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İstemihan Z, Kemeç G, Cebeci T, Çetin O, Genç Uluçeçen S, Rüstemzade A, Nuriyev K, Çavuş B, Çifcibaşi Örmeci A, Akyüz F, Demir K, Beşişik F, Kaymakoğlu S. Results in chronic hepatitis B patients using tenofovir and entecavir for at least 10 years; HBV clearance rare, disease outcomes good: An observational cohort study. Medicine (Baltimore) 2025; 104:e42766. [PMID: 40489803 DOI: 10.1097/md.0000000000042766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/11/2025] Open
Abstract
This study aims to investigate antiviral effectiveness, side effects, and disease outcomes in patients who have been using entecavir (ETV) and tenofovir disoproxil fumarate (TDF) for a long-term in chronic hepatitis B. Patients with chronic hepatitis B who had been using TDF or ETV for at least 10 years were included in this retrospective study. Co-infected patients, those receiving immunosuppressive therapy, and transplant patients were excluded. Of the study's total 173 patients (baseline mean age 43.4 ± 11.7 years), 110 (63.6%) were men. Thirty-three (19.1%) patients were cirrhotic, and hepatitis B e-antigen was negative in 131 (75.7%) patients at the baseline. Ninety-two (53.2%) patients used TDF and 81 (46.8%) used ETV for a mean of 156.76 ± 21.60 (120-204) months. Hepatitis B virus (HBV)-DNA negativity (<10 IU/mL) was achieved in 97.7% of all patients. Biochemical remission was achieved in 98.3% of all patients at the last visit. HBsAg became negative in only 5 (2.9%). Hepatocellular carcinoma (HCC) developed in 9 (5.2%) patients. All HCCs occurred after the 5th year of treatment. The age at HBV diagnosis was higher in HCC patients (P = .023), but the most important risk factor for the development of HCC was to have cirrhosis at baseline. Eight (4.6%) patients died in the follow-up, and 2 were due to liver disease and the remaining non-liver disease. At the end of follow-up, HBV-DNA negativity was achieved in almost all patients, and HBsAg sero-clearance was rarely achieved. Very few patients developed HCC and the long-term mortality rate was similar to the general population.
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Affiliation(s)
- Zülal İstemihan
- Department of Internal Medicine, Division of Gastroenterohepatology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Türkiye
| | - Gamze Kemeç
- Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Türkiye
| | - Timurhan Cebeci
- Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Türkiye
| | - Okan Çetin
- Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Türkiye
| | - Sezen Genç Uluçeçen
- Department of Internal Medicine, Division of Gastroenterohepatology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Türkiye
| | - Aynure Rüstemzade
- Department of Internal Medicine, Division of Gastroenterohepatology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Türkiye
| | - Kanan Nuriyev
- Department of Internal Medicine, Division of Gastroenterohepatology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Türkiye
| | - Bilger Çavuş
- Department of Internal Medicine, Division of Gastroenterohepatology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Türkiye
| | - Asli Çifcibaşi Örmeci
- Department of Internal Medicine, Division of Gastroenterohepatology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Türkiye
| | - Filiz Akyüz
- Department of Internal Medicine, Division of Gastroenterohepatology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Türkiye
| | - Kadir Demir
- Department of Internal Medicine, Division of Gastroenterohepatology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Türkiye
| | - Fatih Beşişik
- Department of Internal Medicine, Division of Gastroenterohepatology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Türkiye
| | - Sabahattin Kaymakoğlu
- Department of Internal Medicine, Division of Gastroenterohepatology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Türkiye
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Hossain MG, Ueda K. Regulation of Hepatitis B Virus Replication by Modulating Endoplasmic Reticulum Stress (ER-Stress). Int J Microbiol 2024; 2024:9117453. [PMID: 39246409 PMCID: PMC11379510 DOI: 10.1155/2024/9117453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Accepted: 08/21/2024] [Indexed: 09/10/2024] Open
Abstract
Hepatitis B virus (HBV), resistant to several antiviral drugs due to viral genomic mutations, has been reported, which aggravates chronic infection and leads to hepatocellular carcinoma. Therefore, host cellular factors/signaling modulation might be an alternative way of treatment for drug-resistant HBV. Here, we investigated the viral protein expression, replication, and virion production using endoplasmic reticulum (ER) stress-modulating chemicals, tunicamycin (an ER-stress inducer), and salubrinal (an ER-stress inhibitor). We found that ER-stress could be induced by HBV replication in transfected HepG2 cells as well as by tunicamycin as demonstrated by dual luciferase assay. HBV intracellular core-associated DNA quantified by qPCR has been significantly increased by tunicamycin in transfected HepG2 cells. Inversely, intracellular core associated and extracellular particle DNA has been significantly decreased in a dose-dependent manner in salubrinal-treated HepG2 cells transfected with HBV-replicating plasmid pHBI. Similar results were found in stably HBV-expressing hepatoblastoma (HB611) cells treated with salubrinal. However, increased or decreased ER-stress by tunicamycin or salubrinal treatment, respectively, has been confirmed by expression analysis of grp78 using Western blot. In addition, Western blot results demonstrated that the expression of HBV core protein and large HBsAg is increased and decreased by tunicamycin and salubrinal, respectively. In conclusion, the sal-mediated inhibition of the HBV replication and virion production might be due to the simultaneous reduction of core and large HBsAg expression and maintaining the ER homeostasis. These results of HBV replication regulation by modulation of ER-stress dynamics would be useful for designing/identifying anti-HBV drugs targeting cellular signaling pathways.
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Affiliation(s)
- Md Golzar Hossain
- Department of Microbiology and Hygiene Bangladesh Agricultural University, Mymensingh 2202, Bangladesh
| | - Keiji Ueda
- Division of Virology Department of Microbiology and Immunology Graduate School of Medicine Osaka University, Osaka, Japan
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Chen J, Hou J, Na R, Zhou B, Hou J, Jiang DK. Higher BST2 Expression Promotes the Anti-HBV Effect of IFN-α and BST2 Genetic Variant Predicts PegIFNα Treatment Response of HBeAg-Positive Chronic Hepatitis B Patients. Clin Pharmacol Ther 2024; 115:361-370. [PMID: 38018367 DOI: 10.1002/cpt.3120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Accepted: 11/21/2023] [Indexed: 11/30/2023]
Abstract
We previously reported that an interferon (IFN)-inducible protein, BST2, was regulated by the JAK-STAT pathway activated by CD40, and subsequently suppressing hepatitis B virus (HBV) repliaction and transcription. The current research attempted to assess the impact of BST2 on the IFN-treated anti-HBV effect, and explore BST2 variants for predicting pegylated IFN alpha (PegIFNα) therapy response of patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB). Using an HBV-transfected cell model, the function of BST2 on HBV DNA replication and transcription driven by IFN was studied. The potentially functional BST2 variants were selected through a strategy of gene-wide screening. The associations of BST2 variants and polygenic score (PGS) model, which was used to quantify the combined influence of several genetic variants, with treatment response were examined in 2 separate PegIFNα-treated cohorts of 238 and 707 patients with CHB, respectively. We found that overexpression of BST2 improved the anti-HBV activity triggered by IFN-α. Among PegIFNα-treated patients with CHB, BST2_rs9576 was screened out to be significantly correlated with combined response (CR; i.e., HBeAg seroconversion along with HBV DNA level <3.3log10 IU/mL, P = 7.12 × 10-5 ). Additionally, there was a strong correlation between the PGS incorporating BST2_rs9576 and other 5 genetic variations (previously described predictors of therapy response to PegIFNα) and CR (P = 1.81 × 10-13 ), hepatitis B surface antigen (HBsAg) level (P = 0.004), as well as HBsAg decline (P = 0.017). In conclusion, higher BST2 expression responded better to IFN-α treatment. BST2_rs9576 is an effective indicator to forecast therapy response of PegIFNα-treated patients with CHB. The PGS possesses the potential to boost the ability of PegIFNα therapy response.
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Affiliation(s)
- Jiaxuan Chen
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
- The Key Laboratory of Molecular Pathology (Hepatic Diseases) of Guangxi, Department of Pathology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
| | - Jia Hou
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Rong Na
- Division of Urology, Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Bin Zhou
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jinlin Hou
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - De-Ke Jiang
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
- The Key Laboratory of Molecular Pathology (Hepatic Diseases) of Guangxi, Department of Pathology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
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Yip RPH, Kwok DCY, Lai LTF, Ho SM, Wong ICK, Chan CP, Lau WCY, Ngo JCK. SRPK2 Mediates HBV Core Protein Phosphorylation and Capsid Assembly via Docking Interaction. PLoS Pathog 2024; 20:e1011978. [PMID: 38324561 PMCID: PMC10878513 DOI: 10.1371/journal.ppat.1011978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 02/20/2024] [Accepted: 01/17/2024] [Indexed: 02/09/2024] Open
Abstract
Members of the serine-arginine protein kinase (SRPK) family, SRPK1 and SRPK2, phosphorylate the hepatitis B core protein (Cp) and are crucial for pregenomic RNA encapsidation during viral nucleocapsid assembly. Among them, SRPK2 exhibits higher kinase activity toward Cp. In this study, we identified Cp sites that are phosphorylated by SRPK2 and demonstrated that the kinase utilizes an SRPK-specific docking groove to interact with and regulate the phosphorylation of the C-terminal arginine rich domain of Cp. We determined that direct interaction between the docking groove of SRPK2 and unphosphorylated Cp inhibited premature viral capsid assembly in vitro, whereas the phosphorylation of the viral protein reactivated the process. Pull-down assays together with the new cryo-electron microscopy structure of the HBV capsid in complex with SRPK2 revealed that the kinases decorate the surface of the viral capsid by interacting with the C-terminal domain of Cp, underscoring the importance of the docking interaction in regulating capsid assembly and pregenome packaging. Moreover, SRPK2-knockout in HepG2 cells suppressed Cp phosphorylation, indicating that SRPK2 is an important cellular kinase for HBV life cycle.
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Affiliation(s)
- Ryan Pak Hong Yip
- School of Life Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China
| | - Doris Ching Ying Kwok
- School of Life Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China
| | - Louis Tung Faat Lai
- School of Life Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China
| | - Siu-Ming Ho
- School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong, Hong Kong SAR, China
- State Key Laboratory of Liver Research (The University of Hong Kong), Pokfulam, Hong Kong, Hong Kong SAR, China
| | - Ivan Chun Kit Wong
- School of Life Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China
| | - Chi-Ping Chan
- School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong, Hong Kong SAR, China
- State Key Laboratory of Liver Research (The University of Hong Kong), Pokfulam, Hong Kong, Hong Kong SAR, China
| | - Wilson Chun Yu Lau
- School of Life Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China
- Center for Soybean Research of the State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Shatin N.T., Hong Kong SAR, China
| | - Jacky Chi Ki Ngo
- School of Life Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China
- Center for Soybean Research of the State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Shatin N.T., Hong Kong SAR, China
- Center for Novel Biomaterials, The Chinese University of Hong Kong, Shatin N.T., Hong Kong SAR, China
- Center for Protein Science and Crystallography, The Chinese University of Hong Kong, Shatin N.T., Hong Kong SAR, China
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Liu ZP, Ouyang GQ, Huang GZ, Wei J, Dai L, He SQ, Yuan GD. Global burden of cirrhosis and other chronic liver diseases due to nonalcoholic fatty liver disease, 1990-2019. World J Hepatol 2023; 15:1210-1225. [PMID: 38075011 PMCID: PMC10698345 DOI: 10.4254/wjh.v15.i11.1210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 08/29/2023] [Accepted: 10/30/2023] [Indexed: 11/24/2023] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) has become the leading cause of cirrhosis and other chronic liver diseases (COCLDs). AIM To conduct a comprehensive and comparable updated analysis of the global, regional, and national burden of COCLDs due to NAFLD in 204 countries and territories from 1990 and 2019 by age, sex, and sociodemographic index. METHODS Data on COCLDs due to NAFLD were collected from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019. Numbers and age-standardized prevalence, death, and disability-adjusted life years (DALYs) were estimated through a systematic analysis of modelled data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019. The estimated annual percentage change was used to determine the burden trend. RESULTS In 2019, the global age-standardized prevalence rate of COCLDs due to NAFLD was 15022.90 per 100000 population [95% uncertainty interval (UI): 13493.19-16764.24], which increased by 24.51% (22.63% to 26.08%) from 1990, with an estimated annual percentage change of 0.78 (95% confidence interval: 0.74-0.82). In the same year, however, the age-standardized death rate and age-standardized DALYs per 100000 population were 1.66 (95%UI: 1.20-2.17) and 43.69 (95%UI: 31.28-58.38), respectively. North Africa and the Middle East had the highest prevalence rates of COCLDs due to NAFLD. The death rate increased with age up to the 95+ age group for both sexes. Males had higher numbers of prevalence, death rate, and DALYs than females across all age groups before the 65-69 age group. The sociodemographic index was negatively correlated with the age-standardized DALYs. CONCLUSION Globally, the age-standardized prevalence rate has increased during the past three decades. However, the age-standardized death rate and age-standardized DALYs decreased. There is geographical variation in the burden of COCLDs due to NAFLD. It is strongly recommended to improve the data quality of COCLDs due to NAFLD across all countries and regions to facilitate better monitoring of the burden of COCLDs due to NAFLD.
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Affiliation(s)
- Zhi-Peng Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Guo-Qing Ouyang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Guo-Zhen Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Jie Wei
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Luo Dai
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Song-Qing He
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China.
| | - Guan-Dou Yuan
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
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Lou S, Wang J, Chen J, Xie H, Chen H, Zhou B, Zhang B, Hou J, Jiang DK. The Role of ALPK1 in Inhibiting Hepatitis B Virus Replication Facilitates the Identification of ALPK1 P660L Variant for Predicting Response to Pegylated Interferon α Therapy. J Infect Dis 2023; 228:694-703. [PMID: 36932045 DOI: 10.1093/infdis/jiad065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 03/06/2023] [Accepted: 03/16/2023] [Indexed: 03/19/2023] Open
Abstract
BACKGROUND Alpha kinase 1 (ALPK1) agonist has recently been reported to demonstrate anti-hepatitis B virus (HBV) efficacy via activating NF-κB signaling, which is crucial for maximizing interferon (IFN) responses. Here, we investigated the impact of ALPK1 on HBV replication and explored ALPK1 variants for predicting the response to pegylated IFN-α (PegIFN-α) treatment. METHODS The potential anti-HBV effect of ALPK1 was evaluated in HBV-integrated and HBV-infected hepatoma cells. The potentially functional genetic variants of ALPK1 were screened out, and their correlations with PegIFN-α treatment response were assessed in 945 hepatitis B e antigen (HBeAg)-positive patients with chronic hepatitis B (CHB). RESULTS We revealed that ALPK1 inhibited HBV replication in hepatocytes via activating the JAK-STAT pathway. ALPK1 overexpression improved the anti-HBV effect of IFN-α in cell models. A missense variant, rs35389530 (P660L), of ALPK1 was strongly associated with combined response (CR; namely, HBeAg seroconversion and HBV DNA level <3.3log10 IU/mL) to PegIFN-α treatment in patients with CHB (P = 2.12 × 10-6). Moreover, a polygenic score integrating ALPK1_rs35389530 and 2 additional genetic variants was further significantly associated with CR (Ptrend = 9.28 × 10-7), hepatitis B surface antigen (HBsAg) level (Ptrend = .0002), and HBsAg loss (Ptrend = .025). CONCLUSIONS The anti-HBV effects of ALPK1 through activating JAK-STAT pathway provides a new perspective for CHB therapy. ALPK1_rs35389530 and polygenic score are potential biomarkers to predict PegIFN-α treatment response and may be used for optimizing CHB treatment.
