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Wang J, Zhang Z, Yin S, Zhang S, Zhu L, Pan Y, Fan T, Cao F, Xiong Y, Jiang C, Wang G, Yang Y, Jia B, Liu J, Xia J, Yan X, Li J, Zhu C, Liu X, Chen Y, Wu C, Huang R. Favourable Prognosis of Patients With Untreated HBeAg-Negative Chronic Hepatitis B Virus Infection With HBsAg < 100 IU/mL. Aliment Pharmacol Ther 2025; 61:472-480. [PMID: 39523981 DOI: 10.1111/apt.18383] [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: 05/25/2024] [Revised: 06/12/2024] [Accepted: 10/24/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND Serum hepatitis B surface antigen (HBsAg) < 100 IU/mL has been recently proposed as one of the key criteria of 'partial cure' in patients with chronic hepatitis B virus (HBV) infection. We analysed the clinical prognosis of hepatitis B e antigen (HBeAg)-negative untreated patients with HBsAg < 100 IU/mL and normal alanine aminotransferase (ALT) levels. METHODS Five hundred and twenty-one untreated patients with HBeAg negativity, HBsAg < 100 IU/mL and normal ALT levels were included from three hospitals. Spontaneous HBsAg seroclearance, phase transition, liver fibrosis progression and hepatocellular carcinoma (HCC) development were analysed. RESULTS The median age was 43.0 years, and 62.2% of the patients were male. After a median follow-up of 25.0 months, 52 (10.0%) patients achieved spontaneous HBsAg seroclearance. The annual HBsAg seroclearance rate is 4.2%. Patients with baseline HBsAg ≤ 10 IU/mL (adjusted hazard ratio [aHR] = 3.490, p < 0.001) and male sex (aHR = 1.980, p = 0.041) were more likely to achieve HBsAg seroclearance. Only 4 (0.8%) and 23 (4.8%) patients transitioned to the immune escape phase and HBeAg-negative indeterminate phase, respectively. Baseline serum HBsAg > 10 IU/mL (aHR = 3.846, p = 0.034) and detectable HBV DNA (aHR = 2.672, p = 0.023) were associated with transition to the HBeAg-negative indeterminate phase. No patient developed HCC or had fatal outcomes. CONCLUSIONS HBeAg-negative patients with serum HBsAg < 100 IU/mL and normal ALT levels had a favourable prognosis. HBsAg ≤ 10 IU/mL and male sex were associated with a higher rate of HBsAg seroclearance, while HBsAg > 10 IU/mL and detectable HBV DNA were associated with a higher risk of transition to the indeterminate phase.
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Affiliation(s)
- Jian Wang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Zhiyi Zhang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Shengxia Yin
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Shaoqiu Zhang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Li Zhu
- Department of Infectious Diseases, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Yifan Pan
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Tao Fan
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Fei Cao
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Ye Xiong
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Chao Jiang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Jiangsu University, Nanjing, Jiangsu, China
| | - Guiyang Wang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Yue Yang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Bei Jia
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Jiacheng Liu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Juan Xia
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Xiaomin Yan
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Jie Li
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Chuanwu Zhu
- Department of Infectious Diseases, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Xingxiang Liu
- Department of Clinical Laboratory, Huai'an No. 4 People's Hospital, Huai'an, Jiangsu, China
| | - Yuxin Chen
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Chao Wu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Rui Huang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Jiangsu University, Nanjing, Jiangsu, China
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Kumar J, Singh A, Tyagi P, Sharma D, Sarin SK, Kumar V. New thiourea derivatives that target the episomal silencing SMC5 protein to inhibit HBx-dependent viral DNA replication and gene transcription. Virusdisease 2024; 35:577-588. [PMID: 39677840 PMCID: PMC11635082 DOI: 10.1007/s13337-024-00895-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Accepted: 09/17/2024] [Indexed: 12/17/2024] Open
Abstract
Antivirals such as nucleotide analogs (NAs) are potent inhibitors of hepatitis B virus (HBV) replication. However, NAs fail to diminish the signaling and mitogenic activities of the transactivator HBx protein. Earlier we have shown that thiourea derivative IR-415 (DSA-00) targeted HBx to down-regulate its target viral and host genes. However, the molecular mechanism of its antiviral action is poorly understood. Here we investigated the anti-HBV properties of DSA-00 and its new derivatives in cell culture models. DSA-00 and its derivatives DSA-02 and DSA-09 not only suppressed HBV DNA levels similar to well-known antiviral Entecavir but also diminished the expression of pgRNA and secretion of HBsAg and HBeAg. Apparently, the three DSA derivatives inhibited the viral pregenomic RNA expression by stabilizing the episomal DNA silencing protein SMC5, suppressed transcription from viral and host gene promoters, and normalized intracellular CDK2 activity. As none the compounds are reportedly cytotoxic, thiourea derivatives could be good candidates for developing future antivirals for a functional cure of hepatitis B infection. Supplementary Information The online version contains supplementary material available at 10.1007/s13337-024-00895-6.
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Affiliation(s)
- Jitendra Kumar
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, D-1, Vasant Kunj, New Delhi, 110 070 India
| | - Ankita Singh
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, D-1, Vasant Kunj, New Delhi, 110 070 India
| | - Purnima Tyagi
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, D-1, Vasant Kunj, New Delhi, 110 070 India
| | - Deepti Sharma
- Department of Chemistry, Sri Venkateswara College, University of Delhi, New Delhi, India
| | - Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Vijay Kumar
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, D-1, Vasant Kunj, New Delhi, 110 070 India
- Present address: Institute of Nuclear Medicine and Allied Sciences, Brig. S. K. Mazumdar Marg, New Delhi, 110054 India
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Li Y, Wang F, Zhou J, Li L, Song C, Chen E. Optimal Treatment Based on Interferon No Longer Makes Clinical Cure of Chronic Hepatitis B Far Away: An Evidence-Based Review on Emerging Clinical Data. Clin Pharmacol Ther 2024; 116:295-303. [PMID: 38686952 DOI: 10.1002/cpt.3287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 04/12/2024] [Indexed: 05/02/2024]
Abstract
Chronic hepatitis B (CHB) remains a major global public health problem. The functional cure is the ideal therapeutic target recommended by the latest guidelines, and pursuing a functional cure has become the key treatment end point of current therapy and for upcoming clinical trials. In this review, based on the latest published clinical research evidence, we analyzed the concept and connotation of clinical cures and elaborated on the benefits of clinical cures in detail. Secondly, we have summarized various potential treatment methods for achieving clinical cures, especially elaborating on the latest research progress of interferon-based optimized treatment strategies in achieving clinical cures. We also analyzed which populations can achieve clinical cures and conducted a detailed analysis of relevant virological and serological markers in screening clinical cure advantage populations and predicting clinical cure achievement. In addition, we also introduced the difficulties that may be encountered in the current pursuit of achieving a clinical cure.
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Affiliation(s)
- Yujing Li
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Fada Wang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Jing Zhou
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Lanqing Li
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Chengrun Song
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Enqiang Chen
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
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Abe-Chayama H, Kawase T, Ichinohe T, Ishida Y, Tateno C, Hijikata M, Chayama K. Hepatitis B virus-specific human stem cell memory T cells differentiate into cytotoxic T cells and eradicate HBV-infected hepatocytes in mice. FEBS Lett 2024; 598:1354-1365. [PMID: 38594179 DOI: 10.1002/1873-3468.14842] [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: 12/03/2023] [Revised: 12/25/2023] [Accepted: 02/08/2024] [Indexed: 04/11/2024]
Abstract
Chronic infection with the hepatitis B virus (HBV) induces progressive hepatic impairment. Achieving complete eradication of the virus remains a formidable challenge. Cytotoxic T lymphocytes, specific to viral antigens, either exhibit a numerical deficiency or succumb to an exhausted state in individuals chronically afflicted with HBV. The comprehension of the genesis and dissemination of stem cell memory T cells (TSCMs) targeting HBV remains inadequately elucidated. We identified TSCMs in subjects with chronic HBV infection and scrutinized their efficacy in a murine model with human hepatocyte transplants, specifically the TK-NOG mice. TSCMs were discerned in all subjects under examination. Introduction of TSCMs into the HBV mouse model precipitated a severe necro-inflammatory response, resulting in the elimination of human hepatocytes. TSCMs may constitute a valuable tool in the pursuit of a remedial therapy for HBV infection.
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Affiliation(s)
- Hiromi Abe-Chayama
- Center for Medical Specialist Graduate Education and Research, Graduate School of Biomedical and Health Sciences, Hiroshima University, Japan
| | - Takakazu Kawase
- Department of Immune Regenerative Medicine, International Center for Cell and Gene Therapy, Fujita Health University, Toyoake, Japan
- Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine (RIRBM), Hiroshima University, Japan
| | - Tatsuo Ichinohe
- Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine (RIRBM), Hiroshima University, Japan
| | | | | | | | - Kazuaki Chayama
- Hiroshima Institute of Life Sciences, Japan
- Collaborative Research Laboratory of Medical Innovation, Graduate School of Biomedical and Health Sciences, Hiroshima University, Japan
- RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
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Buechter M, Günther AM, Manka P, Gerken G, Kahraman A. Factors Positively Correlated with Hepatitis B Surface Antigen Seroconversion in Chronic Hepatitis B. J Pers Med 2024; 14:390. [PMID: 38673017 PMCID: PMC11051014 DOI: 10.3390/jpm14040390] [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: 01/25/2024] [Revised: 03/25/2024] [Accepted: 03/27/2024] [Indexed: 04/28/2024] Open
Abstract
BACKGROUND AND AIMS Chronic hepatitis B virus (HBV) infection is a global public health challenge since more than 250 million individuals are affected worldwide. Since different treatment modalities are available and not all patients are candidates for antiviral treatment, biomarkers that potentially predict the possibility of HBsAg clearance and seroconversion may be useful in clinical practice. PATIENTS AND METHODS In this retrospective study, we aimed to identify factors positively correlated with HBsAg seroconversion in a large cohort of 371 chronic hepatitis B patients treated at a German tertial center between 2005 and 2020. RESULTS Seroconversion occurred in 25/371 (6.7%) and HBsAg loss in 29/371 patients (7.8%) with chronic HBV infection. Antiviral therapy was associated with a lower chance of seroconversion (seroconversion antiviral therapy 14/260 (5.4%) vs. therapy-naïve patients 11/111 (9.9%), p = 0.027). Seroconversion rates were higher in patients with (very) low titers of HBV DNA (best cut-off value 357 IU/mL) and quantitative HBsAg. The best cut-off value with regard to seroconversion was 357 IU/mL for HBV DNA (AUC 0.693 (95%-CI 0.063-0.422), sensitivity 0.714, specificity 0.729; p < 0.0005) and 33,55 IU/mL for HBsAg (AUC 0.794 (95%-CI 0.651-0.937), sensitivity 0.714, specificity 0.949; p < 0.0005). However, male gender was positively associated with seroconversion (seroconversion: males 7.6% vs. females 2.7%, p = 0.036). CONCLUSIONS Treatment-naïve male chronic HBV patients with low viral load and inflammatory activity have the best chance to achieve seroconversion. In the absence of cirrhosis, antiviral therapy should therefore not be performed in this patient collective.
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Affiliation(s)
- Matthias Buechter
- Department of Gastroenterology and Hepatology, University Clinic of Essen, University of Duisburg-Essen, 45147 Essen, Germany; (A.M.G.); (G.G.); (A.K.)
- Department of Gastroenterology and Hepatology, Elisabeth Hospital, 58638 Iserlohn, Germany
| | - Arne Maria Günther
- Department of Gastroenterology and Hepatology, University Clinic of Essen, University of Duisburg-Essen, 45147 Essen, Germany; (A.M.G.); (G.G.); (A.K.)
| | - Paul Manka
- Department of Internal Medicine, University Hospital Knappschaftskrankenhaus, Ruhr-University Bochum, 44801 Bochum, Germany;
| | - Guido Gerken
- Department of Gastroenterology and Hepatology, University Clinic of Essen, University of Duisburg-Essen, 45147 Essen, Germany; (A.M.G.); (G.G.); (A.K.)
- Department of Gastroenterology and Hepatology, Helios Clinic, 42549 Velbert, Germany
| | - Alisan Kahraman
- Department of Gastroenterology and Hepatology, University Clinic of Essen, University of Duisburg-Essen, 45147 Essen, Germany; (A.M.G.); (G.G.); (A.K.)
- Department of Gastroenterology and Hepatology, Max Grundig Clinic, 77815 Bühl, Germany
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Wu Z, Zhao X, Li R, Wen X, Xiu Y, Long M, Li J, Huang X, Wen J, Dong X, Xu Y, Bai Z, Zhan X, Xiao X. The combination of Schisandrin C and Luteolin synergistically attenuates hepatitis B virus infection via repressing HBV replication and promoting cGAS-STING pathway activation in macrophages. Chin Med 2024; 19:48. [PMID: 38500179 PMCID: PMC10946137 DOI: 10.1186/s13020-024-00888-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Accepted: 01/16/2024] [Indexed: 03/20/2024] Open
Abstract
BACKGROUND HBV infection can result in severe liver diseases and is one of the primary causes of liver cell carcinoma-related mortality. Liuwei Wuling tablet (LWWL) is a traditional Chinese medicine formula, with a protecting liver and decreasing enzyme activity, usually used to treat chronic hepatitis B with NAs in clinic. However, its main active ingredients and mechanism of action have not been fully investigated. Hence, we aimed to screen the active ingredient and effective ingredient combinations from Liuwei Wuling tablet to explore the anti-herpatitis B virus activity and mechanism. METHODS Analysis and screening of effective antiviral components in LWWL by network pharmacology, luteolin (Lut) may be a compound with significant antiviral activity. The mechanism of antiviral action of Lut was also found by real-time PCR detection and western blotting. Meanwhile, we established a co-culture model to investigate the antiviral mechanism of Schisandrin C (SC), one of the main active components of Schisandra chinensis fructus (the sovereign drug of LWWL). Next, HBV-infected mice were established by tail vein injection of pAAV-HBV1.2 plasmid and administered continuously for 20 days. And their antiviral capacity was evaluated by checking serum levels of HBsAg, HBeAg, levels of HBV DNA, and liver levels of HBcAg. RESULTS In this study, we conducted network pharmacology analysis on LWWL, and through in vitro experimental validation and data analysis, we found that luteolin (Lut) possessed obviously anti-HBV activity, inhibiting HBV replication by downregulating hepatocyte nuclear factor 4α (HNF4α) via the ERK pathway. Additionally, we established a co-culture system and proved that SC promoted activation of cGAS-STINIG pathway and IFN-β production in THP-1 cells to inhibit HBV replication in HepG2.2.15 cells. Moreover, we found the combination of SC and Lut shows a greater effect in inhibiting HBV compared to SC or Lut alone in HBV-infected mice. CONCLUSION Taken together, our study suggests that combination of SC and Lut may be potential candidate drug for the prevention and treatment of chronic hepatitis B.
