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Han L, Wang Z, Kang L, Cui X, Li Y, Yin H, Gao Y, Li J. Predicting relapse after achieving a functional cure for chronic hepatitis B (CHB) using baseline HBsAg and end-of-treatment HBsAb levels. Sci Rep 2025; 15:13873. [PMID: 40263318 PMCID: PMC12015477 DOI: 10.1038/s41598-025-86555-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2024] [Accepted: 01/13/2025] [Indexed: 04/24/2025] Open
Abstract
Among the factors influencing relapse after clinical cure of chronic hepatitis B(CHB). There is no standardization of baseline HBsAg levels and end-of-treatment HBsAb levels. This multicenter, retrospective study enrolled 136 patients who achieved functional cure from June 2019 to December 2023, and a total of 48 weeks of follow-up was conducted after treatment cessation according to the CHB guidelines. Baseline characteristics of patients were analyzed using univariates. Multifactorial logistic regression was used to analyze the different levels of HBsAg at baseline and HBsAb at the end of treatment in CHB recurrence. The working characteristic curve of the subject was constructed and observed by the column line graphical prediction model. Our data showed the cumulative recurrence rate using Kaplan-Meier survival analysis. At baseline, the level of HBsAg was significantly greater in the group with recurrence than in the group without recurrence (P = 0.038). At EOT, HBsAb levels were lower in the relapsed group than in the nonrelapsed group (P = 0.014). Multivariate logistic regression analysis revealed that a baseline serum HBsAg concentration ≥ 100 IU/mL was a risk factor for recurrence, and an EOT serum HBsAb concentration ≥ 500 mIU/mL was a protective factor for recurrence. Kaplan-Meier survival analysis showed relapse rates of 3.8% and 12.2% for HBsAg ≤ 100 IU/mL at baseline and HBsAb ≥ 500 mIU/mL at the end of treatment, respectively. Functionally cured patients with CHB when baseline HBsAg ≤ 100 IU/mL and HBsAb ≥ 500 mIU/mL at the end of treatment have a low relapse rate.
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Affiliation(s)
- Lianxiu Han
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Zilong Wang
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Luyang Kang
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Xiaoling Cui
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Yi Li
- Division of Life Science and Medicine, Department of Infectious Diseases, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui, China
| | - Huafa Yin
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Yufeng Gao
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
| | - Jiabin Li
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
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Shan Y, Pang H, Tang Y, Yang N, Wang R, Yang F, Qin B. Altered LY6E and TRIM6 expression in PBMCs correlated with HBsAg clearance and response to Peg-IFN-α treatment in HBeAg-negative chronic hepatitis B patients. Virol J 2025; 22:74. [PMID: 40089754 PMCID: PMC11909810 DOI: 10.1186/s12985-025-02689-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2025] [Accepted: 03/01/2025] [Indexed: 03/17/2025] Open
Abstract
BACKGROUND Pegylated interferon alpha (Peg-IFN-α) has the potential to eradicate hepatitis B surface antigen (HBsAg). This study aimed to investigate whether the expression levels of lymphocyte antigen 6 family member E (LY6E) and tripartite motif-containing protein 6 (TRIM6) mRNAs in peripheral blood mononuclear cells (PBMCs) of hepatitis B e antigen (HBeAg)-negative chronic hepatitis B virus (HBV) patients is associated with the response to Peg-IFN-α treatment and HBsAg clearance. METHODS In this prospective study, HBeAg-negative chronic HBV patients treated with Peg-IFN-α were followed for 48 weeks. The participants were classified into two groups, the virological response (VR) group and nonvirological response (NVR) group, according to the changes in HBV DNA and HBsAg levels observed at week 48 of treatment. Furthermore, these patients were divided into a serological response (SR) group and a nonserological response (NSR) group, depending on whether they exhibited a loss of serum HBsAg or evidence of seroconversion. The expression levels of LY6E and TRIM6 mRNAs in PBMCs were evaluated using real-time quantitative PCR with fluorescence detection. The diagnostic performance of LY6E and TRIM6 was assessed by analyzing the receiver operating characteristic (ROC) curve and calculating the area under the ROC curve (AUC). RESULTS After the treatment period, the observed VR and SR rates were 44.64% and 28.57%, respectively. Dynamic changes in LY6E and TRIM6 mRNA levels were significantly different between the VR and NVR groups and between the SR and NSR groups. Multivariate analysis revealed that TRIM6 was independently associated with VR at weeks 12 and 24 of Peg-IFN-α therapy and with SR at week 12; in addition, LY6E was independently associated with VR at week 12 and SR at week 24. At week 24, the area under the curve (AUC) for LY6E in the prediction of VR was 0.6942, and the AUC for the prediction of SR was 0.7766; at week 12, TRIM6 had AUCs of 0.7600 for the prediction of VR and 0.8469 for the prediction of SR. CONCLUSIONS LY6E and TRIM6 are important biomarkers for early therapeutic responses to Peg-IFN-α and HBsAg clearance. TRIAL REGISTRATION Registration number: 2023 - 311. Date of registration: 1 October 2023.
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Affiliation(s)
- Yiru Shan
- Department of Infectious Diseases, Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hao Pang
- Department of Infectious Diseases, Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yao Tang
- Department of Infectious Diseases, Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Na Yang
- Central Laboratory, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Rui Wang
- Central Laboratory, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Fan Yang
- Department of Infectious Diseases, Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
| | - Bo Qin
- Department of Infectious Diseases, Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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Lv YQ, Guo RH, Liu KY, Li JJ, Ji HF. Predictive factors for clinical cure in the treatment of HBeAg(-) chronic hepatitis B or compensated cirrhosis: a prospective observational study. Front Med (Lausanne) 2025; 11:1483744. [PMID: 39850101 PMCID: PMC11754238 DOI: 10.3389/fmed.2024.1483744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Accepted: 12/27/2024] [Indexed: 01/25/2025] Open
Abstract
Background Sequential or combined treatment with nucleos(t)ide analogs (NAs) and pegylated interferon alpha-2b (Peg-IFN-α-2b) can improve the clinical cure rate. However, its clinical application is limited due to the adverse reactions associated with IFN. Methods A multi-center prospective observational study was conducted involving 59 NAs-treated chronic hepatitis B (CHB) patients who were treated with a combination therapy of NAs and Peg-IFN-α-2b for 48 weeks. Another 327 NAs-treated patients received NAs monotherapy for 48 weeks. At the end of the treatment, patients were classified into either the clinically cured group or the non-clinically cured group based on clinical efficacy. The study aimed to analyze the clinical cure rate and the predictive factors. Results After propensity score matching (PSM), a total of 104 patients were included in the exposure and the control groups. After 48 weeks of treatment, 13 patients in the exposed group achieved clinical cure, with a cure rate of 25%. In contrast, in the control group was 1.92%. The clinical cure rate was greater in the population with CHB or compensated cirrhosis treated with sequential or combined Peg-IFN-α-2b and NAs than in the control group (p < 0.001). Patients treated with Peg-IFN-α-2b were divided into a clinical cure group and a non-clinical cure group for single-factor regression and multi-factor binary logistic regression. The results showed that baseline qHBsAg [relative ratio (RR) = 0.997, 95%CI: [0.995, 0.999], p = 0.031] and △TBiL (RR = 0.698, 95%CI: [0.555, 0.879], p = 0.002) were independent influencing factors for achieving clinical cure in patients with CHB or compensated cirrhosis. Conclusion A lower baseline qHBsAg and decrease in TBiL at 24 weeks of treatment are independent influencing factors for achieving clinical cure. The lower the baseline qHBsAg and the higher the △TBiL levels after 24 weeks of treatment, the higher the probability of patients achieving clinical cure.
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Affiliation(s)
| | | | | | | | - Hui-Fan Ji
- Department of Hepatobiliary and Pancreatic Medicine, The First Hospital of Jilin University Changchun, Changchun, Jilin, China
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Boonstra A, Sari G. HBV cccDNA: The Molecular Reservoir of Hepatitis B Persistence and Challenges to Achieve Viral Eradication. Biomolecules 2025; 15:62. [PMID: 39858456 PMCID: PMC11763949 DOI: 10.3390/biom15010062] [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: 11/22/2024] [Revised: 12/30/2024] [Accepted: 01/03/2025] [Indexed: 01/27/2025] Open
Abstract
Hepatitis B virus (HBV) is a major global health issue, with an estimated 254 million people living with chronic HBV infection worldwide as of 2022. Chronic HBV infection is the leading cause of cirrhosis and liver cancer. Current treatment with nucleos(t)ide analogs is effective in the suppression of viral activity but generally requires lifelong treatment. They fail to eradicate the HBV viral reservoir, called covalently closed circular DNA (cccDNA), which replicates in the nucleus of liver cells. The cccDNA serves as the sole template for viral replication, as it generates the pregenomic RNA (pgRNA) necessary for producing new viral genomes. This stable form of viral DNA can reactivate the virus when treatment is stopped. HBV cccDNA is therefore one of the main challenges in curing chronic HBV infections. By targeting steps such as cccDNA formation, capsid assembly, or particle secretion, researchers continue to seek ways to interfere with HBV replication and to reduce its persistence, ultimately to eradicate HBV as a global health problem. This review provides an overview of what is currently known about cccDNA formation and biogenesis and the ongoing efforts to target and eradicate it to cure chronic HBV infections.
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Affiliation(s)
| | - Gulce Sari
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, Wytemaweg 80, 3015CN Rotterdam, The Netherlands
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Nair DM, Vajravelu LK, Thulukanam J, Paneerselvam V, Vimala PB, Lathakumari RH. Tackling hepatitis B Virus with CRISPR/Cas9: advances, challenges, and delivery strategies. Virus Genes 2024; 60:592-602. [PMID: 39196289 DOI: 10.1007/s11262-024-02105-3] [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: 08/03/2024] [Accepted: 08/22/2024] [Indexed: 08/29/2024]
Abstract
Hepatitis B virus (HBV) infection remains a significant global health challenge, with chronic HBV leading to severe liver diseases, including cirrhosis and hepatocellular carcinoma. Current treatments often fail to eradicate the virus, highlighting the need for innovative therapeutic strategies. The CRISPR/Cas9 system has emerged as a dynamic tool for precise genome editing and presents a promising approach to targeting and eliminating HBV infection. This review provides a comprehensive overview of the advances, challenges, and delivery strategies associated with CRISPR/Cas9-based therapies for HBV. We begin by elucidating the mechanism of the CRISPR/Cas9 system and then explore HBV pathogenesis, focusing on the role of covalently closed circular DNA (cccDNA) and integrated HBV DNA in maintaining chronic infection. CRISPR/Cas9 can disrupt these key viral reservoirs, which are critical for persistent HBV replication and associated liver damage. The application of CRISPR/Cas9 in HBV treatment faces significant challenges, such as off-target effects, delivery efficiency, and immune responses. These challenges are addressed by examining current approaches to enhance the specificity, safety, and efficacy of CRISPR/Cas9. A future perspective on the development and clinical translation of CRISPR/Cas9 therapies for HBV is provided, emphasizing the requirement for further research to improve delivery methods and ensure durable safety and effectiveness. This review underscores the transformative potential of CRISPR/Cas9 in combating HBV and sets the stage for future breakthroughs in the field.
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Affiliation(s)
- Dakshina M Nair
- Department of Microbiology, SRM Medical College Hospital and Research Centre, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu, Tamil Nadu, India.
| | - Leela Kakithakara Vajravelu
- Department of Microbiology, SRM Medical College Hospital and Research Centre, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu, Tamil Nadu, India
| | - Jayaprakash Thulukanam
- Department of Microbiology, SRM Medical College Hospital and Research Centre, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu, Tamil Nadu, India
| | - Vishnupriya Paneerselvam
- Department of Microbiology, SRM Medical College Hospital and Research Centre, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu, Tamil Nadu, India
| | - Poornima Baskar Vimala
- Department of Microbiology, SRM Medical College Hospital and Research Centre, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu, Tamil Nadu, India
| | - Rahul Harikumar Lathakumari
- Department of Microbiology, SRM Medical College Hospital and Research Centre, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu, Tamil Nadu, India
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Wan X, Wisskirchen K, Jin T, Yang L, Wang X, Wu X, Liu F, Wu Y, Ma C, Pang Y, Li Q, Zhang K, Protzer U, Du S. Genetically-modified, redirected T cells target hepatitis B surface antigen-positive hepatocytes and hepatocellular carcinoma lesions in a clinical setting. Clin Mol Hepatol 2024; 30:735-755. [PMID: 38808361 PMCID: PMC11540345 DOI: 10.3350/cmh.2024.0058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Revised: 05/28/2024] [Accepted: 05/28/2024] [Indexed: 05/30/2024] Open
Abstract
BACKGROUND/AIMS Hepatitis B virus (HBV)-DNA integration in HBV-related hepatocellular carcinoma (HBV-HCC) can be targeted by HBV-specific T cells. SCG101 is an autologous, HBV-specific T-cell product expressing a T-cell receptor (TCR) after lentiviral transduction recognizing the envelope-derived peptide (S20-28) on HLA-A2. We here validated its safety and efficacy preclinically and applied it to an HBV-related HCC patient (NCT05339321). METHODS Good Manufacturing Practice-grade manufactured cells were assessed for off-target reactivity and functionality against hepatoma cells. Subsequently, a patient with advanced HBV-HCC (Child-Pugh class A, Barcelona Clinic Liver Cancer stage B, Eastern Cooperative Oncology Group performance status 0, hepatitis B e antigen-, serum hepatitis B surface antigen [HBsAg]+, HBsAg+ hepatocytes 10%) received 7.9×107 cells/kg after lymphodepletion. Safety, T-cell persistence, and antiviral and antitumor efficacy were evaluated. RESULTS SCG101, produced at high numbers in a closed-bag system, showed HBV-specific functionality against HBV-HCC cells in vitro and in vivo. Clinically, treatment was well tolerated, and all adverse events, including transient hepatic damage, were reversible. On day 3, ALT levels increased to 1,404 U/L, and concurrently, serum HBsAg started decreasing by 3.84 log10 and remained <1 IU/mL for over six months. HBsAg-expressing hepatocytes in liver biopsies were undetectable after 73 days. The patient achieved a partial response according to modified RECIST with a >70% reduction in target lesion size. Transferred T cells expanded, developed a stem cell-like memory phenotype, and were still detectable after six months in the patient's blood. CONCLUSION SCG101 T-cell therapy showed encouraging efficacy and safety in preclinical models and in a patient with primary HBV-HCC and concomitant chronic hepatitis B with the capability to eliminate HBsAg+ cells and achieve sustained tumor control after single dosing.
