使用B肝表面抗原水平，引导聚乙二醇干扰素治疗HBeAg

StephenW

Hepatology International© Asian Pacific Association for the Study of the Liver 201210.1007/s12072-012-9385-0

Editorial

Are we ready to use the hepatitis B surface antigen level to guide peginterferon treatment in HBeAg-negative chronic hepatitis B?
Henry Lik Yuen Chan1

(1)Department of Medicine and Therapeutics and Institute of Digestive Disease, The Chinese University of Hong Kong, 9/F Prince of Wales Hospital, 30-32 NganShing Street, Shatin, Hong Kong, People’s Republic of China




Henry Lik Yuen Chan
Email: [email protected]



Received: 23 March 2012Accepted: 28 May 2012Published online: 21 June 2012
Without Abstract

                  In chronic hepatitis B virus (HBV) infection, hepatitis B e antigen (HBeAg) seroconversion often indicates host immune clearance. Approximately 30 % of patients, however, still have active viremia and fluctuating alanine aminotransferase (ALT) levels in the HBeAg-negative phase [1]. These patients with HBeAg-negative chronic hepatitis B probably have an immune escape by the virus; a further attempt of immune modulator therapy by interferon might be difficult and the post-treatment relapse rate is high. Early experience in Europe using 12-month interferon-alpha combined with lamivudine only yielded a sustained viral suppression (undetectable by nonpolymerase chain reaction assay) rate of approximately 15 % at 6–12 months post-treatment [2, 3]. With 12-month peginterferon alfa-2a with/without lamivudine combination in the phase III international trial for HBeAg-negative chronic hepatitis B, approximately 22.6 % of patients could achieve sustained viral suppression to ≤10,000 copies/ml at 3-year post-treatment [4]. Owing to the inconvenient subcutaneous route of administration, potential adverse effects, and a high drug cost of peginterferon, one should select patients who have a higher chance of response to the peginterferon therapy. On the other hand, peginterferon is not preferred or should be stopped earlier if the chance of response is too low.
                  On post hoc analysis of the phase III trial of peginterferon alfa-2a (with/without lamivudine combination), HBeAg-negative patients at a younger age and those who had lower HBV DNA at baseline had a higher chance of achieving a response, which was defined as HBV DNA ≤20,000 copies/ml at 24-week post-treatment [5]. Patients infected by genotype C HBV also have a better response than those infected by genotype D HBV. Nonetheless, the differences in response between patients with different baseline predictive factors were too small to guide patient selection for treatment. For example, the mean baseline HBV DNA was 7.1 log copies/ml among responders versus 7.5 log copies/ml among relapsers. Better response predictors for peginterferon treatment are therefore warranted.
                  Serum hepatitis B surface antigen (HBsAg) quantification is a very hot topic of research in recent years. The level of serum HBsAg has been shown to reflect the level and transcriptional activity of covalently closed circular (ccc) DNA [6]. However, among HBeAg-negative patients, the relationship between serum HBsAg level and cccDNA is much weaker than that in HBeAg-positive patients [7]. The exact reason for this observation is uncertain, but could be related to the production of HBsAg by integrated HBV surface gene fragments in the host chromosome or the uncoupling on the regulation of HBsAg and HBV DNA production after HBeAg seroconversion. Nonetheless, in natural history studies, a lower HBsAg level is associated with inactive hepatitis [8, 9] and a higher chance of spontaneous seroclearance of HBsAg [10], suggesting that a lower HBsAg level is associated with better immune control of the virus.
                  In this issue of the Journal, Marcellin et al. [11] reported the use of serum HBsAg as the on-treatment response predictor to peginterferon alfa-2a with/without lamivudine combination in HBeAg-negative patients. This was a subgroup analysis of 120 patients who had HBsAg levels available for analysis among the original cohort of 230 patients in the phase III trial. Efficacy in terms of HBV DNA ≤2,000 IU/ml and HBsAg seroclearance at 1 and 5 years post-treatment were assessed as endpoints. Baseline HBsAg at a cut-off of 5,000 IU/ml had positive and negative predictive values of 34 and 78 % for the HBV DNA response at 1 year and 30 and 80 % for the HBV DNA response at 5-year post-treatment, respectively. A ≥10 % reduction in the log HBsAg level at weeks 12 and 24 could predict post-treatment responses to peginterferon. Comparing patients who had ≥10 versus <10 % reduction in log HBsAg at week 24, 35.8 versus 13.2 % of patients had an HBV DNA level of ≤2,000 IU/ml and 22.4 versus 3.8 % of patients had HBsAg seroconversion at 5-year post-treatment.