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Affiliation(s)
- Zhixin Wu
- School of Pharmacy, Hunan University of Traditional Chinese Medicine, Changsha, 410208, China
- Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
| | - Xiaomei Zhao
- Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
| | - Ruisheng Li
- Research Institute of Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
| | - Xinru Wen
- Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
| | - Ye Xiu
- Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
| | - Minjuan Long
- School of Pharmacy, Hunan University of Traditional Chinese Medicine, Changsha, 410208, China
- Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
| | - Junjie Li
- Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
| | - Xiuqin Huang
- Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
| | - Jincai Wen
- Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
| | - Xu Dong
- Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
| | - Yingjie Xu
- Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
| | - Zhaofang Bai
- Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China.
- National Key Laboratory of Kidney Diseases, Beijing, China.
| | - Xiaoyan Zhan
- Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China.
- National Key Laboratory of Kidney Diseases, Beijing, China.
| | - Xiaohe Xiao
- School of Pharmacy, Hunan University of Traditional Chinese Medicine, Changsha, 410208, China.
- Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China.
- National Key Laboratory of Kidney Diseases, Beijing, China.
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Zhao H, Shao X, Yu Y, Huang L, Amor NP, Guo K, Weng C, Zhao W, Yang A, Hu J, Yang H, Liu Z, Han Q, Shi L, Sun S, Zhang J, Lin A, Yang Y. A therapeutic hepatitis B mRNA vaccine with strong immunogenicity and persistent virological suppression. NPJ Vaccines 2024; 9:22. [PMID: 38310094 PMCID: PMC10838333 DOI: 10.1038/s41541-024-00813-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Accepted: 01/12/2024] [Indexed: 02/05/2024] Open
Abstract
Here we report on the development and comprehensive evaluations of an mRNA vaccine for chronic hepatitis B (CHB) treatment. In two different HBV carrier mouse models generated by viral vector-mediated HBV transfection (pAAV-HBV1.2 and rAAV8-HBV1.3), this vaccine demonstrates sufficient and persistent virological suppression, and robust immunogenicity in terms of induction of strong innate immune activation, high-level virus-specific antibodies, memory B cells and T cells. mRNA platform therefore holds prospects for therapeutic vaccine development to combat CHB.
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Affiliation(s)
- Huajun Zhao
- Institute of Immunopharmaceutical Sciences, Key Laboratory of Chemical Biology, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, China.
| | - Xianyu Shao
- Vaccine Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
- Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing, China
| | - Yating Yu
- Institute of Immunopharmaceutical Sciences, Key Laboratory of Chemical Biology, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, China
| | - Lulu Huang
- Vaccine Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
- Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing, China
| | - Narh Philip Amor
- Vaccine Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
- Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing, China
| | - Kun Guo
- Vaccine Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
- Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing, China
| | - Changzhen Weng
- Vaccine Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
- Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing, China
| | - Weijun Zhao
- Vaccine Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
- Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing, China
| | - Ailu Yang
- Institute of Immunopharmaceutical Sciences, Key Laboratory of Chemical Biology, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, China
| | - Jiesen Hu
- Firestone Biotechnologies, Shanghai, China
| | - Hongbao Yang
- Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing, China
| | - Zhenguang Liu
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Qiuju Han
- Institute of Immunopharmaceutical Sciences, Key Laboratory of Chemical Biology, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, China
| | - Leilei Shi
- Precision Research Center for Refractory Diseases in Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Shiyu Sun
- Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Jian Zhang
- Institute of Immunopharmaceutical Sciences, Key Laboratory of Chemical Biology, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, China.
| | - Ang Lin
- Vaccine Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.
- Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing, China.
| | - Yong Yang
- Vaccine Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.
- Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing, China.
- School of Pharmacy, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, PR China.
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8
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Angelo L, Vaillant A, Blanchet M, Labonté P. Pangenomic antiviral effect of REP 2139 in CRISPR/Cas9 engineered cell lines expressing hepatitis B virus surface antigen. PLoS One 2023; 18:e0293167. [PMID: 37910550 PMCID: PMC10619774 DOI: 10.1371/journal.pone.0293167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 10/06/2023] [Indexed: 11/03/2023] Open
Abstract
Chronic hepatitis B remains a global health problem with 296 million people living with chronic HBV infection and being at risk of developing cirrhosis and hepatocellular carcinoma. Non-infectious subviral particles (SVP) are produced in large excess over infectious Dane particles in patients and are the major source of Hepatitis B surface antigen (HBsAg). They are thought to exhaust the immune system, and it is generally considered that functional cure requires the clearance of HBsAg from blood of patient. Nucleic acid polymers (NAPs) antiviral activity lead to the inhibition of HBsAg release, resulting in rapid clearance of HBsAg from circulation in vivo. However, their efficacy has only been demonstrated in limited genotypes in small scale clinical trials. HBV exists as nine main genotypes (A to I). In this study, the HBsAg ORFs from the most prevalent genotypes (A, B, C, D, E, G), which account for over 96% of human cases, were inserted into the AAVS1 safe-harbor of HepG2 cells using CRISPR/Cas9 knock-in. A cell line producing the D144A vaccine escape mutant was also engineered. The secretion of HBsAg was confirmed into these new genotype cell lines (GCLs) and the antiviral activity of the NAP REP 2139 was then assessed. The results demonstrate that REP 2139 exerts an antiviral effect in all genotypes and serotypes tested in this study, including the vaccine escape mutant, suggesting a pangenomic effect of the NAPs.
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Affiliation(s)
- Léna Angelo
- Institut National de la Recherche Scientifique–Centre Armand-Frappier Santé Biotechnologies, Laval, Canada
| | | | - Matthieu Blanchet
- Institut National de la Recherche Scientifique–Centre Armand-Frappier Santé Biotechnologies, Laval, Canada
- Replicor Inc, Montréal, Canada
| | - Patrick Labonté
- Institut National de la Recherche Scientifique–Centre Armand-Frappier Santé Biotechnologies, Laval, Canada
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Zheng F, Tan Z, Liang Z, Xiang W. Efficacy and Safety of Antiviral Therapy for Immune-tolerant Hepatitis B Viral Infection in Children: A Systematic Review and Meta-analysis. Pediatr Infect Dis J 2023; 42:942-948. [PMID: 37523508 DOI: 10.1097/inf.0000000000004057] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/02/2023]
Abstract
BACKGROUND Chronic hepatitis B virus (HBV) infection burden in children remains a pressing public health concern. Whether antiviral therapy should be administered to children with HBV in the immune-tolerant phase remains controversial. We performed a meta-analysis to evaluate antiviral therapy efficacy and safety in children with immune-tolerant hepatitis B (ITHB). METHODS A search was conducted in multiple databases (PubMed, Embase, Cochrane, Web of Science, CBM, CNKI and Wanfang Data) to identify clinical trials examining antiviral therapy efficacy and safety in children (1-18 years) with ITHB viral infection from inception to February 2023. Outcomes were calculated separately for controlled and single-arm studies. RESULTS Nine trials (442 patients), including 2 randomized controlled trials (RCTs), 3 non-RCTs and 4 single-arm studies, were included in this meta-analysis. In the RCTs, antiviral therapy group exhibited greater rates of HBsAg loss [risk ratio (RR) = 6.11, 95% confidence interval (CI): 1.67-22.31, P Z-test = 0.006], HBsAg serologic response (RR = 5.29, 95% CI: 1.47-19.07, P Z-test = 0.011) and HBeAg loss (RR = 3.00, 95% CI: 1.35-6.66, P Z-test = 0.007) compared with the control group at the end of follow-up. In single-arm studies, the pooled incidences of HBsAg loss, HBeAg loss and HBsAg seroconversion were 24% (95% CI: -0.1% to 48%), 24% (95% CI: -0.1% to 48%) and 24% (95% CI: -5% to 52%), respectively. CONCLUSION Current evidence suggests the effectiveness of antiviral therapy in children with HBV infection in the immune-tolerant stage, with few serious adverse events. Due to the limited quality and number of included studies, more high-quality studies are required to validate our findings.
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Affiliation(s)
- Fengli Zheng
- From the Department of Pediatrics, The People's Hospital of Guigang, Guigang, Guangxi, China
| | - Zhijun Tan
- Department of Infectious Diseases, The People's Hospital of Guigang, Guigang, Guangxi, China
| | - Zhou Liang
- Department of Infectious Diseases, The People's Hospital of Guigang, Guigang, Guangxi, China
| | - Wenyao Xiang
- Department of Infectious Diseases, The People's Hospital of Guigang, Guigang, Guangxi, China
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Tang Q, Ye J, Zhang Y, Zhang P, Xia G, Zhu J, Wei S, Li X, Zhang Z. Establishment of a multi-parameter prediction model for the functional cure of HBeAg-negative chronic hepatitis B patients treated with pegylated interferonα and decision process based on response-guided therapy strategy. BMC Infect Dis 2023; 23:456. [PMID: 37430256 DOI: 10.1186/s12879-023-08443-1] [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: 02/21/2023] [Accepted: 07/04/2023] [Indexed: 07/12/2023] Open
Abstract
BACKGROUND & AIMS This study aimed to establish multivariate prediction models according to a response-guided therapy (RGT) based strategy at baseline and week 12 and 24 of follow-up to predict the functional cure for HBeAg-negative patients with chronic hepatitis B (CHB) treated with pegylated interferonα (PEG-IFNα). METHODS A total of 242 HBeAg-negative patients with CHB were treated with PEG-IFNα for 52 weeks and followed up for 24 weeks. Responses at the end of follow-up (EOF) were defined as hepatitis B surface antigen (HBsAg) loss, and patients were defined as either responders or non-responders. RESULTS The three most meaningful predictors were an age ≤ 40 years, alanine aminotransferase (ALT) levels ≤ 40 U/L, and HBsAg levels ≤ 100 IU/mL at baseline; ALT levels ≥ 80 U/L, anti-HBc levels ≤ 8.42 S/CO, and HBsAg levels ≤ 50 IU/mL at week 12; and ALT levels ≥ 40 U/L, anti-HBc levels ≤ 8.46 S/CO, and HBsAg levels ≤ 0.2 IU/mL at week 24. The response rates of patients with a score of 0-1 and 4-5 at baseline, week 12, and 24 were 13.5%, 7.8%, and 11.7%; and 63.6%, 68.1%, and 98.1%, respectively. At week 12, the cumulative scores were 0-2, 3-4, 5-7, and 8-10 (response rates 5.0%, 18.9%, 41.3%, and 71.4%, respectively). At week 24, the cumulative scores were 0-3, 4-6, 7-10, and 11-15 (response rates: 1.3%, 12.3%, 37.0%, and 92.5%, respectively). At baseline, patients with scores of 0-1 were slightly recommended; at week 12, patients with 0-1 or 0-2 cumulative scores were recommended to stop treatment. At week 24, patients with a score of 0-1 or a cumulative score of 0-6 were recommended to stop treatment. CONCLUSION We established a multi-parameter prediction model for the functional cure of HBeAg-negative patients with CHB treated with PEG-IFNα.
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Affiliation(s)
- Qianqian Tang
- Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Furong Road 678, Hefei, 230601, Anhui, China
| | - Jun Ye
- Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Furong Road 678, Hefei, 230601, Anhui, China
| | - Yafei Zhang
- Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Furong Road 678, Hefei, 230601, Anhui, China
| | - Peixin Zhang
- Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Furong Road 678, Hefei, 230601, Anhui, China
| | - Guomei Xia
- Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Furong Road 678, Hefei, 230601, Anhui, China
| | - Jie Zhu
- Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Furong Road 678, Hefei, 230601, Anhui, China
| | - Shaofeng Wei
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Xu Li
- Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Furong Road 678, Hefei, 230601, Anhui, China
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Zhenhua Zhang
- Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Furong Road 678, Hefei, 230601, Anhui, China.
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Zhang Z, Fu X, Wang Y, Wang J, Feng S, Zhao Z, Zheng L, Zhang J, Zhang X, Peng Y. In vivo anti-hepatitis B activity of Artemisia argyi essential oil-loaded nanostructured lipid carriers. Study of its mechanism of action by network pharmacology and molecular docking. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 116:154848. [PMID: 37163901 DOI: 10.1016/j.phymed.2023.154848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 04/17/2023] [Accepted: 05/01/2023] [Indexed: 05/12/2023]
Abstract
BACKGROUND Hepatitis B virus (HBV) infection remains a major global health burden, due to the increasing risk of complications, such as cirrhosis and hepatocellular carcinoma. Novel anti-HBV agents are critical required. Our previous study suggested that Artemisia argyi essential oil (AAEO) significantly inhibited the replication of HBV DNA and especially the secretion of hepatitis B antigen in vitro. PURPOSE The aim of this study was to prepare AAEO loaded nanostructured lipid carriers (AAEO-NLCs) for the delivery of AAEO to the liver, investigated the therapeutic benefits of AAEO-NLCs against HBV in a duck HBV (DHBV) model and explored its potential mechanism. STUDY DESIGN AND METHODS AAEO-NLCs were prepared by hot homogenization and ultrasonication method. The DHBV-infected ducks were treated with AAEO (4 mg/kg), AAEO-NLCs (0.8, 4, and 20 mg/kg of AAEO), and lamivudine (20 mg/kg) for 15 days. The DHBV DNA levels in the serum and liver were measured by quantitative Real-Time PCR. Pharmacokinetics and liver distribution were performed in rats after oral administration of AAEO-NLCs and AAEO suspension. The potential antiviral mechanism and active compounds of AAEO were investigated by network pharmacology and molecular docking. RESULTS AAEO-NLCs markedly inhibited the replication of DHBV DNA in a dose-dependent manner and displayed a low virologic rebound following withdrawal the treatment in DHBV-infected ducks. Moreover, AAEO-NLCs led to a more pronounced reduction in viral DNA levels than AAEO suspension. Further investigations of pharmacokinetics and liver distribution in rats confirmed that NLCs improved the oral bioavailability and increased the liver exposure of AAEO. The potential mechanisms of AAEO against HBV explored by network pharmacology were associated with signaling pathways related to immune response, such as tumor necrosis factor, nuclear factor kappa B, and sphingolipid signaling pathways. Furthermore, a total of 16 potential targets were obtained, including prostaglandin-endoperoxide synthase-2 (PTGS2), caspase-3, progesterone receptor, etc. Compound-target docking results confirmed that four active compounds of AAEO had strong binding interactions with the active sites of PTGS2. CONCLUSIONS AAEO-NLCs displayed potent anti-HBV activity with improved oral bioavailability and liver exposure of AAEO. Thus, it may be a potential therapeutic strategy for the treatment of HBV infection.