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Affiliation(s)
- Xueshuai Wan
- Department of Liver Surgery, Peking Union Medical College Hospital, PUMC, and Chinese Academy of Medical Sciences, Beijing, P. R. China
| | | | - Tao Jin
- SCG Cell Therapy Pte. Ltd., Singapore, Singapore
| | - Lu Yang
- SCG Cell Therapy Pte. Ltd., Singapore, Singapore
| | - Xiaorui Wang
- SCG Cell Therapy Pte. Ltd., Singapore, Singapore
| | - Xiang’an Wu
- Department of Liver Surgery, Peking Union Medical College Hospital, PUMC, and Chinese Academy of Medical Sciences, Beijing, P. R. China
| | - Fang Liu
- Department of Liver Surgery, Peking Union Medical College Hospital, PUMC, and Chinese Academy of Medical Sciences, Beijing, P. R. China
| | - Yu Wu
- Department of Liver Surgery, Peking Union Medical College Hospital, PUMC, and Chinese Academy of Medical Sciences, Beijing, P. R. China
| | - Christy Ma
- SCG Cell Therapy Pte. Ltd., Singapore, Singapore
| | - Yong Pang
- SCG Cell Therapy Pte. Ltd., Singapore, Singapore
| | - Qi Li
- SCG Cell Therapy Pte. Ltd., Singapore, Singapore
| | - Ke Zhang
- SCG Cell Therapy Pte. Ltd., Singapore, Singapore
| | - Ulrike Protzer
- Institute of Virology, School of Medicine, Technical University of Munich/Helmholtz Munich, Munich, Germany
| | - Shunda Du
- Department of Liver Surgery, Peking Union Medical College Hospital, PUMC, and Chinese Academy of Medical Sciences, Beijing, P. R. China
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Agarwal R, Gupta E, Samal J, Rooge S, Gupta A. Newer Diagnostic Virological Markers for Hepatitis B Virus Infection. Euroasian J Hepatogastroenterol 2024; 14:214-220. [PMID: 39802850 PMCID: PMC11714116 DOI: 10.5005/jp-journals-10018-1450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Accepted: 10/05/2024] [Indexed: 01/16/2025] Open
Abstract
Chronic Hepatitis B (CHB) remains a major public health problem, leading to various complications such as liver fibrosis, cirrhosis, and hepatocellular carcinoma. The existing diagnostic markers for Hepatitis B virus (HBV) are limited in distinguishing different CHB phases and intra-hepatic viral replication activity. In the past few years, several non-invasive potential blood markers that reflect viral intra-hepatic replicative state more accurately have been in progress and are gaining importance. Despite substantial efforts, the clinical utility of these new markers in CHB management is limited and unexplored. Therefore, in this review, we will discuss some of the newer HBV markers, their potential role in the diagnosis and monitoring of CHB patients. How to cite this article Agarwal R, Gupta E, Samal J, et al. Newer Diagnostic Virological Markers for Hepatitis B Virus Infection. Euroasian J Hepato-Gastroenterol 2024;14(2):214-220.
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Affiliation(s)
- Reshu Agarwal
- Department of Clinical Virology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Ekta Gupta
- Department of Clinical Virology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Jasmine Samal
- Department of Clinical Virology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Sheetalnath Rooge
- Department of Clinical Virology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Akshita Gupta
- Department of Clinical Virology, Institute of Liver and Biliary Sciences, New Delhi, India
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Farag MS, van Campenhout MJH, Sonneveld MJ, Fung S, van Erpecum KJ, Wong DK, Verhey E, de Man R, De Knegt RJ, Brouwer JT, Baak HC, Feld JJ, Liem KS, Boonstra A, Hansen BE, Janssen HLA. Addition of PEG-interferon to long-term nucleos(t)ide analogue therapy enhances HBsAg decline and clearance in HBeAg-negative chronic hepatitis B: Multicentre Randomized Trial (PAS Study). J Viral Hepat 2024; 31:197-207. [PMID: 38243144 DOI: 10.1111/jvh.13918] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 12/28/2023] [Accepted: 01/02/2024] [Indexed: 01/21/2024]
Abstract
We studied whether 48 weeks of PEG-IFN alfa-2a add-on increases HBsAg-decline and clearance in HBeAg-negative patients on long-term nucleo(s)tide analogue (NA) therapy. In this investigator-initiated, randomized, controlled trial conducted in Europe and Canada, HBeAg-negative patients treated with NA > 12 months, with HBVDNA < 200 IU/mL, were enrolled. Patients were randomized 2:1 to 48 weeks of PEG-IFN alfa-2a add-on (180 μg per week) or continued NA-monotherapy with subsequent follow-up to Week 72. Endpoints were HBsAg decline (≥1 log10 IU/mL) and HBsAg clearance at Week 48. Of the 86 patients in the modified-intention-to-treat analysis, 58 patients received PEG-IFN add-on, and 28 continued NA monotherapy. At Week 48, 16(28%) patients achieved HBsAg decline ≥1 log10 in the add-on arm versus none on NA-monotherapy (p < .001), and HBsAg clearance was observed in 6 (10%) PEG-IFN add-on patients versus 0% NA-monotherapy (p = .01). HBVRNA was only detected in 2% after PEG-IFN treatment versus 19% in NA-monotherapy (p = .002) at Week 48. PEG-IFN add-on therapy was well tolerated in majority of patients. Low baseline HBsAg levels (<10 IU/mL) identified patients most likely to achieve HBsAg loss with PEG-IFN add-on, whereas an HBsAg level > 200 IU/mL at on-treatment Week 12 was highly predictive of non-response (NPV = 100%). Addition of PEG-IFN to long-term NA enhanced HBsAg decline and increased the chance of HBsAg clearance in HBeAg-negative patients on long-term NA. On-treatment HBsAg levels >200 IU/mL identify patients unlikely to benefit from PEG-IFN add-on and could be used as a potential stopping-rule for PEG-IFN therapy. Our findings support further exploration of immune modulation add-on to antiviral therapy, preferably using response-guided strategies, to increase functional cure rates in patients with CHB.
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Affiliation(s)
- Mina S Farag
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
| | - Margo J H van Campenhout
- Department of Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
| | - M J Sonneveld
- Department of Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Scott Fung
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
| | - Karel J van Erpecum
- Department of Gastroenterology, University Medical Center, Utrecht, The Netherlands
| | - David K Wong
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
| | - Elke Verhey
- Department of Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Robert de Man
- Department of Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Robert J De Knegt
- Department of Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Johannes T Brouwer
- Department of Gastroenterology and Hepatology, Reinier de Graaf Groep, Delft, The Netherlands
| | - Hubertus C Baak
- Department of Gastroenterology and Hepatology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands
| | - Jordan J Feld
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
| | - Kin Seng Liem
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
- Department of Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
| | - André Boonstra
- Department of Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Bettina E Hansen
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
- Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
| | - Harry L A Janssen
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
- Department of Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
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Abdullayeva M, Çelik M, Kuruüzüm Z. The performance of hepatitis B surface antigen quantification as a noninvasive biomarker predicting liver injury and serum hepatitis B virus DNA level. Eur J Gastroenterol Hepatol 2024; 36:245-249. [PMID: 38131428 DOI: 10.1097/meg.0000000000002693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2023]
Abstract
OBJECTIVES Chronic hepatitis B (CHB) is still a major public health problem worldwide. Recently, evidence indicating that serum hepatitis B surface antigen (HBsAg) quantification can be used for monitorization of hepatitis B virus (HBV) infection has been increased. In this study, we evaluated HBsAg levels during the natural course of CHB and identified correlations between HBsAg, HBV DNA levels and liver histopathology. METHODS From 6 August 2016 to 7 June 2017, naive patients, who are ≥18 years old, fulfilled the criteria for the diagnosis of CHB and had a liver biopsy within a year before or after admission, were included. HBsAg levels in serum samples were investigated by electrochemiluminescence immunoassay. Results were correlated with serum HBV DNA levels, histologic activity index (HAI) and fibrosis scores. RESULTS In this study 66 patients were included. There was a moderate and significant correlation between HBsAg levels and fibrosis scores (r = 0.386, P = 0.001), but no correlation with HAI. Serum HBsAg levels showed a positive, strong and significant (r = 0.740, P < 0.001) correlation with HBV DNA levels. In hepatitis B e antigen-negative patients, serum HBsAg levels were perfectly correlated with HBV DNA levels (r = 0.992, P < 0.001) and moderately correlated with fibrosis scores (r = 0.360, P = 0.006). CONCLUSION We found a positive correlation between serum HBsAg levels and the severity of fibrosis scores and serum HBV DNA levels. These findings suggest that serum HBsAg quantification might be a useful noninvasive diagnostic test for the prediction of fibrosis severity and HBV DNA level.
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Affiliation(s)
- Madina Abdullayeva
- Department of Infectious Diseases and Clinical Microbiology, Central Custom Hospital, Baku, Azerbaijan
| | - Muammer Çelik
- Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Dokuz Eylul University, İzmir, Turkey
| | - Ziya Kuruüzüm
- Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Dokuz Eylul University, İzmir, Turkey
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Mimura S, Fujita K, Takuma K, Nakahara M, Oura K, Tadokoro T, Tani J, Morishita A, Ono M, Himoto T, Masaki T. Predictors of therapeutic response to peginterferon α‑2a and nucleos(t)ide analog combination therapy for HBeAg‑negative chronic hepatitis B: 1‑year follow‑up after treatment. Exp Ther Med 2023; 26:587. [PMID: 38023352 PMCID: PMC10665991 DOI: 10.3892/etm.2023.12286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Accepted: 10/18/2023] [Indexed: 12/01/2023] Open
Abstract
Chronic hepatitis B (CHB) is a major global health concern. Guidelines for the management of hepatitis B virus (HBV) indicate that the loss of hepatitis B surface antigen (HBsAg) is a key endpoint of interest. The present study aimed to examine long-term changes in HBsAg levels in HBV-DNA-negative, hepatitis B e-antigen (HBeAg)-negative patients treated with peginterferon (Peg-IFN) α-2a and nucleos(t)ide analog (NA), and to examine the conditions that make them susceptible to HBsAg decline. A total of 17 patients with CHB treated with NA and Peg-IFN were observed for 96 weeks (48 weeks of Peg-IFN therapy and 48 weeks of post-treatment follow-up). In this study, responders were defined as those with a 50% or greater decrease in HBsAg levels from baseline at week 96. Beginning at week 16 of Peg-IFN therapy, there was a significant difference in the decrease in HBsAg levels from baseline between the responders and non-responders. In responders, HBsAg levels tended to be >60% lower 16 weeks after Peg-IFN initiation than before initiation. Age at the start of NA use and the duration of NA use before Peg-IFN treatment initiation were significant pretreatment factors associated with HBsAg response. In conclusion, Peg-IFN was revealed to be more effective in HBeAg-negative patients with CHB who started NA at a young age and have been on long-term treatment, particularly if the HBsAg levels decreased to less than 60% of the starting level at week 16 after starting Peg-IFN treatment.
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Affiliation(s)
- Shima Mimura
- Department of Gastroenterology and Neurology, Kagawa University Hospital, Kita, Kagawa 761-0793, Japan
| | - Koji Fujita
- Department of Gastroenterology and Neurology, Kagawa University Hospital, Kita, Kagawa 761-0793, Japan
| | - Kei Takuma
- Department of Gastroenterology and Neurology, Kagawa University Hospital, Kita, Kagawa 761-0793, Japan
| | - Mai Nakahara
- Department of Gastroenterology and Neurology, Kagawa University Hospital, Kita, Kagawa 761-0793, Japan
| | - Kyoko Oura
- Department of Gastroenterology and Neurology, Kagawa University Hospital, Kita, Kagawa 761-0793, Japan
| | - Tomoko Tadokoro
- Department of Gastroenterology and Neurology, Kagawa University Hospital, Kita, Kagawa 761-0793, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Kagawa University Hospital, Kita, Kagawa 761-0793, Japan
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Kagawa University Hospital, Kita, Kagawa 761-0793, Japan
| | - Masafumi Ono
- Department of Gastroenterology and Neurology, Kagawa University Hospital, Kita, Kagawa 761-0793, Japan
| | - Takashi Himoto
- Department of Medical Technology, Kagawa Prefectural University of Health Sciences, Takamatsu, Kagawa 761-0123, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Kagawa University Hospital, Kita, Kagawa 761-0793, Japan
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11
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Combination treatment of pegylated interferon and tenofovir versus tenofovir for people with chronic hepatitis B. Cochrane Database Syst Rev 2023; 2023:CD015730. [PMCID: PMC10401907 DOI: 10.1002/14651858.cd015730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2024]
Abstract
This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To evaluate the benefits and harms of pegylated interferon combined with tenofovir versus tenofovir monotherapy in adults with chronic hepatitis B.
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12
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He J, Guo Y, Zhang Y, Han J, Chen J, Jia Y, Ma Z, Wu J, Zhang S, Li F, Mao R, Zhang J. Comparison of Pegylated Interferon Alfa Therapy in Combination with Tenofovir Alafenamide Fumarate or Tenofovir Disoproxil Fumarate for Treatment of Chronic Hepatitis B Patients. Infect Drug Resist 2023; 16:3929-3941. [PMID: 37361938 PMCID: PMC10290461 DOI: 10.2147/idr.s411183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 06/02/2023] [Indexed: 06/28/2023] Open
Abstract
Purpose The study aims to evaluate the effectiveness of a tenofovir alafenamide fumarate (TAF) and pegylated interferon alfa (PegIFN-α) regimen compared to a tenofovir disoproxil fumarate (TDF) and PegIFN-α therapy in patients with chronic hepatitis B (CHB). Patients and Methods Patients who were treated with PegIFN-α in combination with TAF or TDF were retrospectively enrolled. The primary outcome measured was the HBsAg loss rate. The rates of virological response, serological response for HBeAg, and normalization of alanine aminotransferase (ALT) were also calculated. The cumulative incidences of response rates were compared between the two groups using Kaplan-Meier analysis. Results A total of 114 patients were retrospectively enrolled in the study, with 33 receiving TAF plus PegIFN-α treatment and 81 receiving TDF plus PegIFN-α treatment. The HBsAg loss rate for the TAF plus PegIFN-α group was 15.2% at 24 weeks and 21.2% at 48 weeks, while the TDF plus PegIFN-α group had rates of 7.4% at 24 weeks and 12.3% at 48 weeks (P=0.204 at 24 weeks, P=0.228 at 48 weeks). In subgroup analysis of HBeAg positive patients, the TAF group had a higher HBsAg loss rate of 25% at week 48, compared to 3.8% in the TDF group (P=0.033). According to Kaplan-Meier analysis, the TAF plus PegIFN-α group achieved virological response more quickly than the TDF plus PegIFN-α group (p=0.013). There was no statistical difference in HBeAg serological rate or ALT normalization rate. Conclusion There was no significant difference in the HBsAg loss between the two groups. However, subgroup analysis revealed that TAF plus PegIFN-α treatment had a higher HBsAg loss rate than TDF plus PegIFN-α treatment in HBeAg-positive patients. Additionally, TAF plus PegIFN-α treatment demonstrated better virological suppression for CHB patients. Therefore, TAF plus PegIFN-α treatment regimen is recommended for CHB patients who aim to achieve functional cure.
