Liver biopsy of chronic hepatitis B patients indicates HBV integration profile may complicate the endpoint and effect of entecavir treatment

Mingyuan Zhang; Haikun Zhang; Xiaoming Cheng; Xiaomei Wang; Hongqin Xu; Xiuzhu Gao; Ruihong Wu; Dake Zhang; Yuchen Xia; Junqi Niu

doi:10.1016/j.antiviral.2022.105363

Liver biopsy of chronic hepatitis B patients indicates HBV integration profile may complicate the endpoint and effect of entecavir treatment

Antiviral Res. 2022 Aug:204:105363. doi: 10.1016/j.antiviral.2022.105363. Epub 2022 Jun 13.

Authors

Mingyuan Zhang¹, Haikun Zhang², Xiaoming Cheng³, Xiaomei Wang⁴, Hongqin Xu⁵, Xiuzhu Gao⁶, Ruihong Wu⁷, Dake Zhang⁸, Yuchen Xia⁹, Junqi Niu¹⁰

Affiliations

¹ Department of Hepatology, First Hospital of Jilin University, Changchun, 130021, PR China; Center for Pathogen Biology and Infectious Diseases, Department of Hepatology, Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, 130061, PR China. Electronic address: mingyuanzhang@jlu.edu.cn.
² Key Laboratory of Biomechanics and Mechanobiology, Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Engineering Medicine, Beihang University, Beijing, 100083, PR China. Electronic address: hkZhang@buaa.edu.cn.
³ State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, School of Basic Medical Sciences, Wuhan University, Wuhan, PR China. Electronic address: xiaoming.cheng@whu.edu.cn.
⁴ Department of Hepatology, First Hospital of Jilin University, Changchun, 130021, PR China; Center for Pathogen Biology and Infectious Diseases, Department of Hepatology, Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, 130061, PR China. Electronic address: xiaomeiwang@jlu.edu.cn.
⁵ Department of Hepatology, First Hospital of Jilin University, Changchun, 130021, PR China; Center for Pathogen Biology and Infectious Diseases, Department of Hepatology, Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, 130061, PR China. Electronic address: hongqinxu@jlu.edu.cn.
⁶ Department of Hepatology, First Hospital of Jilin University, Changchun, 130021, PR China; Center for Pathogen Biology and Infectious Diseases, Department of Hepatology, Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, 130061, PR China. Electronic address: xiuzhugao@jlu.edu.cn.
⁷ Department of Hepatology, First Hospital of Jilin University, Changchun, 130021, PR China; Center for Pathogen Biology and Infectious Diseases, Department of Hepatology, Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, 130061, PR China. Electronic address: wuruihong@jlu.edu.cn.
⁸ Key Laboratory of Biomechanics and Mechanobiology, Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Engineering Medicine, Beihang University, Beijing, 100083, PR China. Electronic address: dakezhang@buaa.edu.cn.
⁹ State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, School of Basic Medical Sciences, Wuhan University, Wuhan, PR China. Electronic address: yuchenxia@whu.edu.cn.
¹⁰ Department of Hepatology, First Hospital of Jilin University, Changchun, 130021, PR China; Center for Pathogen Biology and Infectious Diseases, Department of Hepatology, Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, 130061, PR China. Electronic address: junqiniu@jlu.edu.cn.

PMID: 35709897
DOI: 10.1016/j.antiviral.2022.105363

Abstract

Aims: Viral integration profiles attract increased interest in the study of HBV-related hepatocellular carcinoma (HCC), but their features in the early stage of infection and changes due to antiviral treatments remain largely unknown.

Methods: Liver biopsies and paired blood samples were obtained from HBeAg-positive patients before and after 48 weeks of entecavir treatment, and a probe-based capture strategy was applied for analyzing the HBV integrations in these samples. Serum HBV markers, including viral DNA, pgRNA, and HBsAg, were longitudinally assessed.

Results: Entecavir treatment successfully reduced the levels of ALT, AST, and HBV serological markers (HBeAg, HBV pgRNA, and HBV DNA) in all patients (<40 years old). As expected, HBV integrations contributed to HBsAg production, with the total number of integrations positively correlated with serum HBsAg level (r = 0.47, P = 0.04). Along with repressed HBV replication, the number of viral integrations in liver biopsies decreased by about 1.94-fold after ETV treatment, with viral breakpoints significantly enriched within nt 1600-1900 of the HBV genome. No recurrent events were observed both at baseline and after treatment for the same individual, and only one same integration was found in two patients. Unlike in tumors, integrations in CHB biopsies seemed to have no chromosomal preference. Moreover, CHB integrations demonstrated lower enrichment scores for open active states than tumors, such as DNase, TssA, and ZNF/Rpts, and the scores reduced after ETV treatment. The antiviral therapy led to the disappearance of the enrichment tendency of integrations in both open chromatin and heterochromatin regions.

Conclusion: Reduced HBV replications by the nucleoside analogue may lead to decreased viral integrations in the liver, and those contributing to the HBsAg production may consistently occur. The pattern of HBV integration after ETV treatment is more random and irregular, which may contribute to a reduced risk of liver cancer due to antiviral treatment.

Keywords: Antiviral therapy; Hepatitis B; Hepatitis B surface Antigen; Integration.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Antiviral Agents / pharmacology
Biopsy
Carcinoma, Hepatocellular* / drug therapy
DNA, Viral
Guanine / analogs & derivatives
Hepatitis B Surface Antigens
Hepatitis B e Antigens
Hepatitis B virus
Hepatitis B, Chronic*
Humans
Liver Neoplasms* / drug therapy

Substances

Antiviral Agents
DNA, Viral
Hepatitis B Surface Antigens
Hepatitis B e Antigens
entecavir
Guanine