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Affiliation(s)
- Zhuangli Zhang
- Henan Key Laboratory for Pharmacology of Liver Diseases, BGI College & Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Xiaoqian Fu
- Henan Key Laboratory for Pharmacology of Liver Diseases, BGI College & Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; School of Basic Medical Science, Academy of Medical Science, Zhengzhou University, Zhengzhou 450001, China
| | - Yarong Wang
- Henan Key Laboratory for Pharmacology of Liver Diseases, BGI College & Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Jian Wang
- Henan Institute for Drug and Medical Device Control, Zhengzhou 450018, China
| | - Shiyang Feng
- Henan Key Laboratory for Pharmacology of Liver Diseases, BGI College & Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Zhihong Zhao
- Henan Key Laboratory for Pharmacology of Liver Diseases, BGI College & Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Liyun Zheng
- Henan Key Laboratory for Pharmacology of Liver Diseases, BGI College & Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Jingmin Zhang
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450001, China
| | - Xiaojun Zhang
- Henan Key Laboratory for Pharmacology of Liver Diseases, BGI College & Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Youmei Peng
- Henan Key Laboratory for Pharmacology of Liver Diseases, BGI College & Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
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Chen J, Lou S, Chen H, Zhou B, Sun J, Hou J, Jiang DK. CD55 Variant Associated with Pegylated-interferon α Therapy Response in HBeAg-positive Chronic Hepatitis B Patients. J Clin Transl Hepatol 2023; 11:295-303. [PMID: 36643051 PMCID: PMC9817056 DOI: 10.14218/jcth.2022.00057] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Revised: 04/20/2022] [Accepted: 05/04/2022] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND AND AIMS Only a small percentage of chronic hepatitis B (CHB) patients effectively respond to treatment with pegylated-interferon alpha (PegIFNα) or nucleos(t)ide analogues (NUCs). We aimed to detect the correlations of complement regulators-associated single-nucleotide polymorphisms (SNPs) with treatment response of hepatitis B e antigen (HBeAg)-positive CHB patients. METHODS A total of 1,763 HBeAg-positive CHB patients were enrolled, 894 received PegIFNα for at least 48 weeks and were followed up for 24 weeks, and 869 received NUCs for 104 weeks. For each patient, nine SNPs in genes encoding for complement regulators were determined and genotyped. To assess the cumulative effect of numerous SNPs, a polygenic score (PGS) was utilized. The correlations of SNPs and PGS with the levels of combined response (CR) and hepatitis B s antigen (HBsAg) loss were also investigated. RESULTS In PegIFNα-treated patients, an intronic SNP of CD55, rs28371597, was strongly related to CR, and the CR rate in rs28371597_GG genotype carriers was only approximately half that of rs28371597_GT/TT genotype carriers (20.29% vs. 37.10%, p=2.00 × 10-3). A PGS incorporating CD55_rs28371597 and two additional SNPs, CFB_rs12614 and STAT4_rs7574865, which had been considered as predictors for PegIFNα treatment response before, was strongly correlated with the levels of CR (p-trend=7.94×10-6) and HBsAg loss (p-trend=9.40×10-3) in PegIFNα-treated patients. In NUCs-treated individuals, however, none of the nine SNPs were shown to be significantly linked to CHB treatment response. CONCLUSIONS CD55_rs28371597 is a promising biomarker for predicting CHB patients' responsiveness to PegIFNα therapy. The updated PGS may be used for optimizing CHB treatment.
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Affiliation(s)
- Jiaxuan Chen
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- The Key Laboratory of Molecular Pathology (Hepatic Diseases) of Guangxi, Department of Pathology, the Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, China
| | - Shuang Lou
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Haitao Chen
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Bin Zhou
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Jian Sun
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Jinlin Hou
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - De-Ke Jiang
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- The Key Laboratory of Molecular Pathology (Hepatic Diseases) of Guangxi, Department of Pathology, the Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, China
- Correspondence to: De-Ke Jiang, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China. ORCID: https://orcid.org/0000-0002-7888-2344. Tel/Fax: +86-20-62786533, E-mail:
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13
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Chen SL, Xiao H, Li GJ, Shen YJ. Expression Pattern of Cytokines in Patients with Chronic Hepatitis B Receiving PEGinterferon Therapy. Int J Gen Med 2023; 16:1771-1782. [PMID: 37193251 PMCID: PMC10183186 DOI: 10.2147/ijgm.s402524] [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: 01/09/2023] [Accepted: 04/27/2023] [Indexed: 05/18/2023] Open
Abstract
Purpose Chronic hepatitis B virus (CHB) infection is a worldwide health problem. Polyethylene glycol (PEG)ylated interferon (PEG-IFN) is an available therapy for CHB that has antiviral and immunomodulatory effects. However, PEG-IFN therapy is limited by the fact that only a subset of patients show a sustained response, its severe side effects, and high cost. The aim of this study was to explore novel biomarkers for the early prediction of PEG-IFN treatment response and to uncover its underlying mechanism. Patients and Methods We enrolled 10 paired patients with Hepatitis B e antigen (HBeAg)-positive CHB who received PEG-IFN-α2a monotherapy. Patient serum samples were collected at 0, 4, 12, 24, and 48 weeks and serum samples were collected from eight healthy people as healthy controls. For confirmation, we enrolled 27 patients with HBeAg-positive CHB receiving PEG-IFN therapy and serum samples at 0 and 12 weeks were obtained. Serum samples were analyzed using Luminex technology. Results Among 27 assessed cytokines, 10 cytokines were identified to have high expression levels. Among them, six cytokines had significant differences in their levels between the patients with HBeAg-positive CHB and the healthy controls (P < 0.05). Potentially, treatment response could be predicted using the early time points of 4, 12, and 24 weeks. Moreover, after 12 weeks of PEG-IFN treatment, increased levels of pro-inflammatory cytokines and decreased levels of anti-inflammatory cytokines were observed. The fold change of IP-10 between 12 weeks and 0 weeks correlated with the decrease in ALT levels from 0 to 12 weeks (r = 0.2675, P = 0.0024). Conclusion In patients with CHB, we observed a certain pattern in the levels of cytokines during treatment with PEG-IFN, and the cytokine IP-10 might be a potential biomarker for treatment response.
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Affiliation(s)
- Shao-Long Chen
- Shulan International Medical College, Zhejiang Shuren University, Hangzhou, 310015, People’s Republic of China
- Correspondence: Shao-Long Chen, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, 310015, People’s Republic of China, Email
| | - Hong Xiao
- Department of Infectious Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, People’s Republic of China
| | - Guo-Jun Li
- Department of Hepatology, The Second Hospital of Yinzhou of Ningbo, Ningbo, 315100, People’s Republic of China
| | - Yao-Jie Shen
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, People’s Republic of China
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Yardeni D, Chang KM, Ghany MG. Current Best Practice in Hepatitis B Management and Understanding Long-term Prospects for Cure. Gastroenterology 2023; 164:42-60.e6. [PMID: 36243037 PMCID: PMC9772068 DOI: 10.1053/j.gastro.2022.10.008] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 09/25/2022] [Accepted: 10/04/2022] [Indexed: 02/03/2023]
Abstract
The hepatitis B virus (HBV) is a major cause of cirrhosis and hepatocellular carcinoma worldwide. Despite an effective vaccine, the prevalence of chronic infection remains high. Current therapy is effective at achieving on-treatment, but not off-treatment, viral suppression. Loss of hepatitis B surface antigen, the best surrogate marker of off-treatment viral suppression, is associated with improved clinical outcomes. Unfortunately, this end point is rarely achieved with current therapy because of their lack of effect on covalently closed circular DNA, the template of viral transcription and genome replication. Major advancements in our understanding of HBV virology along with better understanding of immunopathogenesis have led to the development of a multitude of novel therapeutic approaches with the prospect of achieving functional cure (hepatitis B surface antigen loss) and perhaps complete cure (clearance of covalently closed circular DNA and integrated HBV DNA). This review will cover current best practice for managing chronic HBV infection and emerging novel therapies for HBV infection and their prospect for cure.
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Affiliation(s)
- David Yardeni
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Kyong-Mi Chang
- Medical Research, Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, Pennsylvania; Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Marc G Ghany
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
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Teng Y, Zhu M, Chi Y, Li L, Jin Y. Can G-quadruplex become a promising target in HBV therapy? Front Immunol 2022; 13:1091873. [PMID: 36591216 PMCID: PMC9797731 DOI: 10.3389/fimmu.2022.1091873] [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: 11/07/2022] [Accepted: 11/28/2022] [Indexed: 12/23/2022] Open
Abstract
The chronic infection with hepatitis B virus (HBV) is an important health problem that affects millions of people worldwide. Current therapies for HBV always suffer from a poor response rate, common side effects, and the need for lifelong treatment. Novel therapeutic targets are expected. Interestingly, non-canonical structures of nucleic acids play crucial roles in the regulation of gene expression. Especially the formation of G-quadruplexes (G4s) in G-rich strands has been demonstrated to affect many bioprocesses including replication, transcription, and translation, showing great potential as targets in anticancer and antiviral therapies. In this review, we summarize recent antiviral studies about G4s and discuss the potential roles of G4 structures in antiviral therapy for HBV.
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Affiliation(s)
- Ye Teng
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Ming Zhu
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Yuan Chi
- Pharmaceutical Department, The Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, China
| | - Lijing Li
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China,*Correspondence: Lijing Li, ; Ye Jin,
| | - Ye Jin
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China,*Correspondence: Lijing Li, ; Ye Jin,
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Yin GQ, Chen KP, Gu XC. Heterogeneity of immune control in chronic hepatitis B virus infection: Clinical implications on immunity with interferon-α treatment and retreatment. World J Gastroenterol 2022; 28:5784-5800. [PMID: 36353205 PMCID: PMC9639659 DOI: 10.3748/wjg.v28.i40.5784] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 09/08/2022] [Accepted: 10/10/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a global public health issue. Interferon-α (IFN-α) treatment has been used to treat hepatitis B for over 20 years, but fewer than 5% of Asians receiving IFN-α treatment achieve functional cure. Thus, IFN-α retreatment has been introduced to enhance antiviral function. In recent years, immune-related studies have found that the complex interactions between immune cells and cytokines could modulate immune response networks, in-cluding both innate and adaptive immunity, triggering immune responses that control HBV replication. However, heterogeneity of the immune system to control HBV infection, particularly HBV-specific CD8+ T cell heterogeneity, has consequ-ential effects on T cell-based immunotherapy for treating HBV infection. Altogether, the host’s genetic variants, negative-feedback regulators and HBV components affecting the immune system's ability to control HBV. In this study, we reviewed the literature on potential immune mechanisms affecting the immune control of HBV and the clinical effects of IFN-α treatment and retreatment.
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Affiliation(s)
- Guo-Qing Yin
- Center of Hepatology, Zhong-Da Hospital, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Ke-Ping Chen
- Center of Hepatology, Zhong-Da Hospital, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Xiao-Chun Gu
- Center of Hepatology, Zhong-Da Hospital, Southeast University, Nanjing 210009, Jiangsu Province, China
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Yang Z, Sun B, Xiang J, Wu H, Kan S, Hao M, Chang L, Liu H, Wang D, Liu W. Role of epigenetic modification in interferon treatment of hepatitis B virus infection. Front Immunol 2022; 13:1018053. [PMID: 36325353 PMCID: PMC9618964 DOI: 10.3389/fimmu.2022.1018053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 09/27/2022] [Indexed: 11/28/2022] Open
Abstract
Human hepatitis B virus (HBV) is a small, enveloped DNA virus that causes acute and chronic hepatitis. Chronic hepatitis B (CHB) is associated with hepatocellular carcinoma pathogenesis. Interferons (IFNs) have been used for the treatment of CHB for a long time, with advantages including less treatment duration and sustained virological response. Presently, various evidence suggests that epigenetic modification of the viral covalently closed circular DNA (cccDNA) and the host genome is crucial for the regulation of viral activity. This modification includes histone acetylation, DNA methylation, N6-methyladenosine, and non-coding RNA modification. IFN treatment for CHB can stimulate multiple IFN-stimulated genes for inhibiting virus replication. IFNs can also affect the HBV life cycle through epigenetic modulation. In this review, we summarized the different mechanisms through which IFN-α inhibits HBV replication, including epigenetic regulation. Moreover, the mechanisms underlying IFN activity are discussed, which indicated its potential as a novel treatment for CHB. It is proposed that epigenetic changes such as histone acetylation, DNA methylation, m6A methylation could be the targets of IFN, which may offer a novel approach to HBV treatment.