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Affiliation(s)
- Jingjing He
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Yifei Guo
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Yao Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Jiajia Han
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Jingwen Chen
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Yidi Jia
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Zhenxuan Ma
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Jingwen Wu
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Shenyan Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Fahong Li
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Richeng Mao
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Jiming Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China
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Keskin O, Yurdaydin C. Emerging drugs for hepatitis D. Expert Opin Emerg Drugs 2023:1-12. [PMID: 37096555 DOI: 10.1080/14728214.2023.2205639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/26/2023]
Abstract
INTRODUCTION Chronic hepatitis delta (CHD) is the most severe form of chronic viral hepatitis. Until recently, its treatment consisted of pegylated interferon alfa (pegIFN) use. AREAS COVERED Current and new drugs for treating CHD. Virus entry inhibitor bulevirtide has received conditional approval by the European Medicines Agency. Prenylation inhibitor lonafarnib and pegIFN lambda are in phase 3 and nucleic acid polymers in phase 2 of drug development. EXPERT OPINION Bulevirtide appears to be safe. Its antiviral efficacy increases with treatment duration. Combining bulevirtide with pegIFN has the highest antiviral efficacy short-term. The prenylation inhibitor lonafarnib prevents hepatitis D virus assembly. It is associated with dose dependent gastrointestinal toxicity and is better used with ritonavir which increases liver lonafarnib concentrations. Lonafarnib also possesses immune modulatory properties which explains some post-treatment beneficial flare cases. Combining lonafarnib/ritonavir with pegIFN has superior antiviral efficacy. Nucleic acid polymers are amphipathic oligonucleotides whose effect appears to be a consequence of phosphorothioate modification of internucleotide linkages. These compounds led to HBsAg clearance in a sizeable proportion of patients. PegIFN lambda is associated with less IFN typical side effects. In a phase 2 study it led to 6 months off treatment viral response in one third of patients.
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Affiliation(s)
- Onur Keskin
- Department of Gastroenterology, Hacettepe University Medical School, Ankara, Turkey
| | - Cihan Yurdaydin
- Department of Gastroenterology & Hepatology, Koc University Medical School, Istanbul, Turkey
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14
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Murata K, Mizokami M. Possible biological mechanisms of entecavir versus tenofovir disoproxil fumarate on reducing the risk of hepatocellular carcinoma. J Gastroenterol Hepatol 2023; 38:683-691. [PMID: 36918402 DOI: 10.1111/jgh.16178] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 03/08/2023] [Indexed: 03/16/2023]
Abstract
Hepatitis B virus (HBV) is a life-threatening infectious virus associated with the risk of liver failure and hepatocellular carcinoma (HCC). Regarding HBV treatment, the recent development of nucleoside/nucleotide analogs (NUC), HBV reverse transcriptase inhibitors, enabled favorable viral control as well as improved prognosis in patients with chronic hepatitis B. However, NUC fails to clear HBV because the formation of covalently closed circular DNA or HBV surface antigen occurs upstream of the point of action of NUC. Recently, we found that acyclic nucleoside phosphonates (ANP) such as adefovir or tenofovir, but not lamivudine or entecavir, induced IFN-λ3 productions in the gastrointestinal tract and modulated lipopolysaccharide (LPS)-mediated cytokine profiles in peripheral blood mononuclear cells, such as interleukin (IL)-12p70 induction and IL-10 inhibition, which are immunologically favorable cytokine profiles for HBV elimination. Furthermore, IFN-α, in combination with ANP, showed additional and synergistic effects on IFN-λ3 and IL-12p70 production, respectively, while not affecting IL-10 levels. Mechanistic analyses of the cytokine modulation by ANP revealed that ANP blocked the mammalian target of the rapamycin (mTOR) pathway by inhibiting Akt translocation to the plasma membrane, thereby inhibiting Akt phosphorylation. As it has been reported that IFN-λ inhibits tumor growth directly or indirectly and the mTOR pathway is generally activated in most cancer cells, ANP might have potential anti-HCC effects. Our in vitro and ex vivo findings might stir the debate on whether types of NUC affect the risk of HBV-related HCC incidence.
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Affiliation(s)
- Kazumoto Murata
- Division of Virology, Department of Infection and Immunity, Jichi Medical University, Shimotsuke, Japan
- Genome Medical Sciences Project, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Masashi Mizokami
- Genome Medical Sciences Project, National Center for Global Health and Medicine, Ichikawa, Japan
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Chang KC, Lin MT, Wang JH, Hung CH, Chen CH, Chiu SYH, Hu TH. HBcrAg Predicts Hepatocellular Carcinoma Development in Chronic B Hepatitis Related Liver Cirrhosis Patients Undergoing Long-Term Effective Anti-Viral. Viruses 2022; 14:v14122671. [PMID: 36560675 PMCID: PMC9782149 DOI: 10.3390/v14122671] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 11/21/2022] [Accepted: 11/25/2022] [Indexed: 12/02/2022] Open
Abstract
Hepatitis B core-related antigen (HBcrAg) is a predictor of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients. Studies on anti-viral therapy have shown that the use of NUC therapy in HBV patients could reduce the incidence of HCC. However, the incidence of HCC continues to increase after long-term anti-viral therapy. The relationship between HBcrAg and HCC development in CHB-related liver cirrhosis (LC) patients undergoing long-term anti-viral therapy is still unclear. This study enrolled 1108 treatment-naïve CHB patients diagnosed with HBV-related LC receiving NUC therapy from April 1999 to February 2015. The baseline biomarkers, disease history, and following results were collected by the hospital. Among the 1108 patients, 219 developed HCC within a median follow-up period of 6.85 years. A multivariable Cox regression model was used, with adjustment for age, gender, FIB-4, DM, and HBsAg-HQ. The adjusted hazard ratios for the HBcrAg tertile levels were 1.70 (95%CI: 1.21, 2.39) and 2.14 (95%CI: 1.50, 3.05) for levels 3.4-4.9 and >4.9 logU/mL, respectively, compared with levels ≤3.4. The effect of the HBcrAg level on HCC incidence was found to be significantly modified by HBsAg-HQ, where lower HBsAg-HQ (≤ 3) values were associated with a significantly higher risk, but HBsAg-HQ levels >3 were not. Our results highlight that, after adjustment for potential confounding factors, patients with CHB-related LC and higher HBcrAg levels are at significant risk for HCC development, even while undergoing long-term effective anti-viral therapy. The HBcrAg level is therefore an independent risk factor for HCC development, especially for patients with HBsAg-HQ levels <3.
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Affiliation(s)
- Kuo-Chin Chang
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
| | - Ming-Tsung Lin
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
| | - Jing-Houng Wang
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
| | - Chao-Hung Hung
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
| | - Chien-Hung Chen
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
| | - Sherry Yueh-Hsia Chiu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
- Department of Health Care Management, College of Management, and Healthy Aging Research Center, Chang Gung University, Taoyuan 333, Taiwan
- Correspondence: (S.Y.-H.C.); (T.-H.H.)
| | - Tsung-Hui Hu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
- Correspondence: (S.Y.-H.C.); (T.-H.H.)
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A Predictive Model to Evaluate the HbeAg Positivity of Chronic Hepatitis B Virus Patients in Clinics: A Cross-Sectional Study. Medicina (B Aires) 2022; 58:medicina58091279. [PMID: 36143956 PMCID: PMC9500857 DOI: 10.3390/medicina58091279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 08/31/2022] [Accepted: 09/11/2022] [Indexed: 11/17/2022] Open
Abstract
Background and Objective: The study aims to investigate the correlation between Hepatitis B ‘e’ antigen (HBeAg) and HBV DNA levels, and to find a convenient tool to estimate the HBV DNA level for clinicians. Materials and Methods: We enrolled 1020 patients in this cross-sectional study and divided them into four groups: an HbeAg-positive and -negative group, and high and low HBV DNA levels groups. Results: Alanine aminotransferase (ALT), Albumin (ALB) and HBeAg are independent risk factors for CHB patients. When the level of HBeAg is higher than 16.15 S/CO, it is four times more likely that the patients will have high levels of HBV DNA than those who do not. The ALT and TB are independent risk factors in HBeAg-negative patients with a high HBV DNA level. We have drawn three predictive models to estimate the HBV DNA levels for those with the chronic hepatitis B virus (CHB), and those that are HBeAg-positive and HBeAg-negative (Y1 = 0.004 × ALT(IU/L) + 1.412 × HBeAg (S/CO) − 0.029 × ALB (g/L) + 0.779, the AUC is 0.672, and the cutoff value is −0.072, there the sensitivity is 0.615, the specificity is 0.648, PPV is 65.182% and NPV is 60.837%; Y2 = 0.007 × HBeAg (S/CO) − 0.016 × HGB (g/L) + 3.070, the AUC is 0.724, and the cutoff value is 1.216, where the sensitivity is 0.626, the specificity is 0.897, PPV is 94.118% and NPV is 34.437%; Y3 = −0.005 × ALT(IU/L) + 0.006 × TB (umol/L) + 0.385, the AUC is 0.661, and the cutoff value is 0.263, where the sensitivity is 0.677, the specificity is 0.587, PPV is 66.820% and NPV is 40.774%, respectively). We propose that HBeAg is the most important risk factor for the patient with a high HBV DNA level, however, it is not as important in the HBeAg-positive group. Conclusions: HBeAg is an independent risk factor that reflects the level of HBV DNA with a strong correlation. Patient with HBeAg (−) should combine TB and ALT to estimate the level of HBV DNA.
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17
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Chu JH, Huang Y, Xie DY, Deng H, Wei J, Guan YJ, Li GJ, Zeng YL, Yang JH, Chen XY, Shang J, Li JB, Gao N, Gao ZL. Real-world study on HBsAg loss of combination therapy in HBeAg-negative chronic hepatitis B patients. J Viral Hepat 2022; 29:765-776. [PMID: 35718996 DOI: 10.1111/jvh.13722] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 04/11/2022] [Accepted: 05/21/2022] [Indexed: 12/22/2022]
Abstract
Combination therapy with pegylated interferon (PEG-IFN) and nucleos(t)ide analogues (NAs) can enhance hepatitis B surface antigen (HBsAg) clearance. However, the specific treatment strategy and the patients who would benefit the most are unclear. Therefore, we assessed the HBsAg loss rate of add-on PEG-IFN and explored the factors associated with HBsAg loss in chronic hepatitis B (CHB) patients. This was a real-world cohort study of adults with CHB. Hepatitis B e antigen (HBeAg)-negative NAs-treated patients with baseline HBsAg ≤1500 IU/ml and HBV DNA < the lower limit of detection, or 100 IU/ml, received 48 weeks of add-on PEG-IFN. The primary outcome of the study was the rate of HBsAg loss at 48 weeks of combination treatment. Using multivariable logistic regression analysis, we determined factors associated with HBsAg loss. HBsAg loss in 2579 patients (mean age: 41.2 years; 80.9% male) was 36.7% (947 patients) at 48 weeks. HBsAg loss was highest in patients from south-central and southwestern China (40.0%). Factors independently associated with HBsAg loss included: increasing age (odds ratio = 0.961); being male (0.543); baseline HBsAg level (0.216); HBsAg decrease at 12 weeks (between 0.5 and 1.0 log10 IU/ml [2.405] and >1.0 log10 IU/ml [7.370]); alanine aminotransferase (ALT) increase at 12 weeks (1.365); haemoglobin (HGB) decrease at 12 weeks (1.558). There was no difference in the primary outcomes associated with the combination regimen. In conclusion, HBsAg loss by combination therapy was higher in patients from southern China than those from the north. An increased chance of HBsAg loss was associated with baseline characteristics and dynamic changes in clinical indicators.
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Affiliation(s)
- Jun-Hao Chu
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Yan Huang
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Dong-Ying Xie
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.,Guandong Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.,Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou, Guangdong, China
| | - Hong Deng
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.,Guandong Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.,Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou, Guangdong, China
| | - Jia Wei
- Department of Gastroenterology, the Second People's Hospital Yunnan Province, Kunming, Yunnan, China
| | - Yu-Juan Guan
- Department of Hepatology, Guangzhou Eighth People's Hospital, Guangzhou, Guangdong, China
| | - Guo-Jun Li
- Department of Hepatology, Shenzhen Third People's Hospital, Shenzhen, Guangdong, China
| | - Yi-Lan Zeng
- Department of Hepatology, Chengdu Public Health Clinical Medical Center, Chengdu, Sichuan, China
| | - Jia-Hong Yang
- Department of Infectious Diseases, Deyang People's Hospital, Deyang, Sichuan, China
| | - Xin-Yue Chen
- Department of Hepatology, Beijing You'an Hospital, Capital Medical University, Beijing, China
| | - Jia Shang
- Department of Infectious Diseases, Henan Provincial People's Hospital, Zhengzhou, Henan, China
| | - Jia-Bin Li
- Department of Infectious Diseases, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Na Gao
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Zhi-Liang Gao
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.,Guandong Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.,Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou, Guangdong, China
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18
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Broquetas T, Carrión JA. Current Perspectives on Nucleos(t)ide Analogue Therapy for the Long-Term Treatment of Hepatitis B Virus. Hepat Med 2022; 14:87-100. [PMID: 35936810 PMCID: PMC9346298 DOI: 10.2147/hmer.s291976] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 07/12/2022] [Indexed: 01/27/2023] Open
Affiliation(s)
- Teresa Broquetas
- Liver Section, Gastroenterology Department, Hospital del Mar, Barcelona, Spain
- IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
| | - José A Carrión
- Liver Section, Gastroenterology Department, Hospital del Mar, Barcelona, Spain
- IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
- Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain
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Watanabe T, Hayashi S, Tanaka Y. Drug Discovery Study Aimed at a Functional Cure for HBV. Viruses 2022; 14:1393. [PMID: 35891374 PMCID: PMC9321005 DOI: 10.3390/v14071393] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 06/19/2022] [Accepted: 06/23/2022] [Indexed: 02/04/2023] Open
Abstract
Hepatitis B virus (HBV) causes acute and, most importantly, chronic hepatitis B worldwide. Antiviral treatments have been developed to reduce viral loads but few patients with chronic hepatitis B (CHB) achieve a functional cure. The development of new therapeutic agents is desirable. Recently, many novel agents have been developed, including drugs targeting HBV-DNA and HBV-RNA. This review provides an overview of the developmental status of these drugs, especially direct acting antiviral agents (DAAs). Serological biomarkers of HBV infection are essential for predicting the clinical course of CHB. It is also important to determine the amount and activity of covalently closed circular DNA (cccDNA) in the nuclei of infected hepatocytes. Hepatitis B core-associated antigen (HBcrAg) is a new HBV marker that has an important role in reflecting cccDNA in CHB, because it is associated with hepatic cccDNA, as well as serum HBV DNA. The highly sensitive HBcrAg (iTACT-HBcrAg) assay could be a very sensitive HBV activation marker and an alternative to HBV DNA testing for monitoring reactivation. Many of the drugs currently in clinical trials have shown efficacy in reducing hepatitis B surface antigen (HBsAg) levels. Combination therapies with DAAs and boost immune response are also under development; finding the best combinations will be important for therapeutic development.
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Affiliation(s)
| | | | - Yasuhito Tanaka
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan; (T.W.); (S.H.)