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Affiliation(s)
- Shuang Lou
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
- The Key Laboratory of Molecular Pathology (Hepatic Diseases) of Guangxi, Department of Pathology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, China
| | - Jialin Wang
- Food Safety and Health Research Center, School of Public Health, Southern Medical University, Guangzhou, China
| | - Jiaxuan Chen
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Haisheng Xie
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Haitao Chen
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
- School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, China
| | - Bin Zhou
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Bo Zhang
- Food Safety and Health Research Center, School of Public Health, Southern Medical University, Guangzhou, China
| | - Jinlin Hou
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - De-Ke Jiang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
- The Key Laboratory of Molecular Pathology (Hepatic Diseases) of Guangxi, Department of Pathology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, China
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Olenginski LT, Attionu SK, Henninger EN, LeBlanc RM, Longhini AP, Dayie TK. Hepatitis B Virus Epsilon (ε) RNA Element: Dynamic Regulator of Viral Replication and Attractive Therapeutic Target. Viruses 2023; 15:1913. [PMID: 37766319 PMCID: PMC10534774 DOI: 10.3390/v15091913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 09/01/2023] [Accepted: 09/05/2023] [Indexed: 09/29/2023] Open
Abstract
Hepatitis B virus (HBV) chronically infects millions of people worldwide, which underscores the importance of discovering and designing novel anti-HBV therapeutics to complement current treatment strategies. An underexploited but attractive therapeutic target is ε, a cis-acting regulatory stem-loop RNA situated within the HBV pregenomic RNA (pgRNA). The binding of ε to the viral polymerase protein (P) is pivotal, as it triggers the packaging of pgRNA and P, as well as the reverse transcription of the viral genome. Consequently, small molecules capable of disrupting this interaction hold the potential to inhibit the early stages of HBV replication. The rational design of such ligands necessitates high-resolution structural information for the ε-P complex or its individual components. While these data are currently unavailable for P, our recent structural elucidation of ε through solution nuclear magnetic resonance spectroscopy marks a significant advancement in this area. In this review, we provide a brief overview of HBV replication and some of the therapeutic strategies to combat chronic HBV infection. These descriptions are intended to contextualize our recent experimental efforts to characterize ε and identify ε-targeting ligands, with the ultimate goal of developing novel anti-HBV therapeutics.
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Affiliation(s)
- Lukasz T. Olenginski
- Center for Biomolecular Structure and Organization, Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA (R.M.L.)
- Department of Biochemistry, University of Colorado, Boulder, CO 80309, USA
| | - Solomon K. Attionu
- Center for Biomolecular Structure and Organization, Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA (R.M.L.)
| | - Erica N. Henninger
- Center for Biomolecular Structure and Organization, Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA (R.M.L.)
| | - Regan M. LeBlanc
- Center for Biomolecular Structure and Organization, Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA (R.M.L.)
| | - Andrew P. Longhini
- Center for Biomolecular Structure and Organization, Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA (R.M.L.)
- Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA
- Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA
| | - Theodore K. Dayie
- Center for Biomolecular Structure and Organization, Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA (R.M.L.)
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Liu W, Yao Q, Su X, Deng Y, Yang M, Peng B, Zhao F, Du C, Zhang X, Zhu J, Wang D, Li W, Li H. Molecular insights into Spindlin1-HBx interplay and its impact on HBV transcription from cccDNA minichromosome. Nat Commun 2023; 14:4663. [PMID: 37537164 PMCID: PMC10400593 DOI: 10.1038/s41467-023-40225-w] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 07/11/2023] [Indexed: 08/05/2023] Open
Abstract
Molecular interplay between host epigenetic factors and viral proteins constitutes an intriguing mechanism for sustaining hepatitis B virus (HBV) life cycle and its chronic infection. HBV encodes a regulatory protein, HBx, which activates transcription and replication of HBV genome organized as covalently closed circular (ccc) DNA minichromosome. Here we illustrate how HBx accomplishes its task by hijacking Spindlin1, an epigenetic reader comprising three consecutive Tudor domains. Our biochemical and structural studies have revealed that the highly conserved N-terminal 2-21 segment of HBx (HBx2-21) associates intimately with Tudor 3 of Spindlin1, enhancing histone H3 "K4me3-K9me3" readout by Tudors 2 and 1. Functionally, Spindlin1-HBx engagement promotes gene expression from the chromatinized cccDNA, accompanied by an epigenetic switch from an H3K9me3-enriched repressive state to an H3K4me3-marked active state, as well as a conformational switch of HBx that may occur in coordination with other HBx-binding factors, such as DDB1. Despite a proposed transrepression activity of HBx2-21, our study reveals a key role of Spindlin1 in derepressing this conserved motif, thereby promoting HBV transcription from its chromatinized genome.
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Affiliation(s)
- Wei Liu
- State Key Laboratory of Molecular Oncology, MOE Key Laboratory of Protein Sciences, Beijing Frontier Research Center for Biological Structure, SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, School of Medicine, Tsinghua University, Beijing, 100084, China
- Tsinghua-Peking Center for Life Sciences, Beijing, 100084, China
| | - Qiyan Yao
- National Institute of Biological Sciences, Beijing, 102206, China
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Xiaonan Su
- State Key Laboratory of Molecular Oncology, MOE Key Laboratory of Protein Sciences, Beijing Frontier Research Center for Biological Structure, SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, School of Medicine, Tsinghua University, Beijing, 100084, China
- Tsinghua-Peking Center for Life Sciences, Beijing, 100084, China
| | - Yafang Deng
- State Key Laboratory of Molecular Oncology, MOE Key Laboratory of Protein Sciences, Beijing Frontier Research Center for Biological Structure, SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, School of Medicine, Tsinghua University, Beijing, 100084, China
| | - Mo Yang
- National Center for Nanoscience and Technology, Beijing, 100190, China
- Chemical Biology Laboratory, National Cancer Institute, 1050 Boyles Str., Frederick, MD, 21702, USA
| | - Bo Peng
- National Institute of Biological Sciences, Beijing, 102206, China
| | - Fan Zhao
- State Key Laboratory of Molecular Oncology, MOE Key Laboratory of Protein Sciences, Beijing Frontier Research Center for Biological Structure, SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, School of Medicine, Tsinghua University, Beijing, 100084, China
- Tsinghua-Peking Center for Life Sciences, Beijing, 100084, China
| | - Chao Du
- State Key Laboratory of Molecular Oncology, MOE Key Laboratory of Protein Sciences, Beijing Frontier Research Center for Biological Structure, SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, School of Medicine, Tsinghua University, Beijing, 100084, China
- Tsinghua-Peking Center for Life Sciences, Beijing, 100084, China
| | - Xiulan Zhang
- State Key Laboratory of Molecular Oncology, MOE Key Laboratory of Protein Sciences, Beijing Frontier Research Center for Biological Structure, SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, School of Medicine, Tsinghua University, Beijing, 100084, China
| | - Jinsong Zhu
- National Center for Nanoscience and Technology, Beijing, 100190, China
- Suzhou Puxin Life Science Technology, Ltd, Suzhou, 215124, China
| | - Daliang Wang
- State Key Laboratory of Molecular Oncology, MOE Key Laboratory of Protein Sciences, Beijing Frontier Research Center for Biological Structure, SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, School of Medicine, Tsinghua University, Beijing, 100084, China.
| | - Wenhui Li
- National Institute of Biological Sciences, Beijing, 102206, China.
- Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, 100084, China.
| | - Haitao Li
- State Key Laboratory of Molecular Oncology, MOE Key Laboratory of Protein Sciences, Beijing Frontier Research Center for Biological Structure, SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, School of Medicine, Tsinghua University, Beijing, 100084, China.
- Tsinghua-Peking Center for Life Sciences, Beijing, 100084, China.
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Meng CY, Sun S, Liang Y, Xu H, Zhang C, Zhang M, Wang FS, Fu YX, Peng H. Engineered anti-PDL1 with IFNα targets both immunoinhibitory and activating signals in the liver to break HBV immune tolerance. Gut 2023; 72:1544-1554. [PMID: 36316098 PMCID: PMC10359590 DOI: 10.1136/gutjnl-2022-327059] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 10/12/2022] [Indexed: 11/04/2022]
Abstract
OBJECTIVE The purpose of this study is to develop an anti-PDL1-based interferon (IFN) fusion protein to overcome the chronic hepatitis B virus (HBV)-induced immune tolerance, and combine this immunotherapy with a HBV vaccine to achieve the functional cure of chronic hepatitis B (CHB) infection. DESIGN We designed an anti-PDL1-IFNα heterodimeric fusion protein, in which one arm was derived from anti-PDL1 antibody and the other arm was IFNα, to allow targeted delivery of IFNα into the liver by anti-PDL1 antibody. The effect of the anti-PDL1-IFNα heterodimer on overcoming hepatitis B surface antigen (HBsAg) vaccine resistance was evaluated in chronic HBV carrier mice. RESULTS The anti-PDL1-IFNα heterodimer preferentially targeted the liver and resulted in viral suppression, the PD1/PDL1 immune checkpoint blockade and dendritic cell activation/antigen presentation to activate HBsAg-specific T cells, thus breaking immune tolerance in chronic HBV carrier mice. When an HBsAg vaccine was administered soon after anti-PDL1-IFNα heterodimer treatment, we observed strong anti-HBsAg antibody and HBsAg-specific T cell responses for efficient HBsAg clearance in chronic HBV carrier mice that received the combination treatment but not in those that received either single treatment. CONCLUSIONS Targeting the liver with an engineered anti-PDL1-IFNα heterodimer can break HBV-induced immune tolerance to an HBsAg vaccine, offering a promising translatable therapeutic strategy for the functional cure of CHB.
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Affiliation(s)
- Chao-Yang Meng
- Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Shiyu Sun
- Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Yong Liang
- Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China
| | - Hairong Xu
- Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Chao Zhang
- Senior Department of Infectious Diseases, 5th Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Min Zhang
- Senior Department of Liver Disease, 5th Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Fu-Sheng Wang
- Senior Department of Infectious Diseases, 5th Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Yang-Xin Fu
- Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China
| | - Hua Peng
- Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
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Chen J, Lou S, Chen H, Zhou B, Sun J, Hou J, Jiang DK. CD55 Variant Associated with Pegylated-interferon α Therapy Response in HBeAg-positive Chronic Hepatitis B Patients. J Clin Transl Hepatol 2023; 11:295-303. [PMID: 36643051 PMCID: PMC9817056 DOI: 10.14218/jcth.2022.00057] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Revised: 04/20/2022] [Accepted: 05/04/2022] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND AND AIMS Only a small percentage of chronic hepatitis B (CHB) patients effectively respond to treatment with pegylated-interferon alpha (PegIFNα) or nucleos(t)ide analogues (NUCs). We aimed to detect the correlations of complement regulators-associated single-nucleotide polymorphisms (SNPs) with treatment response of hepatitis B e antigen (HBeAg)-positive CHB patients. METHODS A total of 1,763 HBeAg-positive CHB patients were enrolled, 894 received PegIFNα for at least 48 weeks and were followed up for 24 weeks, and 869 received NUCs for 104 weeks. For each patient, nine SNPs in genes encoding for complement regulators were determined and genotyped. To assess the cumulative effect of numerous SNPs, a polygenic score (PGS) was utilized. The correlations of SNPs and PGS with the levels of combined response (CR) and hepatitis B s antigen (HBsAg) loss were also investigated. RESULTS In PegIFNα-treated patients, an intronic SNP of CD55, rs28371597, was strongly related to CR, and the CR rate in rs28371597_GG genotype carriers was only approximately half that of rs28371597_GT/TT genotype carriers (20.29% vs. 37.10%, p=2.00 × 10-3). A PGS incorporating CD55_rs28371597 and two additional SNPs, CFB_rs12614 and STAT4_rs7574865, which had been considered as predictors for PegIFNα treatment response before, was strongly correlated with the levels of CR (p-trend=7.94×10-6) and HBsAg loss (p-trend=9.40×10-3) in PegIFNα-treated patients. In NUCs-treated individuals, however, none of the nine SNPs were shown to be significantly linked to CHB treatment response. CONCLUSIONS CD55_rs28371597 is a promising biomarker for predicting CHB patients' responsiveness to PegIFNα therapy. The updated PGS may be used for optimizing CHB treatment.
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Affiliation(s)
- Jiaxuan Chen
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- The Key Laboratory of Molecular Pathology (Hepatic Diseases) of Guangxi, Department of Pathology, the Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, China
| | - Shuang Lou
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Haitao Chen
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Bin Zhou
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Jian Sun
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Jinlin Hou
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - De-Ke Jiang
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- The Key Laboratory of Molecular Pathology (Hepatic Diseases) of Guangxi, Department of Pathology, the Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, China
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Olenginski LT, Kasprzak WK, Attionu SK, Shapiro BA, Dayie TK. Virtual Screening of Hepatitis B Virus Pre-Genomic RNA as a Novel Therapeutic Target. Molecules 2023; 28:1803. [PMID: 36838792 PMCID: PMC9963113 DOI: 10.3390/molecules28041803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 02/07/2023] [Accepted: 02/11/2023] [Indexed: 02/17/2023] Open
Abstract
The global burden imposed by hepatitis B virus (HBV) infection necessitates the discovery and design of novel antiviral drugs to complement existing treatments. One attractive and underexploited therapeutic target is ε, an ~85-nucleotide (nt) cis-acting regulatory stem-loop RNA located at the 3'- and 5'-ends of the pre-genomic RNA (pgRNA). Binding of the 5'-end ε to the viral polymerase protein (P) triggers two early events in HBV replication: pgRNA and P packaging and reverse transcription. Our recent solution nuclear magnetic resonance spectroscopy structure of ε permits structure-informed drug discovery efforts that are currently lacking for P. Here, we employ a virtual screen against ε using a Food and Drug Administration (FDA)-approved compound library, followed by in vitro binding assays. This approach revealed that the anti-hepatitis C virus drug Daclatasvir is a selective ε-targeting ligand. Additional molecular dynamics simulations demonstrated that Daclatasvir targets ε at its flexible 6-nt priming loop (PL) bulge and modulates its dynamics. Given the functional importance of the PL, our work supports the notion that targeting ε dynamics may be an effective anti-HBV therapeutic strategy.
