乙肝表面抗原定量跨越慢性HBV感染不同阶段

StephenW

HBsAg Quantification Across Different Phases of Chronic HBV Infection
Chung KH, Kim W, Kim BG, et al. Hepatitis B Surface Antigen Quantification across Difference Phases of Chronic Hepatitis B Virus Infection Using an Immunoradiometric Assay. Gut Liver. 2015 Sep;9(5):657–664


   
The disease course of hepatitis B is divided into phases based on the immune response to the infection.1 These include the immune-tolerant phase, immune-clearance phase, immune-reactive phase, low-replicative phase, and the reactivation phase.2 Other phase characterizations are also noted in the literature. Patients may move from phase to phase, return to a prior phase, or skip or never enter a particular phase. Thus, individual patient categorization is difficult, especially without longitudinal evaluation of markers. Several studies have looked at the HBsAg quantification as a marker for disease activity as well as for response to treatment.3-6

HBsAg is synthesized in the hepatocytes infected with hepatitis B, and its serum concentration correlates to the amount of intrahepatic covalently closed circular DNA (ccc-DNA). This article looks at the relation of HBsAg serum load and the HBV DNA during the various phases of chronic HBV infection. The use of HBsAg as a marker of treatment response is also examined.

The authors quantified serum HBsAg levels of 785 patients at the Seoul Metropolitan Government Seoul National University Boramae Medical Center over a period of seven months. Of these, 534 test results were included in the analysis. Definitions of the four phases of CHB were adopted from EASL guidelines: immunotolerant (IT), immunoreactive (IR), low replicative (LR) and HBeAg-negative chronic HBV (ENH). Definitions of response to treatment were determined based on the HBeAg status as well as the degree of decrease in HBsAg.

All subjects were Asian, and 64.3% were male. Samples were divided into eight groups, based on their treatment status (IT, IR, LR, ENH) for the treated vs untreated patients, and their titers were compared. The HBsAg titer was higher in patients in IT compared to those in IR phase (P = .043). However, no difference was noted in patients in LR compared to ENH phases. Virologic response was defined as undetectable HBV DNA, while partial response was defined as decrease in HBV DNA of more than 1 log10 IU/ml. In the treatment groups, HBsAg titers in HBeAg+ patients with virologic response (E+VR) were much lower than in those with partial response (E+pVR; P = .027). For HBeAb negative patients with virologic response (E-VR), titers of HBsAg were significantly lower than those for HBeAg negative patients with partial response (E-pVR; P = .009). Comparing different phases, HBsAg titers were higher in the IT and IR phases compared to low replicative (LR) and ENH groups (P < .001). Between the eAg+ and eAg- groups, HbsAg titers were higher in the former (P < .001).

A correlation was noted between the HbsAg and the HBV DNA in the IT and IR phases P < .001), but not in the LR or the ENH phases. No correlation was noted between the two in all types of the treatment response groups as described above.

HbsAg decreased gradually with each 10-year patient age stratum (P < .001) and was five times higher in noncirrhotic patients than in those with cirrhosis (P < .001) when divided into patients older or younger than 60 years. Similar trends were seen when comparing patients without HCC (higher titers) compared to those with HCC, though the trend was only statistically significant in patients older than 60 years.

There is evidence to suggest that the concentration of HBsAg decreases with increasing fibrosis and varies from genotype to genotype.7 The relationship of the HBsAg to various phases, as well as the drop in HBsAg and the HBV DNA titers as predictors of response, have also been outlined in previous studies.8 Although there is a clear correlation to phases of disease, clear cutoffs were not assigned and receiver-operator curves of sensitivity/specificity were not provided. However, this work leading to more precisely characterizing disease stages has significant implications for decisions about treatment candidacy and in treatment-intervention clinical trials. In the future, the HBsAg quantification may become a routine part of monitoring disease activity as well as the response to treatment.



References:

1. Lok AS, Lai CL. A longitudinal follow-up of asymptomatic hepatitis B surface antigen-positive Chinese children. Hepatology. 1988;8:1130-1133.

2. Sarin SK, Kumar M, Lau GK, et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int. 2016 Jan;10(1):1–98.doi: 10.1007/s12072-015-9675-4.

3. Boyd A, Maylin S, Moh R, et al. Hepatitis B surface antigen quantification as a predictor of seroclearance during treatment in HIV-hepatitis B virus coinfected patients from Sub-Saharan Africa. J Gastroenterol Hepatol. 2016 Mar;31(3):634-644.

4. Kuo YH, Chang KC, Wang JH, et al. Changing serum levels of quantitative hepatitis B surface antigen and hepatitis B virus DNA in hepatitis B virus surface antigen carriers: a follow-up study of an elderly cohort. Kaohsiung J Med Sci. 2015;31:102–107

5. Suh SJ, Bae SI, Kim JH, Kang K, Yeon JE, Byun KS. Clinical implications of the titer of serum hepatitis B surface antigen during the natural history of hepatitis B virus infection. J Med Viro., 2014;86:117–123.

6. Park H, Lee JM, Seo JH, et al. Predictive value of HbsAg quantification for determining the clinical course of genotype C HBeAg-negative carriers. Liver Int. 012;32:796–802.

7. Goyal SK, Jain AK, Dixit VK, et al. HBsAg Level as Predictor of Liver Fibrosis in HBeAg Positive Patients With Chronic Hepatitis B Virus Infection. J Clin Exp Hepatol. 2015 Sep;5(3):213-20. doi: 10.1016/j.jceh.2015.04.008. Epub 2015 May 27.

