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HBsAg clearance is considered the final goal of antiviral therapy and is associated with a better long-term prognosis, including the reduction of cirrhosis and HCC incidence [Trepo et al., 2014]. The study also demonstrated that, among all responders, patients who achieved HBsAg clearance exhibited a significant decline in HBsAg levels compared to those without HBsAg seroclearance. Specifically, responders with HBsAg clearance exhibited a greater decline of HBsAg by 4.4 log10, compared to 2.0 log10 in those without HBsAg clearance. In contrast, the mean reduction of intrahepatic cccDNA levels did not differ significantly between responders with or without HBsAg clearance (1.8 vs. 1.6 log10 copies/cEq, P = 0.780). The clarification of these discrepancies remains unknown but might be in part related to the small number of responders in this study. Alternatively, uneven distributions of cccDNA in various parts of the liver might also contribute to alterations in cccDNA quantification obtained by needle liver biopsy [Dandri and Locarnini, 2012]. In addition, molecular mechanisms regulating cccDNA activity, such as epigenetic modifications including histone acetylation and DNA methylation, appear to be complex [Nassal, 2015]. Whether these factors might influence the correlation between serum and intrahepatic viral markers needs further clarification. Of interest, small amount of intrahepatic cccDNA was detected in responders who achieved HBsAg seroclearance. These data are consistent with previous reports presenting low levels of cccDNA detectability in a high proportion of individuals who achieved HBsAg clearance spontaneously or following antiviral therapy [Yuen et al., 2008].
As a parallel decline of serum and intrahepatic, viral kinetics was documented in this report, the end-of-treatment reduction of serum HBsAg might represent an appropriate predictor of treatment response. In fact, the curve and reduction of quantitative HBsAg was the best predictor of eventual VR and HBsAg clearance in both HBeAg-positive and HBeAg-negative groups. Overall, patients who demonstrated at least 1.0 log10 drop of serum HBsAg levels could archive subsequent VR and HBsAg clearance of approximately 80% and 30 %, respectively. A greater reduction of serum HBsAg level might represent durable immune modulation, which in turn explains higher response rates in these patients. In line with this study, Brunetto et al. [2009] reported that on-treatment HBsAg decline >1.0 log10 IU/ml after receiving 48-week PEG-IFN-based therapy was associated with sustained viral suppression and a high probability of HBsAg clearance in patients with HBeAg-negative CHB.
There are some limitations in this study. First, the number of patients was relatively small considering the heterogeneity in gender, age, HBeAg status, and HBV genotypes. Thus, a larger sample size would increase the statistical power and reliability of the results. Second, we evaluated the distribution of HBV genotypes, but did not yet examine viral mutations such as variants in the preS/S genomic region. In fact, the emergence of these common mutants can cause dissociation between viral replicative and protein synthetic pathways, which in turn might influence the clinical utility of HBsAg quantification [Pollicino et al., 2012]. Whether the measurement of HBsAg levels is applicable in monitoring treatment response to PEG-IFN in patients harboring these mutants awaits further investigation. Moreover, it is of noted that a consensus or standard protocol in detecting intrahepatic cccDNA levels has not been well characterized [Lucifora and Protzer, 2016]. Thus, the quantification of cccDNA by other primers or methods is still needed to confirm these results. Additionally, monitoring of novel surrogate serum markers of intrahepatic cccDNA levels such as hepatitis B core-related antigen (HBcrAg), which represents a reliable predictor of HCC development [Tada et al., 2016], could also help in predicting outcome in patients with HBeAg-positive and HBeAg-negative CHB receiving PEG-IFN therapy.
In conclusion, the baseline correlation between quantitative serum HBsAg and intrahepatic markers differed between patients with HBeAg-positive and HBeAg-negative CHB. However, kinetics of serum HBsAg levels showed positive correlation with intrahepatic cccDNA levels in both groups of patients during PEG-IFN monotherapy. Thus, a reduction in serum HBsAg could reflect the efficacy of PEG-IFN in decreasing the levels of intrahepatic cccDNA and help predict therapeutic outcome. The data also showed that decline HBsAg at the end of treatment of at least 1.0 log10 IU/ml was strongly predictive for response. As the number of patients recruited in this report was restricted, further studies with larger sample sizes are warranted to confirm these observations.