                  Based on the results of this study, the HBsAg level at baseline is not good enough as a stand-alone marker to guide patient selection for peginterferon treatment [11]. In this study, the investigators have not explored whether the HBsAg level has any additional value to the conventional baseline predictive factors such as age, HBV DNA level, and HBV genotype. In natural history studies among untreated patients, an HBsAg level of <1,000 IU/ml seems to be a prerequisite and an HBsAg level of <100 IU/ml is a good predictor of HBsAg seroclearance [10]. Furthermore, patients who have an HBV DNA level of <2,000 IU/ml and an HBsAg level of <100 IU/ml have the highest chance of clearing HBsAg in subsequent years of follow-up. It is therefore reasonable to believe that patients who have lower baseline HBV DNA and HBsAg levels will have a stronger immune response to the peginterferon therapy. Future research is needed to explore whether the addition of baseline serum HBsAg quantification can improve the prediction of response to peginterferon in HBeAg-negative patients.
                  From the experience of HBeAg-positive chronic hepatitis B, HBsAg level is a useful on-treatment monitoring tool to predict the response to peginterferon. In essence, a lower absolute HBsAg level at weeks 12 and 24 of peginterferon therapy is associated with a higher chance of sustained HBeAg seroconversion post-treatment [12]. In the current report by Marcellin et al. [11], a ≥10 % reduction in log HBsAg at weeks 12 and 24 was found to be the best predictor of the post-treatment response, but no absolute HBsAg level could be identified as a useful response predictor. Similarly, a small study in France also found that an early reduction of the HBsAg level by 0.5 log IU/ml, but not an absolute HBsAg level, could predict the virological response 6-month post-treatment [13]. The reason behind the conflicting observations between HBeAg-positive and HBeAg-negative patients is largely unknown. One possibility is a very wide range of HBsAg levels in HBeAg-negative patients; some patients can have a very low HBsAg level but yet active disease. In a previous report among 19 HBeAg-negative patients with active disease (elevated ALT and/or HBV DNA >10,000 copies/ml), the HBsAg level could range from 1.57 to 3.85 log IU/ml [14]. In another case series, the range of the HBsAg level among 46 HBeAg-negative patients with elevated ALT varied from −0.42 to 4.09 log IU/ml [8]. The relative lack of relationship between HBsAg level and disease activity might reflect an uncoupling of HBV DNA and HBsAg production in the HBeAg-negative phase. In line with natural history studies, a reduction in HBsAg is probably reflecting a stepping up of immune clearance [8], which is a logical predictor of response to peginterferon therapy in HBeAg-negative patients.
                  In a multicenter European study among 107 HBeAg-negative patients, the absence of an HBsAg decline together with an HBV DNA decline of <2 log at week 12 could predict the nonresponse to peginterferon with a 100 % negative predictive value, and this was suggested to be a stopping rule [15]. This European study composed of predominantly genotype D HBV infected patients, and this stopping rule has been externally validated by two other cohorts of predominantly genotype D HBV infected patients [16]. Whether the same rule holds true for patients infected with other HBV genotypes requires future studies to validate. In the current study by Marcellin et al. [11], as there were only 58 patients who received peginterferon monotherapy while the remaining patients had lamivudine combination, the small sample size rendered it difficult to assess the role of on-treatment HBV DNA as a predictor of response to peginterferon. With an HBsAg reduction of <10 % at week 24, 13.2 % patients could still achieve HBV DNA level of ≤2,000 IU/ml and 3.8 % patients could clear HBsAg at 5-year post-treatment. Therefore, a reduction of HBsAg by <10 % on-treatment is not a good stopping rule for peginterferon in HBeAg-negative patients.
                  In summary, Marcellin et al. have defined serum HBsAg level as an on-treatment predictor of the sustained response to peginterferon in HBeAg-negative patients. Although a ≥10 % reduction in HBsAg on-treatment can predict a long-term post-treatment response, it is insufficient to guide the regime of the peginterferon therapy. Future research should focus on how to integrate serum HBsAg into the currently available markers to improve patient selection and guide the treatment for peginterferon therapy in HBeAg-negative patients.