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Affiliation(s)
- Zhijing Yang
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Baozhen Sun
- Department of Hepatobiliary and Pancreas Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Jingcheng Xiang
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Han Wu
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Shaoning Kan
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Ming Hao
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Lu Chang
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Huimin Liu
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Dongxu Wang
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
- *Correspondence: Dongxu Wang, ; Weiwei Liu,
| | - Weiwei Liu
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
- *Correspondence: Dongxu Wang, ; Weiwei Liu,
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Jiang W, Wu D, Zeng Q, Liu C, Chen E, Bai L, Tang H. USP18 attenuates the anti-hepatitis B virus effect of IFN by down-regulating JAK-STAT pathway. Future Virol 2022. [DOI: 10.2217/fvl-2022-0063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Aim: USP18 is a type of IFN-stimulated gene, which is associated with virological responses to IFN therapy in HBV (hepatitis B virus). However, its detailed molecular mechanism needs to be explored. Materials & methods: With HBV replication cells and mouse models, the USP18 was overexpressed or inhibited, followed by treatment with IFN or Poly (I:C). The expressions of HBV DNA, HBsAg, HBeAg and protein factors in the samples were detected. Results: Overexpression of USP18 attenuates anti-HBV effect of IFN in vitro and in vivo by inhibiting JAK-STAT pathway and reducing the expression of MX1 and OAS. While, the inhibition of USP18 can promote to activate JAK-STAT pathway to enhance the antiviral effect of IFN. Conclusion: USP18 negatively regulates the anti-HBV effect of IFN by regulating JAK-STAT pathway. It may provide new insights into innate immunity mechanisms in CHB patients receiving IFN treatment.
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Affiliation(s)
- Wei Jiang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, 610041, China
| | - Dongbo Wu
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, 610041, China
| | - Qingmin Zeng
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, 610041, China
| | - Cong Liu
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, 610041, China
| | - Enqiang Chen
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, 610041, China
| | - Lang Bai
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, 610041, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, 610041, China
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Tian X, Dong H, Lai X, Ou G, Cao J, Shi J, Xiang C, Wang L, Zhang X, Zhang K, Song J, Deng J, Deng H, Lu S, Zhuang H, Li T, Xiang K. TRIM56 impairs HBV infection and replication by inhibiting HBV core promoter activity. Antiviral Res 2022; 207:105406. [PMID: 36084850 DOI: 10.1016/j.antiviral.2022.105406] [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: 01/21/2022] [Revised: 08/04/2022] [Accepted: 08/31/2022] [Indexed: 11/02/2022]
Abstract
Members of the tripartite motif (TRIM) protein family strongly induced by interferons (IFNs) are parts of the innate immune system with antiviral activity. However, it is still unclear which TRIMs could play important roles in hepatitis B virus (HBV) inhibition. Here, we identified that TRIM56 expression responded in IFN-treated HepG2-NTCP cells and HBV-infected liver tissues, which was a potent IFN-inducible inhibitor of HBV replication. Mechanistically, TRIM56 suppressed HBV replication via its Ring and C-terminal domain. C-terminal domain was essential for TRIM56 translocating from cytoplasm to nucleus during HBV infection. Further analysis revealed that TRIM56's Ring domain targeted IκBα for ubiquitination. This modification induced phosphorylation of p65, which subsequently inhibited HBV core promoter activity, resulting in the inhibition of HBV replication. The p65 was found to be necessary for NF-κB signal pathway to inhibit HBV replication. We verified our findings using HepG2-NTCP and primary human hepatocytes. Our findings reveal that TRIM56 is a critical antiviral immune effector and exerts an anti-HBV activity via NF-κB signal pathway, which is essential for inhibiting transcription of HBV covalently closed circular DNA.
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Affiliation(s)
- Xing Tian
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China
| | - Huijun Dong
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China
| | - Xinyuan Lai
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China
| | - Guomin Ou
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China
| | - Junning Cao
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital, Beijing, 100089, China
| | - Jihang Shi
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital, Beijing, 100089, China
| | - Chengang Xiang
- School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic, Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua, Center for Life Sciences, Peking University, Beijing, 100191, China; Renal Division, Peking University First Hospital, Beijing, China
| | - Lei Wang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China
| | - Xuechao Zhang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China
| | - Kai Zhang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China
| | - Ji Song
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China
| | - Juan Deng
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China
| | - Hongkui Deng
- School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic, Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua, Center for Life Sciences, Peking University, Beijing, 100191, China
| | - Shichun Lu
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital, Beijing, 100089, China
| | - Hui Zhuang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China.
| | - Tong Li
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China.
| | - Kuanhui Xiang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China.
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20
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Xiong J, Jiang Y, Zhang J, Chen Y, Hu Y. CK1α upregulates the IFNAR1 expression to prompt the anti-HBV effect of type I IFN in hepatoma carcinoma cells. Virol Sin 2022; 37:894-903. [PMID: 35985475 PMCID: PMC9797371 DOI: 10.1016/j.virs.2022.08.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 08/08/2022] [Indexed: 01/01/2023] Open
Abstract
Casein kinase 1α (CK1α) mediates the phosphorylation and degradation of interferon-α/β receptor 1 (IFNAR1) in response to viral infection. However, how CK1α regulates hepatitis B virus (HBV) replication and the anti-HBV effects of IFN-α are less reported. Here we show that CK1α can interact with IFNAR1 in hepatoma carcinoma cells and increased the abundance of IFNAR1 by reducing the ubiquitination levels in the presence of HBV. Furthermore, CK1α promotes the IFN-α triggered JAK-STAT signaling pathway and consequently enhances the antiviral effects of IFN-α against HBV replication. Our results collectively provide evidence that CK1α positively regulates the anti-HBV activity of IFN-α in hepatoma carcinoma cells, which would be a promising therapeutic target to improve the effectiveness of IFN-α therapy to cure CHB.
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21
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Ito A, Okada T, Minato N, Hattori F. Possible internal viral shedding and interferon production after clinical recovery from COVID-19: Case report. Front Med (Lausanne) 2022; 9:959196. [PMID: 35983089 PMCID: PMC9379344 DOI: 10.3389/fmed.2022.959196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 07/05/2022] [Indexed: 11/13/2022] Open
Abstract
A 70-year-old man underwent off-pump coronary artery bypass grafting 28 days after his recovery from coronavirus disease 2019 (COVID-19), which was confirmed by a negative polymerase chain reaction (PCR) test result for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from a nasopharyngeal swab. The PCR test result was also negative for nasopharyngeal sampling 5 days prior to the surgery. However, his redundant saphenous vein and sputum through the endotracheal tube that was taken on the operative day showed the presence of SARS-CoV-2 by PCR. Immunohistochemical analysis of Spike and Nucleoprotein of the saphenous vein showed small clusters of each antigen-positive speckle. Ultrastructural imaging of the saphenous vein showed virus-like particles. The cell-based assay suggested that the patient’s serum contained a higher concentration of type-I interferons than that of healthy control sera. These observations suggest that internal viral shedding and, to some extent, innate immune responses continue after COVID-19 recovery.
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Affiliation(s)
- Asuka Ito
- Department of Anesthesiology, School of Medicine, Kansai Medical University, Osaka, Japan
| | - Takayuki Okada
- Department of Cardiovascular Surgery, School of Medicine, Kansai Medical University, Osaka, Japan
| | - Naoki Minato
- Department of Cardiovascular Surgery, School of Medicine, Kansai Medical University, Osaka, Japan
| | - Fumiyuki Hattori
- Innovative Regenerative Medicine, Graduate School of Medicine, Kansai Medical University, Osaka, Japan
- *Correspondence: Fumiyuki Hattori,
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22
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Lei V, Handfield C, Kwock JT, Kirchner SJ, Lee MJ, Coates M, Wang K, Han Q, Wang Z, Powers JG, Wolfe S, Corcoran DL, Fanelli B, Dadlani M, Ji RR, Zhang JY, MacLeod AS. Skin Injury Activates a Rapid TRPV1-Dependent Antiviral Protein Response. J Invest Dermatol 2022; 142:2249-2259.e9. [PMID: 35007556 PMCID: PMC9259761 DOI: 10.1016/j.jid.2021.11.041] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 11/19/2021] [Accepted: 11/23/2021] [Indexed: 02/08/2023]
Abstract
The skin serves as the interface between the body and the environment and plays a fundamental role in innate antimicrobial host immunity. Antiviral proteins (AVPs) are part of the innate host defense system and provide protection against viral pathogens. How breach of the skin barrier influences innate AVP production remains largely unknown. In this study, we characterized the induction and regulation of AVPs after skin injury and identified a key role of TRPV1 in this process. Transcriptional and phenotypic profiling of cutaneous wounds revealed that skin injury induces high levels of AVPs in both mice and humans. Remarkably, pharmacologic and genetic ablation of TRPV1-mediated nociception abrogated the induction of AVPs, including Oas2, Oasl2, and Isg15 after skin injury in mice. Conversely, stimulation of TRPV1 nociceptors was sufficient to induce AVP production involving the CD301b+ cells‒IL-27‒mediated signaling pathway. Using IL-27 receptor‒knockout mice, we show that IL-27 signaling is required in the induction of AVPs after skin injury. Finally, loss of TRPV1 signaling leads to increased viral infectivity of herpes simplex virus. Together, our data indicate that TRPV1 signaling ensures skin antiviral competence on wounding.
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Affiliation(s)
- Vivian Lei
- Department of Dermatology, Duke University School of Medicine, Durham, North Carolina, USA
| | - Chelsea Handfield
- Department of Dermatology, Duke University School of Medicine, Durham, North Carolina, USA
| | - Jeffery T Kwock
- Department of Dermatology, Duke University School of Medicine, Durham, North Carolina, USA
| | - Stephen J Kirchner
- Department of Dermatology, Duke University School of Medicine, Durham, North Carolina, USA; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, USA
| | - Min Jin Lee
- Department of Dermatology, Duke University School of Medicine, Durham, North Carolina, USA; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, USA
| | - Margaret Coates
- Department of Dermatology, Duke University School of Medicine, Durham, North Carolina, USA
| | - Kaiyuan Wang
- Duke Center for Translational Pain Medicine, Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina, USA; Department of Cell Biology, Duke University School of Medicine, Durham, North Carolina, USA
| | - Qingjian Han
- Duke Center for Translational Pain Medicine, Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina, USA; Department of Cell Biology, Duke University School of Medicine, Durham, North Carolina, USA
| | - Zilong Wang
- Duke Center for Translational Pain Medicine, Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina, USA; Department of Cell Biology, Duke University School of Medicine, Durham, North Carolina, USA
| | - Jennifer G Powers
- Department of Dermatology, Duke University School of Medicine, Durham, North Carolina, USA; Department of Dermatology, Carver College of Medicine, University of Iowa Health Care, Iowa, USA
| | - Sarah Wolfe
- Department of Dermatology, Duke University School of Medicine, Durham, North Carolina, USA
| | - David L Corcoran
- Duke Center for Genomic and Computational Biology, Duke University School of Medicine, Durham, North Carolina, USA
| | | | | | - Ru-Rong Ji
- Duke Center for Translational Pain Medicine, Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina, USA; Department of Cell Biology, Duke University School of Medicine, Durham, North Carolina, USA
| | - Jennifer Y Zhang
- Department of Dermatology, Duke University School of Medicine, Durham, North Carolina, USA; Department of Pathology, Duke University School of Medicine, Durham, North Carolina, USA.
| | - Amanda S MacLeod
- Department of Dermatology, Duke University School of Medicine, Durham, North Carolina, USA; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, USA; Department of Immunology, Duke University School of Medicine, Durham, North Carolina, USA
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23
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Shiue SJ, Cheng CL, Shiue HS, Chen CN, Cheng SW, Wu LW, Jargalsaikhan G, Chan TS, Lin HY, Wu MS. Arthrospira Enhances Seroclearance in Patients with Chronic Hepatitis B Receiving Nucleos(t)ide Analogue through Modulation of TNF-α/IFN-γ Profile. Nutrients 2022; 14:2790. [PMID: 35889747 PMCID: PMC9325115 DOI: 10.3390/nu14142790] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 06/30/2022] [Accepted: 07/04/2022] [Indexed: 12/12/2022] Open
Abstract
Chronic hepatitis B (CHB) virus infection, causing immune dysfunction and chronic hepatitis, is one of the leading risk factors for hepatocellular cancer. We investigated how Arthrospira affected hepatitis B surface antigen (HBsAg) reduction in CHB patients under continued nucleos(t)ide analogues (NA). Sixty CHB patients who had been receiving NA for at least one year with undetectable HBV DNA were randomized into three groups: control and oral Arthrospira at 3 or 6 g daily add-on therapy groups. Patients were followed up for 6 months. Oral Arthrospira-diet mice were established to investigate the possible immunological mechanism of Arthrospira against HBV. Within 6 months, mean quantitative HBsAg (qHBsAg) decreased in the oral Arthrospira add-on therapy group. Interestingly, interferon gamma (IFN-γ) increased but TNF-α, interleukin 6 (IL-6), hepatic fibrosis, and steatosis decreased in the add-on groups. In mice, Arthrospira enhanced both innate and adaptive immune system, especially natural killer (NK) cell cytotoxicity, B cell activation, and the interleukin 2 (IL-2), IFN-γ immune response. Arthrospira may modulate IL-2- and TNF-α/IFN-γ-mediated B and T cell activation to reduce HBsAg. Also, Arthrospira has the potential to restore immune tolerance and enhance HBsAg seroclearance in CHB patients through promoting T, B, and NK cell activation.
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Affiliation(s)
- Sheng-Jie Shiue
- Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan; (S.-J.S.); (C.-L.C.); (H.-S.S.); (C.-N.C.); (S.-W.C.); (T.-S.C.)
- Integrative Therapy Center for Gastroenterologic Cancers, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan
| | - Chao-Ling Cheng
- Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan; (S.-J.S.); (C.-L.C.); (H.-S.S.); (C.-N.C.); (S.-W.C.); (T.-S.C.)
| | - Han-Shiang Shiue
- Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan; (S.-J.S.); (C.-L.C.); (H.-S.S.); (C.-N.C.); (S.-W.C.); (T.-S.C.)
| | - Chun-Nan Chen
- Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan; (S.-J.S.); (C.-L.C.); (H.-S.S.); (C.-N.C.); (S.-W.C.); (T.-S.C.)
| | - Sheng-Wei Cheng
- Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan; (S.-J.S.); (C.-L.C.); (H.-S.S.); (C.-N.C.); (S.-W.C.); (T.-S.C.)
- Division of Gastroenterology, Department of Internal Medicine, Taiwan Adventist Hospital, Taipei 105, Taiwan
| | - Li-Wei Wu
- Department of Internal Medicine, National Taiwan University Hospital, YunLin Branch, YunLin 640, Taiwan;
| | | | - Tze-Sian Chan
- Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan; (S.-J.S.); (C.-L.C.); (H.-S.S.); (C.-N.C.); (S.-W.C.); (T.-S.C.)
