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1
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Debing Y, Vanrusselt H, Degrauwe L, Silva de Oliveira DA, Kariuki CK, Ebwanga EJ, Bashir S, Merckx W, Thatikonda SK, Rajwanshi V, Gohil V, Hong J, Kum DB, Acosta Sanchez A, Chanda S, Blatt LM, Jekle A, Symons JA, Smith DB, Raboisson P, Lin TI, Beigelman L, Paeshuyse J. An in vivo duck hepatitis B virus model recapitulates key aspects of nucleic acid polymer treatment outcomes in chronic hepatitis B patients. Antiviral Res 2024; 224:105835. [PMID: 38401714 DOI: 10.1016/j.antiviral.2024.105835] [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: 12/11/2023] [Revised: 01/30/2024] [Accepted: 02/13/2024] [Indexed: 02/26/2024]
Abstract
Nucleic acid polymers (NAPs) are an attractive treatment modality for chronic hepatitis B (CHB), with REP2139 and REP2165 having shown efficacy in CHB patients. A subset of patients achieve functional cure, whereas the others exhibit a moderate response or are non-responders. NAP efficacy has been difficult to recapitulate in animal models, with the duck hepatitis B virus (DHBV) model showing some promise but remaining underexplored for NAP efficacy testing. Here we report on an optimized in vivo DHBV duck model and explore several characteristics of NAP treatment. REP2139 was efficacious in reducing DHBV DNA and DHBsAg levels in approximately half of the treated ducks, whether administered intraperitoneally or subcutaneously. Intrahepatic or serum NAP concentrations did not correlate with efficacy, nor did the appearance of anti-DHBsAg antibodies. Furthermore, NAP efficacy was only observed in experimentally infected ducks, not in endogenously infected ducks (vertical transmission). REP2139 add-on to entecavir treatment induced a deeper and more sustained virological response compared to entecavir monotherapy. Destabilized REP2165 showed a different activity profile with a more homogenous antiviral response followed by a faster rebound. In conclusion, subcutaneous administration of NAPs in the DHBV duck model provides a useful tool for in vivo evaluation of NAPs. It recapitulates many aspects of this class of compound's efficacy in CHB patients, most notably the clear division between responders and non-responders.
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Affiliation(s)
| | | | - Lars Degrauwe
- Laboratory of Host Pathogen Interactions, Department of Biosystems, KU Leuven, Leuven, Belgium
| | | | | | - Ebanja Joseph Ebwanga
- Laboratory of Host Pathogen Interactions, Department of Biosystems, KU Leuven, Leuven, Belgium
| | - Shahbaz Bashir
- Laboratory of Host Pathogen Interactions, Department of Biosystems, KU Leuven, Leuven, Belgium
| | - Wouter Merckx
- TRANSfarm, Science, Engineering & Technology Group, KU Leuven, Leuven, Belgium
| | | | | | - Vikrant Gohil
- Aligos Therapeutics, Inc., South San Francisco, CA, USA
| | - Jin Hong
- Aligos Therapeutics, Inc., South San Francisco, CA, USA
| | | | | | | | | | - Andreas Jekle
- Aligos Therapeutics, Inc., South San Francisco, CA, USA
| | | | - David B Smith
- Aligos Therapeutics, Inc., South San Francisco, CA, USA
| | | | | | | | - Jan Paeshuyse
- Laboratory of Host Pathogen Interactions, Department of Biosystems, KU Leuven, Leuven, Belgium.
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2
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Patra S, Pareek D, Gupta PS, Wasnik K, Singh G, Yadav DD, Mastai Y, Paik P. Progress in Treatment and Diagnostics of Infectious Disease with Polymers. ACS Infect Dis 2024; 10:287-316. [PMID: 38237146 DOI: 10.1021/acsinfecdis.3c00528] [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] [Indexed: 02/10/2024]
Abstract
In this era of advanced technology and innovation, infectious diseases still cause significant morbidity and mortality, which need to be addressed. Despite overwhelming success in the development of vaccines, transmittable diseases such as tuberculosis and AIDS remain unprotected, and the treatment is challenging due to frequent mutations of the pathogens. Formulations of new or existing drugs with polymeric materials have been explored as a promising new approach. Variations in shape, size, surface charge, internal morphology, and functionalization position polymer particles as a revolutionary material in healthcare. Here, an overview is provided of major diseases along with statistics on infection and death rates, focusing on polymer-based treatments and modes of action. Key issues are discussed in this review pertaining to current challenges and future perspectives.