8. Martinot-Peignoux M, Lapalus M, Asselah T, Marcellin P. HBsAg quantification: useful for monitoring natural history and treatment outcome

StephenW

乙肝表面抗原定量跨越慢性HBV感染不同阶段
钟KH，金宽，金BG等。乙肝表面抗原定量跨越慢性乙型肝炎病毒感染的差异阶段使用免疫分析。肠肝。 2015年9月; 9（5）：657-664


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乙型肝炎的病程分为基于到infection.1免疫应答相这些包括免疫耐受期，免疫清除期，免疫反应相，低复制阶段，并且重新激活phase.2其他相刻画在文献中还指出。患者可能从第一阶段转向阶段，返回到前阶段，或跳过或从未进入特定阶段。因此，个别病人的分类是困难的，尤其是没有标记的纵向评估。几项研究在HBsAg的定量作为疾病活动的标记已经看过以及用于响应于treatment.3-6

的HBsAg在感染乙型肝炎的肝细胞合成的，其血清浓度相关肝内共价闭合环状DNA（CCC-DNA）的量。本文着眼于血清乙肝表面抗原负载和HBV DNA的慢性HBV感染的各个阶段的关系。作为治疗反应的标记物的用途的HBsAg也检查。

作者历时七个月量化的785例患者血清HBsAg水平在首尔市政府首尔国立大学Boramae医疗中心。这些中，534测试结果包括在分析中。 CHB的四个阶段的定义从EASL准则获得通过：免疫耐受（IT），免疫反应（IR），低复制（LR）和HBeAg阴性慢性乙肝病毒（ENH）。对治疗的反应的定义进行了测定基础上，HBeAg状态，以及降低在HBsAg的程度。

所有受试者都是亚裔，64.3％为男性。样品分为8组，是根据他们的治疗状态（IT，红外，LR ENH）用于处理的相对于未经治疗的患者，他们的滴度进行了比较。相比那些在IR期（P = 0.043）患者在它的HBsAg滴度较高。但是，没有差异患者LR相比ENH阶段被记录在案。病毒学应答定义为检测不到HBV DNA，而局部响应被定义为超过1 log10的国际单位/毫升的HBV DNA减少。在治疗组，在e抗原的HBsAg滴度+患者的病毒学应答（E + VR）比在那些与部分响应低得多（E + PVR; P = 0.027）。对于抗 - HBe阴性患者病毒学应答（E-VR），乙肝表面抗原滴度均较HBeAg阴性患者部分缓解显著降低（E-PVR; P = 0.009）。比较不同阶段，乙肝表面抗原滴度比较低复制（LR）和ENH组（P <0.001），在IT和IR阶段更高。东亚运动会+和eAg-群体之间，乙型肝炎表面抗原滴度前（P <0.001）高。

一个相关讨论中指出，乙肝表面抗原和HBV DNA在IT和IR阶段P <0.001）之间，而不是在LR或ENH阶段。没有相关性的所有类型的治疗的反应基团的两个之间注意到如上所述。

乙型肝炎表面抗原每10年患者年龄层（P <0.001）逐渐下降，是五高于非肝硬化患者比那些肝硬化倍（P <0.001），当分为老年患者或小于60岁。比较例时无肝癌（较高滴度）相比，那些与肝癌类似的趋势看出，尽管趋势是仅在病人60岁以上统计学显著。

有证据表明，HBsAg的浓度随纤维化降低，并且从基因型变化到genotype.7所述的HBsAg到各个阶段的关系，以及在HBsAg和乙型肝炎病毒DNA滴度作为应答的预测下降，有也在以前的studies.8中概述尽管对疾病的阶段明确的相关性，清晰截断未被分配和灵敏度的接收器的操作员的曲线/不提供特异性。然而，这项工作导致更精确地表征疾病阶段有关于治疗和候选人治疗干预的临床试验的决定显著影响。在将来，HBsAg的定量可能成为监测疾病活动的常规部分以及对治疗的反应。



参考文献：

1.乐AS，赖CL。纵向后续无症状乙肝表面抗原阳性的中国儿童。肝病。 1988; 8：1130至1133年。

2.沙林SK，库马尔男，刘GK等。亚洲太平洋乙型肝炎的管理临床实践指南：2015年更新。肝脏病诠释。 2016年一月; 10（1）：1-98.doi：10.1007 / s12072-015-9675-4。

3.博伊德A，Maylin S，莫R等人。乙肝表面抗原定量转阴如在HIV乙肝病毒合并感染的患者从撒哈拉以南非洲治疗期间的预测。 ĴGastroenterol肝脏病。 2016年3月; 31（3）：634-644。

4.郭YH，张KC，王建华，等。改变定量乙肝表面抗原和乙肝病毒DNA血清中乙肝病毒表面抗原携带者：老人队列研究的后续研究。高雄医学杂志科学。 2015年; 31：102-107

5.徐SJ，裴SI，金JH，康K，妍JE，卞KS。乙型肝炎病毒感染的自然史中血清乙肝表面抗原的效价的临床意义。医学杂志VIRO，2014年; 86：117-123。

6.公园H，李JM，徐JH，等。确定C基因型的HBeAg阴性，临床病程乙肝表面抗原定量的预测价值。肝诠释。 012; 32：796-802。

7.戈亚尔SK，耆那教的AK，迪克西特VK等。乙肝表面抗原水平，肝纤维化的预测HBeAg阳性慢性乙型肝炎患者HBV感染。 Ĵ临床实验肝脏病。 2015年9月; 5（3）：213-20。 DOI：10.1016 / j.jceh.2015.04.008。 EPUB 2015年5月27日。

8.马丁诺特-Peignoux男，Lapalus男，Asselah T，Marcellin P.的HBsAg定量：用于监控自然史和治疗结果有效