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
| | - Hsin-Yi Lin
- Institute of Chemical Engineering, National Taipei University of Technology, Taipei 106, Taiwan
- Institute of Biochemical and Biomedical Engineering, National Taipei University of Technology, Taipei 106, Taiwan
| | - Ming-Shun Wu
- Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan; (S.-J.S.); (C.-L.C.); (H.-S.S.); (C.-N.C.); (S.-W.C.); (T.-S.C.)
- Integrative Therapy Center for Gastroenterologic Cancers, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
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24
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Yardeni D, Heller T, Koh C. Chronic hepatitis D-What is changing? J Viral Hepat 2022; 29:240-251. [PMID: 35122369 DOI: 10.1111/jvh.13651] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 01/03/2022] [Indexed: 01/04/2023]
Abstract
Hepatitis D virus (HDV) infection is a chronic viral disease of the liver that is still largely considered to be incurable due to lack of effective treatment options. Without treatment, the risk for the development of advanced liver disease, cirrhosis and hepatocellular carcinoma is significantly high. Currently, new therapeutic options are emerging out of ongoing phase 3 clinical trials, promising a new hope of cure for this devastating liver infection. Recently, bulevirtide, a first in its class HDV entry inhibitor, has received conditional authorization of use from the European Medicines Agency (EMA) and was also submitted for approval in the United States. Other novel therapeutic options in clincal trials include interferon lambda, the prenylation inhibitor lonafarnib and nucleic acidic polymers (NAPs). This review describes all recent advances and ongoing changes to the field of HDV therpaeutics.
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Affiliation(s)
- David Yardeni
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Theo Heller
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Christopher Koh
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
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25
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Nagra N, Kozarek RA, Burman BE. Therapeutic Advances in Viral Hepatitis A-E. Adv Ther 2022; 39:1524-1552. [PMID: 35220557 DOI: 10.1007/s12325-022-02070-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 01/31/2022] [Indexed: 11/25/2022]
Abstract
Viral hepatitis remains a significant global health problem. All forms of viral hepatitis A through E (A-E) can lead to acute symptomatic infection, while hepatitis B and C can lead to chronic infection associated with significant morbidity and mortality related to progression to cirrhosis, end-stage-liver disease, and liver cancer. Viral hepatitis occurs worldwide, though certain regions are disproportionately affected. We now, remarkably, have highly effective curative regimens for hepatitis C, and safe and tolerable medications to suppress hepatitis B activity, and to prevent liver damage and slow disease progression. We have effective vaccines for hepatitis A and B which provide long-lasting immunity, while improved sanitation and awareness can curb outbreaks of hepatitis A and E. However, more effective and available preventive and curative strategies are needed to achieve global eradication of viral hepatitis. This review provides an overview of the epidemiology, transmission, diagnosis, and clinical features of each viral hepatitis with a primary focus on current and future therapeutic and curative options.
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Affiliation(s)
- Navroop Nagra
- Department of Gastroenterology, University of Louisville, Louisville, KY, 40202, USA
| | - Richard A Kozarek
- Center for Digestive Health, Virginia Mason Franciscan Health, 1100 9th Ave., Seattle, WA, 98101, USA
| | - Blaire E Burman
- Center for Digestive Health, Virginia Mason Franciscan Health, 1100 9th Ave., Seattle, WA, 98101, USA.
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26
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Yardeni D, Ghany MG. Review article: hepatitis B-current and emerging therapies. Aliment Pharmacol Ther 2022; 55:805-819. [PMID: 35224760 DOI: 10.1111/apt.16828] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 01/17/2022] [Accepted: 02/04/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND The hepatitis B virus (HBV) affects an estimated 290 million individuals worldwide and is responsible for approximately 900 000 deaths annually, mostly from complications of cirrhosis and hepatocellular carcinoma. Although current treatment is effective at preventing complications of chronic hepatitis B, it is not curative, and often must be administered long term. There is a need for safe, effective, finite duration curative therapy. AIM Our aim was to provide a concise, up to date review of all currently available and emerging treatment options for chronic hepatitis B. METHODS We conducted a search of PubMed, clinicaltrials.gov, major meeting abstracts and pharmaceutical websites for publications and communications on current and emerging therapies for HBV. RESULTS Currently approved treatment options for chronic hepatitis B include peginterferon alpha-2a and nucleos(t)ide analogues. Both options do not offer a 'complete cure' (clearance of covalently closed circular DNA (cccDNA) and integrated HBV DNA) and rarely achieve a 'functional cure' (hepatitis B surface antigen (HBsAg) loss). An improved understanding of the viral lifecycle, immunopathogenesis and recent advances in drug delivery technologies have led to many novel therapeutic approaches that are currently being evaluated in clinical trials including targeting of viral entry, cccDNA, viral transcription, core protein, and release of HBsAg and HBV polymerase. Additionally, novel immunological approaches that include targeting the innate and adaptive immune system and therapeutic vaccination are being pursued. CONCLUSION The breadth and scope of novel therapies in development hold promise for regimen/s that will achieve functional cure.
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Affiliation(s)
- David Yardeni
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Marc G Ghany
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
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27
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Zhang J, Liu K, Zhang G, Ling N, Chen M. Interleukin-17A pretreatment attenuates the anti-hepatitis B virus efficacy of interferon-alpha by reducing activation of the interferon-stimulated gene factor 3 transcriptional complex in hepatitis B virus-expressing HepG2 cells. Virol J 2022; 19:28. [PMID: 35144643 PMCID: PMC8830041 DOI: 10.1186/s12985-022-01753-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 01/26/2022] [Indexed: 11/16/2022] Open
Abstract
Background Some cytokine signaling pathways can interact with interferon (IFN)-α pathway and thus regulate cell responses to IFN-α. Levels of the pro-inflammatory cytokine interleukin-17A (IL-17A) were found to be elevated in both the peripheral blood and liver in chronic hepatitis B (CHB) patients. However, how IL-17A affects the anti-HBV activity of IFN-α remains unclear. Methods The effects of IL-17A on anti-HBV activity of IFN-α were evaluated in HBV-expressing HepG2 cells (HepG2-HBV1.3) with IL-17A pretreatment and IFN-α stimulation. Culture supernatant levels of HBsAg, HBeAg, and HBV DNA, or intracellular expression of HBsAg and HBcAg were detected by ELISA, real-time quantitative PCR (RT-qPCR), or western blotting (WB). The expression of canonical IFN-α signaling pathway components, including the interferon-α/β receptor (IFNAR), Janus Kinase 1 (JAK1), Tyrosine Kinase 2 (TYK2), the Interferon Stimulated Gene Factor 3 complex (ISGF3) and IFN-stimulated genes (ISGs), was also examined by RT-qPCR, Immunofluorescence or WB. The effects of IL-17A were further investigated by the suppression of the IL-17A pathway with a TRAF6 inhibitor. Results Compared to IFN-α stimulation alone, IL-17A pretreatment followed by IFN-α stimulation increased the levels of HBsAg, HBeAg, and HBV DNA, and decreased the levels of ISGF3 complex (phosphorylated (p)-signal transducer and activator of transcription (STAT1)/p-STAT2/IRF9) and antiviral-related ISGs (ISG15, ISG20 and Mx1). Interestingly, IL-17A pretreatment increased the expression of suppressor of cytokine signaling (SOCS) 1, SOCS3 and USP18, which were also the ISGs negatively regulating activity of ISGF3. Moreover, IFNAR1 protein expression declined more sharply in the group with IL-17A pretreatment than in the group with IFN-α stimulation alone. Blocking the IL-17A pathway reversed the effects of IL-17A on the IFN-α-induced activation of ISGF3 and anti-HBV efficacy. Conclusions Our results demonstrate that IL-17A pretreatment could attenuate IFN-α-induced anti-HBV activity by upregulating negative regulators of the critical transcriptional ISGF3 complex. Thus, this might be a potential target for improving response to IFN-α therapy. Supplementary Information The online version contains supplementary material available at 10.1186/s12985-022-01753-x.
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Affiliation(s)
- Jiaxuan Zhang
- Department of Infectious Diseases, Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Kai Liu
- Department of Clinical Laboratory, The People's Hospital of Leshan, Chongqing, China
| | - Gaoli Zhang
- Department of Infectious Diseases, Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ning Ling
- Department of Infectious Diseases, Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Min Chen
- Department of Infectious Diseases, Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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28
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Abstract
Chronic hepatitis B virus (HBV) infection remains a global health burden. Timely and effective antiviral therapy is beneficial for patients with HBV infection. With existing antiviral drugs, including nucleos(t)ide analogs and interferon-alfa, patients can achieve viral suppression with improved prognosis. However, the rate of hepatitis B surface antigen loss is low. To achieve a functional cure and even complete cure in chronic hepatitis B patients, new antivirals need to be developed. In this review, we summarized the advantages and disadvantages of existing antiviral drugs and focused on new antivirals including direct-acting antiviral drugs and immunotherapeutic approaches.
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Clinical and Preclinical Single-Dose Pharmacokinetics of VIR-2218, an RNAi Therapeutic Targeting HBV Infection. Drugs R D 2021; 21:455-465. [PMID: 34741731 PMCID: PMC8602582 DOI: 10.1007/s40268-021-00369-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/06/2021] [Indexed: 12/05/2022] Open
Abstract
Background and Objective VIR-2218 is an investigational N-acetylgalactosamine–conjugated RNA interference therapeutic in development for chronic hepatitis B virus (HBV) infection. VIR-2218 was designed to silence HBV transcripts across all genotypes and uses Enhanced Stabilization Chemistry Plus (ESC+) technology. This study was designed to evaluate the single-dose pharmacokinetics of VIR-2218 in preclinical species and healthy volunteers. Methods Preclinically, a single subcutaneous dose of VIR-2218 (10 mg/kg) was administered to rats and nonhuman primates (NHPs), and the pharmacokinetics were assessed in plasma, urine, and liver using standard noncompartmental analysis (NCA) methods. Clinically, healthy volunteers were randomized (6:2 active:placebo) to receive a single subcutaneous dose of VIR-2218 (50–900 mg) or placebo. Pharmacokinetics were similarly assessed within human plasma and urine using NCA methods. Results In rats and NHPs, VIR-2218 was stable in plasma and was converted to AS(N-1)3’VIR-2218, the most prominent circulating metabolite, at < 10% plasma exposure compared with parent. VIR-2218 rapidly distributed to the liver, reaching peak liver concentrations within 7 and 24 h in rats and NHPs, respectively. In humans, VIR-2218 was rapidly absorbed, with a median time to peak plasma concentration (tmax) of 4–7 h, and had a short median plasma half-life of 2–5 h. Plasma exposures for area under the plasma concentration–time curve up to 12 h (AUC0–12) and mean maximum concentrations (Cmax) increased in a slightly greater-than-dose-proportional manner across the dose range studied. Interindividual pharmacokinetic variability was low to moderate, with a percent coefficient of variation of < 32% for AUC and < 43% for Cmax. A portion of VIR-2218 was converted to an active metabolite, AS(N-1)3’VIR-2218, with a median tmax of 6–10 h, both of which declined below the lower limit of quantification in plasma within 48 h. The pharmacokinetic profile of AS(N-1)3’VIR-2218 was similar to that of VIR-2218, with plasma AUC0–12 and Cmax values ≤ 12% of VIR-2218. VIR-2218 and AS(N-1)3’VIR-2218 were detectable in urine through the last measured time point, with approximately 17–48% of the administered dose recovered in urine as unchanged VIR-2218 over 0–24 h postdose. Based on pharmacokinetics in preclinical species, VIR-2218 localizes to the liver and likely exhibits prolonged hepatic exposure. Overall, no severe or serious adverse events or discontinuations due to adverse events were observed within the dose range evaluated for VIR-2218 in healthy volunteers (Vir Biotechnology, Inc., unpublished data). Conclusions VIR-2218 showed favorable pharmacokinetics in healthy volunteers supportive of subcutaneous dosing and continued development in patients with chronic HBV infection. Clinical Trial Registration No NCT03672188, September 14, 2018. Supplementary Information The online version contains supplementary material available at 10.1007/s40268-021-00369-w.
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Ma H, Lim TH, Leerapun A, Weltman M, Jia J, Lim YS, Tangkijvanich P, Sukeepaisarnjaroen W, Ji Y, Le Bert N, Li D, Zhang Y, Hamatake R, Tan N, Li C, Strasser SI, Ding H, Yoon JH, Stace NH, Ahmed T, Anderson DE, Yan L, Bertoletti A, Zhu Q, Yuen MF. Therapeutic vaccine BRII-179 restores HBV-specific immune responses in patients with chronic HBV in a phase Ib/IIa study. JHEP Rep 2021; 3:100361. [PMID: 34661089 PMCID: PMC8502773 DOI: 10.1016/j.jhepr.2021.100361] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 08/02/2021] [Accepted: 08/25/2021] [Indexed: 01/12/2023] Open
Abstract
Background & Aims Functional cure of chronic HBV infection (CHB) without life-long treatment requires the restoration of defective HBV-specific humoral and cellular immunity. Therapeutic vaccines based on the major structural and non-structural proteins have been tested in patients with CHB but have shown scarce immunogenicity. BRII-179, also known as VBI-2601, is a novel formulation comprised of all 3 HBV surface envelope proteins (Pre-S1, Pre-S2, and S). Safety, antiviral activity, and immunogenicity of BRII-179 admixed with co-adjuvant interferon (IFN)-α were assessed in patients with CHB. Method This randomized, open-label, controlled phase Ib/IIa study included 2 dose levels, 20 μg BRII-179 (Part 1, n = 25) and 40 μg BRII-179 (Part 2, n = 24). Patients, virally suppressed under nucleos(t)ide analogue (NA) therapy were randomized 1:2:2 into 3 cohorts in Part 1 and 1:1 into 2 cohorts in Part 2 to receive 4 monthly intramuscular injections of BRII-179 admixed with/without 3 MIU IFN-α. Antibody and cellular responses to HBsAg, as well as evolution of circulating HBsAg were monitored. Results Both 20 μg and 40 μg BRII-179 with/without IFN-α were well tolerated with no severe adverse events. BRII-179 induced anti-HBs responses in >30% patients in all treatment cohorts, however, moderate anti-Pre-S1 or anti-Pre-S2 antibody responses were only observed in patients receiving BRII-179 with IFN-α. BRII-179 also restored S-, Pre-S1-, Pre-S2-specific IFN-γ-producing T-cells in the majority of treated patients. Overall, no notable reduction of HBsAg was observed after BRII-179 treatment. Conclusion In patients with CHB under NA therapy, BRII-179 with/without IFN-α exhibited a good safety profile and induced HBV-specific B- and T-cell immune responses. These data support further clinical evaluation of BRII-179 in combination with other therapies. Clinical Trial Number ACTRN12619001210167. Lay summary BRII-179 is a therapeutic vaccine designed to improve the immune response in patients with chronic hepatitis B. In this study, BRII-179 alone or with a low dose of interferon-α was safe, well tolerated, and induced enhanced HBV-specific antibody and T-cell responses in patients with chronic hepatitis B. However, BRII-179 treatment alone had minimal effect on patient's virological status. The potential of BRII-179 to achieve a functional cure in conjunction with other agents is being evaluated in the clinic.