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Affiliation(s)
- Lukasz T. Olenginski
- Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA
| | - Wojciech K. Kasprzak
- Bioinformatics and Computational Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
| | - Solomon K. Attionu
- Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA
| | - Bruce A. Shapiro
- RNA Biology Laboratory, National Cancer Institute, Frederick, MD 21702, USA
| | - Theodore K. Dayie
- Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA
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Min Y, Wei X, Xia X, Wei Z, Li R, Jin J, Liu Z, Hu X, Peng X. Hepatitis B virus infection: An insight into the clinical connection and molecular interaction between hepatitis B virus and host extrahepatic cancer risk. Front Immunol 2023; 14:1141956. [PMID: 36936956 PMCID: PMC10014788 DOI: 10.3389/fimmu.2023.1141956] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 02/20/2023] [Indexed: 03/05/2023] Open
Abstract
The evidence for chronic hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC) occurrence is well established. The hepatocyte epithelium carcinogenesis caused by HBV has been investigated and reviewed in depth. Nevertheless, recent findings from preclinical and observational studies suggested that chronic HBV infection is equally important in extrahepatic cancer occurrence and survival, specifically gastrointestinal system-derived cancers. Immune microenvironment changes (immune-suppressive cytokine infiltration), epigenetic modification (N6-methyladenosine), molecular signaling pathways (PI3K-Akt and Wnt), and serum biomarkers such as hepatitis B virus X (HBx) protein are potential underlying mechanisms in chronic HBV infection-induced extrahepatic cancers. This narrative review aimed to comprehensively summarize the most recent advances in evaluating the association between chronic HBV infection and extrahepatic cancer risk and explore the potential underlying molecular mechanisms in the carcinogenesis induction of extrahepatic cancers in chronic HBV conditions.
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Affiliation(s)
- Yu Min
- Department of Biotherapy and National Clinical Research Center for Geriatrics, Cancer Center, West China Hospital, Sichuan University, Sichuan, China
| | - Xiaoyuan Wei
- Department of Head and Neck Oncology, Department of Radiation Oncology, Cancer Center, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Sichuan, China
| | - Xi Xia
- Research and Development Department Shanghai ETERN Biopharma Co., Ltd., Shanghai, China
| | - Zhigong Wei
- Department of Biotherapy and National Clinical Research Center for Geriatrics, Cancer Center, West China Hospital, Sichuan University, Sichuan, China
| | - Ruidan Li
- Department of Biotherapy and National Clinical Research Center for Geriatrics, Cancer Center, West China Hospital, Sichuan University, Sichuan, China
| | - Jing Jin
- Department of Biotherapy and National Clinical Research Center for Geriatrics, Cancer Center, West China Hospital, Sichuan University, Sichuan, China
| | - Zheran Liu
- Department of Biotherapy and National Clinical Research Center for Geriatrics, Cancer Center, West China Hospital, Sichuan University, Sichuan, China
| | - Xiaolin Hu
- West China School of Nursing, West China Hospital, Sichuan University, Sichuan, China
- *Correspondence: Xingchen Peng, ; Xiaolin Hu,
| | - Xingchen Peng
- Department of Biotherapy and National Clinical Research Center for Geriatrics, Cancer Center, West China Hospital, Sichuan University, Sichuan, China
- *Correspondence: Xingchen Peng, ; Xiaolin Hu,
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Sheena BS, Hiebert L, Han H, Ippolito H, Abbasi-Kangevari M, Abbasi-Kangevari Z, Abbastabar H, Abdoli A, Abubaker Ali H, Adane MM, Adegboye OA, Adnani QES, Advani SM, Afzal MS, Afzal S, Aghaie Meybodi M, Ahadinezhad B, Ahinkorah BO, Ahmad S, Ahmad T, Ahmadi S, Ahmed H, Ahmed MB, Ahmed Rashid T, Akalu GT, Aklilu A, Akram T, Al Hamad H, Alahdab F, Alem AZ, Alem DT, Alhalaiqa FAN, Alhassan RK, Ali L, Ali MA, Alimohamadi Y, Alipour V, Alkhayyat M, Almustanyir S, Al-Raddadi RM, Altawalah H, Amini S, Amu H, Ancuceanu R, Andrei CL, Andrei T, Anoushiravani A, Ansar A, Anyasodor AE, Arabloo J, Arab-Zozani M, Argaw AM, Argaw ZG, Arshad M, Artamonov AA, Ashraf T, Atlaw D, Ausloos F, Ausloos M, Azadnajafabad S, Azangou-Khyavy M, Azari Jafari A, Azarian G, Bagheri S, Bahadory S, Baig AA, Banach M, Barati N, Barrow A, Batiha AMM, Bejarano Ramirez DF, Belgaumi UI, Berhie AY, Bhagat DS, Bhardwaj N, Bhardwaj P, Bhattacharyya K, Bhojaraja VS, Bijani A, Biondi A, Bodicha BBA, Bojia HA, Boloor A, Bosetti C, Braithwaite D, Briko NI, Butt ZA, Cámera LA, Chakinala RC, Chakraborty PA, Charan J, Chen S, Choi JYJ, Choudhari SG, Chowdhury FR, Chu DT, Chung SC, Cortesi PA, Cowie BC, Culbreth GT, et alSheena BS, Hiebert L, Han H, Ippolito H, Abbasi-Kangevari M, Abbasi-Kangevari Z, Abbastabar H, Abdoli A, Abubaker Ali H, Adane MM, Adegboye OA, Adnani QES, Advani SM, Afzal MS, Afzal S, Aghaie Meybodi M, Ahadinezhad B, Ahinkorah BO, Ahmad S, Ahmad T, Ahmadi S, Ahmed H, Ahmed MB, Ahmed Rashid T, Akalu GT, Aklilu A, Akram T, Al Hamad H, Alahdab F, Alem AZ, Alem DT, Alhalaiqa FAN, Alhassan RK, Ali L, Ali MA, Alimohamadi Y, Alipour V, Alkhayyat M, Almustanyir S, Al-Raddadi RM, Altawalah H, Amini S, Amu H, Ancuceanu R, Andrei CL, Andrei T, Anoushiravani A, Ansar A, Anyasodor AE, Arabloo J, Arab-Zozani M, Argaw AM, Argaw ZG, Arshad M, Artamonov AA, Ashraf T, Atlaw D, Ausloos F, Ausloos M, Azadnajafabad S, Azangou-Khyavy M, Azari Jafari A, Azarian G, Bagheri S, Bahadory S, Baig AA, Banach M, Barati N, Barrow A, Batiha AMM, Bejarano Ramirez DF, Belgaumi UI, Berhie AY, Bhagat DS, Bhardwaj N, Bhardwaj P, Bhattacharyya K, Bhojaraja VS, Bijani A, Biondi A, Bodicha BBA, Bojia HA, Boloor A, Bosetti C, Braithwaite D, Briko NI, Butt ZA, Cámera LA, Chakinala RC, Chakraborty PA, Charan J, Chen S, Choi JYJ, Choudhari SG, Chowdhury FR, Chu DT, Chung SC, Cortesi PA, Cowie BC, Culbreth GT, Dadras O, Dai X, Dandona L, Dandona R, De la Hoz FP, Debela SA, Dedefo MG, Demeke FM, Demie TGG, Demissie GD, Derbew Molla M, Desta AA, Dhamnetiya D, Dhimal ML, Dhimal M, Didehdar M, Doan LP, Dorostkar F, Drake TM, Eghbalian F, Ekholuenetale M, El Sayed I, El Sayed Zaki M, Elhadi M, Elmonem MA, Elsharkawy A, Enany S, Enyew DB, Erkhembayar R, Eskandarieh S, Esmaeilzadeh F, Ezzikouri S, Farrokhpour H, Fetensa G, Fischer F, Foroutan M, Gad MM, Gaidhane AM, Gaidhane S, Galles NC, Gallus S, Gebremeskel TG, Gebreyohannes EA, Ghadiri K, Ghaffari K, Ghafourifard M, Ghamari SH, Ghashghaee A, Gholami A, Gholizadeh A, Gilani A, Goel A, Golechha M, Goleij P, Golinelli D, Gorini G, Goshu YA, Griswold MG, Gubari MIM, Gupta B, Gupta S, Gupta VB, Gupta VK, Haddadi R, Halwani R, Hamid SS, Hamidi S, Hanif A, Haque S, Harapan H, Hargono A, Hariri S, Hasaballah AI, Hasan SMM, Hassanipour S, Hassankhani H, Hay SI, Hayat K, Heidari G, Herteliu C, Heyi DZ, Hezam K, Holla R, Hosseini MS, Hosseini M, Hosseinzadeh M, Hostiuc M, Househ M, Huang J, Hussein NR, Iavicoli I, Ibitoye SE, Ilesanmi OS, Ilic IM, Ilic MD, Irham LM, Islam JY, Ismail NE, Jacobsen KH, Jadidi-Niaragh F, Javadi Mamaghani A, Jayaram S, Jayawardena R, Jebai R, Jha RP, Joseph N, Joukar F, Kaambwa B, Kabir A, Kabir Z, Kalhor R, Kandel H, Kanko TKT, Kantar RS, Karaye IM, Kassa BG, Kemp Bohan PM, Keykhaei M, Khader YS, Khajuria H, Khan G, Khan IA, Khan J, Khan MAB, Khanali J, Khater AM, Khatib MN, Khodadost M, Khoja AT, Khosravizadeh O, Khubchandani J, Kim GR, Kim H, Kim MS, Kim YJ, Kocarnik JM, Kolahi AA, Koteeswaran R, Kumar GA, La Vecchia C, Lal DK, Landires I, Lasrado S, Lazarus JV, Ledda C, Lee DW, Lee SW, Lee YY, Levi M, Li J, Lim SS, Lobo SW, Lopukhov PD, Loureiro JA, MacLachlan JH, Magdy Abd El Razek H, Magdy Abd El Razek M, Majeed A, Makki A, Malekpour MR, Malekzadeh R, Malik AA, Mansour-Ghanaei F, Mansournia MA, Martins-Melo FR, Matthews PC, Mendoza W, Menezes RG, Meretoja TJ, Mersha AG, Mestrovic T, Miller TR, Minh LHN, Mirica A, Mirmoeeni S, Mirrakhimov EM, Misra S, Mithra P, Moazen B, Mohamadkhani A, Mohammadi M, Mohammed S, Moka N, Mokdad AH, Moludi J, Momtazmanesh S, Monasta L, Moradi G, Moradzadeh M, Moradzadeh R, Moraga P, Mostafavi E, Mubarik S, Muniyandi M, Murray CJL, Naghavi M, Naimzada MD, Narasimha Swamy S, Natto ZS, Nayak BP, Nazari J, Negoi I, Negru SM, Nejadghaderi SA, Neupane Kandel S, Nguyen HLT, Ngwa CH, Niazi RK, Nnaji CA, Noubiap JJ, Nowroozi A, Nuñez-Samudio V, Oancea B, Ochir C, Odukoya OO, Oh IH, Olagunju AT, Olakunde BO, Omar Bali A, Omer E, Otstavnov SS, Oumer B, Padubidri JR, Pana A, Pandey A, Park EC, Pashazadeh Kan F, Patel UK, Paudel U, Petcu IR, Piracha ZZ, Pollok RCG, Postma MJ, Pourshams A, Poustchi H, Rabiee M, Rabiee N, Rafiei A, Rafiei S, Raghuram PM, Rahman M, Rahmani AM, Rahmawaty S, Rajesh A, Ranasinghe P, Rao CR, Rao SJ, Rashidi M, Rashidi MM, Rawaf DL, Rawaf S, Rawassizadeh R, Rezaei N, Rezapour A, Rezazadeh-Khadem S, Rodriguez JAB, Rwegerera GM, Sabour S, Saddik B, Saeb MR, Saeed U, Sahebkar A, Saif-Ur-Rahman KM, Salahi S, Salimzadeh H, Sampath C, Samy AM, Sanabria J, Sanmarchi F, Santric-Milicevic MM, Sarveazad A, Sathian B, Sawhney M, Seidu AA, Sepanlou SG, Seylani A, Shahabi S, Shaikh MA, Shaker E, Shakhmardanov MZ, Shannawaz M, Shenoy SM, Shetty JK, Shetty PH, Shibuya K, Shin JI, Shobeiri P, Sibhat MM, Singh AD, Singh JA, Singh S, Skryabin VY, Skryabina AA, Sohrabpour AA, Song S, Tabaeian SP, Tadesse EG, Taheri M, Tampa M, Tan KK, Tavakoli A, Tbakhi A, Tefera BN, Tehrani-Banihashemi A, Tesfaw HM, Thapar R, Thavamani A, Tohidast SA, Tollosa DN, Tosti ME, Tovani-Palone MR, Traini E, Tran MTN, Trihandini I, Tusa BS, Ullah I, Vacante M, Valadan Tahbaz S, Valdez PR, Varthya SB, Vo B, Waheed Y, Weldesenbet AB, Woldemariam M, Xu S, Yahyazadeh Jabbari SH, Yaseri M, Yeshaw Y, Yiğit V, Yirdaw BW, Yonemoto N, Yu C, Yunusa I, Zahir M, Zaki L, Zamani M, Zamanian M, Zastrozhin MS, Vos T, Ward JW, Dirac MA. Global, regional, and national burden of hepatitis B, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Gastroenterol Hepatol 2022; 7:796-829. [PMID: 35738290 PMCID: PMC9349325 DOI: 10.1016/s2468-1253(22)00124-8] [Show More Authors] [Citation(s) in RCA: 387] [Impact Index Per Article: 129.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 04/02/2022] [Accepted: 04/04/2022] [Indexed: 12/23/2022]
Abstract
BACKGROUND Combating viral hepatitis is part of the UN Sustainable Development Goals (SDGs), and WHO has put forth hepatitis B elimination targets in its Global Health Sector Strategy on Viral Hepatitis (WHO-GHSS) and Interim Guidance for Country Validation of Viral Hepatitis Elimination (WHO Interim Guidance). We estimated the global, regional, and national prevalence of hepatitis B virus (HBV), as well as mortality and disability-adjusted life-years (DALYs) due to HBV, as part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019. This included estimates for 194 WHO member states, for which we compared our estimates to WHO elimination targets. METHODS The primary data sources were population-based serosurveys, claims and hospital discharges, cancer registries, vital registration systems, and published case series. We estimated chronic HBV infection and the burden of HBV-related diseases, defined as an aggregate of cirrhosis due to hepatitis B, liver cancer due to hepatitis B, and acute hepatitis B. We used DisMod-MR 2.1, a Bayesian mixed-effects meta-regression tool, to estimate the prevalence of chronic HBV infection, cirrhosis, and aetiological proportions of cirrhosis. We used mortality-to-incidence ratios modelled with spatiotemporal Gaussian process regression to estimate the incidence of liver cancer. We used the Cause of Death Ensemble modelling (CODEm) model, a tool that selects models and covariates on the basis of out-of-sample performance, to estimate mortality due to cirrhosis, liver cancer, and acute hepatitis B. FINDINGS In 2019, the estimated global, all-age prevalence of chronic HBV infection was 4·1% (95% uncertainty interval [UI] 3·7 to 4·5), corresponding to 316 million (284 to 351) infected people. There was a 31·3% (29·0 to 33·9) decline in all-age prevalence between 1990 and 2019, with a more marked decline of 76·8% (76·2 to 77·5) in prevalence in children younger than 5 years. HBV-related diseases resulted in 555 000 global deaths (487 000 to 630 000) in 2019. The number of HBV-related deaths increased between 1990 and 2019 (by 5·9% [-5·6 to 19·2]) and between 2015 and 2019 (by 2·9% [-5·9 to 11·3]). By contrast, all-age and age-standardised death rates due to HBV-related diseases decreased during these periods. We compared estimates for 2019 in 194 WHO locations to WHO-GHSS 2020 targets, and found that four countries achieved a 10% reduction in deaths, 15 countries achieved a 30% reduction in new cases, and 147 countries achieved a 1% prevalence in children younger than 5 years. As of 2019, 68 of 194 countries had already achieved the 2030 target proposed in WHO Interim Guidance of an all-age HBV-related death rate of four per 100 000. INTERPRETATION The prevalence of chronic HBV infection declined over time, particularly in children younger than 5 years, since the introduction of hepatitis B vaccination. HBV-related death rates also decreased, but HBV-related death counts increased as a result of population growth, ageing, and cohort effects. By 2019, many countries had met the interim seroprevalence target for children younger than 5 years, but few countries had met the WHO-GHSS interim targets for deaths and new cases. Progress according to all indicators must be accelerated to meet 2030 targets, and there are marked disparities in burden and progress across the world. HBV interventions, such as vaccination, testing, and treatment, must be strategically supported and scaled up to achieve elimination. FUNDING Bill & Melinda Gates Foundation.