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Novel Neplanocin A Derivatives as Selective Inhibitors of Hepatitis B Virus with a Unique Mechanism of Action. Antimicrob Agents Chemother 2022; 66:e0207321. [PMID: 35604213 DOI: 10.1128/aac.02073-21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Novel neplanocin A derivatives have been identified as potent and selective inhibitors of hepatitis B virus (HBV) replication in vitro. These include (1S,2R,5R)-5-(5-bromo-4-methyl-7H-pyrrolo[2,3-d]-pyrimidin-7-yl)-3-(hydroxymethyl)cyclopent-3-ene-1,2-diol (AR-II-04-26) and (1S,2R,5R)-5-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-(hydroxylmethyl)cyclopent-3-ene-1,2-diol (MK-III-02-03). The 50% effective concentrations of AR-II-04-26 and MK-III-02-03 were 0.77 ± 0.23 and 0.83 ± 0.36 μM in HepG2.2.15.7 cells, respectively. These compounds reduced intracellular HBV RNA levels in HepG2.2.15.7 cells and infected primary human hepatocytes. Accordingly, they could reduce HBs and HBe antigen production in the culture supernatants, which was not observed with clinically approved anti-HBV nucleosides and nucleotides (reverse transcriptase inhibitors). The neplanocin A derivatives also inhibited HBV RNA derived from cccDNA. In addition, unlike neplanocin A itself, the compounds did not inhibit S-adenosyl-l-homocysteine hydrolase activity. Thus, it appears that the mechanism of action of AR-II-04-26 and MK-III-02-03 differs from that of the clinically approved anti-HBV agents. Although their exact mechanism (target molecule) remains to be elucidated, the novel neplanocin A derivatives are considered promising candidate drugs for inhibition of HBV replication.
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Zhu L, Li J, Xu J, Chen F, Wu X, Zhu C. Significance of T-Cell Subsets for Clinical Response to Peginterferon Alfa-2a Therapy in HBeAg-Positive Chronic Hepatitis B Patients. Int J Gen Med 2022; 15:4441-4451. [PMID: 35509606 PMCID: PMC9058244 DOI: 10.2147/ijgm.s356696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Accepted: 04/14/2022] [Indexed: 11/23/2022] Open
Abstract
Introduction The adaptive immune response may reflect the immunomodulatory efficacy during peginterferon alfa-2a (PEG-IFN α-2a) treatment in chronic hepatitis B (CHB) patients. We evaluated the predictive efficiency of T-cell subsets on patient's response to PEG-IFN α-2a treatment. Methods The proportions of CD8+PD-1+, CD8+Tim-3+ and CD4+CD25high T-cells were measured at baseline and week 52 in CHB patients who underwent PEG-IFN α-2a treatment. The proportions of T-cell subsets were compared among different responders and non-responders (determined by biochemical, serological, and virological responses). Results The baseline proportions of the three T-cell subsets were significantly higher in CHB patients (65 cases) than in healthy controls (28 cases), while the proportions declined significantly after 52 weeks of PEG-IFN treatment. Responders (ALT < 40 IU/L, 89.2% [58/65]; HBV DNA < 2.7 log10 IU/ml, 66.2% [43/65]; and HBeAg seroconversion [SR], 53.9% [35/65]) experienced more pronounced declines in the proportion of T-cell subsets compared to non-responders. In particular, the baseline proportions of CD4+CD25high T-cells displayed significant difference between SR and non-SR groups. The stepwise logistic regression analysis identified that CD4+CD25high T-cells combined with baseline HBV DNA and ALT can predict SR and CR (ALT < 40 IU/L, HBV DNA < 2.7 log10 IU/mL and HBeAg seroconversion) after 52 weeks of PEG-IFN treatment with high accuracy. Conclusion PEG-IFN therapy induces significant declines in the proportion of some key T-cell subsets in HBeAg-positive patients. The model constructed with CD4+CD25high T-cells combined with ATL and HBV DNA may help to predict the efficacy of PEG-IFN α-2a therapy.
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Affiliation(s)
- Li Zhu
- Department of Infectious Diseases, the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, People’s Republic of China
- Department of Hepatology, the Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, Jiangsu, People’s Republic of China
- Department of Hepatology, the Fifth People’s Hospital of Suzhou, Suzhou, Jiangsu, People’s Republic of China
| | - Jin Li
- Central Laboratory, the Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, Jiangsu, People’s Republic of China
- Central Laboratory, the Fifth People’s Hospital of Suzhou, Suzhou, Jiangsu, People’s Republic of China
| | - Junchi Xu
- Central Laboratory, the Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, Jiangsu, People’s Republic of China
- Central Laboratory, the Fifth People’s Hospital of Suzhou, Suzhou, Jiangsu, People’s Republic of China
| | - Fan Chen
- Department of Hepatology, the Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, Jiangsu, People’s Republic of China
- Department of Hepatology, the Fifth People’s Hospital of Suzhou, Suzhou, Jiangsu, People’s Republic of China
| | - Xunxun Wu
- Department of Hepatology, the Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, Jiangsu, People’s Republic of China
- Department of Hepatology, the Fifth People’s Hospital of Suzhou, Suzhou, Jiangsu, People’s Republic of China
| | - Chuanwu Zhu
- Department of Infectious Diseases, the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, People’s Republic of China
- Department of Hepatology, the Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, Jiangsu, People’s Republic of China
- Department of Hepatology, the Fifth People’s Hospital of Suzhou, Suzhou, Jiangsu, People’s Republic of China
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Kang B, Yi DY, Choe BH. Translational Strategies to Eliminate Chronic Hepatitis B in Children: Prophylaxis and Management in East Asian Countries. Front Pediatr 2022; 9:809838. [PMID: 35186829 PMCID: PMC8854863 DOI: 10.3389/fped.2021.809838] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 12/27/2021] [Indexed: 12/14/2022] Open
Abstract
Translational medical research on hepatitis B virus (HBV) infection and chronic hepatitis B (CHB) pathogenesis provides guidance on strengthening the treatment and prevention strategies of CHB. Preventing vertical transmission is the key to eliminating HBV infection in children. The understanding of HBV replication, hepatocyte turnover, and the fate of covalently closed circular DNA (cccDNA) would help establish a personalized application of the guidelines, especially concerning the discontinuation of nucleos(t)ide analog (NA) treatment in children. Transplacental leakage of HBV-infected maternal blood is suggested as the leading cause of vertical transmission. Prenatal maternal prophylaxis could diminish maternal HBV viremia at delivery, to reduce the risk of neonatal HBV infection. The meaning of the expression "no additional risk of breast milk feeding" is thereby explained. Understanding the untreated natural course of CHB in children and the course changeable by treatment is important to apply individualistic strategies and avoid the immoral selection of treatment indications. NAs with potent efficacy and a high barrier to drug resistance should be used as first-line treatment to reduce the likelihood of NA-resistant HBV development because the rate of mutant HBV emergence might count on the infected hepatocyte turnover rate in chronic HBV infection. Although elimination of intranuclear cccDNA is difficult by NAs alone, a cure is possible by human immunity and hepatocyte turnover. The reduction of intranuclear cccDNA occurs after the destruction of HBV-infected hepatocytes, non-cytolytic immune response, apoptosis of hepatocytes, and compensatory cell proliferation. Therefore, consolidation therapy after NA-induced hepatitis B e-antigen seroconversion must be necessary for a sufficient period. This review also summarizes the treatment strategies of CHB in children based on the practical application of translational research.
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Affiliation(s)
- Ben Kang
- Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu, South Korea
| | - Dae Yong Yi
- Department of Pediatrics, College of Medicine, Chung-Ang University Hospital, Chung-Ang University, Seoul, South Korea
| | - Byung-Ho Choe
- Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu, South Korea
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Yim HJ, Kim W, Ahn SH, Jung YK, Um SH, Sohn JH, Jang JY, Kim DJ, Park ES, Jin SY, Kim KH. Besifovir therapy improves hepatic histology and reduces covalently closed circular DNA in chronic hepatitis B patients. J Gastroenterol Hepatol 2022; 37:378-386. [PMID: 34653281 DOI: 10.1111/jgh.15710] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 09/15/2021] [Accepted: 10/04/2021] [Indexed: 12/20/2022]
Abstract
BACKGROUND AND AIM Besifovir dipivoxil maleate (BSV) was reported to have comparable antiviral efficacy and superior renal and bone safety to tenofovir disoproxil fumarate (TDF) in chronic hepatitis B (CHB) patients. The present study aims to evaluate changes of liver histology and intrahepatic covalently closed circular DNA (cccDNA) levels by BSV treatment in comparison with TDF therapy. METHODS This is a subset study of the phase 3 trial comparing BSV with TDF. Among them, only CHB patients willing to participate in a histologic evaluation study were enrolled. Liver histologic examination and intrahepatic cccDNA quantification were performed. RESULTS A total of 46 CHB patients received liver biopsies (BSV, n = 29; TDF, n = 17). After 48 weeks of treatment, virological response rate was comparable between the groups (P = 0.707). Follow-up liver biopsies showed that necroinflammation was significantly improved in the both groups. However, the histological response rate defined as the proportion of subjects whose modified histologic activity index score decreased by ≥ 2 without deterioration in fibrosis was higher in the BSV group than in the TDF group (77.8% vs 36.4%, P = 0.048). The proportion of subjects with Ishak fibrosis score 3 or more decreased from 77.7% to 55.5% in the BSV and that decreased from 72.7% to 45.4% in the TDF group. The intrahepatic cccDNA significantly decreased from baseline after 48 weeks of BSV or TDF treatment (P < 0.001) without intergroup differences (P = 0.349). CONCLUSIONS The BSV therapy improves hepatic histology and decreases intrahepatic cccDNA in CHB patients.
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Affiliation(s)
- Hyung Joon Yim
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Won Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Republic of Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Young Kul Jung
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Soon Ho Um
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Joo Hyun Sohn
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea
| | - Jae Young Jang
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Seoul, Republic of Korea
| | - Dong Joon Kim
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, Republic of Korea
| | - Eun-Sook Park
- Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, Konkuk University School of Medicine, Seoul, Republic of Korea
| | - So-Young Jin
- Department of Pathology, Soonchunhyang University College of Medicine, Seoul, Republic of Korea
| | - Kyun-Hwan Kim
- Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon, Republic of Korea
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Nosaka T, Naito T, Murata Y, Matsuda H, Ohtani M, Hiramatsu K, Nishizawa T, Okamoto H, Nakamoto Y. Regulatory function of interferon-inducible 44-like for hepatitis B virus covalently closed circular DNA in primary human hepatocytes. Hepatol Res 2022; 52:141-152. [PMID: 34697871 DOI: 10.1111/hepr.13722] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 10/13/2021] [Accepted: 10/17/2021] [Indexed: 12/12/2022]
Abstract
AIM Curing hepatitis B virus (HBV) infection requires elimination of covalently closed circular DNA (cccDNA). Interferon (IFN)-γ has noncytolytic antiviral potential; however, elimination of cccDNA could not be achieved. To enhance the regulatory effect, we comprehensively analyzed the host factors associated with cccDNA amplification and IFN-γ and IFN-α effects using an in vitro HBV infection system showing various transcription levels. METHODS Primary human hepatocytes were infected with HBV using genomic plasmids carrying the basic core promoter mutation A1762T/G1764A and/or the precore mutation G1896A and treated with IFN-γ and IFN-α. Comprehensive and functional studies involving microarray and small interfering RNA analysis revealed the host factors related to cccDNA regulation. RESULTS The HBV infection system reproduced the HBV life cycle and showed various propagation levels. Microarray analysis revealed 53 genes correlated with the cccDNA levels. Of the 53 genes, expression of IFN-induced protein 44-like (IFI44L) was significantly upregulated by IFN-γ and IFN-α. The anti-HBV effect of IFI44L is exerted regardless of IFN-γ or IFN-α by inhibiting the activation of nuclear factor-κB and signal transducer and activator of transcription 1 pathways. CONCLUSIONS Using the in vitro HBV infection system, an IFN-inducible molecule, IFI44L, associated with cccDNA amplification, was identified. These results suggest an innovative molecular strategy for the regulation of HBV cccDNA by controlling a novel host factor, IFI44L.
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Affiliation(s)
- Takuto Nosaka
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Tatsushi Naito
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Yosuke Murata
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Hidetaka Matsuda
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Masahiro Ohtani
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Katsushi Hiramatsu
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Tsutomu Nishizawa
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Tochigi, Japan
| | - Hiroaki Okamoto
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Tochigi, Japan
| | - Yasunari Nakamoto
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
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Wei S, Yang M, Geng X, Xiong Q, Hou H, Zhou D, Cui X. Prognostic factors in hepatocellular carcinoma patients with Child-Pugh A liver function after hepatectomy: Not related to the surgical approach. Ann Hepatol 2022; 27 Suppl 1:100580. [PMID: 34788657 DOI: 10.1016/j.aohep.2021.100580] [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] [Received: 03/20/2021] [Revised: 05/21/2021] [Accepted: 05/22/2021] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVES Improving the prognosis of patients with hepatocellular carcinoma (HCC) undergoing hepatectomy is critical. This article aims to investigate the risk factors affecting the prognosis of HCC patients with Child-Pugh A (CPA) liver function after hepatectomy and to compare the prognosis of patients with anatomical resection (AR) and nonanatomical resection (NAR). METHODS In total, 186 patients diagnosed with HCC between 2013 and 2019 were retrospectively enrolled. Univariate and multivariate analyses were performed using a Cox proportional hazard regression model to explore the factors related to prognosis. Overall survival (OS) and progression-free survival (PFS) were analyzed by log-rank tests and are shown by Kaplan-Meier curves. Chi-square tests and Mann-Whitney U tests were used to compare the difference in clinical characteristics between AR and NAR patients. RESULTS Among the 186 enrolled patients, only 73 were followed over 60 months. The 1-, 3-, and 5-year survival rates were 74.5%, 46.7% and 26.0%, respectively. Multivariate analyses demonstrated that portal vein invasion (PVI) and tumor size were independent risk factors for OS and PFS. Preoperative hepatitis B surface antigen (HBsAg) and a-fetoprotein (AFP) levels were identified as independent risk factors only for PFS. In univariate analysis, the NAR group had a better OS rate than the AR group (1-year: 80.4% vs. 63.6%, 3-year: 55.9% vs. 30.3%, 5-year: 34.8% vs. 11.1%), but this was not confirmed by multivariate analysis. CONCLUSIONS PVI and tumor size > 5 cm are risk factors for the prognosis of CPA HCC patients after hepatectomy, but the surgical type is not.
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Affiliation(s)
- Sheng Wei
- Department of General Surgery, The Second Hospital of Anhui Medical University, Hefei, China
| | - Minghao Yang
- Department of General Surgery, The Second Hospital of Anhui Medical University, Hefei, China
| | - Xiaoping Geng
- Department of General Surgery, The Second Hospital of Anhui Medical University, Hefei, China
| | - Qiru Xiong
- Department of General Surgery, The Second Hospital of Anhui Medical University, Hefei, China
| | - Hui Hou
- Department of General Surgery, The Second Hospital of Anhui Medical University, Hefei, China
| | - Dachen Zhou
- Department of General Surgery, The Second Hospital of Anhui Medical University, Hefei, China.
| | - Xiao Cui
- Department of General Surgery, The Second Hospital of Anhui Medical University, Hefei, China.