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Key Words
- AE, adverse event
- ALT, alanine aminotransferase
- Anti-HBs, hepatitis B surface antibody
- BMI, body mass index
- BRII-179
- CHB
- CHB, chronic hepatitis B
- ELISpot, enzyme-linked immune absorbent spot
- HBV, hepatitis B virus
- HBV-specific immune response
- HBeAg, hepatitis B e antigen
- HBsAg, hepatitis B surface antigen
- IFN-alpha
- IFN-α, interferon-α
- IM, intramuscular
- IU, international units
- NA, nucleos(t)ide analogue
- PBMCs, peripheral blood mononuclear cells
- PEG-IFN-α, pegylated interferon-α
- SAE, serious adverse events
- Th1, T helper type 1
- immunotherapy
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Affiliation(s)
- Haiyan Ma
- Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore
| | | | | | | | - Jidong Jia
- Beijing Friendship Hospital, Beijing, China
| | - Young-Suk Lim
- Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Pisit Tangkijvanich
- Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | | | - Yun Ji
- Brii Biosciences Inc. Durham, NC, USA
| | - Nina Le Bert
- Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore
| | - Dong Li
- Brii Biosciences Inc. Beijing, PR China
| | - Yao Zhang
- Brii Biosciences Inc. Beijing, PR China
| | | | - Nicole Tan
- Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore
| | | | | | - Huiguo Ding
- Beijing You 'an Hospital affiliated to Capital Medical University, Beijing, China
| | | | - Nigel H Stace
- Capital & Coast District Health Board, Wellington, New Zealand
| | | | | | - Li Yan
- Brii Biosciences Inc. Durham, NC, USA
| | - Antonio Bertoletti
- Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore
| | - Qing Zhu
- Brii Biosciences Inc. Durham, NC, USA
| | - Man-Fung Yuen
- Department of Medicine and State Key Laboratory of Liver Research, The University of Hong Kong, Queen Mary Hospital, Hong Kong
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Moon IY, Kim JW. Methylation profile of hepatitis B virus is not influenced by interferon α in human liver cancer cells. Mol Med Rep 2021; 24:715. [PMID: 34396432 PMCID: PMC8383030 DOI: 10.3892/mmr.2021.12354] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Accepted: 07/12/2021] [Indexed: 12/17/2022] Open
Abstract
Interferon (IFN) α is used for the treatment of chronic hepatitis B virus (HBV) infection, but the molecular mechanisms underlying its antiviral effect have not been fully elucidated. Epigenetic modifications regulate the transcriptional activity of covalently closed circular DNA (cccDNA) in cells with chronic HBV infection. IFN‑α has been shown to modify cccDNA‑bound histones, but it is not known whether the anti‑HBV effect of IFN‑α involves methylation of cccDNA. The present study aimed to determine whether IFN‑α induced methylation of HBV cccDNA in a cell‑based model in which HepG2 cells were directly infected with wild‑type HBV virions. Methylation status of HBV cccDNA was assessed using global DNA methylation ELISA assay, methylation‑specific PCR and bisulfite sequencing. IFN‑α suppressed HBV DNA and RNA transcripts, but methylation profiles were similar between the control and IFN‑α treated groups. Chromatin immunoprecipitation results revealed binding of DNA methyltransferases (DNMT) 3A and DNMT3B to HBV cccDNA and treatment with IFN‑α suppressed the recruitment of DNMT3B to cccDNA. Taken together, these results suggest that IFN‑α does not induce methylation of HBV cccDNA. Therefore, it was concluded that methylation is unlikely to contribute to the anti‑HBV effect of IFN‑α in HepG2 cells, and that alternative mechanisms need to be sought to enhance cccDNA methylation as a novel therapy against HBV.
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Affiliation(s)
- In Young Moon
- Department of Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi 13620, Republic of Korea
| | - Jin-Wook Kim
- Department of Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi 13620, Republic of Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
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Li Y, Yin S, Issa R, Tong X, Wang G, Xia J, Huang R, Chen G, Weng D, Chen C, Wu C, Chen Y. B Cell-mediated Humoral Immunity in Chronic Hepatitis B Infection. J Clin Transl Hepatol 2021; 9:592-597. [PMID: 34447690 PMCID: PMC8369012 DOI: 10.14218/jcth.2021.00051] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 04/24/2021] [Accepted: 05/06/2021] [Indexed: 12/12/2022] Open
Abstract
B cell-mediated humoral immunity plays a vital role in viral infections, including chronic hepatitis B virus (HBV) infection, which remains a critical global public health issue. Despite hepatitis B surface antigen-specific antibodies are essential to eliminate viral infections, the reduced immune functional capacity of B cells was identified, which was also correlated with chronic hepatitis B (CHB) progression. In addition to B cells, T follicular helper (Tfh) cells, which assist B cells to produce antibodies, might also be involved in the process of anti-HBV-specific antibody production. Here, we provide a comprehensive review of the role of various subsets of B cells and Tfh cells during CHB progression and discuss current novel treatment strategies aimed at restoring humoral immunity. Understanding the mechanism of dysregulated B cells and Tfh cells will facilitate the ultimate functional cure of CHB patients.
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Affiliation(s)
- Yang Li
- School of Environmental and Biological Engineering, Nanjing University of Science & Technology, Nanjing, Jiangsu, China
| | - Shengxia Yin
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Rahma Issa
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xin Tong
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Guiyang Wang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Juan Xia
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Rui Huang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Guangmei Chen
- Department of Infectious Diseases, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, China
| | - Dan Weng
- School of Environmental and Biological Engineering, Nanjing University of Science & Technology, Nanjing, Jiangsu, China
| | - Chen Chen
- Department of Clinical Pharmacology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Chao Wu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, China
- Correspondence to: Yuxin Chen, Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu 210008, China. ORCID: https://orcid.org/0000-0001-5955-687X. Tel: +86-25-8968-3827, Fax: +86-25-8330-7115, E-mail: ; Wu Chao, Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu 210008, China. ORCID: https://orcid.org/0000-0002-1657-010X. Tel: +86-25-8310-5890, Fax: +86-25-8330-7115, E-mail:
| | - Yuxin Chen
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, China
- Correspondence to: Yuxin Chen, Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu 210008, China. ORCID: https://orcid.org/0000-0001-5955-687X. Tel: +86-25-8968-3827, Fax: +86-25-8330-7115, E-mail: ; Wu Chao, Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu 210008, China. ORCID: https://orcid.org/0000-0002-1657-010X. Tel: +86-25-8310-5890, Fax: +86-25-8330-7115, E-mail:
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Campos-Valdez M, Monroy-Ramírez HC, Armendáriz-Borunda J, Sánchez-Orozco LV. Molecular Mechanisms during Hepatitis B Infection and the Effects of the Virus Variability. Viruses 2021; 13:v13061167. [PMID: 34207116 PMCID: PMC8235420 DOI: 10.3390/v13061167] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 06/10/2021] [Accepted: 06/11/2021] [Indexed: 12/16/2022] Open
Abstract
The immunopathogenesis and molecular mechanisms involved during a hepatitis B virus (HBV) infection have made the approaches for research complex, especially concerning the patients’ responses in the course of the early acute stage. The study of molecular bases involved in the viral clearance or persistence of the infection is complicated due to the difficulty to detect patients at the most adequate points of the disease, especially in the time lapse between the onset of the infection and the viral emergence. Despite this, there is valuable data obtained from animal and in vitro models, which have helped to clarify some aspects of the early immune response against HBV infection. The diversity of the HBV (genotypes and variants) has been proven to be associated not only with the development and outcome of the disease but also with the response to treatments. That is why factors involved in the virus evolution need to be considered while studying hepatitis B infection. This review brings together some of the published data to try to explain the immunological and molecular mechanisms involved in the different stages of the infection, clinical outcomes, viral persistence, and the impact of the variants of HBV in these processes.
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Affiliation(s)
- Marina Campos-Valdez
- Centro Universitario de Ciencias de la Salud, Departamento de Biología Molecular y Genómica, Instituto de Biología Molecular en Medicina, Universidad de Guadalajara, Guadalajara 44340, Jalisco, México; (M.C.-V.); (H.C.M.-R.); (J.A.-B.)
| | - Hugo C. Monroy-Ramírez
- Centro Universitario de Ciencias de la Salud, Departamento de Biología Molecular y Genómica, Instituto de Biología Molecular en Medicina, Universidad de Guadalajara, Guadalajara 44340, Jalisco, México; (M.C.-V.); (H.C.M.-R.); (J.A.-B.)
| | - Juan Armendáriz-Borunda
- Centro Universitario de Ciencias de la Salud, Departamento de Biología Molecular y Genómica, Instituto de Biología Molecular en Medicina, Universidad de Guadalajara, Guadalajara 44340, Jalisco, México; (M.C.-V.); (H.C.M.-R.); (J.A.-B.)
- Escuela de Medicina y Ciencias de la Salud, Tecnológico de Monterrey, Campus Guadalajara, Zapopan 45201, Jalisco, México
| | - Laura V. Sánchez-Orozco
- Centro Universitario de Ciencias de la Salud, Departamento de Biología Molecular y Genómica, Instituto de Biología Molecular en Medicina, Universidad de Guadalajara, Guadalajara 44340, Jalisco, México; (M.C.-V.); (H.C.M.-R.); (J.A.-B.)
- Correspondence: ; Tel.: +52-33-3954-5677
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Virological and immunological predictors of long term outcomes of peginterferon alfa-2a therapy for HBeAg-negative chronic hepatitis B. J Formos Med Assoc 2020; 120:1676-1685. [PMID: 33339708 DOI: 10.1016/j.jfma.2020.12.001] [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: 08/11/2020] [Revised: 11/04/2020] [Accepted: 12/01/2020] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND/PURPOSE Predictors of long-term outcomes of peginterferon (PegIFN) therapy for patients with chronic hepatitis B (CHB) remain to be explored. This study aimed to evaluate the predictive value of virological and immunological biomarkers and outcomes of PegIFN for CHB. METHODS 57 HBeAg-negative CHB patients receiving 48 weeks of PegIFN therapy were prospectively followed for a median period of 5.3 years after the end of treatment (EOT). Serum CXCL9 and IP-10 levels were measured. Flow cytometry analysis for T cell subsets was performed in 23 patients. Factors associated with long-term outcomes were analyzed. RESULTS The cumulative incidences of virological relapse, clinical relapse and HBsAg loss at year 7 were 18.1%, 0%, 31.6%, respectively, in patients with sustained off-treatment virological response (SVR), and 100%, 67.4%, 6.7%, respectively, in patients without SVR. By multivariate analysis, baseline CXCL9 > 80 pg/mL (hazard ratio (HR) = 0.418, p = 0.018) and on-treatment HBsAg declines were associated with a lower risk of virological relapse. Non-SVR was the only predictor of clinical relapse. CXCL9 >200 pg/mL (HR = 8.154, p = 0.038) and HBsAg <750 IU/mL (HR = 10.507, p = 0.036) were baseline predictors of HBsAg loss, while HBsAg decline >1 log at EOT (HR = 23.296, p = 0.005) was the on-treatment predictor of HBsAg loss. In subgroup patients with available PBMC, populations of T cell subsets correlated with virological and clinical relapses in univariate analysis. CONCLUSION Baseline serum CXCL9 and HBsAg levels could predict HBsAg loss after PegIFN therapy for HBeAg-negative CHB. Combining virological and immunological biomarkers could predict long-term outcomes of PegIFN therapy for HBeAg-negative CHB.
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Lau KC, Burak KW, Coffin CS. Impact of Hepatitis B Virus Genetic Variation, Integration, and Lymphotropism in Antiviral Treatment and Oncogenesis. Microorganisms 2020; 8:E1470. [PMID: 32987867 PMCID: PMC7599633 DOI: 10.3390/microorganisms8101470] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 09/16/2020] [Accepted: 09/22/2020] [Indexed: 12/14/2022] Open
Abstract
Chronic Hepatitis B Virus (HBV) infection poses a significant global health burden. Although, effective treatment and vaccinations against HBV are available, challenges still exist, particularly in the development of curative therapies. The dynamic nature and unique features of HBV such as viral variants, integration of HBV DNA into host chromosomes, and extrahepatic reservoirs are considerations towards understanding the virus biology and developing improved anti-HBV treatments. In this review, we highlight the importance of these viral characteristics in the context of treatment and oncogenesis. Viral genotype and genetic variants can serve as important predictive factors for therapeutic response and outcomes in addition to oncogenic risk. HBV integration, particularly in coding genes, is implicated in the development of hepatocellular carcinoma. Furthermore, we will discuss emerging research that has identified various HBV nucleic acids and infection markers within extrahepatic sites (lymphoid cells). Intriguingly, the presence of hepatocellular carcinoma (HCC)-associated HBV variants and viral integration within the lymphoid cells may contribute towards the development of extrahepatic malignancies. Improved understanding of these HBV characteristics will enhance the development of a cure for chronic HBV infection.