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In Vivo Modelling of Hepatitis B Virus Subgenotype A1 Replication Using Adeno-Associated Viral Vectors. Viruses 2021; 13:v13112247. [PMID: 34835053 PMCID: PMC8618177 DOI: 10.3390/v13112247] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 10/30/2021] [Accepted: 11/04/2021] [Indexed: 12/23/2022] Open
Abstract
The paucity of animal models that simulate the replication of the hepatitis B virus (HBV) is an impediment to advancing new anti-viral treatments. The work reported here employed recombinant adeno-associated viruses (AAVs) to model HBV subgenotype A1 and subgenotype D3 replication in vitro and in vivo. Infection with subgenotype A1 is endemic to parts of sub-Saharan Africa, and it is associated with a high risk of hepatocellular carcinoma. Recombinant AAV serotype 2 (AAV2) and 8 (AAV8) vectors bearing greater-than-genome-length sequences of HBV DNA from subgenotype A1 and D3, were produced. Transduced liver-derived cultured cells produced HBV surface antigen and core antigen. Administration of AAV8 carrying HBV subgenotype A1 genome (AAV8-A1) to mice resulted in the sustained production of HBV replication markers over a six-month period, without elevated inflammatory cytokines, expression of interferon response genes or alanine transaminase activity. Markers of replication were generally higher in animals treated with subgenotype D3 genome-bearing AAVs than in those receiving the subgenotype A1-genome-bearing vectors. To validate the use of the AAV8-A1 murine model for anti-HBV drug development, the efficacy of anti-HBV artificial primary-microRNAs was assessed. Significant silencing of HBV markers was observed over a 6-month period after administering AAVs. These data indicate that AAVs conveniently and safely recapitulate the replication of different HBV subgenotypes, and the vectors may be used to assess antivirals’ potency.
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Clinical and Preclinical Single-Dose Pharmacokinetics of VIR-2218, an RNAi Therapeutic Targeting HBV Infection. Drugs R D 2021; 21:455-465. [PMID: 34741731 PMCID: PMC8602582 DOI: 10.1007/s40268-021-00369-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/06/2021] [Indexed: 12/05/2022] Open
Abstract
Background and Objective VIR-2218 is an investigational N-acetylgalactosamine–conjugated RNA interference therapeutic in development for chronic hepatitis B virus (HBV) infection. VIR-2218 was designed to silence HBV transcripts across all genotypes and uses Enhanced Stabilization Chemistry Plus (ESC+) technology. This study was designed to evaluate the single-dose pharmacokinetics of VIR-2218 in preclinical species and healthy volunteers. Methods Preclinically, a single subcutaneous dose of VIR-2218 (10 mg/kg) was administered to rats and nonhuman primates (NHPs), and the pharmacokinetics were assessed in plasma, urine, and liver using standard noncompartmental analysis (NCA) methods. Clinically, healthy volunteers were randomized (6:2 active:placebo) to receive a single subcutaneous dose of VIR-2218 (50–900 mg) or placebo. Pharmacokinetics were similarly assessed within human plasma and urine using NCA methods. Results In rats and NHPs, VIR-2218 was stable in plasma and was converted to AS(N-1)3’VIR-2218, the most prominent circulating metabolite, at < 10% plasma exposure compared with parent. VIR-2218 rapidly distributed to the liver, reaching peak liver concentrations within 7 and 24 h in rats and NHPs, respectively. In humans, VIR-2218 was rapidly absorbed, with a median time to peak plasma concentration (tmax) of 4–7 h, and had a short median plasma half-life of 2–5 h. Plasma exposures for area under the plasma concentration–time curve up to 12 h (AUC0–12) and mean maximum concentrations (Cmax) increased in a slightly greater-than-dose-proportional manner across the dose range studied. Interindividual pharmacokinetic variability was low to moderate, with a percent coefficient of variation of < 32% for AUC and < 43% for Cmax. A portion of VIR-2218 was converted to an active metabolite, AS(N-1)3’VIR-2218, with a median tmax of 6–10 h, both of which declined below the lower limit of quantification in plasma within 48 h. The pharmacokinetic profile of AS(N-1)3’VIR-2218 was similar to that of VIR-2218, with plasma AUC0–12 and Cmax values ≤ 12% of VIR-2218. VIR-2218 and AS(N-1)3’VIR-2218 were detectable in urine through the last measured time point, with approximately 17–48% of the administered dose recovered in urine as unchanged VIR-2218 over 0–24 h postdose. Based on pharmacokinetics in preclinical species, VIR-2218 localizes to the liver and likely exhibits prolonged hepatic exposure. Overall, no severe or serious adverse events or discontinuations due to adverse events were observed within the dose range evaluated for VIR-2218 in healthy volunteers (Vir Biotechnology, Inc., unpublished data). Conclusions VIR-2218 showed favorable pharmacokinetics in healthy volunteers supportive of subcutaneous dosing and continued development in patients with chronic HBV infection. Clinical Trial Registration No NCT03672188, September 14, 2018. Supplementary Information The online version contains supplementary material available at 10.1007/s40268-021-00369-w.
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Ma X, Liu S, Wang M, Wang Y, Du S, Xin Y, Xuan S. Tenofovir Alafenamide Fumarate, Tenofovir Disoproxil Fumarate and Entecavir: Which is the Most Effective Drug for Chronic Hepatitis B? A Systematic Review and Meta-analysis. J Clin Transl Hepatol 2021; 9:335-344. [PMID: 34221919 PMCID: PMC8237148 DOI: 10.14218/jcth.2020.00164] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 01/23/2021] [Accepted: 03/09/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND AND AIMS The therapeutic effect of tenofovir alafenamide fumarate (TAF), tenofovir disoproxil fumarate (TDF) and entecavir (ETV) on chronic hepatitis B (CHB) patients remains inconsistent. The aim of this study was to explore the differences in virological responses to TAF, TDF and ETV in patients with CHB. METHODS Literature searches were conducted of the PubMed, EMBASE, and the Cochrane Library databases to identify randomized controlled trials and observational studies published up to July 21, 2020. Statistical comparisons of virological response between TDF, ETV, and TAF were carried out with pooled odds ratio (OR) values. RESULTS The virological response in TDF-treated CHB patients was notably superior to that of the ETV-treated CHB patients after 12-weeks [OR=1.12, 95% confidence interval (CI): 0.89-1.41], 24-weeks (OR=1.33, 95% CI: 1.11-1.61), 48-weeks (OR=1.62, 95% CI: 1.16-2.25), 72-weeks (OR=1.43, 95% CI: 0.78-2.62), and 96-weeks (OR=1.56, 95% CI: 0.87-2.81) treatment. No significant difference was observed for the virological responses in CHB patients after 48-weeks treatment with TAF or TDF. The virological response in TDF+ETV-treated CHB patients was superior to that of TDF-treated CHB patients after 24-weeks, 48-weeks (OR=1.54, 95% CI: 1.17-2.02), 96-weeks, and 144-weeks. CONCLUSIONS The virological response in TDF-treated CHB patients was superior to that in ETV-treated CHB patients, but there was no significant difference between TAF and TDF. In addition, the therapeutic effect of TDF+ETV was superior to TDF alone.
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Affiliation(s)
- Xuefeng Ma
- Department of Infectious Disease, Qingdao Municipal Hospital, Qingdao University, Qingdao, Shandong, China
| | - Shousheng Liu
- Clinical Research Center, Qingdao Municipal Hospital, Qingdao University, Qingdao, Shandong, China
- Digestive Disease Key Laboratory of Qingdao, Qingdao, Shandong, China
| | - Mengke Wang
- Department of Infectious Disease, Qingdao Municipal Hospital, Qingdao University, Qingdao, Shandong, China
| | - Yifen Wang
- Department of Infectious Disease, Qingdao Municipal Hospital, Qingdao University, Qingdao, Shandong, China
| | - Shuixian Du
- Department of Infectious Disease, Qingdao Municipal Hospital, Qingdao University, Qingdao, Shandong, China
| | - Yongning Xin
- Department of Infectious Disease, Qingdao Municipal Hospital, Qingdao University, Qingdao, Shandong, China
- Digestive Disease Key Laboratory of Qingdao, Qingdao, Shandong, China
- Correspondence to: Yongning Xin, Department of Infectious Disease, Qingdao Municipal Hospital, 1 Jiaozhou Road, Qingdao, Shandong 266011, China. ORCID: https://orcid.org/0000-0002-3692-7655. Tel: +86-532-8278-9463, Fax: +86-532-8596-8434, E-mail: ; Shiying Xuan, Department of Infectious Disease, Qingdao Municipal Hospital, 1 Jiaozhou Road, Qingdao, Shandong 266011, China. ORCID: https://orcid.org/0000-0002-9849-1877. Tel: +86-532-8890-5508, Fax: +86-532-8890-5293, E-mail:
| | - Shiying Xuan
- Department of Infectious Disease, Qingdao Municipal Hospital, Qingdao University, Qingdao, Shandong, China
- Digestive Disease Key Laboratory of Qingdao, Qingdao, Shandong, China
- Correspondence to: Yongning Xin, Department of Infectious Disease, Qingdao Municipal Hospital, 1 Jiaozhou Road, Qingdao, Shandong 266011, China. ORCID: https://orcid.org/0000-0002-3692-7655. Tel: +86-532-8278-9463, Fax: +86-532-8596-8434, E-mail: ; Shiying Xuan, Department of Infectious Disease, Qingdao Municipal Hospital, 1 Jiaozhou Road, Qingdao, Shandong 266011, China. ORCID: https://orcid.org/0000-0002-9849-1877. Tel: +86-532-8890-5508, Fax: +86-532-8890-5293, E-mail:
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Gu Y, Li X, Gu L, Lian Y, Wang K, Chen Y, Lai J, Mei Y, Liu J, Huang Z, Zhang M, Chen L, Huang Y. An Immuno-Clinic score model for evaluating T cell immunity and predicting early antiviral therapy effectiveness in chronic hepatitis B. Aging (Albany NY) 2020; 12:26063-26079. [PMID: 33401245 PMCID: PMC7803537 DOI: 10.18632/aging.202274] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 11/13/2020] [Indexed: 12/20/2022]
Abstract
We generated an Immuno-Clinic score (ICS) model to evaluate T cell immunity based on the clustering of antiviral cytokines and inhibitory molecules in 229 naïve chronic hepatitis B (CHB) patients. 126 patients receiving antiviral therapy were used to validate the model for predicting antiviral therapy effectiveness. Through receiver-operator characteristic curve analysis, the area under the curve, sensitivity, and specificity of the ICS model were 0.801 (95%CI 0.703-0.900), 0.727, and 0.722, respectively. The cut-off value was 0.442. Re-evaluation of T cell immunity in different phases of CHB showed that patients in the immune tolerant phase had the lowest percentage of ICS-high (15%), while patients in the inactive carrier phase had the highest percentage of ICS-high (92%). Patients in the immune active and gray zone phases had 17% and 56% ICS-high, respectively. Elevation of ICS as early as four weeks after treatment could predict the effectiveness of hepatitis B virus (HBV) DNA loss and normalization of alanine aminotransferase, while eight weeks after treatment could predict HBV surface antigen decline. Thus, this ICS model helps clinicians choose an optimal time for initiating antiviral therapy and predicting its efficacy.
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Affiliation(s)
- Yurong Gu
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Xiaoyan Li
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Lin Gu
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Yifan Lian
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Ke Wang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Youming Chen
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Jing Lai
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Yongyu Mei
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Jing Liu
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Zexuan Huang
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Min Zhang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Lubiao Chen
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Yuehua Huang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China.,Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
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Guvenir M, Arikan A. Hepatitis B Virus: From Diagnosis to Treatment. Pol J Microbiol 2020; 69:391-399. [PMID: 33574867 PMCID: PMC7812357 DOI: 10.33073/pjm-2020-044] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 09/22/2020] [Accepted: 09/24/2020] [Indexed: 02/07/2023] Open
Abstract
Hepatitis B infection is still a global concern progressing as acute-chronic hepatitis, severe liver failure, and death. The infection is most widely transmitted from the infected mother to a child, with infected blood and body fluids. Pregnant women, adolescents, and all adults at high risk of chronic infection are recommended to be screened for hepatitis B infection. The initial analysis includes serological tests that allow differentiation of acute and chronic hepatitis. Molecular assays performed provide detection and quantification of viral DNA, genotyping, drug resistance, and precore/core mutation analysis to confirm infection and monitor disease progression in chronic hepatitis B patients. All patients with chronic hepatitis B should be treated with antiviral medications and regularly monitored for efficient treatment. The current treatment is based on nucleos(t)ide analogs and pegylated interferons that save lives by decreasing liver cancer death, liver transplant, slow or reverse the progression of liver disease as well as the virus infectivity.
