Hepatitis B Virus (HBV) Core-Related Antigen During Nucleos(t)ide Analog Therapy Is Related to Intra-hepatic HBV Replication and Development of Hepatocellular Carcinoma
Hepatitis B Virus (HBV) Core-Related Antigen During Nucleos(t)ide Analog Therapy Is Related to Intra-hepatic HBV Replication and Development of Hepatocellular Carcinoma
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DOI：
10.1093/infdis/jiv572
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发表时间：
2016-04-01
影响因子：
6.4
通讯作者：
Kaneko, Shuichi
中科院分区：
文献类型：
--
作者：
Honda, Masao;Shirasaki, Takayoshi;Kaneko, Shuichi
背景虽然核苷（酸）类似物（NA）治疗有效地降低了慢性B型肝炎患者血清中的B型肝炎病毒（HBV）DNA载量，但并不能完全降低肝细胞癌（HCC）的发病率。共109例慢性B型肝炎患者接受NA治疗进行了分析。多变量考克斯回归分析显示，年龄（> 60岁，风险比[HR]为2.66）、FIB-4指数（指数> 2.1，风险比为2.57）和治疗期间HBV核心相关抗原（HBcrAg; HR，3.53）的存在与HCC的发生显著相关。16例HBcrAg阳性患者肝组织中HBV DNA和前基因组RNA的含量显著高于12例HBcrAg阴性患者，提示HBcrAg阳性肝组织中HBV复制活跃。肝脏基因表达谱显示，HBV促进转录因子，包括HNF 4 α，PPAR α和LRH 1，在HBcrAg阳性的肝脏上调。在长期暴露于恩替卡韦期间，过表达LRH 1的HepAD 38细胞增加了HBV复制，其特征是HBV DNA和前基因组RNA水平较高。相反，在HepG 2细胞中过表达前核心/核心增加了这些转录因子的水平。二甲双胍有效抑制HBV在原代人肝细胞中的复制。二甲双胍联合NA治疗调节HBV转录因子可增强抗HBV活性，降低HBcrAg阳性患者的HCC发病率。
Background. Although nucleos(t) ide analog (NA) therapy effectively reduces the hepatitis B virus (HBV) DNA load in the serum of patients with chronic hepatitis B, it does not completely reduce the incidence of hepatocellular carcinoma (HCC).Methods and Results. A total of 109 patients who had chronic hepatitis B and were receiving NA therapy were analyzed. Multivariate Cox regression analysis showed that age (> 60 years had a hazard ratio [HR] of 2.66), FIB-4 index (an index of > 2.1 had a HR of 2.57), and the presence of HBV core-related antigen (HBcrAg; HR, 3.53) during treatment were significantly associated with the development of HCC. The amount of HBV DNA and pregenomic RNA in liver were significantly higher in 16 HBcrAg-positive patients, compared with 12 HBcrAg-negative patients, suggesting active HBV replication in HBcrAg-positive livers. Hepatic gene expression profiling showed that HBV-promoting transcriptional factors, including HNF4 alpha, PPAR alpha, and LRH1, were upregulated in HBcrAg-positive livers. HepAD38 cells overexpressing LRH1 increased HBV replication, characterized by higher HBV DNA and pregenomic RNA levels, during long-term exposure to entecavir. Conversely, overexpression of precore/core in HepG2 cells increased levels of these transcriptional factors. Metformin efficiently repressed HBV replication in primary human hepatocytes.Conclusions. Modulating HBV transcriptional factors by metformin in combination with NA therapy would potentiate anti-HBV activity and reduce the incidence of HCC in HBcrAg-positive patients.