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Affiliation(s)
- Keith C.K. Lau
- Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada;
- Calgary Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada;
| | - Kelly W. Burak
- Calgary Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada;
| | - Carla S. Coffin
- Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada;
- Calgary Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada;
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Gerasi M, Frakolaki E, Papadakis G, Chalari A, Lougiakis N, Marakos P, Pouli N, Vassilaki N. Design, synthesis and anti-HBV activity evaluation of new substituted imidazo[4,5-b]pyridines. Bioorg Chem 2020; 98:103580. [DOI: 10.1016/j.bioorg.2020.103580] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Revised: 12/18/2019] [Accepted: 01/10/2020] [Indexed: 02/08/2023]
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George R, Ma A, Motyka B, Shi YE, Liu Q, Griebel P. A dendritic cell-targeted chimeric hepatitis B virus immunotherapeutic vaccine induces both cellular and humoral immune responses in vivo. Hum Vaccin Immunother 2019; 16:779-792. [PMID: 31687875 PMCID: PMC7227651 DOI: 10.1080/21645515.2019.1689081] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Chimigen® HBV Immunotherapeutic Vaccine (C-HBV), a recombinant chimeric fusion protein comprising hepatitis B virus (HBV) S1 and S2 surface antigen fragments, Core antigen and a murine monoclonal antibody heavy chain fragment (Fc), was designed and produced in Sf9 insect cells. C-HBV targets the host immune system through specific receptors present on dendritic cells (DCs) which facilitates antigen internalization, processing, and presentation on MHC class I and II to induce both cellular and humoral immune responses against HBV antigens. T cell responses, previously assessed by ex vivo antigen presentation assays using human peripheral blood mononuclear cell (PBMC)-derived DCs and T cells from uninfected and HBV chronic-infected donors, demonstrated that C-HBV was highly immunogenic. A vaccine dose response study was performed in sheep to analyze the immunogenicity of C-HBV in vivo. Sheep (n = 8/group) received three consecutive subcutaneous injections of each dose of C-HBV at four-week intervals. Analysis of serum antibody levels confirmed C-HBV induced a dose-dependent antibody response to C-HBV and S1/S2-Core. Kinetics of the S1/S2-Core specific antibody response was similar to hepatitis B surface antigen (HBsAg)-specific antibody responses induced by ENGERIX-B. Analysis of cell-mediated immune responses (CMI) confirmed C-HBV induced both dose-dependent S1/S2-Core-specific lymphocyte proliferative responses and IFN-γ secretion. These responses were stronger with blood lymphocytes than with cells isolated from the lymph node draining the vaccination site. No correlation was seen between antibody titers and CMI. The results confirm C-HBV is an effective delivery vehicle for the induction of T cell responses and may be an appropriate candidate for immunotherapy for chronic HBV infections.
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Affiliation(s)
| | - Allan Ma
- Akshaya Bio Inc., Edmonton, Alberta, Canada
| | - Bruce Motyka
- Department of Pediatrics, University of Alberta, Edmonton, AB, Canada
| | - Yuenian Eric Shi
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Qiang Liu
- Vaccine and Infectious Disease Organization-International Vaccine Centre (VIDO-InterVac), University of Saskatchewan, Saskatoon, SK, Canada.,School of Public Health, University of Saskatchewan, Saskatoon, SK, Canada.,Department of Veterinary Microbiology, University of Saskatchewan, Saskatoon, SK, Canada
| | - Philip Griebel
- Vaccine and Infectious Disease Organization-International Vaccine Centre (VIDO-InterVac), University of Saskatchewan, Saskatoon, SK, Canada.,School of Public Health, University of Saskatchewan, Saskatoon, SK, Canada
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Tao Y, Wu D, Zhou L, Chen E, Liu C, Tang X, Jiang W, Han N, Li H, Tang H. Present and Future Therapies for Chronic Hepatitis B. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1179:137-186. [PMID: 31741336 DOI: 10.1007/978-981-13-9151-4_6] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Chronic hepatitis B (CHB) remains the leading cause of liver-related morbidity and mortality across the world. If left untreated, approximately one-third of these patients will progress to severe end-stage liver diseases including liver failure, cirrhosis, and hepatocellular carcinoma (HCC). High level of serum HBV DNA is strongly associated with the development of liver failure, cirrhosis, and HCC. Therefore, antiviral therapy is crucial for the clinical management of CHB. Current antiviral drugs including nucleoside/nucleotide analogues (NAs) and interferon-α (IFN-α) can suppress HBV replication and reduce the progression of liver disease, thus improving the long-term outcomes of CHB patients. This chapter will discuss the standard and optimization antiviral therapies in treatment-naïve and treatment-experienced patients, as well as in the special populations. The up-to-date advances in the development of new anti-HBV agents will be also discussed. With the combination of the current antiviral drugs and the newly developed antiviral agents targeting the different steps of the viral life cycle or the newly developed agents modulating the host immune responses, the ultimate eradication of HBV will be achieved in the future.
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Affiliation(s)
- Yachao Tao
- Center of Infectious Diseases, Division of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Dongbo Wu
- Center of Infectious Diseases, Division of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Lingyun Zhou
- Center of Infectious Diseases, Division of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Enqiang Chen
- Center of Infectious Diseases, Division of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Changhai Liu
- Center of Infectious Diseases, Division of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xiaoqiong Tang
- Center of Infectious Diseases, Division of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Wei Jiang
- Center of Infectious Diseases, Division of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Ning Han
- Center of Infectious Diseases, Division of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Hong Li
- Center of Infectious Diseases, Division of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
| | - Hong Tang
- Center of Infectious Diseases, Division of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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39
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Ito K. Difference between genotypes B and C in the decline and disappearance of hepatitis B surface antigen: Toward an era of direct-acting antiviral agents for hepatitis B virus. Hepatol Res 2019; 49:1253-1255. [PMID: 31820538 DOI: 10.1111/hepr.13456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Revised: 10/26/2019] [Accepted: 11/04/2019] [Indexed: 02/08/2023]
Affiliation(s)
- Kiyoaki Ito
- Department of Gastroenterology, Aichi Medical University School of Medicine, Nagakute, Japan
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40
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Hagiwara S, Nishida N, Watanabe T, Ida H, Sakurai T, Ueshima K, Takita M, Komeda Y, Nishijima N, Osaki Y, Kudo M. Sustained antiviral effects and clearance of hepatitis surface antigen after combination therapy with entecavir and pegylated interferon in chronic hepatitis B. Antivir Ther 2019; 23:513-521. [PMID: 29438098 DOI: 10.3851/imp3225] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/16/2018] [Indexed: 01/12/2023]
Abstract
BACKGROUND Although the efficacy of combination therapy with lamivudine or tenofovir and pegylated interferon (PEG-IFN) has been reported in patients with chronic hepatitis B (CHB), the long-term effect of the combination based on the observation of clinical course remains to be clarified. We previously reported the efficacy of combination therapy with entecavir (ETV) and PEG-IFN. Here, we investigated the long-term effect of this combination in patients with CHB. METHODS We administered both ETV and PEG-IFN-α2a or -2b simultaneously to 26 patients with HBV genotype C infection. Treatment was continued for 48 weeks followed by 24 weeks of observation period; we examined the virological and biochemical responses. We also analysed characteristics related to the post-treatment relapse. Finally, we investigated the long-term therapeutic effects. RESULTS Average reduction of intra-hepatic cccDNA level was 1.2 log copies/μg at the completion of administration. Pretreatment hepatitis B surface antigen (HBsAg) level with more than 3.5 log U/ml was identified as a predictive factor for relapse. Furthermore, the cumulative rates of HBsAg-negative patients at 1, 3 and 5 years after the completion of administration were 3.8, 8.4 and 15%, respectively (mean follow-up period: 4.8 years). CONCLUSIONS Baseline HBsAg level with more than 3.5 log U/ml is a useful predictor for relapse 24 weeks after the completion of administration in patients treated with combination therapy. Combination with ETV and PEG-IFN could be an option for treatment of CHB patients especially in those with baseline HBsAg levels of less than 3.5 log U/ml.
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Affiliation(s)
- Satoru Hagiwara
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Naoshi Nishida
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Tomohiro Watanabe
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Hiroshi Ida
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Toshiharu Sakurai
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Kazuomi Ueshima
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Masahiro Takita
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Yoriaki Komeda
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Norihiro Nishijima
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
| | - Yukio Osaki
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
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41
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Onitsuka K, Tokuda R, Kuwata-Higashi N, Kumamoto H, Aoki M, Amano M, Kohgo S, Das D, Haraguchi K, Mitsuya H, Imoto S. Synthesis and evaluation of the anti-hepatitis B virus activity of 4'-Azido-thymidine analogs and 4'-Azido-2'-deoxy-5-methylcytidine analogs: structural insights for the development of a novel anti-HBV agent. NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS 2019; 39:518-529. [PMID: 31514570 DOI: 10.1080/15257770.2019.1664749] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Hepatitis B virus (HBV) infection is a major worldwide health problem that requires the development of improved antiviral therapies. Here, a series of 4'-Azido-thymidine/4'-Azido-2'-deoxy-5-methylcytidine derivatives (6, 10-15) were synthesized, and their anti-HBV activities evaluated. Compounds 10-15 were synthesized via an SNAr reaction of 18, in which the 4-position of the thymine moiety was activated as the 2,4,6-triisopropylbenzenesulfonate. Compounds 11-15 showed no antiviral activity. However, 4'-Azido thymidine (6) and 4'-Azido-2'-deoxy-5-methylcytidine (10) displayed significant anti-HBV activity (EC50 = 0.63 and 5.99 µM, respectively) with no detectable cytotoxicity against MT-2 cells up to 100 µM.
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Affiliation(s)
- Kengo Onitsuka
- Department of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan
| | - Ryoh Tokuda
- Department of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan
| | - Nobuyo Kuwata-Higashi
- Department of Refractory Viral Infections, National Center for Global Health and Medicine Research Institute, Tokyo, Japan
| | - Hiroki Kumamoto
- Department of Pharmaceutical Sciences, Nihon Pharmaceutical University, Saitama, Japan
| | - Manabu Aoki
- Experimental Retrovirology Section, HIV & AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Masayuki Amano
- Departments of Infectious Diseases and Hematology, Kumamoto University School of Medicine, Kumamoto, Japan
| | - Satoru Kohgo
- Department of Refractory Viral Infections, National Center for Global Health and Medicine Research Institute, Tokyo, Japan
| | - Debananda Das
- Experimental Retrovirology Section, HIV & AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Kazuhiro Haraguchi
- Department of Pharmaceutical Sciences, Nihon Pharmaceutical University, Saitama, Japan
| | - Hiroaki Mitsuya
- Department of Refractory Viral Infections, National Center for Global Health and Medicine Research Institute, Tokyo, Japan.,Experimental Retrovirology Section, HIV & AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.,Departments of Infectious Diseases and Hematology, Kumamoto University School of Medicine, Kumamoto, Japan
| | - Shuhei Imoto
- Department of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan
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42
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Liu W, Liang H, Wang S, Wu C, Liu Y, Liu Y, Zhang M, Xiong L, Zhong Z, Chen Y, Mao Q, Ge S, Xia N. Transcriptional response of USP18 predicts treatment outcomes of interferon-alpha in HBeAg-positive chronic hepatitis B patientsefere. J Viral Hepat 2019; 26:1050-1058. [PMID: 31074081 DOI: 10.1111/jvh.13120] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 04/11/2019] [Accepted: 04/16/2019] [Indexed: 12/30/2022]
Abstract
Ubiquitin-specific protease 18 (USP18) is an important inhibitor of interferon (IFN) antiviral activity, and the aim of this study was to investigate the association between the USP18 mRNA level change in peripheral blood mononuclear cells (PBMCs) when stimulated with IFN in vitro before initiating treatment and the treatment outcomes in HBeAg-positive chronic hepatitis B (CHB) patients treated with IFN. A total of 44 patients who received standard IFN-based anti-HBV therapy and follow-up were enrolled in the study. The in vitro IFN-induced USP18 mRNA change (USP18IFN-N ) was measured via comparison of quantitative PCR-determined USP18 transcription levels of BPMCs cultured with and without IFN stimulation. Either for virological (VR) or serological response (SR), the baseline USP18IFN-N was significantly higher (P = 0.018 for VR, P = 0.008 for SR) among nonresponders (n = 23 for VR, n = 33 for SR) than that of responders (n = 21 for VR, n = 11 for SR). Multivariate analyses revealed baseline USP18IFN-N was a novel independent predictor for either VR (OR = 0.292, 95% CI = 0.102-0.835, P = 0.022) or SR (OR = 0.173, 95% CI = 0.035-0.849, P = 0.031) in our cohort. In addition, baseline USP18IFN-N in combination with HBV DNA loads or HBeAg levels showed improved accuracy of pretreatment prediction for VR or SR responders, respectively. Baseline USP18IFN-N levels are associated with both virological and serological response, and have the potential to become a clinical predictor for treatment outcomes in HBeAg-positive CHB patients before initiating IFN-α therapy.