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Mani N, Cole AG, Phelps JR, Ardzinski A, Burns R, Chiu T, Cuconati A, Dorsey BD, Evangelista E, Fan K, Guo F, Harasym TO, Kadhim S, Kowalski R, Kultgen SG, Lee ACH, Li AH, Majeski SA, Miller A, Pasetka C, Reid SP, Rijnbrand R, Micolochick Steuer HM, Stever K, Tang S, Teng X, Wang X, Sofia MJ. Preclinical characterization of AB-506, an inhibitor of HBV replication targeting the viral core protein. Antiviral Res 2021; 197:105211. [PMID: 34826506 DOI: 10.1016/j.antiviral.2021.105211] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Revised: 11/19/2021] [Accepted: 11/22/2021] [Indexed: 02/06/2023]
Abstract
AB-506, a small-molecule inhibitor targeting the HBV core protein, inhibits viral replication in vitro (HepAD38 cells: EC50 of 0.077 μM, CC50 > 25 μM) and in vivo (HBV mouse model: ∼3.0 log10 reductions in serum HBV DNA compared to the vehicle control). Binding of AB-506 to HBV core protein accelerates capsid assembly and inhibits HBV pgRNA encapsidation. Furthermore, AB-506 blocks cccDNA establishment in HBV-infected HepG2-hNTCP-C4 cells and primary human hepatocytes, leading to inhibition of viral RNA, HBsAg, and HBeAg production (EC50 from 0.64 μM to 1.92 μM). AB-506 demonstrated activity across HBV genotypes A-H and maintains antiviral activity against nucleos(t)ide analog-resistant variants in vitro. Evaluation of AB-506 against a panel of core variants showed that T33N/Q substitutions results in >200-fold increase in EC50 values, while L30F, L37Q, and I105T substitutions showed an 8 to 20-fold increase in EC50 values in comparison to the wild-type. In vitro combinations of AB-506 with NAs or an RNAi agent were additive to moderately synergistic. AB-506 exhibits good oral bioavailability, systemic exposure, and higher liver to plasma ratios in rodents, a pharmacokinetic profile supporting clinical development for chronic hepatitis B.
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Affiliation(s)
- Nagraj Mani
- Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, PA, 18974, USA.
| | - Andrew G Cole
- Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, PA, 18974, USA
| | - Janet R Phelps
- Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, PA, 18974, USA
| | - Andrzej Ardzinski
- Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, PA, 18974, USA
| | - Robbin Burns
- Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, PA, 18974, USA
| | - Tim Chiu
- Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, PA, 18974, USA
| | - Andrea Cuconati
- Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, PA, 18974, USA
| | - Bruce D Dorsey
- Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, PA, 18974, USA
| | - Ellen Evangelista
- Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, PA, 18974, USA
| | - Kristi Fan
- Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, PA, 18974, USA
| | - Fang Guo
- Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, PA, 18974, USA
| | - Troy O Harasym
- Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, PA, 18974, USA
| | - Salam Kadhim
- Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, PA, 18974, USA
| | - Roseann Kowalski
- Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, PA, 18974, USA
| | - Steven G Kultgen
- Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, PA, 18974, USA
| | - Amy C H Lee
- Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, PA, 18974, USA
| | - Alice H Li
- Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, PA, 18974, USA
| | - Sara A Majeski
- Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, PA, 18974, USA
| | - Angela Miller
- Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, PA, 18974, USA
| | - Chris Pasetka
- Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, PA, 18974, USA
| | - Stephen P Reid
- Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, PA, 18974, USA
| | - Rene Rijnbrand
- Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, PA, 18974, USA
| | | | - Kim Stever
- Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, PA, 18974, USA
| | - Sunny Tang
- Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, PA, 18974, USA
| | - Xiaowei Teng
- Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, PA, 18974, USA
| | - Xiaohe Wang
- Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, PA, 18974, USA
| | - Michael J Sofia
- Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, PA, 18974, USA
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Charatcharoenwitthaya P, Kaewdech A, Piratvisuth T. Controversies in Treating Chronic HBV: The Role of PEG-interferon-alfa. Clin Liver Dis 2021; 25:741-762. [PMID: 34593151 DOI: 10.1016/j.cld.2021.06.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Pegylated interferon-alpha therapy is one of the first-line chronic hepatitis B treatment. Finite treatment duration, absence of drug resistance, delayed response, and higher hepatitis B surface antigen loss than nucleos(t)ides analog therapy are the advantages of pegylated interferon-alpha treatment. Common side effects and subcutaneous injections requirement limit its use. Identifying patients likely to respond to pegylated interferon-alpha and optimizing treatment is reasonable. Motivating patients to complete the 48-week treatment is necessary. Treatment is stopped or switched to other treatment strategies in patients with stopping rule criteria. Combination therapy with nucleos(t)ides analog may improve response, but remains controversial.
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Affiliation(s)
- Phunchai Charatcharoenwitthaya
- Gastroenterology Division, Department of Internal Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Wang-Lang Road, Bangkok 10700, Thailand
| | - Apichat Kaewdech
- Gastroenterology and Hepatology Unit, Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Kanchanawanich Road, Songkhla 90110, Thailand
| | - Teerha Piratvisuth
- Gastroenterology and Hepatology Unit, Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Kanchanawanich Road, Songkhla 90110, Thailand; NKC Institute of Gastroenterology and Hepatology, Songklanagarind Hospital, Prince of Songkla University, Kanchanawanich Road, Songkhla 90110, Thailand.
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Wu F, Lu R, Liu Y, Wang Y, Tian Y, Li Y, Li M, Wang W, Zhang X, Jia X, Dang S. Efficacy and safety of peginterferon alpha monotherapy in Chinese inactive chronic hepatitis B virus carriers. Liver Int 2021; 41:2032-2045. [PMID: 33896094 DOI: 10.1111/liv.14897] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Revised: 02/27/2021] [Accepted: 03/31/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS The effectiveness and safety of peginterferon alpha (peg-IFN-α) monotherapy in inactive hepatitis B virus (HBV) carriers (IHCs) have not been fully evaluated. METHODS This observational study prospectively enrolled 298 IHCs in China from 2015 to 2019. Participants were given the right to choose to either receive peg-IFN-α monotherapy (treatment group, n = 142) or be monitored without treatment (control group, n = 156) according to their wishes. The scheduled treatment duration was 48 weeks. All participants were followed up to 72 weeks. The main efficacy endpoint was hepatitis B surface antigen (HBsAg) clearance at 72 weeks. RESULTS Baseline characteristics were similar between both groups. At 72 weeks, intention-to-treat analysis showed that the rates of HBsAg clearance and seroconversion of the treatment group were 47.9% (68/142) and 36.6% (52/142), respectively, which were significantly higher than the HBsAg clearance rate of 1.9% (3/156) and the seroconversion rate of 0.6% (1/156) in the control group (both P < .001). Baseline HBV DNA < 20 IU/mL, lower HBsAg levels at baseline, 12 and 24 weeks, alanine aminotransferase elevation at 12 weeks, and greater HBsAg reduction from baseline to 12 and 24 weeks were independent predictors of HBsAg clearance. Generally, the therapy was well tolerated. Only five participants discontinued therapy as a result of peg-IFNα-related adverse events. CONCLUSIONS Peg-IFN-α monotherapy results in high rates of HBsAg clearance and seroconversion and the treatment is safe for IHCs.
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Affiliation(s)
- Fengping Wu
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Rui Lu
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yixin Liu
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yikai Wang
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yan Tian
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yaping Li
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Mei Li
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Wenjun Wang
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xin Zhang
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xiaoli Jia
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Shuangsuo Dang
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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Ohsaki E, Suwanmanee Y, Ueda K. Chronic Hepatitis B Treatment Strategies Using Polymerase Inhibitor-Based Combination Therapy. Viruses 2021; 13:v13091691. [PMID: 34578273 PMCID: PMC8473100 DOI: 10.3390/v13091691] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 08/19/2021] [Accepted: 08/25/2021] [Indexed: 12/12/2022] Open
Abstract
Viral polymerase is an essential enzyme for the amplification of the viral genome and is one of the major targets of antiviral therapies. However, a serious concern to be solved in hepatitis B virus (HBV) infection is the difficulty of eliminating covalently closed circular (ccc) DNA. More recently, therapeutic strategies targeting various stages of the HBV lifecycle have been attempted. Although cccDNA-targeted therapies are attractive, there are still many problems to be overcome, and the development of novel polymerase inhibitors remains an important issue. Interferons and nucleos(t)ide reverse transcriptase inhibitors (NRTIs) are the only therapeutic options currently available for HBV infection. Many studies have reported that the combination of interferons and NRTI causes the loss of hepatitis B surface antigen (HBsAg), which is suggestive of seroconversion. Although NRTIs do not directly target cccDNA, they can strongly reduce the serum viral DNA load and could suppress the recycling step of cccDNA formation, improve liver fibrosis/cirrhosis, and reduce the risk of hepatocellular carcinoma. Here, we review recent studies on combination therapies using polymerase inhibitors and discuss the future directions of therapeutic strategies for HBV infection.
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Chen J, Qi M, Fan XG, Hu XW, Liao CJ, Long LY, Zhao XT, Tan M, Li HF, Chen RC, Huang ZB, Huang Y. Efficacy of Peginterferon alfa-2b in Nucleoside Analogue Experienced Patients with Negative HBeAg and Low HBsAg: A Non-Randomized Clinical Trial. Infect Dis Ther 2021; 10:2259-2270. [PMID: 34309813 PMCID: PMC8572941 DOI: 10.1007/s40121-021-00497-5] [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: 04/07/2021] [Accepted: 06/30/2021] [Indexed: 02/07/2023] Open
Abstract
INTRODUCTION Hepatitis B surface antigen (HBsAg) clearance is the treatment goal for hepatitis B e antigen (HBeAg)-negative patients with chronic hepatitis B (CHB). However, its rate is extremely low with nucleoside (acid) analogues (NAs) monotherapy. Peginterferon could enhance HBsAg clearance. This study aimed to evaluate the efficacy of peginterferon alfa-2b (PegIFNα-2b) in NAs-experienced patients with CHB with negative HBeAg and low HBsAg level. METHODS HBeAg-negative patients with CHB who had received NAs therapy over 24 weeks with HBsAg < 1500 IU/mL and HBV DNA < 100 IU/mL were enrolled. Patients received either PegIFNα-2b add-on therapy (n = 108) or continuous NAs monotherapy (n = 75). The primary endpoint was HBsAg clearance rate at week 48. RESULTS At week 48, serum HBV DNA was undetectable among all PegIFNα-2b add-on therapy patients. Almost all patients maintained HBV DNA suppression in the PegIFNα-2b add-on group (100%, 108/108) and NAs monotherapy group (97.33%, 73/75). Only patients with PegIFNα-2b add-on therapy achieved HBsAg clearance (50.93%, 55/108) and HBsAg seroconversion (48.15%, 52/108) at week 48. Patients with baseline HBsAg < 100 IU/mL achieved the highest HBsAg clearance rate and HBsAg seroconversion rate at week 48 (60.87%, 28/46 and 58.70%, 27/46 respectively). HBsAg clearance and HBsAg seroconversion at week 72 had no significant difference with continuing or discontinuing PegIFNα-2b therapy after 48 weeks of treatment. PegIFNα-2b add-on therapy was well tolerated. CONCLUSIONS PegIFNα-2b add-on therapy increases HBsAg clearance rate and seroconversion rate for HBeAg-negative patients with CHB, particularly for those with lower HBsAg level. It would be unnecessary to prolong PegIFNα-2b duration after 48 weeks of PegIFNα-2b treatment.
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Affiliation(s)
- Jun Chen
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Xiangya Road 87, Kaifu District, Changsha, 410008, China.,Key Laboratory of Viral Hepatitis, Hunan, China
| | - Min Qi
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Xiangya Road 87, Kaifu District, Changsha, 410008, China
| | - Xue-Gong Fan
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Xiangya Road 87, Kaifu District, Changsha, 410008, China.,Key Laboratory of Viral Hepatitis, Hunan, China
| | - Xing-Wang Hu
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Xiangya Road 87, Kaifu District, Changsha, 410008, China.,Key Laboratory of Viral Hepatitis, Hunan, China
| | - Cheng-Jin Liao
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Xiangya Road 87, Kaifu District, Changsha, 410008, China
| | - Li-Yuan Long
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Xiangya Road 87, Kaifu District, Changsha, 410008, China
| | - Xiao-Ting Zhao
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Xiangya Road 87, Kaifu District, Changsha, 410008, China
| | - Min Tan
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Xiangya Road 87, Kaifu District, Changsha, 410008, China
| | - Hai-Fu Li
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Xiangya Road 87, Kaifu District, Changsha, 410008, China
| | - Ruo-Chan Chen
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Xiangya Road 87, Kaifu District, Changsha, 410008, China.,Key Laboratory of Viral Hepatitis, Hunan, China
| | - Ze-Bing Huang
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Xiangya Road 87, Kaifu District, Changsha, 410008, China. .,Key Laboratory of Viral Hepatitis, Hunan, China.
| | - Yan Huang
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Xiangya Road 87, Kaifu District, Changsha, 410008, China. .,Key Laboratory of Viral Hepatitis, Hunan, China.
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Saraceni C, Birk J. A Review of Hepatitis B Virus and Hepatitis C Virus Immunopathogenesis. J Clin Transl Hepatol 2021; 9:409-418. [PMID: 34221927 PMCID: PMC8237136 DOI: 10.14218/jcth.2020.00095] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 02/21/2021] [Accepted: 04/22/2021] [Indexed: 12/13/2022] Open
Abstract
Despite the advances in therapy, hepatitis B virus (HBV) and hepatitis C virus (HCV) still represent a significant global health burden, both as major causes of cirrhosis, hepatocellular carcinoma, and death worldwide. HBV is capable of incorporating its covalently closed circular DNA into the host cell's hepatocyte genome, making it rather difficult to eradicate its chronic stage. Successful viral clearance depends on the complex interactions between the virus and host's innate and adaptive immune response. One encouraging fact on hepatitis B is the development and effective distribution of the HBV vaccine. This has significantly reduced the spread of this virus. HCV is a RNA virus with high mutagenic capacity, thus enabling it to evade the immune system and have a high rate of chronic progression. High levels of HCV heterogeneity and its mutagenic capacity have made it difficult to create an effective vaccine. The recent advent of direct acting antivirals has ushered in a new era in hepatitis C therapy. Sustained virologic response is achieved with DAAs in 85-99% of cases. However, this still leads to a large population of treatment failures, so further advances in therapy are still needed. This article reviews the immunopathogenesis of HBV and HCV, their properties contributing to host immune system avoidance, chronic disease progression, vaccine efficacy and limitations, as well as treatment options and common pitfalls of said therapy.
