Department of Research and Molecular Development, Victorian Infectious Diseases Reference Laboratory, North Melbourne, Victoria, Australia.
Hepatology. 2010 Jun;51(6):1933-44. doi: 10.1002/hep.23571.
Although threshold levels for hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) titers have recently been proposed to guide therapy for chronic hepatitis B (CHB), their relationship to circulating hepatitis B virus (HBV) DNA and intrahepatic HBV replicative intermediates, and the significance of emerging viral variants, remains unclear. We therefore tested the hypothesis that HBsAg and HBeAg titers may vary independently of viral replication in vivo. In all, 149 treatment-naïve CHB patients were recruited (HBeAg-positive, n = 71; HBeAg-negative, n = 78). Quantification of HBeAg and HBsAg was performed by enzyme immunoassay. Virological characterization included serum HBV DNA load, HBV genotype, basal core promoter (BCP)/precore (PC) sequence, and, in a subset (n = 44), measurement of intrahepatic covalently closed circular DNA (cccDNA) and total HBV DNA, as well as quantitative immunohistochemical (IHC) staining for HBsAg. In HBeAg-positive CHB, HBsAg was positively correlated with serum HBV DNA and intrahepatic cccDNA and total HBV DNA (r = 0.69, 0.71, 0.76, P < 0.01). HBeAg correlated with serum HBV DNA (r = 0.60, P < 0.0001), although emerging BCP/PC variants reduced HBeAg titer independent of viral replication. In HBeAg-negative CHB, HBsAg correlated poorly with serum HBV DNA (r = 0.28, P = 0.01) and did not correlate with intrahepatic cccDNA nor total HBV DNA. Quantitative IHC for hepatocyte HBsAg confirmed a relationship with viral replication only in HBeAg-positive patients.
The correlation between quantitative HBsAg titer and serum and intrahepatic markers of HBV replication differs between patients with HBeAg-positive and HBeAg-negative CHB. HBeAg titers may fall independent of viral replication as HBeAg-defective variants emerge prior to HBeAg seroconversion. These findings provide new insights into viral pathogenesis and have practical implications for the use of quantitative serology as a clinical biomarker.
尽管乙型肝炎表面抗原（HBsAg）和乙型肝炎 e 抗原（HBeAg）滴度的阈值水平最近被提议用于指导慢性乙型肝炎（CHB）的治疗，但它们与循环乙型肝炎病毒（HBV）DNA 和肝内 HBV 复制中间体的关系，以及新出现的病毒变异体的意义仍不清楚。因此，我们检验了这样一种假设，即 HBsAg 和 HBeAg 滴度可能与体内病毒复制无关。共招募了 149 名未经治疗的 CHB 患者（HBeAg 阳性，n=71；HBeAg 阴性，n=78）。通过酶免疫分析法检测 HBeAg 和 HBsAg 的定量。病毒学特征包括血清 HBV DNA 载量、HBV 基因型、基本核心启动子（BCP）/前核心（PC）序列，以及亚组（n=44）测量肝内共价闭合环状 DNA（cccDNA）和总 HBV DNA，以及 HBsAg 的定量免疫组化（IHC）染色。在 HBeAg 阳性的 CHB 中，HBsAg 与血清 HBV DNA 和肝内 cccDNA 及总 HBV DNA 呈正相关（r=0.69、0.71、0.76，P<0.01）。HBeAg 与血清 HBV DNA 相关（r=0.60，P<0.0001），尽管出现 BCP/PC 变异体可独立于病毒复制降低 HBeAg 滴度。在 HBeAg 阴性的 CHB 中，HBsAg 与血清 HBV DNA 相关性差（r=0.28，P=0.01），与肝内 cccDNA 及总 HBV DNA 均无相关性。HBsAg 肝细胞定量 IHC 仅在 HBeAg 阳性患者中证实与病毒复制有关。
在 HBeAg 阳性和 HBeAg 阴性 CHB 患者中，HBsAg 定量滴度与血清和肝内 HBV 复制标志物之间的相关性不同。随着 HBeAg 缺陷型变异体在 HBeAg 血清学转换前出现，HBeAg 滴度可能独立于病毒复制而下降。这些发现为病毒发病机制提供了新的见解，并对定量血清学作为临床生物标志物的应用具有实际意义。
