Abstract：
Hepatitis B virus (HBV) infection is a dynamic disease where patients progress through several stages defined by HBV e-antigen (HBeAg) status, HBV-DNA levels and transaminase elevations, with antiviral therapy indicated only in specific stages. However, some patients cannot be classified into one of the stages and are said to fall into an \'indeterminate phase\' or \'grey zone\'. Exact definitions of the indeterminate phase vary from guideline to guideline as a result of different cut-off values for biomarker measurements. Data suggest that as many as 50% of HBV patients may be in an indeterminate phase and may not rapidly transition out of this phase. Clinical data that suggest these patients are at increased risk of hepatocellular carcinoma (HCC) are complemented by molecular evidence of integrations of HBV-DNA into the host genome, chromosomal translocations and immune activation despite liver enzymes that may suggest lack of inflammation. Antiviral therapy reduces these hepatocarcinogenic mechanisms and is reflected in a reduction of fibrosis and HCC risk. We review key data on patients in the indeterminate phase, with emphasis on HCC as an outcome. We take a holistic approach and link new biological data with clinical observations as well as examine the potential role of antiviral therapy in reducing HCC risk among patients in the indeterminate phase. With the availability of safe and effective oral antivirals, consideration must be given as to how much residual risk of HCC should be tolerated among patients in the indeterminate phase.
摘要：
乙型肝炎病毒（HBV）感染是一种动态疾病，患者通过HBVe抗原（HBeAg）状态定义的几个阶段进展，HBV-DNA水平和转氨酶升高，抗病毒治疗仅在特定阶段显示。然而,有些病人不能被归入其中一个阶段，据说属于“不确定阶段”或“灰色地带”。由于生物标志物测量的不同截止值，不确定阶段的确切定义因指南而异。数据表明，多达50％的HBV患者可能处于不确定的阶段，并且可能不会迅速过渡到这一阶段。临床数据表明这些患者的肝细胞癌（HCC）的风险增加，补充HBV-DNA整合到宿主基因组的分子证据，尽管肝酶可能表明缺乏炎症，但染色体易位和免疫激活。抗病毒治疗减少这些肝癌机制，并反映在纤维化和HCC风险的降低。我们回顾了不确定阶段患者的关键数据，强调HCC作为结果。我们采取整体方法，将新的生物学数据与临床观察联系起来，并研究抗病毒治疗在不确定阶段患者中降低HCC风险的潜在作用。有了安全有效的口服抗病毒药物,必须考虑在不确定阶段的患者中应该耐受多少HCC的残余风险。