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Affiliation(s)
- Corey Saraceni
- Correspondence to: Corey Saraceni, University of Connecticut School of Medicine, Department of Medicine, Division of Gastroenterology and Hepatology, 263 Farmington Avenue, Farmington, CT 06030-8074, USA. Tel: +1-203-733-7408, Fax: +1-860-679-3159, E-mail:
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Innate immunity in hepatitis B and D virus infection: consequences for viral persistence, inflammation, and T cell recognition. Semin Immunopathol 2021; 43:535-548. [PMID: 34019142 PMCID: PMC8443521 DOI: 10.1007/s00281-021-00864-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 04/30/2021] [Indexed: 12/16/2022]
Abstract
Chronic infections with human hepatitis viruses continue to be a major health burden worldwide. Despite the availability of an effective prophylactic vaccine against the hepatitis B virus (HBV) and of antiviral agents efficiently suppressing HBV replication, more than 250 million people are currently chronically infected with this hepatotropic DNA virus, and resolution of chronic hepatitis B (CHB) is rarely achieved. Moreover, coinfection with the hepatitis D virus (HDV), a human RNA satellite virus requiring the envelope proteins of HBV for productive viral spreading, substantially aggravates the disease course of CHB. The molecular mechanisms by which these viruses interact with each other and with the intrinsic innate responses of the hepatocytes are not fully understood. While HBV appears to avoid innate immune recognition, HDV elicits a strong enhancement of innate responses. Notwithstanding, such induction does not hamper HDV replication but contributes to liver inflammation and pathogenesis. Intriguingly, HDV appears to influence the ability of T cells to recognize infected hepatocytes by boosting antigen presentation. This review focuses on current knowledge regarding how these viruses can shape and counteract the intrinsic innate responses of the hepatocytes, thus affecting the immune system and pathogenesis. Understanding the distinct strategies of persistence that HBV and HDV have evolved is central for advancing the development of curative therapies.
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Entecavir add-on Peg-interferon therapy plays a positive role in reversing hepatic fibrosis in treatment-naïve chronic hepatitis B patients: a prospective and randomized controlled trial. Chin Med J (Engl) 2021; 133:1639-1648. [PMID: 32568867 PMCID: PMC7401765 DOI: 10.1097/cm9.0000000000000857] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND The efficacy of entecavir (ETV) add-on peg-interferon therapy compared with ETV monotherapy in treatment-naïve hepatitis B virus (HBV) patients remains controversial. We investigated whether adding peg-interferon to ongoing ETV treatment leads to a better curative effect or not. METHODS All patients have been recruited between August 2013 and January 2015 from the Shanghai Public Health Clinical Center and Zhongshan Hospital (China). Eligible HBV patients (n = 144) were randomly divided (1:1) to receive either ETV monotherapy (n = 70) or peg-interferon add-on therapy from week 26 to 52 (n = 74). Patients were followed-up for at least 2 years. Indexes including hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) seroconversion rate, sustained virologic response, transient elastography value, and histological scores were evaluated every 3 months until the end of the study. The rate of patients with HBsAg loss was defined as the primary endpoint criteria. RESULTS At week 26, no patient achieved HBsAg seroconversion in either group. At week 52, one patient in the monotherapy group was HBsAg-negative but there was none in the combination therapy group. The monotherapy group showed significantly better liver function recovery results than the combination therapy group. At week 78, one patient in the combination group had HBsAg seroconverted. At week 104, only three patients in the combination therapy group were HBsAg-negative compared with one patient in monotherapy. The mean alanine aminotransferase and aspartate aminotransferase levels and transient elastography values decreased significantly compared with baseline. Both groups showed a favorable decrease in alpha-fetoprotein (monotherapy: 4.5 [2.8, 7.1] vs. 2.2 [1.8, 3.1] ng/mL, P < 0.001; combination therapy: 5.7 [3.0, 18.8] vs. 3.2 [2.0, 4.3] ng/mL, P < 0.001) and an improved result of liver biopsy examination scores. The combination group showed a better improvement in histology compared with the monotherapy group (mean transient elastography value 6.6 [4.9, 9.8] vs. 7.8 [5.4, 11.1] kPa, P = 0.028). But there was no significant difference in HBsAg conversion rate (1.8% [1/56] vs. 4.1% [3/73], P = 0.809) and HBeAg conversion rate (12.5% [7/56] vs. 11.0% [8/73], P = 0.787), as well as HBV-DNA, sustained virologic response (93.2% vs. 98.5%, P = 0.150) between the two groups. CONCLUSIONS Both therapies supported liver function recovery and histology improvement. Combination therapy did not show better anti-viral efficacy in HBsAg or HBeAg seroconversion compared with monotherapy. However, combination therapy played a more positive role in reversing hepatic fibrosis compared with monotherapy. TRIAL REGISTRATION ClinicalTrials.gov: NCT02849132; https://clinicaltrials.gov/ct2/show/NCT02849132.
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Yeh ML, Huang JF, Yu ML, Chuang WL. Hepatitis b infection: progress in identifying patients most likely to respond to peginterferon alfa. Expert Rev Gastroenterol Hepatol 2021; 15:427-435. [PMID: 33338385 DOI: 10.1080/17474124.2021.1866985] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Accepted: 12/17/2020] [Indexed: 02/07/2023]
Abstract
Introduction: Despite the disadvantage of side effects, pegylated interferon alpha (Peg-IFN α) remains an indispensable agent for chronic hepatitis B (CHB) due to its immunomodulatory effect. The selection of a patient most likely to have a favorable response becomes an essential issue for Peg-IFN α therapy.Areas covered: Recent progress in the prediction of the treatment response to Peg-IFN α.Expert opinion: Before Peg-IFN α therapy, baseline host and viral factors, including female sex, younger age, a high alanine aminotransferase level, HBV genotype A or B, and low viral load, predict a favorable response. In addition, on-treatment viral kinetics of hepatitis B surface antigen (HBsAg), e antigen (HBeAg) and HBV DNA help clinicians determine whether to continue or discontinue Peg-IFN α therapy. The novel HBV markers hepatitis B core-related antigen and HBV RNA have recently been investigated as useful predictors. The limited efficacy of Peg-IFN α monotherapy facilitated the development of new strategies of 'add-on' or 'switch to' Peg-IFN α in patients receiving long-term nucleot(s)ide analog treatment, which may lead to an increase in HBeAg and HBsAg loss. In summary, tailored Peg-IFN α therapeutic strategies based on predictors extended the landscape for CHB treatment.
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Affiliation(s)
- Ming-Lun Yeh
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine, Lipid Science and Aging Research Center, and Hepatitis Research Center, College of Medicine, and Center for Cancer Research and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jee-Fu Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine, Lipid Science and Aging Research Center, and Hepatitis Research Center, College of Medicine, and Center for Cancer Research and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine, Lipid Science and Aging Research Center, and Hepatitis Research Center, College of Medicine, and Center for Cancer Research and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wan-Long Chuang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine, Lipid Science and Aging Research Center, and Hepatitis Research Center, College of Medicine, and Center for Cancer Research and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
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Lee S, Goyal A, Perelson AS, Ishida Y, Saito T, Gale M. Suppression of hepatitis B virus through therapeutic activation of RIG-I and IRF3 signaling in hepatocytes. iScience 2021; 24:101969. [PMID: 33458618 PMCID: PMC7797372 DOI: 10.1016/j.isci.2020.101969] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 10/29/2020] [Accepted: 12/16/2020] [Indexed: 12/18/2022] Open
Abstract
Hepatitis B virus (HBV) mediates persistent infection, chronic hepatitis, and liver disease. HBV covalently closed circular (ccc)DNA is central to viral persistence such that its elimination is considered the cornerstone for HBV cure. Inefficient detection by pathogen recognition receptors (PRRs) in the infected hepatocyte facilitates HBV persistence via avoidance of innate immune activation and interferon regulatory factor (IRF)3 induction of antiviral gene expression. We evaluated a small molecule compound, F7, and 5'-triphosphate-poly-U/UC pathogen-associated-molecular-pattern (PAMP) RNA agonists of RIG-I, a PRR that signals innate immunity, for ability to suppress cccDNA. F7 and poly-U/UC PAMP treatment of HBV-infected cells induced RIG-I signaling of IRF3 activation to induce antiviral genes for suppression of cccDNA formation and accelerated decay of established cccDNA, and were additive to the actions of entecavir. Our study shows that activation of the RIG-I pathway and IRF3 to induce innate immune actions offers therapeutic benefit toward elimination of cccDNA.
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Affiliation(s)
- Sooyoung Lee
- Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington, Seattle, WA 98109, USA
| | - Ashish Goyal
- Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM, USA
| | - Alan S. Perelson
- Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM, USA
| | - Yuji Ishida
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- PhoenixBio Co., Ltd., Research and Development Unit, Higashi-Hiroshima, Japan
| | - Takeshi Saito
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Michael Gale
- Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington, Seattle, WA 98109, USA
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Kadelka S, Dahari H, Ciupe SM. Understanding the antiviral effects of RNAi-based therapy in HBeAg-positive chronic hepatitis B infection. Sci Rep 2021; 11:200. [PMID: 33420293 PMCID: PMC7794570 DOI: 10.1038/s41598-020-80594-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 12/21/2020] [Indexed: 01/29/2023] Open
Abstract
The RNA interference (RNAi) drug ARC-520 was shown to be effective in reducing serum hepatitis B virus (HBV) DNA, hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg) in HBeAg-positive patients treated with a single dose of ARC-520 and daily nucleosidic analogue (entecavir). To provide insights into HBV dynamics under ARC-520 treatment and its efficacy in blocking HBV DNA, HBsAg, and HBeAg production we developed a multi-compartmental pharmacokinetic-pharamacodynamic model and calibrated it with frequent measured HBV kinetic data. We showed that the time-dependent single dose ARC-520 efficacies in blocking HBsAg and HBeAg are more than 96% effective around day 1, and slowly wane to 50% in 1-4 months. The combined single dose ARC-520 and entecavir effect on HBV DNA was constant over time, with efficacy of more than 99.8%. The observed continuous HBV DNA decline is entecavir mediated, the strong but transient HBsAg and HBeAg decays are ARC-520 mediated. The modeling framework may help assess ongoing RNAi drug development for hepatitis B virus infection.
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Affiliation(s)
- Sarah Kadelka
- Department of Mathematics, Virginia Tech, Blacksburg, VA, 24060, USA
| | - Harel Dahari
- Program for Experimental and Theoretical Modeling, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, 60153, USA
| | - Stanca M Ciupe
- Department of Mathematics, Virginia Tech, Blacksburg, VA, 24060, USA.
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Broquetas T, Garcia-Retortillo M, Micó M, Canillas L, Puigvehí M, Cañete N, Coll S, Viu A, Hernandez JJ, Bessa X, Carrión JA. Hepatitis B surface antigen and hepatitis B core-related antigen kinetics after adding pegylated-interferon to nucleos(t)ids analogues in hepatitis B e antigen-negative patients. World J Hepatol 2020; 12:1076-1088. [PMID: 33312431 PMCID: PMC7701972 DOI: 10.4254/wjh.v12.i11.1076] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 06/23/2020] [Accepted: 09/04/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatitis B e antigen-negative chronic hepatitis B patients under nucleos(t)ids analogues (NAs) rarely achieve hepatitis B surface antigen (HBsAg) loss.
AIM To evaluate if the addition of pegylated interferon (Peg-IFN) could decrease HBsAg and hepatitis B core-related antigen (HBcrAg) levels and increase HBsAg loss rate in patients under NAs therapy.
METHODS Prospective, non-randomized, open-label trial evaluating the combination of Peg-IFN 180 µg/week plus NAs during forty-eight weeks vs NAs in monotherapy. Hepatitis B e antigen-negative non-cirrhotic chronic hepatitis B patients of a tertiary hospital, under NAs therapy for at least 2 years and with undetectable viral load, were eligible. Patients with hepatitis C virus, hepatitis D virus or human immunodeficiency virus co-infection and liver transplanted patients were excluded. HBsAg and HBcrAg levels (log10 U/mL) were measured at baseline and during ninety-six weeks. HBsAg loss rate was evaluated in both groups. Adverse events were recorded in both groups. The kinetic of HBsAg for each treatment group was evaluated from baseline to weeks 24 and 48 by the slope of the HBsAg decline (log10 IU/mL/week) using a linear regression model.
RESULTS Sixty-five patients were enrolled, 61% receiving tenofovir and 33% entecavir. Thirty-six (55%) were included in Peg-IFN-NA group and 29 (44%) in NA group. After matching by age and treatment duration, baseline HBsAg levels were comparable between groups (3.1 vs 3.2) (P = 0.25). HBsAg levels at weeks 24, 48 and 96 declined in Peg-IFN-NA group (-0.26, -0.40 and -0.44) and remained stable in NA group (-0.10, -0.10 and -0.10) (P < 0.05). The slope of HBsAg decline in Peg-IFN-NA group (-0.02) was higher than in NA group (-0.00) (P = 0.015). HBcrAg levels did not change. Eight (22%) patients discontinued Peg-IFN due to adverse events. The HBsAg loss was achieved in 3 (8.3%) patients of the Peg-IFN-NA group and 0 (0%) of the NA group.
CONCLUSION The addition of Peg-IFN to NAs caused a greater and faster decrease of HBsAg levels compared to NA therapy. Side effects of Peg-IFN can limit its use in clinical practice.
