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Yang Z, Sun B, Xiang J, Wu H, Kan S, Hao M, Chang L, Liu H, Wang D, Liu W. Role of epigenetic modification in interferon treatment of hepatitis B virus infection. Front Immunol 2022; 13:1018053. [PMID: 36325353 PMCID: PMC9618964 DOI: 10.3389/fimmu.2022.1018053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 09/27/2022] [Indexed: 11/28/2022] Open
Abstract
Human hepatitis B virus (HBV) is a small, enveloped DNA virus that causes acute and chronic hepatitis. Chronic hepatitis B (CHB) is associated with hepatocellular carcinoma pathogenesis. Interferons (IFNs) have been used for the treatment of CHB for a long time, with advantages including less treatment duration and sustained virological response. Presently, various evidence suggests that epigenetic modification of the viral covalently closed circular DNA (cccDNA) and the host genome is crucial for the regulation of viral activity. This modification includes histone acetylation, DNA methylation, N6-methyladenosine, and non-coding RNA modification. IFN treatment for CHB can stimulate multiple IFN-stimulated genes for inhibiting virus replication. IFNs can also affect the HBV life cycle through epigenetic modulation. In this review, we summarized the different mechanisms through which IFN-α inhibits HBV replication, including epigenetic regulation. Moreover, the mechanisms underlying IFN activity are discussed, which indicated its potential as a novel treatment for CHB. It is proposed that epigenetic changes such as histone acetylation, DNA methylation, m6A methylation could be the targets of IFN, which may offer a novel approach to HBV treatment.
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Affiliation(s)
- Zhijing Yang
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Baozhen Sun
- Department of Hepatobiliary and Pancreas Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Jingcheng Xiang
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Han Wu
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Shaoning Kan
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Ming Hao
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Lu Chang
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Huimin Liu
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Dongxu Wang
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
- *Correspondence: Dongxu Wang, ; Weiwei Liu,
| | - Weiwei Liu
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
- *Correspondence: Dongxu Wang, ; Weiwei Liu,
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Yano Y, Seo Y, Hayashi H, Hatazawa Y, Hirano H, Minami A, Kawano Y, Saito M, Ninomiya T, Sugano M, Yamada H, Kitajima N, Yoon S, Hayashi Y. Factors associated with the decrease in hepatitis B surface antigen titers following interferon therapy in patients with chronic hepatitis B: Is interferon and adefovir combination therapy effective? Biomed Rep 2017; 7:257-262. [PMID: 28819561 DOI: 10.3892/br.2017.944] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Accepted: 07/15/2017] [Indexed: 12/15/2022] Open
Abstract
The purpose of antiviral therapy in chronic hepatitis B (CHB) is generally to achieve a decrease and ultimately disappearance of HBs antigen (HBsAg). Interferon (IFN) therapy of CHB appears to be less effective in Asian countries than in European countries, and the advantage of IFN and nucleotide(s) analog (NA) combination therapy has yet to be fully investigated. The present study focused on the factors associated with a decrease in HBs antigen following IFN monotherapy or IFN + NA combination therapy. A total of 35 patients with CHB who received IFN-based therapy (mean ± standard deviation age 36.7±8.5 years; 27 males and 8 females) were enrolled in this study. Of the 35 patients, 21 patients received pegylated IFN monotherapy and 14 patients received IFN and adefovir (ADV) combination therapy. We examined the factors associated with reductions in the HBsAg titer of >1.0 log IU/ml from the initial HBsAg titer to the end of treatment and to 24 weeks after treatment. Although 13 patients (37%) had a reduction in HBsAg of >1.0 IU/ml at the end of treatment, it was only maintained to 24 weeks after treatment in 7 patients (20%). The HBV core-related antigen (HBcrAg) titer before treatment was significantly higher in patients with a decrease in HBsAg at the end of treatment than in patients without a decrease in HBsAg (6.56±0.78 vs. 5.30±1.66 log IU/ml, P<0.05). Moreover, an increase in alanine aminotransferase (ALT) of >2 times from baseline occurred significantly more frequently in patients with a decrease in HBsAg (62 vs. 14%, P<0.05). The proportion of patients with a decrease in HBsAg was significantly greater in patients who received IFN monotherapy than in patients who received IFN and ADV combination therapy (43 vs. 29%, P<0.05). The present results revealed that the HBcr antigen titer before therapy and an on-treatment elevation of ALT (indicative of host instruction flare) are important factors associated with a decrease in HBsAg titers after IFN-based therapy. The efficacy of IFN and ADV combination therapy was not apparent in terms of a reduction in the HBsAg titer.