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Affiliation(s)
- Meryem Guvenir
- Near East University, Vocational School of Health Services, Nicosia, Northern Cyprus
| | - Ayse Arikan
- Near East University, Faculty of Medicine, Department of Medical Microbiology, Nicosia, Northern Cyprus
- Near East University, DESAM Institute, Nicosia, Northern Cyprus
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19
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Gu Y, Lian Y, Zheng Q, Huang Z, Gu L, Bi Y, Li J, Huang Y, Wu Y, Chen L, Huang Y. Association among cytokine profiles of innate and adaptive immune responses and clinical-virological features in untreated patients with chronic hepatitis B. BMC Infect Dis 2020; 20:509. [PMID: 32664850 PMCID: PMC7362653 DOI: 10.1186/s12879-020-05233-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Accepted: 07/07/2020] [Indexed: 02/07/2023] Open
Abstract
Background Complete clearance of intracellular viruses depends on effector cells of innate and adaptive immune systems. This study aimed to identify the relationships among antiviral cytokines produced by natural killer (NK) and T cells and clinical-virological characteristics in untreated chronic hepatitis B (CHB) patients. Methods We measured antiviral cytokines interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and interleukin-2 (IL-2) produced by T, NK and natural killer T (NKT) cells, respectively, in a cohort with chronic hepatitis B virus (HBV) infection (CHB). We also correlated these cytokines with clinical-virological characteristics using a linear regression model. Results levels of IFN-γ+ and TNF-α+ CD4+ and CD8+ T cells were significantly higher in immune active (IA) phase than in other phases. Immune tolerant (IT) patients showed the lowest expression of IFN-γ by NK and NKT cells, and TNF-α by NK cells. IFN-γ+, TNF-α+ and IL-2+ CD4+ and CD8+ T cells frequencies were similar between IA and gray zone (GZ) phases. Principal component analysis based on cytokines confirmed that most IT patients significantly differed from inactive carriers (IC) and IA patients, while GZ patients were widely scattered. Multivariate analysis showed both T and NK cells producing IFN-γ and TNF-α, but not IL-2, had significant association with serum alanine aminotransferase (ALT). Moreover, IFN-γ+ NKT cells were associated with HBV DNA, while IFN-γ+ CD4+ and CD8+ T cells were correlated with age. Conclusion HBV clinical phases are characterized by distinct cytokine signatures, which showed relationship to viral features in these untreated CHB patients.
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Affiliation(s)
- Yurong Gu
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tian He Rd, Guangzhou, 510630, China
| | - Yifan Lian
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tian He Rd, Guangzhou, 510630, China
| | - Qiaolan Zheng
- Journal Center, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tian He Rd, Guangzhou, 510630, China
| | - Zexuan Huang
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tian He Rd, Guangzhou, 510630, China
| | - Lin Gu
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tian He Rd, Guangzhou, 510630, China
| | - Yanhua Bi
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tian He Rd, Guangzhou, 510630, China
| | - Jing Li
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tian He Rd, Guangzhou, 510630, China
| | - Yanlin Huang
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tian He Rd, Guangzhou, 510630, China
| | - Yuankai Wu
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tian He Rd, Guangzhou, 510630, China
| | - Lubiao Chen
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tian He Rd, Guangzhou, 510630, China.
| | - Yuehua Huang
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tian He Rd, Guangzhou, 510630, China. .,Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tian He Rd, Guangzhou, 510630, China.
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20
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Wu FP, Yang Y, Li M, Liu YX, Li YP, Wang WJ, Shi JJ, Zhang X, Jia XL, Dang SS. Add-on pegylated interferon augments hepatitis B surface antigen clearance vs continuous nucleos(t)ide analog monotherapy in Chinese patients with chronic hepatitis B and hepatitis B surface antigen ≤ 1500 IU/mL: An observational study. World J Gastroenterol 2020; 26:1525-1539. [PMID: 32308352 PMCID: PMC7152523 DOI: 10.3748/wjg.v26.i13.1525] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 01/09/2020] [Accepted: 03/09/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Nucleos(t)ide analog (NA) has shown limited effectiveness against hepatitis B surface antigen (HBsAg) clearance in chronic hepatitis B (CHB) patients. AIM To evaluate the efficacy and safety of add-on peginterferon α-2a (peg-IFN α-2a) to an ongoing NA regimen in CHB patients. METHODS In this observational study, 195 CHB patients with HBsAg ≤ 1500 IU/mL, hepatitis B e antigen (HBeAg)-negative (including HBeAg-negative patients or HBeAg-positive patients who achieved HBeAg-negative after antiviral treatment with NA) and hepatitis B virus-deoxyribonucleic acid < 1.0 × 102 IU/mL after over 1 year of NA therapy were enrolled between November 2015 and December 2018 at the Second Affiliated Hospital of Xi'an Jiaotong University, China. Patients were given the choice between receiving either peg-IFN α-2a add-on therapy to an ongoing NA regimen (add-on group, n = 91) or continuous NA monotherapy (monotherapy group, n = 104) after being informed of the benefits and risks of the peg-IFN α-2a therapy. Total therapy duration of peg-IFN α-2a was 48 wk. All patients were followed-up to week 72 (24 wk after discontinuation of peg-IFN α-2a). The primary endpoint was the proportion of patients with HBsAg clearance at week 72. RESULTS Demographic and baseline characteristics were comparable between the two groups. Intention-to-treatment analysis showed that the HBsAg clearance rate in the add-on group and monotherapy group was 37.4% (34/91) and 1.9% (2/104) at week 72, respectively. The HBsAg seroconversion rate in the add-on group was 29.7% (27/91) at week 72, and no patient in the monotherapy group achieved HBsAg seroconversion at week 72. The HBsAg clearance and seroconversion rates in the add-on group were significantly higher than in the monotherapy group at week 72 (P < 0.001). Younger patients, lower baseline HBsAg concentration, lower HBsAg concentrations at weeks 12 and 24, greater HBsAg decline from baseline to weeks 12 and 24 and the alanine aminotransferase ≥ 2 × upper limit of normal during the first 12 wk of therapy were strong predictors of HBsAg clearance in patients with peg-IFN α-2a add-on treatment. Regarding the safety of the treatment, 4.4% (4/91) of patients in the add-on group discontinued peg-IFN α-2a due to adverse events. No severe adverse events were noted. CONCLUSION Peg-IFN α-2a as an add-on therapy augments HBsAg clearance in HBeAg-negative CHB patients with HBsAg ≤ 1500 IU/mL after over 1 year of NA therapy.
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Affiliation(s)
- Feng-Ping Wu
- Department of Infectious Diseases, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, China
| | - Ying Yang
- Department of Infectious Diseases, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, China
| | - Mei Li
- Department of Infectious Diseases, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, China
| | - Yi-Xin Liu
- Department of Infectious Diseases, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, China
| | - Ya-Ping Li
- Department of Infectious Diseases, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, China
| | - Wen-Jun Wang
- Department of Infectious Diseases, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, China
| | - Juan-Juan Shi
- Department of Infectious Diseases, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, China
| | - Xin Zhang
- Department of Infectious Diseases, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, China
| | - Xiao-Li Jia
- Department of Infectious Diseases, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, China
| | - Shuang-Suo Dang
- Department of Infectious Diseases, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, China
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On the future of therapeutic vaccination in chronic hepatitis B. Future Sci OA 2019; 5:FSO426. [PMID: 31827895 PMCID: PMC6900968 DOI: 10.2144/fsoa-2019-0104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
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Liu Y, Jin J, Ji J, Gao XM, Fan YC. Tumor necrosis factor-α-induced protein 8-like 2 mRNA in peripheral blood mononuclear cells is associated with the disease progression of chronic hepatitis B virus infection. Virol J 2019; 16:120. [PMID: 31661000 PMCID: PMC6819530 DOI: 10.1186/s12985-019-1224-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2019] [Accepted: 09/23/2019] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Tumor necrosis factor-alpha-induced protein 8-like 2 (TIPE2) is a novel target and molecule in the negative regulation of immune homeostasis. The present study aimed to investigate the dynamic expression of TIPE2 mRNA during the progression of chronic hepatitis B virus (HBV) infection. METHODS A total of 193 patients with chronic HBV infection were retrospectively recruited into this cross-sectional study, including 97 patients with chronic hepatitis B (CHB), 55 with liver cirrhosis and 41 with HBV-related hepatocellular carcinoma (HCC). TIPE2 mRNA was determined using real-time quantitative polymerase chain reaction. RESULTS The expression of TIPE2 levels in patients with HCC was significantly decreased compared with expression in patients with liver cirrhosis, CHB and healthy controls (P < 0.05); meanwhile, the TIPE2 mRNA levels in patients with CHB and liver cirrhosis were significantly increased compared with levels in healthy controls (P < 0.01). In liver cirrhosis, the TIPE2 mRNA level in the decompensated state was significantly higher than that in the compensated state (P < 0.05). In HCC patients, TIPE2 mRNA was significantly associated with venous invasion, tumor size and tumor node metastasis stage. Furthermore, the optimal cutoff of 0.78 for the level of TIPE2 mRNA has a sensitivity of 97.56% and a specificity of 88.16% for discriminating HCC from patients with CHB and liver cirrhosis. CONCLUSIONS TIPE2 mRNA was associated with various stages of chronic HBV infection, ranging from CHB to liver cirrhosis and HCC. Furthermore, TIPE2 mRNA with an optional cutoff value of 0.78 might serve as a promising biomarker to discriminate HBV-associated HCC from CHB and LC patients.
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Affiliation(s)
- Yi Liu
- Department of Gastroenterology, Shanxian Central Hospital, Heze, 274399, China
| | - Jia Jin
- Department of Cardiology, Zhangqiu District People's Hospital of Jinan, Jinan, 250200, China
| | - Jian Ji
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, 250012, China
| | - Xi-Mei Gao
- Department of International Medicine, Qilu Hospital of Shandong University, Wenhuaxi Road 107#, Jinan, 250012, China.
| | - Yu-Chen Fan
- Department of Hepatology, Qilu Hospital of Shandong University, Wenhuaxi Road 107#, Jinan, 250012, China.
- Department of Immunology, Shandong University School of Basic Medical Science, Shandong University, Wenhuaxi Road 44#, Jinan, 250012, Shandong, China.
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Xiong X, Lei F, Haque M, Song J. Stem Cell-Derived Viral Ag-Specific T Lymphocytes Suppress HBV Replication in Mice. J Vis Exp 2019. [PMID: 31609353 DOI: 10.3791/60043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
Abstract
Hepatitis B virus (HBV) infection is a global health issue. With over 350 million people affected worldwide, HBV infection remains the leading cause of liver cancer. This is a major concern, especially in developing countries. Failure of the immune system to mount an effective response against HBV leads to chronic infection. Although HBV vaccine is present and novel antiviral medicines are being created, eradication of virus-reservoir cells remains a major health topic. Described here is a method for the generation of viral antigen (Ag) -specific CD8+ cytotoxic T lymphocytes (CTLs) derived from induced pluripotent stem cells (iPSCs) (i.e., iPSC-CTLs), which have the ability to suppress HBV replication. HBV replication is efficiently induced in mice through hydrodynamic injection of an HBV expression plasmid, pAAV/HBV1.2, into the liver. Then, HBV surface Ag-specific mouse iPSC-CTLs are adoptively transferred, which greatly suppresses HBV replication in the liver and blood as well as prevents HBV surface Ag expression in hepatocytes. This method demonstrates HBV replication in mice after hydrodynamic injection and that stem cell-derived viral Ag-specific CTLs can suppress HBV replication. This protocol provides a useful method for HBV immunotherapy.
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Affiliation(s)
- Xiaofang Xiong
- Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center
| | - Fengyang Lei
- Department of Ophthalmology, Harvard Medical School
| | - Mohammad Haque
- Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center
| | - Jianxun Song
- Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center;
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Oliveira MSD, Silva RPM, Valle SDCND, Souza RMD, Figueiredo END, Taminato M, Fram DS. Hepatitis B and Delta: clinical aspects of patients in the Brazilian Western Amazonia. Rev Bras Enferm 2019; 72:1265-1270. [PMID: 31531650 DOI: 10.1590/0034-7167-2018-0100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Accepted: 08/13/2018] [Indexed: 11/21/2022] Open
Abstract
OBJECTIVE to analyze clinical, serological, biochemical and hematological aspects in patients infected with the hepatitis B (HBV) and Delta (HDV) viruses. METHOD cross-sectional, descriptive and retrospective study, performed with patients chronically infected with HBV and superinfected with HDV. RESULTS among the 112 patients selected, 74% were monoinfected with HBV (Group HBV) and 26% were superinfected with HDV (Group HBV+HDV). There was no difference in gender distribution. The average age was 36 years with standard deviation of ±12 years. The symptoms and signs presented a higher proportion in Group HBV+HDV (p=0.001). In both groups, most patients had non-reactive AgHBe. The records of biochemical and hematologic changes showed highest proportion in Group VHB+VHD Group (p<0.05). CONCLUSION the study found that patients were in clinical stages of the disease different from those in the initial examination for monitoring their chronic condition. The clinical profile suggests greater severity of liver disease among the patients superinfected with HDV.
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Affiliation(s)
| | | | | | | | | | - Mônica Taminato
- Universidade Federal de São Paulo. São Paulo, São Paulo, Brazil
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Tenofovir Response Rate and Adverse Effects in Patients with Chronic Hepatitis B Attending to Hepatitis Clinic at Labbafinejad Hospital. Jundishapur J Nat Pharm Prod 2019. [DOI: 10.5812/jjnpp.63023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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26
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Hagiwara S, Nishida N, Ida H, Ueshima K, Minami Y, Takita M, Komeda Y, Kudo M. Switching from entecavir to tenofovir alafenamide versus maintaining entecavir for chronic hepatitis B. J Med Virol 2019; 91:1804-1810. [PMID: 31199513 DOI: 10.1002/jmv.25515] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Accepted: 06/09/2019] [Indexed: 12/26/2022]
Abstract
Tenofovir alafenamide (TAF) is a newly developed prodrug of tenofovir (TFV). We divided 48 chronic hepatitis B patients who had taken entecavir (ETV) for ≥2 years into two groups: the ETV continuation (n = 24) and the TAF switching (n = 24) groups, and compared the antiviral effects and safety until 48 weeks after the start of the study. There were no significant differences in the alterations in the serum levels of HBs antigen (HBsAg) level between the ETV continuation and the TAF switching groups at 24 or 48 weeks. We also examined the effect of baseline HBsAg level on the decrease of HBsAg during the treatment; in the TAF switching group, the decrease of HBsAg level at 48 weeks was more significant in patients with low baseline HBsAg (<800 IU/mL) than those with high baseline HBsAg ( >800 IU/mL) (change of HBsAg; - 0.029 vs - 0.132 for high and low baseline HBsAg, respectively, P = .007). Also, the effect on renal function was found to be comparable between the TAF switch group and the ETV continuation group. In this study, switching from ETV to TAF may represent higher efficacy for a decrease of HBsAg than a continuation of ETV among the patients with low baseline HBsAg level.