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Affiliation(s)
- Teresa Broquetas
- Department of Gastroenterology, Liver Section, Hospital del Mar Medical Research Institute, Barcelona 08003, Spain
- Departament of de Medicina, Universitat Autònoma de Barcelona, Barcelona 08003, Spain
| | - Montserrat Garcia-Retortillo
- Department of Gastroenterology, Liver Section, Hospital del Mar Medical Research Institute, Barcelona 08003, Spain
- Departament of de Medicina, Universitat Autònoma de Barcelona, Barcelona 08003, Spain
| | - Miquel Micó
- Laboratori de Referencia de Catalunya, El Prat de Llobregat, Barcelona 08820, Spain
| | - Lidia Canillas
- Department of Gastroenterology, Liver Section, Hospital del Mar Medical Research Institute, Barcelona 08003, Spain
| | - Marc Puigvehí
- Department of Gastroenterology, Liver Section, Hospital del Mar Medical Research Institute, Barcelona 08003, Spain
- Departament of de Medicina, Universitat Autònoma de Barcelona, Barcelona 08003, Spain
| | - Nuria Cañete
- Department of Gastroenterology, Liver Section, Hospital del Mar Medical Research Institute, Barcelona 08003, Spain
- Departament of de Medicina, Universitat Autònoma de Barcelona, Barcelona 08003, Spain
| | - Susana Coll
- Department of Gastroenterology, Liver Section, Hospital del Mar Medical Research Institute, Barcelona 08003, Spain
- Departament of de Medicina, Universitat Autònoma de Barcelona, Barcelona 08003, Spain
| | - Ana Viu
- Department of Gastroenterology, Liver Section, Hospital del Mar Medical Research Institute, Barcelona 08003, Spain
| | - Juan Jose Hernandez
- Laboratori de Referencia de Catalunya, El Prat de Llobregat, Barcelona 08820, Spain
| | - Xavier Bessa
- Department of Gastroenterology, Liver Section, Hospital del Mar Medical Research Institute, Barcelona 08003, Spain
- Departament of de Medicina, Universitat Autònoma de Barcelona, Barcelona 08003, Spain
| | - José A Carrión
- Department of Gastroenterology, Liver Section, Hospital del Mar Medical Research Institute, Barcelona 08003, Spain
- Departament of de Medicina, Universitat Autònoma de Barcelona, Barcelona 08003, Spain
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Ringlander J, Skoglund C, Prakash K, Andersson ME, Larsson SB, Tang KW, Rydell GE, Abrahamsson S, Castedal M, Norder H, Hellstrand K, Lindh M. Deep sequencing of liver explant transcriptomes reveals extensive expression from integrated hepatitis B virus DNA. J Viral Hepat 2020; 27:1162-1170. [PMID: 32592629 DOI: 10.1111/jvh.13356] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 06/09/2020] [Accepted: 06/15/2020] [Indexed: 12/20/2022]
Abstract
Hepatitis B virus (HBV) is a major cause of hepatocellular carcinoma (HCC). Integration of HBV DNA into the human genome may contribute to oncogenesis and to the production of the hepatitis B surface antigen (HBsAg). Whether integrations contribute to HBsAg levels in the blood is poorly known. Here, we characterize the HBV RNA profile of HBV integrations in liver tissue in patients with chronic HBV infection, with or without concurrent hepatitis D infection, by transcriptome deep sequencing. Transcriptomes were determined in liver tissue by deep sequencing providing 200 million reads per sample. Integration points were identified using a bioinformatic pipeline. Explanted liver tissue from five patients with end-stage liver disease caused by HBV or HBV/HDV was studied along with publicly available transcriptomes from 21 patients. Almost all HBV RNA profiles were devoid of reads in the core and the 3' redundancy (nt 1830-1927) regions, and contained a large number of chimeric viral/human reads. Hence, HBV transcripts from integrated HBV DNA rather than from covalently closed circular HBV DNA (cccDNA) predominated in late-stage HBV infection, in particular in cases with hepatitis D virus co-infection. The findings support the suggestion that integrated HBV DNA can be a significant source of HBsAg in humans.
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Affiliation(s)
- Johan Ringlander
- Department of Infectious Diseases, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Catarina Skoglund
- The Transplant Institute, Department of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden.,Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Kasthuri Prakash
- Department of Infectious Diseases, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Maria E Andersson
- Department of Infectious Diseases, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Simon B Larsson
- Department of Infectious Diseases, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Ka-Wei Tang
- Department of Infectious Diseases, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Gustaf E Rydell
- Department of Infectious Diseases, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Sanna Abrahamsson
- Bioinformatics Core Facility, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Maria Castedal
- The Transplant Institute, Department of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden.,Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Heléne Norder
- Department of Infectious Diseases, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Kristoffer Hellstrand
- Department of Infectious Diseases, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Magnus Lindh
- Department of Infectious Diseases, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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39
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Dandri M, Petersen J. cccDNA Maintenance in Chronic Hepatitis B - Targeting the Matrix of Viral Replication. Infect Drug Resist 2020; 13:3873-3886. [PMID: 33149632 PMCID: PMC7605611 DOI: 10.2147/idr.s240472] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 10/02/2020] [Indexed: 12/11/2022] Open
Abstract
Chronic hepatitis B is a numerically important cause of cirrhosis and hepatocellular carcinoma, despite an effective prophylactic vaccine and well-tolerated and effective oral antivirals. Both the incapacity of the immune system to clear hepatitis B virus (HBV) infection and the unique replication strategies adopted by HBV are considered key determinants of HBV chronicity. In this regard, the formation of the HBV DNA minichromosome, the covalently closed circular DNA (cccDNA), in the nucleus of infected hepatocytes, is essential not only for the production of all viral proteins but also for HBV persistence even after long-term antiviral therapy. Licensed polymerase inhibitors target the HBV reverse transcriptase activity, control the disease with long-term therapy but fail to eliminate the cccDNA. Consequently, the production of viral RNAs and proteins, including the hepatitis B surface antigen (HBsAg), is not abolished. Novel therapeutic efforts that are in the pipeline for early clinical trials explore novel targets and molecules. Such therapeutic efforts focus on achieving a functional cure, which is defined by the loss of HBsAg and undetectable HBV DNA levels in serum. Since a true cure of HBV infection requires the elimination of the cccDNA from infected cells, comprehension of the mechanisms implicated in cccDNA biogenesis, regulation and stability appears necessary to achieve HBV eradication. In this review, we will summarize the state of knowledge on cccDNA metabolism, focusing on insights suggesting potential weak points of the cccDNA that may be key for the development of therapeutic approaches and design of clinical trials aiming at lowering cccDNA loads and activity.
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Affiliation(s)
- Maura Dandri
- Department of Internal Medicine, University Medical Center Hamburg - Eppendorf, Hamburg, Germany.,German Center for Infection Research (DZIF), Hamburg-Luebeck-Borstel-Riems Site, Germany
| | - Joerg Petersen
- Institute for Interdisciplinary Medicine, Asklepios Klinik St Georg, University of Hamburg, Hamburg, Germany
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40
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Rydell GE, Larsson SB, Prakash K, Andersson M, Norder H, Hellstrand K, Norkrans G, Lindh M. Abundance of non-circular intrahepatic hepatitis B virus DNA may reflect frequent integration into human DNA in chronically infected patients. J Infect Dis 2020; 225:1982-1990. [PMID: 32910825 PMCID: PMC9159317 DOI: 10.1093/infdis/jiaa572] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 09/07/2020] [Indexed: 12/29/2022] Open
Abstract
Background Hepatitis B virus (HBV) integration has implications for cancer development and surface antigen (HBsAg) production, but methods to quantify integrations are lacking. The aim of this study was to develop a droplet digital PCR (ddPCR) assay discriminating between circular and integrated HBV DNA, and to relate the distribution between the two forms to other HBV markers. Methods ddPCR with primers spanning the typical linearization breakpoint in the HBV genome allowed for quantification of the absolute copy numbers of total and circular HBV DNA, and calculation of linear HBV DNA. Results Analysis of 70 liver biopsies from patients with chronic HBV infection revealed that the fraction of linear HBV DNA, which includes integrations, was higher in HBeAg-negative patients than HBeAg-positive. The ratio between HBsAg and HBV DNA levels in serum correlated with the intrahepatic proportion of linear HBV DNA. Furthermore, ddPCR experiments on serum samples and experiments with nuclease indicated the contribution of encapsidated double-stranded linear DNA and replication intermediates to be limited. Conclusions The degree of integration of intrahepatic HBV DNA in the HBeAg-negative stage may be higher than previously anticipated, and integrated DNA may explain the persistence of high HBsAg serum levels in patients with low HBV DNA levels.
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Affiliation(s)
- Gustaf E Rydell
- Department of Infectious Diseases, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Simon B Larsson
- Department of Infectious Diseases, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Kasthuri Prakash
- Department of Infectious Diseases, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Maria Andersson
- Department of Infectious Diseases, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Heléne Norder
- Department of Infectious Diseases, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Kristoffer Hellstrand
- Department of Infectious Diseases, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Gunnar Norkrans
- Department of Infectious Diseases, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Magnus Lindh
- Department of Infectious Diseases, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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41
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Chang KC, Lee CY, Chang TS, Hung CH, Chen WM, Chen MY, Huang TJ, Chiu WN, Hu JH, Lin YC, Huang WC, Hsu NT, Lu SN. Usefulness of quantitative hepatitis B surface antigen testing in hepatitis B community-based screening. J Formos Med Assoc 2020; 120:847-853. [PMID: 32896456 DOI: 10.1016/j.jfma.2020.08.031] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 08/15/2020] [Accepted: 08/21/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND/PURPOSE Low viral load (LVL) of hepatitis B virus (HBV) is a predictor of chronic HBV infection. However, the usefulness of quantitative hepatitis B surface antigen (qHBsAg) in predicting LVL in community-based screening has not been well studied. We aimed to measure the prevalence of LVL in HBV carriers and validate the efficacy of qHBsAg in predicting LVL. METHODS This community-based screening study was conducted in Taiwan. HBV DNA was assayed in HBsAg carriers. Participants were randomized to training and validation sets to determine the ability of qHBsAg to predict LVL. Receiver operating characteristic curves were used to identify the best cutoff values in the training set. RESULTS Among the 2919 participants, 359 (12.2%) were HBsAg carriers. There were 132 and 137 carriers in the training and validation sets, respectively. Significant correlations were found between qHBsAg and HBV DNA in both training and validation sets. Thirty and 29 participants with qHBsAg <8 IU/mL in the training and validation sets, respectively, had LVL. Using 8 IU/mL as the cutoff, negative predictive value (NPV) of qHBsAg for HBV DNA levels >2000 IU/mL was 100%. The best cutoff level of qHBsAg to predict HBV LVL was 200 IU/mL, with a sensitivity, specificity, and accuracy of 75.0%, 76.1%, and 75.8%, respectively, in the training set. The positive predictive value and NPV were 70.0% and 77.9%, respectively, in the validation set. CONCLUSION Approximately 60% of HBsAg carriers had HBV LVL, and qHBsAg <8 IU/mL accurately predicts LVL. This quantitative test provides additional information for community-based screening.
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Affiliation(s)
- Kao-Chi Chang
- Division of Hepatology and Gastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Chih-Yi Lee
- Department of Laboratory Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Te-Sheng Chang
- Division of Hepatology and Gastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan; Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Yunlin, Taiwan; School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chao-Hung Hung
- Department of Internal Medicine, Division of Hepato-Gastroenterology, Kaohsiung Chang Gung Memorial Hospital, Taiwan
| | - Wei-Ming Chen
- Division of Hepatology and Gastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Mei-Yen Chen
- College of Nursing, Chang Gung University of Science and Technology, Chiayi, Taiwan
| | - Tung-Jung Huang
- Division of Thoracic Medicine, Chang Gung Memorial Hospital, Yunlin, Taiwan
| | - Wen-Nan Chiu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Yunlin, Taiwan
| | - Jing-Hong Hu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Yunlin, Taiwan
| | - Yu-Chih Lin
- Division of Family Medicine, Chang Gung Memorial Hospital, Yunlin, Taiwan
| | - Wei-Cheng Huang
- Department of Geriatric, Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Nien-Tzu Hsu
- Biostatistics and Bioinformatics Center of Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Sheng-Nan Lu
- Department of Internal Medicine, Division of Hepato-Gastroenterology, Kaohsiung Chang Gung Memorial Hospital, Taiwan; Biostatistics and Bioinformatics Center of Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
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Ma G, Lou B, Lv F, Zhao D, Zhang Z, Chen Y. HBcrAg and pg RNA and the therapeutic effect in HBeAg-positive patients receiving anti-viral therapy, baseline serum HBV-RNA is a powerful predictor of response. J Viral Hepat 2020; 27:837-846. [PMID: 32277539 DOI: 10.1111/jvh.13299] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Revised: 02/04/2020] [Accepted: 03/25/2020] [Indexed: 12/12/2022]
Abstract
We used HBV core antigen (HbcrAg), pre-genomic RNA (pg RNA) and other biomarkers to evaluate the therapeutic effect in HBV infected patients receiving anti-viral therapy. 127HBeAg-positive patients were enrolled: 35 patients received nucleotide therapy, 14 patients received interferon and 78 patients received combination therapy with both. HBcrAg, pg RNA and other biomarkers were detected at different time points, we defined the decreased titre of HBcrAg and HBeAg from baseline to 6 and baseline to 12 months as ∆HBcrAg and ∆HBeAg, which were used to predict HBeAg seroconversion. Furthermore, we used the time-dependent receiver operator curve of different markers to analyse HBeAg seroconversion. For HBeAg seroconversion: at 6 months, 0.75 log10 U/mL of ∆HBcrAg and 1.47 log10 PEI U/mL of ∆HBeAg showed maximum predictive value in receiver operator curve analysis (Youden's index values for area under the curve of 0.687 and 0.646, respectively). At 12 months, 2.05 log10 U/mL of ∆HBcrAg and 1.92 log10 PEI U/mL of ∆HBeAg showed improved prediction (maximum Youden's index values, with areas under the curve of 0.688 and 0.698, respectively).pg RNA was a better predictor of outcome due and the concentrations of 6.20 log10 I U/mL of pg RNA and 8.0 log10 U/mL of HBcrAg were cut-off values for response in a Kaplan-Meier curve analysis. Our results may be used to identify the pg RNA concentration in patients at baseline and ∆HBcrAg during therapy who are likely to achieve HBeAg seroconversion according to the cut-off value at different time points, thus helping to evaluate the therapeutic effect.
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Affiliation(s)
- Guanghua Ma
- Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, Department of Laboratory Medicine, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Bin Lou
- Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, Department of Laboratory Medicine, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Feifei Lv
- Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, Department of Laboratory Medicine, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Dejian Zhao
- Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, Department of Laboratory Medicine, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Zhe Zhang
- Department of Urology, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yu Chen
- Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, Department of Laboratory Medicine, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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Bockmann JH, Stadler D, Xia Y, Ko C, Wettengel JM, Schulze Zur Wiesch J, Dandri M, Protzer U. Comparative Analysis of the Antiviral Effects Mediated by Type I and III Interferons in Hepatitis B Virus-Infected Hepatocytes. J Infect Dis 2020; 220:567-577. [PMID: 30923817 DOI: 10.1093/infdis/jiz143] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2018] [Accepted: 03/27/2019] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Type III interferons (IFNs) (λ1-3) activate similar signaling cascades as type I IFNs (α and β) via different receptors. Since IFN-α and lymphotoxin-β activate cytosine deamination and subsequent purging of nuclear hepatitis B virus (HBV) DNA, we investigated whether IFN-β and -λ may also induce these antiviral effects in differentiated HBV-infected hepatocytes. METHODS After determining the biological activity of IFN-α2, -β1, -λ1, and -λ2 in differentiated hepatocytes, their antiviral effects were analyzed in HBV-infected primary human hepatocytes and HepaRG cells. RESULTS Type I and III IFNs reduced nuclear open-circle DNA and covalently closed circular DNA (cccDNA) levels in HBV-infected cells. IFN-β and -λ were at least as efficient as IFN-α. Differential DNA-denaturing polymerase chain reaction and sequencing analysis revealed G-to-A sequence alterations of HBV cccDNA in IFN-α, -β, and -λ-treated liver cells indicating deamination. All IFNs induced apolipoprotein B messenger RNA-editing enzyme-catalytic polypeptide-like (APOBEC) deaminases 3A and 3G within 24 hours of treatment, but IFN-β and -λ induced longer-lasting expression of APOBEC deaminases in comparison to IFN-α. CONCLUSIONS IFN-β, IFN-λ1, and IFN-λ2 induce cccDNA deamination and degradation at least as efficiently as IFN-α, indicating that these antiviral cytokines are interesting candidates for the design of new therapeutic strategies aiming at cccDNA reduction and HBV cure.