[N.B. emphasis are mine]

StephenW

在慢性乙型肝炎病毒（HBV）感染，B型肝炎e抗原（HBeAg）血清转换通常表明宿主的免疫清除。然而，约30％的患者，仍然有活跃的病毒血症和波动性丙氨酸氨基转移酶（ALT）水平在HBeAg阴性的阶段[1]。这些HBeAg阴性慢性乙型肝炎患者可能有病毒的免疫逃逸的进一步尝试干扰素的免疫调节剂治疗可能会有困难，治疗后复发率很高。早期的经验，在欧洲仅使用12个月，α-干扰素联合拉米夫定产生持续的病毒抑制率（nonpolymerase链反应检测不到）的约15％在6-12个月后治疗[2，3]。在12个月的聚乙二醇干扰素α-2a的/无HBeAg阴性慢性乙型肝炎的拉米夫定组合在第三阶段的国际审判中，约22.6％的患者获得持续的病毒抑制到≤10000拷贝/ ml在3年后处理[4]。由于不方便皮下给药途径，可能造成的不利影响，聚乙二醇干扰素和药物费用高，患者应该选择谁的聚乙二醇干扰素治疗的反应有较高的机会。另一方面，聚乙二醇化是不优选的或应该被停止之前的，如果响应的机会是太低。
在聚乙二醇干扰素α-2a干扰素（有/无拉米夫定组合），在年轻的时候，和那些有较低的HBV DNA的基线，HBeAg阴性患者的III期临床试验的事后分析，有较高的机会，这是实现响应在为期24周的治疗后[5]定义为HBV DNA≤20,000拷贝/ ml。 C基因型HBV感染的患者，也有更好的反应比D基因型HBV感染者。然而，不同的基线预测因素的患者反应之间的差异太小，指导病人选择治疗。例如，平均基线HBV DNA为7.1日志拷贝/ ml之间为7.5日志拷贝/ ml之间复发患者反应。因此，保证更好的响应预测聚乙二醇干扰素治疗。
血清乙肝表面抗原（HBsAg）定量研究是一个非常热门的话题，在最近几年。血清HBsAg的水平，已经显示出，以反映共价闭合环状的水平和转录活性（CCC）DNA [6]。然而，在HBeAg阴性患者中，血清HBsAg水平与cccDNA之间的关系是弱得多，在HBeAg阳性患者[7]。这个观察的确切原因是不确定的，但可能与乙肝表面抗原整合型HBV的表面基因片段HBsAg和HBeAg血清转换后的HBV DNA生产的调节宿主的染色体或解偶联生产。然而，在自然史研究，HBsAg水平较低，相关与非活动性[8，9]和较高的机会自发转阴，乙肝表面抗原[10]，这表明，HBsAg水平较低，具有较好的免疫控制病毒的相关。
在这个问题上的杂志，Marcellin等。 [11]报道​​了使用上的聚乙二醇干扰素α-2a治疗反应的预测有/无拉米夫定组合在HBeAg阴性患者血清HBsAg。这120例患者的HBsAg水平可用于分析之间的原始队列的230例患者的III期临床试验的亚组分析。为端点功效的HBV DNA≤2,000 IU / ml和乙肝表面抗原转阴1年和5年治疗后进行了评估。在截止为5000 IU / ml的基线乙肝表面抗原阳性和阴性预测值分别为34和78％，分别在5年治疗后HBV DNA反应，1年和30至80％的HBV DNA反应。 A≥10％，减少在日志中HBsAg水平可以预测在12周和24周聚乙二醇干扰素治疗后的反应。比较患者有≥10比减少10％在第24周时乙肝表面抗原的日志，35.8与13.2％的患者HBV DNA水平≤2,000 IU / ml和22.4比3.8％的患者在5年后HBsAg血清转换处理。