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Affiliation(s)
- Wei Liu
- State key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China
| | - Huiqing Liang
- Department of Infectious Disease, Xiamen Hospital of Traditional Chinese Medicine, Xiamen, China
| | - Shaojuan Wang
- State key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China
| | - Chuncheng Wu
- Department of Infectious Disease, Xiamen Hospital of Traditional Chinese Medicine, Xiamen, China
| | - Yang Liu
- State key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China
| | - Yongliang Liu
- State key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China
| | - Manying Zhang
- Department of Infectious Disease, Xiamen Hospital of Traditional Chinese Medicine, Xiamen, China
| | - Lixia Xiong
- State key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China
| | - Zhouyue Zhong
- State key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China
| | - Yue Chen
- Department of Infectious Disease, Xiamen Hospital of Traditional Chinese Medicine, Xiamen, China
| | - Qianguo Mao
- Department of Infectious Disease, Xiamen Hospital of Traditional Chinese Medicine, Xiamen, China
| | - Shengxiang Ge
- State key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China
| | - Ningshao Xia
- State key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China
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43
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Wei L, Pavlovic V, Bansal AT, Chen X, Foster GR, He H, Kao JH, Lampertico P, Liaw YF, Motoc A, Papatheodoridis GV, Piratvisuth T, Plesniak R, Wat C. Genetic variation in FCER1A predicts peginterferon alfa-2a-induced hepatitis B surface antigen clearance in East Asian patients with chronic hepatitis B. J Viral Hepat 2019; 26:1040-1049. [PMID: 30972912 DOI: 10.1111/jvh.13107] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Revised: 02/06/2019] [Accepted: 03/14/2019] [Indexed: 12/13/2022]
Abstract
In a multicentre, genome-wide association study to identify host genetic factors associated with treatment response in adult chronic hepatitis B patients, genotype data were obtained by microarray analysis from 1669 patients who received peginterferon alfa-2a for ≥ 24 weeks with/without a nucleos(t)ide analog. Treatment response was assessed at least 24 weeks post-treatment, using serological and/or virological endpoints. Thirty-six single-marker analyses and a gene-by-gene analysis were conducted. No single nucleotide polymorphisms (SNPs) achieved genome-wide significance (P < 5 × 10-8 ) in single-marker analyses, but suggestive associations (P < 1 × 10-5 ) were identified for 116 SNPs. In gene-by-gene analyses, one gene, FCER1A (rs7549785), reached genome-wide significance (P = 2.65 × 10-8 ) in East Asian patients for hepatitis B surface antigen (HBsAg) clearance, with a moderate effect size (odds ratio = 4.74). Eleven of 44 carriers (25%) of the A allele at rs7549785 achieved HBsAg clearance compared with 69/1051 (7%) noncarriers. FCER1A encodes the alpha subunit of the immunoglobulin E receptor. In a post hoc analysis of a homogenous patient subset, the strongest intragenic association was for rs7712322 (POLR3G, P = 7.21 × 10-7 ). POLR3G encodes the G subunit of the polymerase (RNA) III enzyme, involved in sensing and limiting infection by intracellular bacteria and DNA viruses, and as a DNA sensor in innate immune responses. FCER1A (rs7549785) and possibly POLR3G (rs7712322) are shown to be associated with peginterferon alfa-2a response in adult patients with chronic hepatitis B. Independent confirmation of these findings is warranted (clinicaltrials.gov number NCT01855997).
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Affiliation(s)
- Lai Wei
- Peking University People's Hospital, Beijing, China.,Peking University Hepatology Institute, Beijing, China
| | | | | | | | - Graham R Foster
- Queen Mary's University of London, Bart's and The London School of Medicine, London, UK
| | - Hua He
- Roche Products Ltd, Welwyn Garden City, UK
| | - Jia-Horng Kao
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Pietro Lampertico
- AM & A Migliavacca Center for Liver Disease, Gastroenterology and Hepatology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - Yun-Fan Liaw
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
| | - Adriana Motoc
- Infectious and Tropical Diseases Hospital 'Dr. Victor Babes', Bucharest, Romania
| | - George V Papatheodoridis
- Department of Gastroenterology, Medical School of National & Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Teerha Piratvisuth
- NKC Institute of Gastroenterology and Hepatology, Prince of Songkla University, Hat-Yai, Thailand
| | - Robert Plesniak
- Clinical Department Of Infectious Diseases, Faculty of Medicine, University of Rzeszów, Łańcut, Poland
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44
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Li G, Zhang Q, Yu Y, Qiu C, Zhang H, Zhang M, Song Z, Yang Y, Hong J, Lu J, Li N, Tang Q, Xu L, Wang X, Zhang W, Chen Z. Histological responses of peginterferon alpha add-on therapy in patients with chronic hepatitis B with advanced liver fibrosis after long-term nucleos(t)ide analog treatment. J Viral Hepat 2019; 26 Suppl 1:50-58. [PMID: 31380590 DOI: 10.1111/jvh.13152] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2019] [Accepted: 05/15/2019] [Indexed: 01/05/2023]
Abstract
Although long-term antiviral treatment with nucleos(t)ide analogs (NAs) can lead to histological improvement in patients with chronic hepatitis B (CHB), a substantial proportion of patients still fail to achieve regression of fibrosis. Here, we investigated whether peginterferon alpha (Peg-IFNα） add-on therapy had benefits on fibrosis regression in patients with sustained severe fibrosis even after long-term NA treatment. We conducted a retrospective analysis of data from 50 patients with CHB receiving 48 weeks of Peg-IFNα add-on therapy. All enrolled patients had advanced fibrosis or cirrhosis (S score ≥ 3) at baseline and underwent NA treatment for at least 1 year before Peg-IFNα addition. Paired liver biopsies before and after Peg-IFNα add-on treatment and laboratory tests at baseline, 24 weeks of treatment, 48 weeks of treatment and long-term follow-up were analysed. Of the 50 patients enrolled in this study, 34 patients (68.0%) had significant regression of fibrosis, and 42 (84.0%) showed significant remission of inflammation after Peg-IFNα add-on treatment. Compared with nonresponders, patients with significant histological improvement showed faster hepatitis B surface antigen (HBsAg) decline and tended to have higher cumulative hepatitis B e antigen (HBeAg) and HBsAg loss rates during long-term follow-up. Peg-IFNα add-on therapy led to significant regression of fibrosis and resolution of inflammation in patients with advanced fibrosis after long-term NA treatment.
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Affiliation(s)
- Guojun Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Qiran Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Yiqi Yu
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Chao Qiu
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.,Institutes of Biomedical Sciences and Key Laboratory of Medical Molecular Virology of Ministry of Education and Health, Fudan University, Shanghai, China
| | - Hanyue Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Miaoqu Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Zhangzhang Song
- Department of Hepatology, The Second Hospital of Yinzhou of Ningbo, Ningbo, China
| | - Yusheng Yang
- Department of Hepatology, The Second Hospital of Yinzhou of Ningbo, Ningbo, China
| | - Jiemin Hong
- Department of Infectious Diseases, Shenzhen University General Hospital, Guangdong Sheng, China
| | - Jian Lu
- Department of Infectious Diseases, Shenzhen University General Hospital, Guangdong Sheng, China
| | - Niuniu Li
- Department of Infectious Diseases, Shenzhen University General Hospital, Guangdong Sheng, China
| | - Quanzhen Tang
- Department of Infectious Diseases, Shenzhen University General Hospital, Guangdong Sheng, China
| | - Long Xu
- Department of Infectious Diseases, Shenzhen University General Hospital, Guangdong Sheng, China
| | - Xuanyi Wang
- Institutes of Biomedical Sciences and Key Laboratory of Medical Molecular Virology of Ministry of Education and Health, Fudan University, Shanghai, China
| | - Wenhong Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.,Institutes of Biomedical Sciences and Key Laboratory of Medical Molecular Virology of Ministry of Education and Health, Fudan University, Shanghai, China
| | - Zhi Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
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45
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Thomas E, Baumert TF. Hepatitis B Virus-Hepatocyte Interactions and Innate Immune Responses: Experimental Models and Molecular Mechanisms. Semin Liver Dis 2019; 39:301-314. [PMID: 31266064 PMCID: PMC7377277 DOI: 10.1055/s-0039-1685518] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Chronic hepatitis B virus (HBV) infection is a major cause of liver disease and cancer worldwide. While current therapeutic approaches can efficiently control viral infection, efficient curative antivirals are absent. The understanding of virus-hepatocyte interactions and sensing of viral infection is an important prerequisite for the development of novel antiviral therapies for cure. Hepatocyte intrinsic innate immunity provides a rapid first line of defense to combat viral infection through the upregulation of antiviral and inflammatory genes. However, the functional relevance of many of these antiviral signaling pathways in the liver and their role in HBV pathogenesis is still only partially understood. The recent identification of intracellular RNA and DNA sensing pathways and their involvement in disease biology, including viral pathogenesis and carcinogenesis, is currently transforming our understanding of virus-host interactions. Here the authors review the current knowledge on intrinsic antiviral innate immune responses including the role of viral nucleic acid sensing pathways in the liver. Since HBV has been designated as a "stealth virus," the study of the impact of HBV on signaling pathways in the hepatocyte is of significant interest to understand viral pathogenesis. Characterizing the mechanism underlying these HBV-host interactions and targeting related pathways to enhance antiviral innate responses may open new strategies to trigger noncytopathic clearance of covalently closed circular DNA to ultimately cure patients with chronic HBV infection.
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Affiliation(s)
- Emmanuel Thomas
- Schiff Center for Liver Diseases, University of Miami Miller School of Medicine, Miami, Florida,Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, Florida,Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida
| | - Thomas F. Baumert
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France,Laboratory of Excellence HEPSYS, University of Strasbourg, Strasbourg, France,Institut Hospitalo-Universitaire, Pôle hépato-digestif, Nouvel Hôpital Civil, Strasbourg, France
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46
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Zhang Q, Li G, Yu Y, Qiu C, Zheng J, Zhang H, Zhang M, Song Z, Yang Y, Du X, Hong J, Lu J, Li N, Tang Q, Xu L, Wang X, Huang Y, Zhang J, Chen Z, Zhang W. Histological response to combination therapy with nucleos(t)ide analogs and peginterferon alpha in treatment-naïve chronic hepatitis B patients. J Viral Hepat 2019; 26 Suppl 1:59-68. [PMID: 31380588 DOI: 10.1111/jvh.13153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2019] [Accepted: 05/15/2019] [Indexed: 12/09/2022]
Abstract
Although nucleos(t)ide analog (NA) monotherapy is effective in hepatitis B virus suppression and fibrosis regression, serological response rates are not satisfactory. Studies assessing the benefits of combination therapy with NAs and peginterferon alpha (PegIFNα) in patients with chronic hepatitis B (CHB) have produced conflicting results and mainly focused on serological outcomes. Histological changes in response to combination therapy have not been evaluated in real-world practice. This study aimed to evaluate the histological changes in response to NA-PegIFNα combination therapy in CHB patients and to comprehensively compare the efficacy of NA-PegIFNα combination therapy and NA monotherapy. We conducted a retrospective analysis of data from 40 CHB patients who underwent either NA-PegIFNα combination therapy or NA monotherapy. Changes in histology at 48 weeks after treatment initiation were evaluated. Serological characteristics were also analysed and compared between the NA-PegIFNα combination therapy and NA monotherapy groups and between histological responders and nonresponders. Compared to baseline biopsies, both fibrosis staging and necroinflammatory grading scores were significantly lower in the second biopsies examined post-treatment in both groups. Nearly all patients experienced a reduction in inflammation (87.5% in both groups), but there was a subgroup of patients who exhibited either no significant improvement or fibrosis progression (33.3% and 31.2% in the NA monotherapy and NA-PegIFNα combination therapy groups, respectively). Nearly, all patients achieved ALT normalization and sustained virological response (SVR) after 48 weeks of antiviral treatment. Approximately one-third of individuals (36.8% and 30% in the two groups, respectively) achieved HBeAg loss at 48 weeks after treatment initiation. Although there were no significant differences in overall rates of histological, biochemical, virological and serological responses between the two groups, an earlier virological response and a higher cumulative SVR rate over time were observed during long-term follow-up in patients treated with NA-PegIFNα combination therapy (P = 0.0129). Trends of more rapid HBeAg loss and a higher cumulative HBeAg loss rate throughout long-term follow-up were also observed but were not statistically significant. The ALT normalization rates at 24 and 48 weeks after treatment initiation were associated with the histological response. Significant regression of fibrosis and resolution of necroinflammation were induced with either NA-PegIFNα combination therapy or NA monotherapy. Significant biochemical, virological and serological responses were observed in both groups, and the response rates at 48 weeks were similar in the two groups. Over time during long-term follow-up, the virological and serological responses were faster and superior following the combination regimen.
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Affiliation(s)
- Qiran Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Guojun Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Department of Infectious Diseases, Shenzhen University General Hospital, Shenzhen, China
| | - Yiqi Yu
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Chao Qiu
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.,Institutes of Biomedical Sciences and Key Laboratory of Medical Molecular Virology, Fudan University, Shanghai, China
| | - Jianming Zheng
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Hanyue Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Miaoqu Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Zhangzhang Song
- Department of Hepatology, The Second Hospital of Yinzhou of Ningbo, Ningbo, China
| | - Yusheng Yang
- Department of Hepatology, The Second Hospital of Yinzhou of Ningbo, Ningbo, China
| | - Xinfang Du
- Department of Hepatology, Beilun People's Hospital, Ningbo, China
| | - Jiemin Hong
- Department of Infectious Diseases, Shenzhen University General Hospital, Shenzhen, China
| | - Jian Lu
- Department of Infectious Diseases, Shenzhen University General Hospital, Shenzhen, China
| | - Niuniu Li
- Department of Infectious Diseases, Shenzhen University General Hospital, Shenzhen, China
| | - Quanzhen Tang
- Department of Infectious Diseases, Shenzhen University General Hospital, Shenzhen, China
| | - Long Xu
- Department of Infectious Diseases, Shenzhen University General Hospital, Shenzhen, China
| | - Xuanyi Wang
- Institutes of Biomedical Sciences and Key Laboratory of Medical Molecular Virology, Fudan University, Shanghai, China
| | - Yuxian Huang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Jiming Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.,Department of Hepatology, The Second Hospital of Yinzhou of Ningbo, Ningbo, China
| | - Zhi Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Wenhong Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.,Institutes of Biomedical Sciences and Key Laboratory of Medical Molecular Virology, Fudan University, Shanghai, China
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47
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Abstract
Hepatitis B virus infection is the cause of liver diseases such as cirrhosis and liver cancer. Understanding the host-virus mechanisms that mediate virus pathogenesis can help design better preventive measures for disease control. Mathematical models have been used alongside experimental data to provide insight into the role of immune responses during the acute and chronic hepatitis B infections as well as virus dynamics following administration of combined drug therapy. In this paper, we review several modeling studies on virus-host interactions during acute infection, the virus-host characteristics responsible for transition to chronic disease, and the efficacy and optimal control measures of drug therapy. We conclude by presenting our opinion on the future directions of the field.
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Affiliation(s)
- Stanca M Ciupe
- Department of Mathematics, Virginia Tech, Blacksburg, VA, USA
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KASL clinical practice guidelines for management of chronic hepatitis B. Clin Mol Hepatol 2019; 25:93-159. [PMID: 31185710 PMCID: PMC6589848 DOI: 10.3350/cmh.2019.1002] [Citation(s) in RCA: 161] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Accepted: 03/25/2019] [Indexed: 02/06/2023] Open
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Yeo YH, Nguyen MH. Reply. Gastroenterology 2019; 157:267-268. [PMID: 31150598 DOI: 10.1053/j.gastro.2019.05.046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Affiliation(s)
- Yee Hui Yeo
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California
| | - Mindie H Nguyen
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California
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