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Affiliation(s)
- Satoru Hagiwara
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, Osakasayama, Japan
| | - Naoshi Nishida
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, Osakasayama, Japan
| | - Hiroshi Ida
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, Osakasayama, Japan
| | - Kazuomi Ueshima
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, Osakasayama, Japan
| | - Yasunori Minami
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, Osakasayama, Japan
| | - Masahiro Takita
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, Osakasayama, Japan
| | - Yoriaki Komeda
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, Osakasayama, Japan
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, Osakasayama, Japan
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Design, Synthesis, and Bioactive Screen In Vitro of Cyclohexyl ( E)-4-(Hydroxyimino)-4-Phenylbutanoates and Their Ethers for Anti-Hepatitis B Virus Agents. Molecules 2019; 24:molecules24112063. [PMID: 31151219 PMCID: PMC6600592 DOI: 10.3390/molecules24112063] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Revised: 05/24/2019] [Accepted: 05/27/2019] [Indexed: 12/14/2022] Open
Abstract
A series of oxime Cyclohexyl (E)-4-(hydroxyimino)-4-phenylbutanoates and their ethers were designed, synthesized, and evaluated for anti-hepatitis B virus (HBV) activities with HepG 2.2.15 cell line in vitro. Most of these compounds possessed anti-HBV activities, and among them, compound 4B-2 showed significant inhibiting effects on the secretion of HBsAg (IC50 = 63.85 ± 6.26 μM, SI = 13.41) and HBeAg (IC50 = 49.39 ± 4.17 μM, SI = 17.34) comparing to lamivudine (3TC) in HBsAg (IC50 = 234.2 ± 17.17 μM, SI = 2.2) and HBeAg (IC50 = 249.9 ± 21.51 μM, SI = 2.07). Docking study of these compounds binding to a protein residue (PDB ID: 3OX8) from HLA-A2 that with the immunodominant HBcAg18–27 epitope (HLA-A2.1- restricted CTL epitope) active site was carried out by using molecular operation environment (MOE) software. Docking results showed that behaviors of these compounds binding to the active site in HLA-A protein residue partly coincided with their behaviors in vitro anti-HBV active screening.
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Paccoud O, Surgers L, Lacombe K. [Hepatitis B virus infection: Natural history, clinical manifestations and therapeutic approach]. Rev Med Interne 2019; 40:590-598. [PMID: 30982550 DOI: 10.1016/j.revmed.2019.03.333] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Revised: 03/16/2019] [Accepted: 03/23/2019] [Indexed: 12/15/2022]
Abstract
Chronic hepatitis B infection remains a major public-health problem, with approximately 260 million world-wide cases of infection. Recent advances in the understanding of the natural history of chronic hepatitis B infection have led to progress in the care of infected patients. Sustained viral suppression is now possible for a majority of treated patients and is associated with a decrease in the morbidity and mortality attributable to cirrhosis and hepatocellular carcinoma. Complete cure is however not yet possible, due to the long-term persistence of viral DNA in hepatocytes of treated patients. Assessing the risk of viral reactivation in patients receiving immunosuppressive therapy is an increasingly frequent situation in clinical practice and its management is guided by both the patient's serological status and the potency of the immunosuppressive regimen. This review aims to present the clinical and biological presentations of chronic hepatitis B infection, the modalities of antiviral treatment, and how to assess the risk of viral reactivation in patients receiving immunosuppressive therapy.
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Affiliation(s)
- O Paccoud
- Service des maladies infectieuses et tropicales, hôpital Saint-Antoine, AP-HP, 75012 Paris, France
| | - L Surgers
- Service des maladies infectieuses et tropicales, hôpital Saint-Antoine, AP-HP, 75012 Paris, France; Sorbonne université, CIMI équipe 13, Inserm U1135, 75005 Paris, France
| | - K Lacombe
- Service des maladies infectieuses et tropicales, hôpital Saint-Antoine, AP-HP, 75012 Paris, France; Sorbonne université, Inserm UMR-S1136, IPLESP, 75005 Paris, France.
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Antiviral Therapy for AECHB and Severe Hepatitis B (Liver Failure). ACUTE EXACERBATION OF CHRONIC HEPATITIS B 2019. [PMCID: PMC7498919 DOI: 10.1007/978-94-024-1603-9_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
This chapter describes the principles of antiviral therapy, treatment strategies, medications and recommendations for AECHB, HBV-ACLF, HBV-related liver cirrhosis, HBV-related HCC, and liver transplantation.
Severe exacerbation of chronic hepatitis B is closely related to continuous HBV replication. Therefore, inhibiting HBV replication to reduce viral load may block disease progression and improve the quality of life of these patients. ETV or TDF has been recommend first-line drug for the treatment of AECHB. A hyperactive immune response due to continuous HBV replication is the main mechanism for development of severe hepatitis B. In addition to comprehensive treatment, early administration of potent nucleoside analogs can rapidly reduce HBV DNA concentration, relieve immune injury induced by HBV, and reduce liver inflammation and patient mortality. Antiviral agents have become important in the treatment of severe exacerbation of chronic hepatitis B. Long-term antiviral treatment with nucleoside analogs can delay or reverse the progress of liver cirrhosis. Virologic response, viral resistance and adverse drug reactions should be closely monitored during treatment. The treatment should be optimized for maximum effect based on each patient’s responses. Effective antiviral therapy can suppress HBV replication and reduce the incidence of HBV-related HCC. Patients with HBV-related HCC should receive individualized and optimal multidisciplinary comprehensive treatment. Anti-viral drugs with high efficacy, low resistance and low adverse drug reactions should be selected to improve the patient’s quality of life and prolong survival time. Methods to prevent HBV reinfection after liver transplantation include passive immunization (HBIG), antiviral treatment (nucleoside analogs) and active immunization (hepatitis B vaccine). Clinical trials involving sequential combination therapy with NUC and Peg-IFN have shown statistically significant decline in HBsAg levels on treatment and high rates of sustained post-treatment serologic response. Combination therapy with novel DAA and immunotherapeutic approach may hold promise to overcome both cccDNA persistence and immune escape, representing a critical step towards HBV cure.
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Nair S, Li L, Francis S, Turner WW, VanNieuwenhze M, Zlotnick A. Use of a Fluorescent Analogue of a HBV Core Protein-Directed Drug To Interrogate an Antiviral Mechanism. J Am Chem Soc 2018; 140:15261-15269. [PMID: 30375863 DOI: 10.1021/jacs.8b07988] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Heteroaryldihydropyrimidines (HAPs) are antiviral small molecules that enhance assembly of HBV core protein (Cp), lead to assembly of empty and defective particles, and suppress viral replication. These core protein allosteric modulators (CpAMs) bind to the pocket at the interface between two Cp dimers and strengthen interdimer interactions. To investigate the CpAM mechanism, we wanted to examine the cellular distributions of Cp and the CpAM itself. For this reason, we developed a fluorescently labeled CpAM, HAP-ALEX. In vitro, HAP-ALEX modulated assembly of purified Cp and at saturating concentrations induced formation of large structures. HAP-ALEX bound capsids and not dimers, making it a capsid-specific molecular tag. HAP-ALEX labeled HBV in transfected cells, with no detectable background with a HAP-insensitive Cp mutant. HAP-ALEX caused redistribution of Cp in a dose-dependent manner consistent with its 0.7 μM EC50, leading to formation of large puncta and an exclusively cytoplasmic distribution. HAP-ALEX colocalized with the redistributed Cp, but large puncta accumulated long before they appeared saturated with the fluorescent CpAM. CpAMs affect HBV assembly and localization; with a fluorescent CpAM both drug and target can be identified.
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Affiliation(s)
- Smita Nair
- Molecular and Cellular Biochemistry , Indiana University , Bloomington , Indiana 47405 , United States
| | - Lichun Li
- Molecular and Cellular Biochemistry , Indiana University , Bloomington , Indiana 47405 , United States.,Assembly BioSciences , Carmel , Indiana 45032 , United States
| | - Samson Francis
- Assembly BioSciences , Carmel , Indiana 45032 , United States
| | - William W Turner
- Molecular and Cellular Biochemistry , Indiana University , Bloomington , Indiana 47405 , United States.,Assembly BioSciences , Carmel , Indiana 45032 , United States
| | - Michael VanNieuwenhze
- Department of Chemistry , Indiana University , Bloomington , Indiana 47405 , United States
| | - Adam Zlotnick
- Molecular and Cellular Biochemistry , Indiana University , Bloomington , Indiana 47405 , United States
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31
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Han X, Zhou C, Jiang M, Wang Y, Wang J, Cheng Z, Wang M, Liu Y, Liang C, Wang J, Wang Z, Weikert R, Lv W, Xie J, Yu X, Zhou X, Luangsay S, Shen HC, Mayweg AV, Javanbakht H, Yang S. Discovery of RG7834: The First-in-Class Selective and Orally Available Small Molecule Hepatitis B Virus Expression Inhibitor with Novel Mechanism of Action. J Med Chem 2018; 61:10619-10634. [PMID: 30286292 DOI: 10.1021/acs.jmedchem.8b01245] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Chronic hepatitis B virus (HBV) infection is a serious public health burden, and current therapies cannot achieve satisfactory cure rate. There are high unmet medical needs of novel therapeutic agents with differentiated mechanism of action (MOA) from the current standard of care. RG7834, a compound from the dihydroquinolizinone (DHQ) chemical series, is a first-in-class highly selective and orally bioavailable HBV inhibitor which can reduce both viral antigens and viral DNA with a novel mechanism of action. Here we report the discovery of RG7834 from a phenotypic screening and the structure-activity relationship (SAR) of the DHQ chemical series. RG7834 can selectively inhibit HBV but not other DNA or RNA viruses in a virus panel screening. Both in vitro and in vivo profiles of RG7834 are described herein, and the data support further development of this compound as a chronic HBV therapy.
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Developments in Cell-Penetrating Peptides as Antiviral Agents and as Vehicles for Delivery of Peptide Nucleic Acid Targeting Hepadnaviral Replication Pathway. Biomolecules 2018; 8:biom8030055. [PMID: 30013006 PMCID: PMC6165058 DOI: 10.3390/biom8030055] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Revised: 07/10/2018] [Accepted: 07/11/2018] [Indexed: 12/11/2022] Open
Abstract
Alternative therapeutic approaches against chronic hepatitis B virus (HBV) infection need to be urgently developed because current therapies are only virostatic. In this context, cell penetration peptides (CPPs) and their Peptide Nucleic Acids (PNAs) cargoes appear as a promising novel class of biologically active compounds. In this review we summarize different in vitro and in vivo studies, exploring the potential of CPPs as vehicles for intracellular delivery of PNAs targeting hepadnaviral replication. Thus, studies conducted in the duck HBV (DHBV) infection model showed that conjugation of (D-Arg)8 CPP to PNA targeting viral epsilon (ε) were able to efficiently inhibit viral replication in vivo following intravenous administration to ducklings. Unexpectedly, some CPPs, (D-Arg)8 and Decanoyl-(D-Arg)8, alone displayed potent antiviral effect, altering late stages of DHBV and HBV morphogenesis. Such antiviral effects of CPPs may affect the sequence-specificity of CPP-PNA conjugates. By contrast, PNA conjugated to (D-Lys)4 inhibited hepadnaviral replication without compromising sequence specificity. Interestingly, Lactose-modified CPP mediated the delivery of anti-HBV PNA to human hepatoma cells HepaRG, thus improving its antiviral activity. In light of these promising data, we believe that future studies will open new perspectives for translation of CPPs and CPP-PNA based technology to therapy of chronic hepatitis B.
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Naito Y, Hamada-Tsutsumi S, Yamamoto Y, Kogure A, Yoshioka Y, Watashi K, Ochiya T, Tanaka Y. Screening of microRNAs for a repressor of hepatitis B virus replication. Oncotarget 2018; 9:29857-29868. [PMID: 30042818 PMCID: PMC6057454 DOI: 10.18632/oncotarget.25557] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Accepted: 05/13/2018] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) infection is a leading cause of persistent liver diseases, cirrhosis and hepatocellular carcinoma (HCC) worldwide. Since deregulation of microRNA (miRNA) expression by HBV infection contributes to enhanced viral replication and pathogenesis, modulation of miRNA activity can be a novel therapeutic approach towards HBV eradication. As the effects of the vast majority of miRNAs on HBV replication have not been empirically investigated, here, we aim to identify novel therapeutic targets that have a strong antiviral effect on HBV. METHODS HepG2-hNTCP-C4 cells were infected with HBV, and then were individually transfected with the library mimics of 2048 miRNAs. To assess the amount of intracellular and extracellular DNA and HBsAg, qPCR and ELISA were performed respectively. RESULTS From miRNA library screening, we identified 39 miRNAs as candidate repressors of HBV replication. Among them, 9 miRNAs, including miR-204, strongly decreased both HBV DNA and HBsAg in culture supernatant of HepG2-hNTCP-C4 cells. Furthermore, we also showed that inhibition of Rab22a, one of the targets of miR-204, also suppressed intracellular and extracellular HBV DNA expression in HepG2.2.15.7 cells. CONCLUSIONS Our findings contribute to the understanding of the roles of miRNAs underlying HBV replication and show the possibility of developing a novel strategy for miRNA-mediated HBV treatment.
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Affiliation(s)
- Yutaka Naito
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan
| | - Susumu Hamada-Tsutsumi
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Yusuke Yamamoto
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan
| | - Akiko Kogure
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan
| | - Yusuke Yoshioka
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan
| | - Koichi Watashi
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Takahiro Ochiya
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
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Shire NJ. Cure Strategies for Hepatitis B Virus: The Promise of Immunotherapy. Clin Pharmacol Drug Dev 2018; 6:186-194. [PMID: 28263466 DOI: 10.1002/cpdd.317] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2016] [Accepted: 10/05/2016] [Indexed: 12/13/2022]
Abstract
Chronic hepatitits B virus remains a public health challenge, infecting more than 240 million people globally and causing 600,000 deaths per year from end-stage liver disease and/or hepatocellular carcinoma. Current antiviral therapeutic agents are highly effective at blocking viral replication, but discontinuation of therapy prior to loss of hepatitis B surface antigen generally leads to relapse. New modalities that target host factors of viral persistence such as immune response pathway inhibition hold promise. Other experimental approaches may target virally related persistence factors, including covalently closed circular DNA. All these approaches will require creative new means of assessing proof of biology and proof of mechanism, particularly in the relevant compartment of liver tissue. Furthermore, it is likely to require combinations of modalities in defined patient populations to achieve optimal response. A precompetitive consortium approach may enable companies, regulators, and academic researchers to share best practices and evaluate preclinical and clinical pathways for these novel approaches.