根据本研究的结果，在基线HBsAg水平不够好，作为一个独立的标记，以引导患者选择聚乙二醇干扰素治疗[11]。在这项研究中，研究人员还没有探讨HBsAg水平是否有任何额外的价值与传统的基线预测因素，如年龄，HBV DNA水平，HBV基因型。在未经治疗的患者中，HBsAg水平的自然史研究<1,000 IU / ml的似乎是一个先决条件和HBsAg水平<100 IU / ml的乙肝表面抗原转阴是一个很好的预测[10]。此外，患者有HBV DNA水平<2,000 IU / ml和HBsAg水平<100 IU / ml的机会最高结算的乙型肝炎表面抗原（HBsAg），在随后的几年跟进。因此，有理由相信，谁的病人有较低的基线HBV DNA和HBsAg水平将具有更强的免疫反应的聚乙二醇干扰素治疗。未来的研究需要探讨是否增加可以提高预测的聚乙二醇化干扰素在HBeAg阴性患者的基线血清HBsAg定量。
从经验的HBeAg阳性慢性乙型肝炎，乙肝表面抗原水平是一个有用的治疗监测的工具来预测聚乙二醇干扰素的反应。在本质上与持续HBeAg血清转换的机会较高，较低的绝对HBsAg水平在12和24周的聚乙二醇干扰素治疗后治疗[12]。在本报告中Marcellin等。 [11]，A≥10％，减少日志乙肝表面抗原被发现是在12周和24周后治疗反应的最佳预测指标，但没有绝对的HBsAg水平可确定为一个有用的反应预测。同样，在法国的一个小的研究还发现，早期的HBsAg水平下降0.5日志IU /毫升，但不是绝对的HBsAg水平，可预测的病毒学应答6个月的治疗后[13]。 HBeAg阳性和HBeAg阴性患者之间冲突的意见背后的原因，很大程度上是未知的。一种可能性是一个非常广泛的HBeAg阴性患者的HBsAg水平，部分患者可有一个非常低的HBsAg水平，但积极的疾病。在以前的报告在19 HBeAg阴性患者，活动性疾病（ALT升高和/或HBV DNA> 10,000拷贝/毫升），HBsAg水平范围为1.57至3.85日志IU / ml的[14]。在另一起案件系列，ALT升高46例HBeAg阴性患者的HBsAg水平之间的范围为-0.42到4.09日志IU / ml的[8]。 HBsAg水平与疾病的活动性可能反映HBV DNA的解偶联及乙型肝炎病毒表面抗原在HBeAg阴性阶段的生产关系相对不足。在与自然史研究中的乙型肝炎表面抗原（HBsAg），减少可能反映了，加强免疫清除[8]，这是一个合乎逻辑的预测聚乙二醇干扰素治疗HBeAg阴性患者的反应。
在107例HBeAg阴性患者，乙肝表面抗原下降12周时HBV DNA下降<2个100％的阴性预测值，预测聚乙二醇干扰素无应答的情况下，这是建议中的一项多中心欧洲研究停止规则[15]。这家欧洲的主要是D基因型HBV感染的患者，和这个停止的规则组成的研究主要是D基因型HBV感染患者的另外两个同伙已经从外部验证[16]。相同的规则是否适用与其他HBV基因型感染的患者，需要未来的研究来验证。在目前的研究由Marcellin等。 [11]，只有58例，而其余患者接受聚乙二醇干扰素单药治疗拉米夫定组合，小样本的大小使其难以估量的作用，对治疗HBV DNA的预测聚乙二醇干扰素的反应。在第24周时乙肝表面抗原减少<10％，有13.2％的患者仍然可以达到HBV DNA水平≤2,000 IU /毫升和3.8％的患者在5年治疗后可以清除乙肝表面抗原。因此，降低<10％的治疗乙肝表面抗原是不是一个很好的停止规则的聚乙二醇化干扰素在HBeAg阴性患者。
综上所述，Marcellin等。已定义的血清HBsAg水平在HBeAg阴性患者接受长效干扰素的持续性反应的处理预测。 ≥10％，减少乙肝表面抗原的治疗虽然可以预测长期治疗后反应，这是不够的聚乙二醇干扰素治疗指导制度。今后的研究重点应放在如何整合到目前可用的标记，以改善病人的选择和指导治疗的聚乙二醇干扰素治疗HBeAg阴性患者的血清HBsAg。

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