Objective: To retrospectively analyze the serological, virological, biochemical, liver histological status and clinical outcomes in HBeAg-negative chronic hepatitis B (CHB) patients with low HBV viral load, and to explore the necessity of antiviral therapy for these patients. Methods: A total of 99 HBeAg-negative CHB patients with HBV DNA level < 4 lg copies/ml who performed liver biopsy at the baseline were enrolled from the follow-up cohort. Among them, 23 cases received the second liver biopsy during follow-up. The relationships among the degree of inflammation and fibrosis of liver tissues, the status of HBsAg and HBcAg, age, gender, family history, HBV DNA load, serological markers and other indicators were analyzed. The pathological differences between two liver biopsy examinations were compared. The effect of nucleos(t)ide analogues (NAs) treatment on patient's clinical outcomes were analyzed. For multivariate analysis, a binary logistic regression model was performed. Log-rank test was used to compare the cumulative incidence of hepatocellular carcinoma (HCC) in NAs-treated and non-NA streated patients. Results: Baseline liver histology status showed that 58.6% (58/99) patients had obvious liver tissue damage in their baseline liver tissue pathology (G≥2 and /or S≥2). Univariate logistic regression analysis showed that a liver cirrhosis (LC) family history, a HBsAg-positive family history, baseline alanine aminotransferase and aspartate aminotransferase levels were positively correlated factors for liver tissue damage. Multivariate logistic regression analysis showed that a LC family history was the main risk factor for liver tissue damage. Twenty-three cases had received a second liver biopsy after an interval of 4.5 years. In 10 untreated cases, the second liver biopsy results showed the rate of obvious liver tissue damage (G≥2 and/ or S≥2) increased from 50.0% to 90.0%. In the other 13 cases who received NAs treatment, the second liver biopsy showed improvement in liver histology, and the rate of obvious liver tissue damage decreased from 61.5% to 46.2%. The 5-year HCC cumulative incidence in non-NAs-treated patients was significantly higher than that of in NAs-treated patients (17.7% vs. 3.8%, P = 0.046). Conclusion: For most HBeAg-negative CHB patients with low viral load, liver tissue pathology result suggests that it meets the indications for antiviral therapy, especially in patients with a LC familial history. Without antiviral therapy, liver tissue damage for these patients will progressively worse with the high incidence of HCC. Therefore, it is suggested that antiviral therapy should be started as soon as possible for the HBeAg-negative CHB patients with low viral load regardless of the alanine aminotransferase level, especially in patients over 30 years-old with a LC or HCC family history.
目的： 回顾性分析HBeAg阴性的HBV DNA低病毒载量慢性乙型肝炎（CHB）患者的血清学、病毒学、生物化学及肝组织学状态及其临床转归，探讨HBeAg阴性低病毒载量的CHB患者抗病毒治疗的必要性。 方法： 从慢性HBV感染者随访队列中纳入HBV DNA水平< 4 lg拷贝/ml，并做肝活组织病理检查的99例HBeAg阴性的CHB患者，其中23例做了第二次肝活组织病理检查。分析患者肝组织炎症、纤维化程度及肝细胞HBsAg和HBcAg状态与年龄、性别、家族史、HBV DNA载量、血清学标志物等指标的关系。比较两次肝活组织病理检查病理肝组织学差异。分析核苷（酸）类似物（NAs）治疗对患者转归的影响。多因素分析采用二分类logistic回归模型，Log-Rank检验比较未NAs治疗患者与NAs治疗患者的肝细胞癌（HCC）累计发生率。 结果： 基线肝组织学状况：58.6%（58/99）患者肝组织病理达到明显肝组织损伤（G≥2和/或S≥2）；单因素logistic回归分析显示肝硬化（LC）家族史、HBsAg阳性家族史、丙氨酸转氨酶、天冬氨酸转氨酶四个因素与明显肝组织损伤呈正相关，多因素logistic回归显示的LC家族史是患者明显肝组织损伤（G≥2和/或S≥2）的主要危险因素。23例患者间隔4.5年行第二次肝活组织病理检查，其中10例未治疗的患者第二次肝活组织病理检查肝组织学有进展，明显肝组织损伤从50.0%上升到90.0%，另13例NAs治疗后第二次肝活组织病理检查肝组织学有改善，明显肝组织损伤从61.5%下降到46.2%。未抗病毒治疗患者5年HCC累计发生率显著高于NAs治疗患者（17.7%对比3.8%，P = 0.046）。 结论： HBeAg阴性低病毒载量的CHB患者，大多数肝活组织病理检查达到抗病毒指征，尤其是有LC家族史的患者，不抗病毒治疗肝组织损伤进行性加重、HCC发生率高；建议HBeAg阴性低病毒载量的CHB患者，尤其是年龄大于30岁、有LC或HCC家族史的患者，无论丙氨酸转氨酶水平如何，应该及早启动抗病毒治疗。.
Keywords: Hepatic histological fibrosis; Hepatic histological inflammation grades; Hepatitis B, chronic; Hepatocellular carcinoma; Nucleoside (acid) analogues.