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Affiliation(s)
- Jan-Hendrik Bockmann
- Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Munich.,I. Department of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg.,German Center for Infection Research, Munich and Hamburg partner sites, Germany
| | - Daniela Stadler
- Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Munich
| | - Yuchen Xia
- Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Munich.,State Key Laboratory of Virology, School of Basic Medical Sciences, Wuhan University, China
| | - Chunkyu Ko
- Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Munich
| | - Jochen M Wettengel
- Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Munich
| | - Julian Schulze Zur Wiesch
- I. Department of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg.,German Center for Infection Research, Munich and Hamburg partner sites, Germany
| | - Maura Dandri
- I. Department of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg.,German Center for Infection Research, Munich and Hamburg partner sites, Germany
| | - Ulrike Protzer
- Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Munich.,German Center for Infection Research, Munich and Hamburg partner sites, Germany
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Murata K, Tsukuda S, Suizu F, Kimura A, Sugiyama M, Watashi K, Noguchi M, Mizokami M. Immunomodulatory Mechanism of Acyclic Nucleoside Phosphates in Treatment of Hepatitis B Virus Infection. Hepatology 2020; 71:1533-1545. [PMID: 31529730 DOI: 10.1002/hep.30956] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Accepted: 09/06/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Current treatment with nucleos(t)ide analogs (NUCs) safely controls the replication of hepatitis B virus (HBV) and improves prognosis in patients with HBV. However, the inability to completely clear HBV is problematic, and novel therapies are desired. It has been believed that all NUCs have similar functions to inhibit HBV reverse transcriptase. However, our recent findings that only acyclic nucleoside phosphonates (ANPs; adefovir dipivoxil and tenofovir disoproxil fumarate) had an additional effect of inducing interferon (IFN)-λ3 in the gastrointestinal tract suggests that ANPs are not only distinct from nucleoside analogs (lamivudine and entecavir) in their structures but also in their functions. Because enteric lipopolysaccharide (LPS) can cross the intestine and affect peripheral blood mononuclear cells (PBMCs), we hypothesized that orally administered ANPs could have further additional effects to modulate LPS-mediated cytokine profile in PBMCs. APPROACH AND RESULTS This study showed that pretreatment of PBMCs, from either healthy volunteers or patients with HBV, with ANPs inhibited LPS-mediated interleukin (IL)-10 production, which reciprocally induced IL-12p70 and tumor necrosis factor-α production in a dose-dependent manner. Furthermore, the combination of IFN-α and ANPs synergistically enhanced LPS-mediated IL-12p70 production in PBMCs. Mechanistic analyses revealed that cellular metabolites of ANPs directly bound the Akt protein, inhibiting its translocation to the plasma membrane, thereby impairing Akt phosphorylation. Therefore, pretreatment of PBMCs with ANPs impairs LPS-mediated IL-10 production. CONCLUSIONS Among NUCs, only ANPs have an additional pharmacological effect modulating LPS-mediated cytokine production, which is expected to produce favorable immune responses toward HBV elimination. This additional immunomodulation by ANPs in PBMCs, as well as IFN-λ3 induction in the gastrointestinal tract, provides insights into HBV treatment.
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Affiliation(s)
- Kazumoto Murata
- Department of Gastroenterology, Graduate School of Medical Sciences, International University of Health and Welfare, Nasushiobara, Japan.,Genome Medical Sciences Project, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Senko Tsukuda
- RIKEN Center for Integrative Medical Sciences (IMS), Wako, Japan.,Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Futoshi Suizu
- Division of Cancer Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
| | - Akihiro Kimura
- Department of Immunology and Pathology, Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Masaya Sugiyama
- Genome Medical Sciences Project, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Koichi Watashi
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Masayuki Noguchi
- Division of Cancer Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
| | - Masashi Mizokami
- Genome Medical Sciences Project, National Center for Global Health and Medicine, Ichikawa, Japan
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Liu Z, Wang J, Yuan H, Liu L, Bu Y, Zhao M, Yang G, Feng J, Liu Y, Li J, He Q, Zhang X. IFN-α2b inhibits the ethanol enriched-HBV cccDNA through blocking a positive feedback loop of HBx/MSL2/cccDNA/HBV/HBx in liver. Biochem Biophys Res Commun 2020; 527:76-82. [PMID: 32446394 DOI: 10.1016/j.bbrc.2020.04.057] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Accepted: 04/11/2020] [Indexed: 12/12/2022]
Abstract
Hepatitis B virus (HBV) is a major risk factor for liver diseases, in which HBV covalently closed circular DNA (cccDNA), as the genomic form that templates viral transcription, plays crucial roles in sustaining viral persistence. Clinically, the excessive ethanol intake accelerates the progression of liver diseases with HBV infection. Here, we supposed that ethanol might trigger HBV cccDNA in the liver. Interestingly, we observed that the ethanol remarkably elevated the levels of HBeAg, HBsAg, HBV DNA and cccDNA in HBV-expressing hepatoma cells. Mechanically, the ethanol increased the levels of HBx and MSL2 in vivo and in HBV-expressing HepG2 cells, but not in HBV-free HepG2 cells. Moreover, the down-regulation of MSL2 by small interference RNA could block the ethanol-promoted HBV cccDNA in HepG2.2.15 cells. As a commonly administered treatment for HBV, the effect of IFNα on ethanol-triggered HBV cccDNA remains poorly understood. Strikingly, we showed that the treatment with IFN-α2b inhibited the ethanol-promoted cccDNA through depressing MSL2 in the cells. Thus, we conclude that IFN-α2b inhibits the ethanol-enriched HBV cccDNA through blocking a positive feedback loop of HBx/MSL2/cccDNA/HBV/HBx. Our finding provides new insights into the mechanism by which IFN-α2b inhibits ethanol-enhanced HBV cccDNA. Therapeutically, IFNα may contribute to the cccDNA induced by ethanol in liver.
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Affiliation(s)
- Zixian Liu
- Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Jiapei Wang
- Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Hongfeng Yuan
- Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Lei Liu
- Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Yanan Bu
- Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Man Zhao
- Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Guang Yang
- Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Jinyan Feng
- Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Yunxia Liu
- Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Jiangning Li
- Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Qiujia He
- Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Xiaodong Zhang
- Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, 300071, China.
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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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47
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Chen Y, Li JJ, Chen R, Li G, Ji J. Dynamics of HBV surface antigen related end points in chronic hepatitis B infection: a systematic review and meta-analysis. Antivir Ther 2020; 25:203-215. [PMID: 32609658 DOI: 10.3851/imp3366] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/23/2020] [Indexed: 12/23/2022]
Abstract
BACKGROUND In chronic hepatitis B (CHB) treatment, hepatitis B surface antigen (HBsAg) is regarded as a promising clinical end point associated with long-term clinical outcomes. We performed a meta-analysis to characterize the dynamics and influencing factors of HBsAg. METHODS Literature search was conducted through PubMed from January 1995 to May 2015 for papers reporting HBsAg in patients receiving various antiviral treatments. We conducted weighted linear regression to select for potential influencing factors on maximum HBsAg loss percentage, and subgroup analysis to calculate the pooled estimates of maximum HBsAg loss and seroconversion percentage following treatment of interferon (IFN), nucleoside analogue (NUC) or combination therapies (NUC+IFN), respectively. Study heterogeneity was assessed through sensitivity test and I-square statistics. RESULTS We collected data from 24 papers involving 6,674 adult CHB patients. In most studies, average HBsAg level decreased during treatment but relapsed after treatment cessation, while HBsAg loss or seroconversion percentage continued to increase or remained stable after treatment cessation. No strong relationship was observed between maximum HBsAg change and its baseline level. The pooled estimates of maximum HBsAg loss percentage for IFN (5.3%, 2.7-7.9%) and NUC+IFN (5.2%, 3.1-7.4%) were significantly higher than that of NUC (0.93%, 0.29-1.6%). Higher maximum HBsAg loss percentage is associated with longer peak time. Pooled maximum HBsAg seroconversion percentage estimates were 1.6%, 0.56% and 6.2% for IFN, NUC and NUC+IFN. CONCLUSIONS With respect to HBsAg lowering, this meta-analysis confirmed the importance of longer treatment duration and addition of IFN, which revealed the potential value of immune-based therapies.
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Affiliation(s)
- Yusi Chen
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, China.,Present address: Division of Biological Sciences, University of California, San Diego, La Jolla, CA, USA
| | | | - Rong Chen
- School of Pharmaceutical Sciences, Peking University, Beijing, China.,Present address: Center for Drug Evaluation, National Medical Products Administration, Beijing, China
| | - Gailing Li
- Clinical Pharmacology and Pharmacometrics, Janssen China R&D, Beijing, China
| | - Jia Ji
- Clinical Pharmacology and Pharmacometrics, Janssen China R&D, Beijing, China
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Abstract
Chronic hepatitis B (CHB) is a widespread global infection and a leading cause of hepatocellular carcinoma and liver failure. Current approaches to treat CHB involve the suppression of viral replication with either interferon or nucleos(t)ide analog therapy, but neither of these approaches can reliably induce viral eradication, immunologic control or long-lived viral suppression in the absence of continued therapy. In this update, we explore the major obstacles of CHB cure and review new therapeutic strategies and drug candidates.
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Affiliation(s)
- Lydia Tang
- Division of Clinical Care & Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Program in Oncology, University of Maryland Marlene & Stewart Greenebaum Comprehensive Cancer Center, 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
- Program in Oncology, University of Maryland Marlene & Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA
| | - Eleanor Wilson
- Division of Clinical Care & Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Program in Oncology, University of Maryland Marlene & Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA
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Xiong F, Bao X, Gu N, Guo J, Wang J, Ma Y, Yu L, Gao Y, Tan B, Lu J. The combination therapy of Peginterferonα and entecavir for HBeAg-positive chronic hepatitis B with high HCC risk. INFECTION GENETICS AND EVOLUTION 2019; 78:104101. [PMID: 31689542 DOI: 10.1016/j.meegid.2019.104101] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 10/27/2019] [Accepted: 10/30/2019] [Indexed: 02/06/2023]
Abstract
The population of HBV infection with family history of hepatocellular carcinoma (HCC) is the high risk group for the development of HCC. The aim of this study was to evaluate the effect of the de novo combination therapy including pegylated-interferon α-2a (PEG-IFNα-2a) and entecavir (ETV) in this high risk population. The study recruited 58 Hepatitis B e Antigen (HBeAg)-Positive CHB patients patients with HBV-DNA > 107 IU/mL, genotype B or C and HCC family history and were treated for 48 weeks. Patients without HBeAg loss at the 48th week were 40 patients and extended the combination therapy to 96 weeks. All patients were followed up to 120 weeks. The rate of HBeAg loss and HBsAg loss was 12/40(30.0%) and 2/40(5.0%) at week 120 respectively. When logistic regression analysis was used to identify viables of HBeAg loss, HBV-DNA levels <20 IU/mL at week 48 was found to have a 6.02 fold increased probability (95% CI = 1.17-30.40, P = .03) of HBeAg loss. Patients with HBV-DNA levels <20 IU/mL at week 48 had a high probability of HBeAg loss 8/17(47.1%), HBsAg loss 2/17(11.8%), compared to 4/23(17.4%), 0/23(0%) in patients with HBV-DNA ≥ 20 IU/mL. Combination therapy for 96 weeks was well tolerated. During the combination therapy, low-level viremia during treatment is reversely associated with response. The combination therapy of PEG-IFNα and ETV was suggested to extend to 96 weeks when HBV-DNA was completed suppressed at week 48.
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Affiliation(s)
- Fang Xiong
- Hepatology and Cancer Biotherapy Ward, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Xuli Bao
- Hepatology and Cancer Biotherapy Ward, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Na Gu
- Hepatology and Cancer Biotherapy Ward, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Jia Guo
- Hepatology and Cancer Biotherapy Ward, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Jinhuan Wang
- International Medical Department, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Yanpin Ma
- Hepatology and Cancer Biotherapy Ward, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Lele Yu
- Hepatology and Cancer Biotherapy Ward, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Yao Gao
- Hepatology and Cancer Biotherapy Ward, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Bingqin Tan
- Hepatology and Cancer Biotherapy Ward, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Jun Lu
- Hepatology and Cancer Biotherapy Ward, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China.
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Yeh ML, Huang JF, Dai CY, Yu ML, Chuang WL. Pharmacokinetics and pharmacodynamics of pegylated interferon for the treatment of hepatitis B. Expert Opin Drug Metab Toxicol 2019; 15:779-785. [PMID: 31593639 DOI: 10.1080/17425255.2019.1678584] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Accepted: 10/07/2019] [Indexed: 02/06/2023]
Abstract
Introduction: Interferon (IFN) had both antiviral and immunomodulatory effects, and was one of the approved treatments for hepatitis B virus (HBV). Herein, we reviewed the pharmacokinetics and pharmacodynamics of pegylated IFN-α (PegIFN-α) for the treatment of HBV. Areas covered: The steady-state serum levels of PegIFN-α were reached within 5 to 8 weeks, and the week 48 mean trough concentrations were approximately 2-fold higher than week 1. There was also no difference of the pharmacokinetics in male or female, healthy volunteers or patients with hepatitis B or C infection. PegIFN-α did not affect the metabolism of the cytochrome P450 (CYP) isozymes, except inhibition of CYP1A2. There was also no pharmacokinetic interaction between PegIFN-α and HBV nucleot(s)ide analogues (NUCs). Forty-eight weeks of PegIFN-α achieved 32% of HBeAg seroconversion, 32-43% of HBV DNA suppression, 41-59% of ALT normalization, and 3% of HBsAg seroconversion rate with a post-treatment durable response up to 80% in the initial responders. Expert opinion: On-treatment HBsAg titer guided the treatment of HBV with PegIFN-α. The recommendation of PegIFN-α and NUC combination or switch remained controversial. New immunotherapeutic agents are now in development. Although, PegIFN-α should continue to play a role in the treatment of HBV.
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Affiliation(s)
- Ming-Lun Yeh
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital , Kaohsiung , Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine, Kaohsiung Medical University , Kaohsiung , Taiwan
| | - Jee-Fu Huang
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital , Kaohsiung , Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine, Kaohsiung Medical University , Kaohsiung , Taiwan
- Center for Cancer Research and Center for Liquid Biopsy, Kaohsiung Medical University , Kaohsiung , Taiwan
| | - Chia-Yen Dai
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital , Kaohsiung , Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine, Kaohsiung Medical University , Kaohsiung , Taiwan
- Center for Cancer Research and Center for Liquid Biopsy, Kaohsiung Medical University , Kaohsiung , Taiwan
| | - Ming-Lung Yu
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital , Kaohsiung , Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine, Kaohsiung Medical University , Kaohsiung , Taiwan
- Center for Cancer Research and Center for Liquid Biopsy, Kaohsiung Medical University , Kaohsiung , Taiwan
- Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B) and Department of Biological Science and Technology, College of Biological Science and Technology, National Chiao Tung University , Hsin-Chu , Taiwan
- Institute of Biomedical Sciences, National Sun Yat-Sen University , Kaohsiung , Taiwan
| | - Wan-Long Chuang
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital , Kaohsiung , Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine, Kaohsiung Medical University , Kaohsiung , Taiwan
- Center for Cancer Research and Center for Liquid Biopsy, Kaohsiung Medical University , Kaohsiung , Taiwan
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