HBsAg清除被认为是抗病毒治疗的最终目标，并具有更好的长期预后相关联，包括肝硬化和肝癌发病的减少[TREPO等人，2014年]。该研究还证明，在所有响应者中，实现HBsAg清除的患者与不具有HBsAg血清清除的那些相比显示出HBsAg水平的显着下降。具体来说，具有HBsAg清除率的反应者显示HBsAg的更大下降4.4log10，相比之下没有HBsAg清除的患者为2.0log10。与此相反，肝内的cccDNA水平平均降低没有显著应答之间具有或不具有HBsAg清除不同（1.8与1.6 log10拷贝/ CEQ，P = 0.780）。对这些差异的澄清仍然未知，但可能部分与本研究中响应人数较少有关。或者，肝脏各部分的cccDNA分布不均也可能有助于通过针肝活检获得的cccDNA定量的改变[Dandri和Locarnini，2012]。此外，调节cccDNA活性的分子机制，如包括组蛋白乙酰化和DNA甲基化的表观遗传修饰，似乎是复杂的[Nassal，2015]。这些因素是否可能影响血清和肝内病毒标志物之间的相关性需要进一步澄清。感兴趣的是，在获得HBsAg血清清除的应答者中检测到少量肝内cccDNA。这些数据与以前的报告中提出的个人比例高的cccDNA检测能力水平低谁取得HBsAg清除自发或以下的抗病毒治疗一致[玄等人，2008]。
随着血清和肝内的平行下降，在本报告中记录了病毒动力学，治疗结束时血清HBsAg的减少可能代表治疗反应的适当预测因子。事实上，定量HBsAg的曲线和减少是HBeAg阳性和HBeAg阴性组中最终VR和HBsAg清除率的最佳预测因子。总体而言，表现出至少1.0log 10血清HBsAg水平的患者可以分别归档随后的VR和HBsAg清除率约80％和30％。血清HBsAg水平的更大降低可以代表持久的免疫调节，这又解释了这些患者中更高的反应率。根据这项研究，Brunetto et al。 [2009]报道，接受48周PEG-IFN治疗后的治疗HBsAg下降> 1.0 log10 IU / ml与持续的病毒抑制和HBeAg阴性CHB患者中HBsAg清除的高概率相关。
本研究存在一些局限性。首先，考虑到性别，年龄，HBeAg状态和HBV基因型的异质性，患者数量相对较少。因此，较大的样本大小将增加结果的统计功效和可靠性。第二，我们评估了HBV基因型的分布，但尚未检查病毒突变，如前S / S基因组区域中的变体。事实上，这些常见突变体的出现可以导致病毒复制和蛋白质合成途径之间的分离，这反过来可能影响HBsAg定量的临床效用[Pollicino等，2012]。 HBsAg水平的测量是否适用于监测对携带这些突变体的患者对PEG-IFN的治疗应答，等待进一步研究。此外，值得注意的是，在检测肝内cccDNA水平的共识或标准方案尚未被很好地表征[Lucifora和Protzer，2016]。因此，仍需要通过其它引物或方法对cccDNA进行定量以证实这些结果。此外，监测肝内cccDNA水平的新型替代血清标志物如乙型肝炎核心相关抗原（HBcrAg），代表了HCC发展的可靠预测[Tada et al。，2016]，也有助于预测患者的预后HBeAg阳性和HBeAg阴性CHB接受PEG-IFN治疗。
总之，HBeAg阳性和HBeAg阴性CHB患者的定量血清HBsAg和肝内标志物之间的基线相关性不同。然而，在PEG-IFN单一治疗期间，两组患者血清HBsAg水平的动力学显示与肝内cccDNA水平的正相关。因此，血清HBsAg的减少可以反映PEG-IFN降低肝内cccDNA水平的功效，并有助于预测治疗结果。数据还显示在治疗结束时HBsAg下降至少1.0log 10 IU / ml是强烈预测应答。由于本报告中招募的患者数量有限，需要进行更大样本量的进一步研究以确认这些观察结果。
http://onlinelibrary.wiley.com/doi/10.1002/jmv.24601/full |
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发表于 2017-1-21 16:05
