究聚乙二醇干扰素α-2a干扰素（带​​或不带组合拉米夫定）在HBeAg阳性患者中，乙型肝炎表面抗原> 20,000 IU / mL的12周或24周预测患者的治疗failure.10，11，16在PEG- IFN单药治疗，乙肝表面抗原> 20,000 IU / mL的HBV DNA> 10拷贝/毫升（〜20,000 IU / mL）的进一步提高HBeAg血清学转换，阴性预测值（即未能血清转化）到91％，并预测未能实现一个联合应答（HBeAg血清学转换和HBV DNA <10,000拷贝/ ml）在98％的患者更积极的初现下滑开始HBsAg水平在第4周的聚乙二醇干扰素α-2b干扰素治疗持续应答（与HBeAg消失和HBV DNA <2000 IU /毫升，6个月的治疗后），而没有这样的乙肝表面抗原下降12周和24周的阴性预测值分别为97％和92％，分别

Response-Guided Therapy to PEG-IFN 的响应引导治疗

In the future, determining when to stop PEG-IFN might be guided by the on-treatment responses of HBsAg and HBV DNA.17 As more data on extended administration of PEG-IFN to patients with HBV infection emerge,18 the use of on-treatment measurement of quantitative HBsAg as an aid to select patients for extension of PEG-IFN beyond 1 year should be examined. Similarly, more data are needed to determine how to fit serial measures of HBV DNA into the algorithm.
在未来，可能会决定何时停止PEG-IFN指导的HBsAg和HBV DNA.17的对治疗的反应，随着越来越多的数据扩展管理的PEG-IFN与HBV感染患者的出现，使用上应检查作为一种​​辅助手段，选择患者延长超过1年的PEG-IFN治疗HBsAg定量测量。同样的，需要更多的数据，以确定如何适应到算法中的HBV DNA的串行措施。

StephenW

Conclusions结论

Quantitative measurement of HBsAg is an indispensable tool in the clinical assessment and management of chronic hepatitis B viral infection. Quantitative serum HBsAg should be used together with HBV DNA in the diagnosis of the true inactive carrier state and in monitoring the clinical response to PEG-IFN (Table 1).
对HBsAg的定量测量是慢性乙肝病毒感染的临床评估和管理的不可缺少的工具。应使用血清HBsAg定量与HBV DNA的真实惰性载体状态的诊断和监测的临床反应，PEG-IFN（表1）。