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Abstract
With high morbidity and mortality worldwide, there is great interest in effective therapies for chronic hepatitis B (CHB) virus. There are currently several dozen investigational agents being developed for treatment of CHB. They can be broadly divided into two categories: (1) direct-acting antivirals (DAAs) that interfere with a specific step in viral replication; and (2) host-targeting agents that inhibit viral replication by modifying host cell function, with the latter group further divided into the subcategories of immune modulators and agents that target other host functions. Included among the DAAs being developed are RNA interference therapies, covalently closed circular DNA (cccDNA) formation and transcription inhibitors, core/capsid inhibitors, reverse transcriptase inhibitors, hepatitis B surface antigen (HBsAg) release inhibitors, antisense oligonucleotides, and helioxanthin analogues. Included among the host-targeting agents are entry inhibitors, cyclophilin inhibitors, and multiple immunomodulatory agents, including Toll-like receptor agonists, immune checkpoint inhibitors, therapeutic vaccines, engineered T cells, and several cytokine agents, including recombinant human interleukin-7 (CYT107) and SB 9200, a novel therapy that is believed to both have direct antiviral properties and to induce endogenous interferon. In this review we discuss agents that are currently in the clinical stage of development for CHB treatment as well as strategies and agents currently at the evaluation and discovery phase and potential future targets. Effective approaches to CHB may require suppression of viral replication combined with one or more host-targeting agents. Some of the recent research advances have led to the hope that with such a combined approach we may have a functional cure for CHB in the not distant future.
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Affiliation(s)
- Altaf Dawood
- Department of Internal Medicine, Section of Gastroenterology, University of Nevada School of Medicine, Las Vegas, NV, USA
| | - Syed Abdul Basit
- Department of Internal Medicine, Section of Gastroenterology, University of Nevada School of Medicine, Las Vegas, NV, USA
| | - Mahendran Jayaraj
- Department of Internal Medicine, Section of Gastroenterology, University of Nevada School of Medicine, Las Vegas, NV, USA
| | - Robert G Gish
- Department of Internal Medicine, Section of Gastroenterology, University of Nevada School of Medicine, Las Vegas, NV, USA.
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Stanford, CA, USA.
- Hepatitis B Foundation, Doylestown, PA, USA.
- Asian Pacific Health Foundation, San Diego, CA, USA.
- National Viral Hepatitis Roundtable, Washington, DC, USA.
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Asymmetric Modification of Hepatitis B Virus (HBV) Genomes by an Endogenous Cytidine Deaminase inside HBV Cores Informs a Model of Reverse Transcription. J Virol 2018; 92:JVI.02190-17. [PMID: 29491156 DOI: 10.1128/jvi.02190-17] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2017] [Accepted: 02/20/2018] [Indexed: 02/07/2023] Open
Abstract
Cytidine deaminases inhibit replication of a broad range of DNA viruses by deaminating cytidines on single-stranded DNA (ssDNA) to generate uracil. While several lines of evidence have revealed hepatitis B virus (HBV) genome editing by deamination, it is still unclear which nucleic acid intermediate of HBV is modified. Hepatitis B virus has a relaxed circular double-stranded DNA (rcDNA) genome that is reverse transcribed within virus cores from a RNA template. The HBV genome also persists as covalently closed circular DNA (cccDNA) in the nucleus of an infected cell. In the present study, we found that in HBV-producing HepAD38 and HepG2.2.15 cell lines, endogenous cytidine deaminases edited 10 to 25% of HBV rcDNA genomes, asymmetrically with almost all mutations on the 5' half of the minus strand. This region corresponds to the last half of the minus strand to be protected by plus-strand synthesis. Within this half of the genome, the number of mutations peaks in the middle. Overexpressed APOBEC3A and APOBEC3G could be packaged in HBV capsids but did not change the amount or distribution of mutations. We found no deamination on pregenomic RNA (pgRNA), indicating that an intact genome is encapsidated and deaminated during or after reverse transcription. The deamination pattern suggests a model of rcDNA synthesis in which pgRNA and then newly synthesized minus-sense single-stranded DNA are protected from deaminase by interaction with the virus capsid; during plus-strand synthesis, when enough dsDNA has been synthesized to displace the remaining minus strand from the capsid surface, the single-stranded DNA becomes deaminase sensitive.IMPORTANCE Host-induced mutation of the HBV genome by APOBEC proteins may be a path to clearing the virus. We examined cytidine-to-thymidine mutations in the genomes of HBV particles grown in the presence or absence of overexpressed APOBEC proteins. We found that genomes were subjected to deamination activity during reverse transcription, which takes place within the virus capsid. These observations provide a direct insight into the mechanics of reverse transcription, suggesting that newly synthesized dsDNA displaces ssDNA from the capsid walls, making the ssDNA accessible to deaminase activity.
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Tan J, Zhou M, Cui X, Wei Z, Wei W. Discovery of Oxime Ethers as Hepatitis B Virus (HBV) Inhibitors by Docking, Screening and In Vitro Investigation. Molecules 2018. [PMID: 29534537 PMCID: PMC6017342 DOI: 10.3390/molecules23030637] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
A series of oxime ethers with C6-C4 fragment was designed and virtually bioactively screened by docking with a target, then provided by a Friedel–Crafts reaction, esterification (or amidation), and oximation from p-substituted phenyl derivatives (Methylbenzene, Methoxybenzene, Chlorobenzene). Anti-hepatitis B virus (HBV) activities of all synthesized compounds were evaluated with HepG2.2.15 cells in vitro. Results showed that most of compounds exhibited low cytotoxicity on HepG2.2.15 cells and significant inhibition on the secretion of HBsAg and HBeAg. Among them, compound 5c-1 showed the most potent activity on inhibiting HBsAg secretion (IC50 = 39.93 μM, SI = 28.51). Results of the bioactive screening showed that stronger the compounds bound to target human leukocyte antigen A protein in docking, the more active they were in anti-HBV activities in vitro.
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Affiliation(s)
- Jie Tan
- College of Chemistry and Chemical Engineering, Guangxi University, Nanning 53004, China.
| | - Min Zhou
- College of Chemistry and Chemical Engineering, Guangxi University, Nanning 53004, China.
| | - Xinhua Cui
- College of Chemistry and Chemical Engineering, Guangxi University, Nanning 53004, China.
| | - Zhuocai Wei
- College of Chemistry and Chemical Engineering, Guangxi University, Nanning 53004, China.
| | - Wanxing Wei
- College of Chemistry and Chemical Engineering, Guangxi University, Nanning 53004, China.
- Guangxi Colleges and Universities Key Laboratory of Applied Chemistry Technology and Resource Development, Guangxi University, Nanning 53004, China.
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Long Q, Yan R, Hu J, Cai D, Mitra B, Kim ES, Marchetti A, Zhang H, Wang S, Liu Y, Huang A, Guo H. The role of host DNA ligases in hepadnavirus covalently closed circular DNA formation. PLoS Pathog 2017; 13:e1006784. [PMID: 29287110 PMCID: PMC5747486 DOI: 10.1371/journal.ppat.1006784] [Citation(s) in RCA: 91] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Accepted: 12/01/2017] [Indexed: 12/11/2022] Open
Abstract
Hepadnavirus covalently closed circular (ccc) DNA is the bona fide viral transcription template, which plays a pivotal role in viral infection and persistence. Upon infection, the non-replicative cccDNA is converted from the incoming and de novo synthesized viral genomic relaxed circular (rc) DNA, presumably through employment of the host cell’s DNA repair mechanisms in the nucleus. The conversion of rcDNA into cccDNA requires preparation of the extremities at the nick/gap regions of rcDNA for strand ligation. After screening 107 cellular DNA repair genes, we herein report that the cellular DNA ligase (LIG) 1 and 3 play a critical role in cccDNA formation. Ligase inhibitors or functional knock down/out of LIG1/3 significantly reduced cccDNA production in an in vitro cccDNA formation assay, and in cccDNA-producing cells without direct effect on viral core DNA replication. In addition, transcomplementation of LIG1/3 in the corresponding knock-out or knock-down cells was able to restore cccDNA formation. Furthermore, LIG4, a component in non-homologous end joining DNA repair apparatus, was found to be responsible for cccDNA formation from the viral double stranded linear (dsl) DNA, but not rcDNA. In conclusion, we demonstrate that hepadnaviruses utilize the whole spectrum of host DNA ligases for cccDNA formation, which sheds light on a coherent molecular pathway of cccDNA biosynthesis, as well as the development of novel antiviral strategies for treatment of hepatitis B. Hepadnavirus cccDNA is the persistent form of viral genome, and in terms of human hepatitis B virus (HBV), cccDNA is the basis for viral rebound after the cessation of therapy, as well as the elusiveness of a cure with current medications. Therefore, the elucidation of molecular mechanism of cccDNA formation will aid HBV research at both basic and medical levels. In this study, we screened a total of 107 cellular DNA repair genes and identified DNA ligase 1 and 3 as key factors for cccDNA formation from viral relaxed (open) circular DNA. In addition, we found that the cellular DNA ligase 4 is responsible for converting viral double-stranded linear DNA into cccDNA. Our study further confirmed the involvement of host DNA repair machinery in cccDNA formation, and may reveal new antiviral targets for treatment of hepatitis B in future.
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Affiliation(s)
- Quanxin Long
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
- Institute for Viral Hepatitis, Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ran Yan
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
| | - Jieli Hu
- Institute for Viral Hepatitis, Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Dawei Cai
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
| | - Bidisha Mitra
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
| | - Elena S. Kim
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
| | - Alexander Marchetti
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
| | - Hu Zhang
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
| | - Soujuan Wang
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
| | - Yuanjie Liu
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
| | - Ailong Huang
- Institute for Viral Hepatitis, Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Haitao Guo
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
- * E-mail:
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Oliveira MSD, Valle SDCND, Souza RMD, Silva RPM, Figueiredo END, Taminato M, Fram D. Evidências científicas sobre a hepatite Delta no Brasil: revisão integrativa da literatura. ACTA PAUL ENFERM 2017. [DOI: 10.1590/1982-0194201700091] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Resumo Objetivo: Descrever o nível de evidência científica sobre a infecção por vírus da hepatite Delta (VHD) no Brasil. Métodos: Revisão integrativa da literatura, com buscas realizadas nas bases de dados do Medical Literature Analysis and Retrieval System Online, Literatura Latino-americana e do Caribe em Ciências da Saúde, Scientific Eletronic Library Online e Scopus, com análise centrada no nivelamento do rigor metodológico de acordo com o modelo de Melnyk e Fineout-Overholt. Resultados: A busca revelou uma média de duas publicações por ano no intervalo entre 1987 e 2017. Foram selecionados 33 artigos, tendo a maioria (91%) apresentado nível de evidência VI. As publicações ficaram concentradas em periódicos da área de medicina tropical (46%) e virologia (15%). Dos trabalhos, 85% tinha profissional médico com autor e o delineamento mais encontrado foi o descritivo/transversal (69,6%). Conclusão: A produção científica sobre a infecção por VHD no Brasil está centrada em estudos de prevalência, mostrando-se incipiente quanto à produção de estudos com delineamentos mais rígidos como ensaios clínicos.
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Wu D, Ning Q. Toward a Cure for Hepatitis B Virus Infection: Combination Therapy Involving Viral Suppression and Immune Modulation and Long-term Outcome. J Infect Dis 2017; 216:S771-S777. [PMID: 29156046 DOI: 10.1093/infdis/jix355] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection remains a major global health burden. Currently, the approved therapeutic regimens include nucleos(t)ide analogues (NAs) and either interferon or pegylated interferon. NA therapy is generally safe and well tolerated, but the rate of posttreatment virologic relapse is high, making NA treatment a lifetime commitment. The benefits of pegylated interferon treatment include a finite duration, more-durable response and absence of viral resistance. However, sustained response to interferon alone is achieved only in a minority of patients, and side effects are common, which limit its clinical use. Given that HBV covalently closed circular DNA and the integrated HBV genome persist stably in the nuclei of infected hepatocytes, elimination (complete cure) of HBV is rarely achieved. After completion of treatment, sustained HBV surface antigen loss, with or without seroconversion to HBV surface antibody positivity (ie, functional cure), is therefore recommended as the ideal end point for anti-HBV treatment, despite the lack of complete eradication of HBV. Theoretically, combination of antiviral agents with differential mechanisms of actions on HBV, including viral suppression combined with immune modulation (as occurs during treatment with NA plus pegylated interferon), is an encouraging strategy to treat chronic hepatitis B. Recent studies have confirmed certain virological and serological advantages of simultaneous administration of NA and pegylated interferon (de novo combination therapy) or addition of pegylated interferon to ongoing NA therapy (sequential combination therapy) over monotherapy. Few data exist, however, on the long-term outcomes of patients receiving combination therapy. This review summarizes current combination therapy developed to cure chronic HBV infection.
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Affiliation(s)
- Di Wu
- Department and Institute of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qin Ning
- Department and Institute of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Murphy CM, Xu Y, Li F, Nio K, Reszka-Blanco N, Li X, Wu Y, Yu Y, Xiong Y, Su L. Hepatitis B Virus X Protein Promotes Degradation of SMC5/6 to Enhance HBV Replication. Cell Rep 2017; 16:2846-2854. [PMID: 27626656 DOI: 10.1016/j.celrep.2016.08.026] [Citation(s) in RCA: 237] [Impact Index Per Article: 29.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Revised: 07/06/2016] [Accepted: 08/05/2016] [Indexed: 12/15/2022] Open
Abstract
The hepatitis B virus (HBV) regulatory protein X (HBx) activates gene expression from the HBV covalently closed circular DNA (cccDNA) genome. Interaction of HBx with the DDB1-CUL4-ROC1 (CRL4) E3 ligase is critical for this function. Using substrate-trapping proteomics, we identified the structural maintenance of chromosomes (SMC) complex proteins SMC5 and SMC6 as CRL4(HBx) substrates. HBx expression and HBV infection degraded the SMC5/6 complex in human hepatocytes in vitro and in humanized mice in vivo. HBx targets SMC5/6 for ubiquitylation by the CRL4(HBx) E3 ligase and subsequent degradation by the proteasome. Using a minicircle HBV (mcHBV) reporter system with HBx-dependent activity, we demonstrate that SMC5/6 knockdown, or inhibition with a dominant-negative SMC6, enhance HBx null mcHBV-Gluc gene expression. Furthermore, SMC5/6 knockdown rescued HBx-deficient HBV replication in human hepatocytes. These results indicate that a primary function of HBx is to degrade SMC5/6, which restricts HBV replication by inhibiting HBV gene expression.