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Affiliation(s)
- Yoshihiko Yano
- Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.,Department of Gastroenterology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
| | | | - Hiroki Hayashi
- Department of Gastroenterology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
| | - Yuri Hatazawa
- Department of Gastroenterology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
| | - Hirotaka Hirano
- Department of Gastroenterology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
| | - Akihiro Minami
- Department of Gastroenterology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
| | - Yuki Kawano
- Department of Gastroenterology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
| | | | | | | | - Hajime Yamada
- Department of Gastroenterology, Shinko Hospital, Kobe 651-0072, Japan
| | - Naoto Kitajima
- Department of Gastroenterology, Kasai City Hospital, Kasai 675-2393, Japan
| | - Seitetsu Yoon
- Department of Gastroenterology, Kakogawa Municipal Hospital, Kakogawa 675-8555, Japan
| | - Yoshitake Hayashi
- Department of Gastroenterology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
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Chen LP, Zhao J, Du Y, Han YF, Su T, Zhang HW, Cao GW. Antiviral treatment to prevent chronic hepatitis B or C-related hepatocellular carcinoma. World J Virol 2012; 1:174-83. [PMID: 24175223 PMCID: PMC3782279 DOI: 10.5501/wjv.v1.i6.174] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2011] [Revised: 06/18/2012] [Accepted: 11/07/2012] [Indexed: 02/05/2023] Open
Abstract
Antiviral treatment is the only option to prevent or defer the occurrence of hepatocellular carcinoma (HCC) in patients chronically infected with hepatitis B virus (HBV) or hepatitis C virus (HCV). The approved medication for the treatment of chronic HBV infection is interferon-α (IFNα) and nucleos(t)ide analogues (NAs), including lamivudine, adefovir dipivoxil, telbivudine, entecavir and tenofovir disoproxil fumarate. IFNα is the most suitable for young patients with less advanced liver diseases and those infected with HBV genotype A. IFNα treatment significantly decreases the overall incidence of HBV-related HCC in sustained responders. However, side effects may limit its long-term clinical application. Orally administered NAs are typically implemented for patients with more advanced liver diseases. NA treatment significantly reduces disease progression of cirrhosis and therefore HCC incidence, especially in HBV e antigen-positive patients. NA-resistance due to the mutations in HBV polymerase is a major limiting factor. Of the NA resistance-associated mutants, A181T mutant significantly increases the risk of HCC development during the subsequent course of NA therapy. It is important to initiate treatment with NAs that have a high genetic barrier to resistance, to counsel patients on medication adherence and to monitor virological breakthroughs. The recommended treatment for patients with chronic HCV infection is peg-IFN plus ribavirin that can decrease the occurrence of HCC in those who achieve a sustained virological response and have not yet progressed to cirrhosis. IFN-based treatment is reserved for patients with decompensated cirrhosis who are under evaluation of liver transplantation to reduce post-transplant recurrence of HCV. More effective therapeutic options such as direct acting antiviral agents will hopefully increase the response rate in difficult-to-treat patients with HCV genotype 1. However, the risk of HCC remains in cirrhotic patients (both chronic HBV and HCV infection) if treatment is initiated after cirrhosis is established. Future research should focus on investigating new agents, especially for those patients with hepatic decompensation or post-transplantation.
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Affiliation(s)
- Li-Ping Chen
- Li-Ping Chen, Yan Du, Yi-Fang Han, Tong Su, Hong-Wei Zhang, Guang-Wen Cao, Department of Epidemiology, the Second Military Medical University, Shanghai 200433, China
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