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Affiliation(s)
- Christopher M Murphy
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Yanping Xu
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Feng Li
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Kouki Nio
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Natalia Reszka-Blanco
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Xiaodong Li
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Yaxu Wu
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Yanbao Yu
- J. Craig Venter Institute, 9714 Medical Center Drive, Rockville, MD 20850, USA
| | - Yue Xiong
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
| | - Lishan Su
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
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Chen K, Liu J, Liu S, Xia M, Zhang X, Han D, Jiang Y, Wang C, Cao X. Methyltransferase SETD2-Mediated Methylation of STAT1 Is Critical for Interferon Antiviral Activity. Cell 2017; 170:492-506.e14. [PMID: 28753426 DOI: 10.1016/j.cell.2017.06.042] [Citation(s) in RCA: 208] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2017] [Revised: 05/04/2017] [Accepted: 06/27/2017] [Indexed: 01/02/2023]
Abstract
Interferon-α (IFNα) signaling is essential for antiviral response via induction of IFN-stimulated genes (ISGs). Through a non-biased high-throughput RNAi screening of 711 known epigenetic modifiers in cellular models of IFNα-mediated inhibition of HBV replication, we identified methyltransferase SETD2 as a critical amplifier of IFNα-mediated antiviral immunity. Conditional knockout mice with hepatocyte-specific deletion of Setd2 exhibit enhanced HBV infection. Mechanistically, SETD2 directly mediates STAT1 methylation on lysine 525 via its methyltransferase activity, which reinforces IFN-activated STAT1 phosphorylation and antiviral cellular response. In addition, SETD2 selectively catalyzes the tri-methylation of H3K36 on promoters of some ISGs such as ISG15, leading to gene activation. Our study identifies STAT1 methylation on K525 catalyzed by the methyltransferase SETD2 as an essential signaling event for IFNα-dependent antiviral immunity and indicates potential of SETD2 in controlling viral infections.
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Affiliation(s)
- Kun Chen
- Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China; National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai 200433, China
| | - Juan Liu
- National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai 200433, China
| | - Shuxun Liu
- National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai 200433, China
| | - Meng Xia
- Department of Immunology & Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China
| | - Xiaomin Zhang
- National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai 200433, China
| | - Dan Han
- Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Yingming Jiang
- National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai 200433, China
| | - Chunmei Wang
- Department of Immunology & Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China
| | - Xuetao Cao
- Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China; National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai 200433, China; Department of Immunology & Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China.
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Lin TF, Hsu PI, Lin KH, Tsay FW, Tsai TJ, Chen YH, Yu HC. Factors Related to Significant Improvement of Estimated Glomerular Filtration Rates in Chronic Hepatitis B Patients Receiving Telbivudine Therapy. Gastroenterol Res Pract 2017; 2017:4192169. [PMID: 28757867 PMCID: PMC5516758 DOI: 10.1155/2017/4192169] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2017] [Revised: 06/04/2017] [Accepted: 06/12/2017] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND AND AIM The improvement of estimated glomerular filtration rates (eGFRs) in chronic hepatitis B (CHB) patients receiving telbivudine therapy is well known. The aim of this study was to clarify the kinetics of eGFRs and to identify the significant factors related to the improvement of eGFRs in telbivudine-treated CHB patients in a real-world setting. METHODS Serial eGFRs were calculated every 3 months using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. The patients were classified as CKD-1, -2, or -3 according to a baseline eGFR of ≥90, 60-89, or <60 mL/min/1.73 m2, respectively. A significant improvement of eGFR was defined as a more than 10% increase from the baseline. RESULTS A total of 129 patients were enrolled, of whom 36% had significantly improved eGFRs. According to a multivariate analysis, diabetes mellitus (DM) (p = 0.028) and CKD-3 (p = 0.043) were both significantly related to such improvement. The rates of significant improvement of eGFR were about 73% and 77% in patients with DM and CKD-3, respectively. CONCLUSIONS Telbivudine is an alternative drug of choice for the treatment of hepatitis B patients for whom renal safety is a concern, especially patients with DM and CKD-3.
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Affiliation(s)
- Te-Fu Lin
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Ping-I Hsu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- National Yang-Ming University, Taipei, Taiwan
| | - Kung-Hung Lin
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- National Yang-Ming University, Taipei, Taiwan
- Department of Nursing, Meiho University, Pingtung, Taiwan
| | - Feng-Woei Tsay
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- National Yang-Ming University, Taipei, Taiwan
| | - Tzung-Jiun Tsai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- National Yang-Ming University, Taipei, Taiwan
| | - Yan-Hua Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- National Yang-Ming University, Taipei, Taiwan
- Department of Nursing, Meiho University, Pingtung, Taiwan
| | - Hsien-Chung Yu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- National Yang-Ming University, Taipei, Taiwan
- Department of Nursing, Meiho University, Pingtung, Taiwan
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Abdul Basit S, Dawood A, Ryan J, Gish R. Tenofovir alafenamide for the treatment of chronic hepatitis B virus infection. Expert Rev Clin Pharmacol 2017; 10:707-716. [PMID: 28460547 DOI: 10.1080/17512433.2017.1323633] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
INTRODUCTION In April 2017 tenofovir alafenamide (TAF) was added to the list of first-line therapies recommended for chronic hepatitis B (CHB). TAF has pharmacology similar to tenofovir disoproxil fumarate (TDF) with higher cell delivery to the hepatocytes but less systemic exposure. Areas covered: We review here studies leading to TAF's approval and comparing it to TDF. In two major clinical trials, TAF was non-inferior to TDF in achieving HBV DNA levels below 29 IU/ml. TAF-treated patients had significantly smaller decreases in bone mineral density (BMD) at the hip and spine in both HBeAg-positive and HBeAg-negative patients, and smaller mean increases in serum creatinine, although the difference was only statistically significant in HBeAg-positive patients. Patients treated with TDF for 96 weeks and then switched to TAF had improvements in renal and BMD measures only 24 weeks after switching. Expert commentary: With clear evidence from major studies showing that TAF is safe, tolerable, and non-inferior to TDF, its recommendation as a first-line therapy is appropriate. Longer term follow up will be required to determine if the differences in adverse bone and kidney effects seen with TAF in comparison to TDF will be clinically relevant.
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Affiliation(s)
- Syed Abdul Basit
- a Department of Internal Medicine, Division of Gastroenterology and Hepatology , University of Nevada School of Medicine , Las Vegas , NV , USA
| | - Altaf Dawood
- a Department of Internal Medicine, Division of Gastroenterology and Hepatology , University of Nevada School of Medicine , Las Vegas , NV , USA
| | - John Ryan
- b Comprehensive Digestive Institute of Nevada (CDIN) , Las Vegas , NV , USA.,c Roseman University of Health Sciences , Henderson , NV , USA
| | - Robert Gish
- a Department of Internal Medicine, Division of Gastroenterology and Hepatology , University of Nevada School of Medicine , Las Vegas , NV , USA.,d Division of Gastroenterology and Hepatology, Department of Medicine , Stanford University Medical Center , Stanford , CA , USA.,e Hepatitis B Foundation , Doylestown , PA , USA.,f Asian Pacific Health Foundation , San Diego , CA , USA.,g National Viral Hepatitis Roundtable , Washington , D.C , USA
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Haga Y, Kanda T, Nakamoto S, Nakamura M, Sasaki R, Wu S, Yokosuka O. Interferon induces interleukin 8 and bone marrow stromal cell antigen 2 expression, inhibiting the production of hepatitis B virus surface antigen from human hepatocytes. Biochem Biophys Res Commun 2017; 486:858-863. [PMID: 28363866 DOI: 10.1016/j.bbrc.2017.03.150] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Accepted: 03/27/2017] [Indexed: 02/07/2023]
Abstract
Hepatitis B virus (HBV) surface antigen (HBsAg) loss is one of the treatment goals of chronic HBV infection. Bone marrow stromal cell antigen 2 (BST2) is one of the interferon (IFN)-stimulated genes (ISGs) and inhibits the release of various enveloped viruses. Here we examined the effects of antiviral treatment on HBsAg levels and its intracellular mechanism in HBsAg-producing hepatocytes. In PLC/PRF/5 and Huh1, IFNα-2a treatment decreased HBsAg levels in their conditioned media. Upregulation of interleukin 8 (IL8), toll-like receptor 2 (TLR2) and interferon gamma-induced protein 10 (IP10) mRNAs was associated with the reduction of HBsAg in both PLC/PRF/5 and Huh1. The HBsAg level was upregulated by knockdown of IL8, TLR2 or IP10. Exogenous addition of IL8 enhanced BST2 promoter activity and BST2 mRNA expression. Additionally, knockdown of IL8 could lead to the downregulation of BST2 mRNA. Transfection of poly(I-C) enhanced IL8 and BST2 mRNA expression and inhibited HBsAg secretion from PLC/PRF/5 cells. In conclusion, IL8 might play an important role in the enhancement of BST2 and be involved in HBsAg eradication.
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Affiliation(s)
- Yuki Haga
- Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan
| | - Tatsuo Kanda
- Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan.
| | - Shingo Nakamoto
- Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan; Department of Molecular Virology, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan
| | - Masato Nakamura
- Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan
| | - Reina Sasaki
- Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan
| | - Shuang Wu
- Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan
| | - Osamu Yokosuka
- Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan
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Cost-Effectiveness and Clinical Impact of Antiviral Strategies of HBeAg-Positive and -Negative Chronic Hepatitis B. Ann Hepatol 2017. [DOI: 10.5604/01.3001.0009.8590] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/22/2023]
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47
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Complete and Incomplete Hepatitis B Virus Particles: Formation, Function, and Application. Viruses 2017; 9:v9030056. [PMID: 28335554 PMCID: PMC5371811 DOI: 10.3390/v9030056] [Citation(s) in RCA: 209] [Impact Index Per Article: 26.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Revised: 03/11/2017] [Accepted: 03/17/2017] [Indexed: 12/12/2022] Open
Abstract
Hepatitis B virus (HBV) is a para-retrovirus or retroid virus that contains a double-stranded DNA genome and replicates this DNA via reverse transcription of a RNA pregenome. Viral reverse transcription takes place within a capsid upon packaging of the RNA and the viral reverse transcriptase. A major characteristic of HBV replication is the selection of capsids containing the double-stranded DNA, but not those containing the RNA or the single-stranded DNA replication intermediate, for envelopment during virion secretion. The complete HBV virion particles thus contain an outer envelope, studded with viral envelope proteins, that encloses the capsid, which, in turn, encapsidates the double-stranded DNA genome. Furthermore, HBV morphogenesis is characterized by the release of subviral particles that are several orders of magnitude more abundant than the complete virions. One class of subviral particles are the classical surface antigen particles (Australian antigen) that contain only the viral envelope proteins, whereas the more recently discovered genome-free (empty) virions contain both the envelope and capsid but no genome. In addition, recent evidence suggests that low levels of RNA-containing particles may be released, after all. We will summarize what is currently known about how the complete and incomplete HBV particles are assembled. We will discuss briefly the functions of the subviral particles, which remain largely unknown. Finally, we will explore the utility of the subviral particles, particularly, the potential of empty virions and putative RNA virions as diagnostic markers and the potential of empty virons as a vaccine candidate.
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Lomonosova E, Tavis JE. In Vitro Enzymatic and Cell Culture-Based Assays for Measuring Activity of HBV RNaseH Inhibitors. Methods Mol Biol 2017; 1540:179-192. [PMID: 27975316 PMCID: PMC10591453 DOI: 10.1007/978-1-4939-6700-1_14] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
HBV is a small, enveloped DNA virus that replicates by reverse transcription via an RNA intermediate. Current anti-HBV treatment regiments that include interferon α and nucleos(t)ide analogs have insufficient efficiency, are of long duration and can be accompanied by systemic side effects. Though HBV RNaseH is essential for viral replication, it is unexploited as a drug target against HBV. RNaseH inhibitors that actively block viral replication would represent an important addition to the potential new drugs for treating HBV infection. Here we describe two methods to measure the activity of RNaseH inhibitors. DNA oligonucleotide-directed RNA cleavage assay allows low-throughput screening of compounds for potential anti-HBV RNaseH activity in vitro. Analysis of preferential inhibition of plus-polarity DNA strand synthesis by HBV RNaseH inhibitors in a cell culture model of HBV replication can be used to validate the efficiency of these compounds to block viral replication.
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Affiliation(s)
- Elena Lomonosova
- Department of Molecular Microbiology and Immunology, Saint Louis University Liver Center, Saint Louis University School of Medicine, 1100 S. Grand Blvd., Saint Louis, MO, 63104, USA
| | - John E Tavis
- Department of Molecular Microbiology and Immunology, Saint Louis University Liver Center, Saint Louis University School of Medicine, 1100 S. Grand Blvd., Saint Louis, MO, 63104, USA.
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49
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Meta-analysis of CYP2E1 polymorphisms in liver carcinogenesis. Dig Liver Dis 2017; 49:77-83. [PMID: 27637154 DOI: 10.1016/j.dld.2016.08.114] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Revised: 08/03/2016] [Accepted: 08/08/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND The CYP2E1 protein is a monooxygenase with certain polymorphisms linked to liver cancer. However, results from individual studies remain controversial. AIMS To evaluate CYP2E1 polymorphisms in liver carcinogenesis through meta-analysis. METHODS All studies about CYP2E1 polymorphisms and liver cancer were retrieved from seven major databases. Original data from each study were pooled and re-analyzed. RESULTS Total of 16 articles with 4862 cases were selected, including 1820 cases of liver cancer and 3042 cases of controls. The c1 allelic frequency in the cases and controls was 83.3% and 85.3%, respectively. Five genetic variations were compared: dominant c1c2/c2c2 vs. c1/c1 (OR=0.987 (0.853, 1.141)), homozygous c2c2 vs. c1c1 (OR=0.767 (0.526, 1.119)), heterozygous c1c2 vs. c1c1 (OR=1.005 (0.854, 1.182)), recessive c2c2 vs. c1c2/c2c2 (OR=0.771 (0.530, 1.122)), and different alleles c2 vs. c1 (OR=0.947 (0.828, 1.082)). Pooled data were further analyzed based on ethnicity, control sources, and HWE (Hardy-Weinberg equilibrium). These results from stratified groups were similar to that of nonstratified groups. CONCLUSIONS Our meta-analysis results suggest that there is no evidence for a major role of CYP2E1 polymorphism in liver carcinogenesis, but do not rule out the possibility in certain cases.
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Ward H, Tang L, Poonia B, Kottilil S. Treatment of hepatitis B virus: an update. Future Microbiol 2016; 11:1581-1597. [PMID: 27855500 DOI: 10.2217/fmb-2016-0128] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Chronic hepatitis B virus infection is a global health concern as it affects over 240 million people worldwide and an estimated 686,000 people die annually as a result of complications of the disease. With the development of newer antiviral drugs, viral suppression of HBV is achievable, however elimination of HBV from infected individuals (functional cure) remains an issue. Due to persistence of HBV DNA (cccDNA) in infected cells, chronically infected patients who discontinue therapy prior to HBsAg loss or seroconversion are likely to relapse. Several novel therapeutic strategies are being researched and studied in clinical trials. Here we review these novel strategies to achieve sustained cure or elimination of HBV. These strategies include the targeting of the host or viral factors required for viral persistence as well as therapeutic vaccines.
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Affiliation(s)
- Haley Ward
- Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA
| | - Lydia Tang
- Division of Clinical Care & Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Bhawna Poonia
- Division of Clinical Care & Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Shyam Kottilil
- Division of Clinical Care & Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
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