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Affiliation(s)
- Sukanya Patra
- School of Biomedical Engineering, Indian Institute of Technology-BHU, Varanasi 221005, India
| | - Divya Pareek
- School of Biomedical Engineering, Indian Institute of Technology-BHU, Varanasi 221005, India
| | - Prem Shankar Gupta
- School of Biomedical Engineering, Indian Institute of Technology-BHU, Varanasi 221005, India
| | - Kirti Wasnik
- School of Biomedical Engineering, Indian Institute of Technology-BHU, Varanasi 221005, India
| | - Gurmeet Singh
- School of Biomedical Engineering, Indian Institute of Technology-BHU, Varanasi 221005, India
| | - Desh Deepak Yadav
- School of Biomedical Engineering, Indian Institute of Technology-BHU, Varanasi 221005, India
| | - Yitzhak Mastai
- Department of Chemistry, Bar-Ilan University, Ramat-Gan 5290002, Israel
| | - Pradip Paik
- School of Biomedical Engineering, Indian Institute of Technology-BHU, Varanasi 221005, India
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3
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Ye Y, Wang Y, Li H, Liu Y, Meng C, Zhu J, Liu G, Li C. Genetic characterization of duck hepatitis B viruses from Anhui Province, China. Braz J Microbiol 2023; 54:3299-3305. [PMID: 37673839 PMCID: PMC10689712 DOI: 10.1007/s42770-023-01120-0] [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: 05/25/2023] [Accepted: 08/30/2023] [Indexed: 09/08/2023] Open
Abstract
Duck hepatitis B virus (DHBV) infection model was frequently used as the experimental model for human hepatitis B virus (HBV) research. In order to decipher the genetic characteristics of DHBVs from Anhui province of China, 120 duck liver tissue samples were collected and subjected to PCR screening, and 28 samples were detected as DHBV positive. Subsequently, five DHBV-positive samples were selected for genome-wide amplification and a comprehensive analysis. Comparative analysis of complete genome sequences using the MegAlign program showed that five strains of DHBVs shared 94.5-96.3% with each other and 93.2-98.7% with other reference strains in GenBank. The phylogenetic analysis showed that all five DHBV strains belonged to the evolutionary branch of "Chinese DHBV" isolates or DHBV-2. Importantly, three potential intra-genotypic recombination events, between strains AAU-6 and Guilin, strains AAU-1 and GD3, and strains AAU-6 and AAU-1, were respectively found using the RDP and SimPlot softwares and considered the first report in avihepadnaviruses. These results not only improve our understanding for molecular prevalence status of DHBV among ducks, but also provide a reference for recombination mechanism of HBV.
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Affiliation(s)
- Yumeng Ye
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences (CAAS), Shanghai, 200241, China
- College of Animal Science and Technology, Anhui Agricultural University, Hefei, 230036, China
| | - Yong Wang
- College of Animal Science and Technology, Anhui Agricultural University, Hefei, 230036, China
| | - Hang Li
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences (CAAS), Shanghai, 200241, China
| | - Yuhan Liu
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences (CAAS), Shanghai, 200241, China
- College of Veterinary Medicine, Xinjiang Agricultural University, Wulumuqi, 830052, China
| | - Chunchun Meng
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences (CAAS), Shanghai, 200241, China
| | - Jie Zhu
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences (CAAS), Shanghai, 200241, China
| | - Guangqing Liu
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences (CAAS), Shanghai, 200241, China.
| | - Chuanfeng Li
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences (CAAS), Shanghai, 200241, China.
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4
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Roca Suarez AA, Batbold E, Bartosch B, Dashdorj N, Testoni B, Zoulim F. Emerging anti-HDV drugs and HBV cure strategies with anti-HDV activity. Liver Int 2023; 43 Suppl 1:87-95. [PMID: 37017060 DOI: 10.1111/liv.15417] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 08/25/2022] [Accepted: 09/05/2022] [Indexed: 04/06/2023]
Abstract
Hepatitis delta virus (HDV) is a satellite RNA virus that requires the presence of hepatitis B virus (HBV) for its replication. HDV/HBV co-infection is often associated with a faster disease progression of chronic hepatitis in comparison to HBV mono-infection. Therefore, the development of novel antiviral therapies targeting HDV represents a high priority and an urgent medical need. In this review, we summarize the ongoing efforts to evaluate promising HDV-specific drugs, such as lonafarnib (LNF), pegylated interferon lambda (PEG-IFN-λ) and their use as a combination therapy. Furthermore, we review the most recent developments in the area of anti-HBV drugs with potential effects against HDV, including therapeutic agents targeting hepatitis B surface antigen (HBsAg) expression, secretion and function. Finally, we consider the important insights that have emerged from the development of these potential antiviral strategies, as well as the intriguing questions that remain to be elucidated in this rapidly changing field.
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Affiliation(s)
- Armando A Roca Suarez
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, France
- University of Lyon, Université Claude-Bernard (UCBL), Lyon, France
| | | | - Birke Bartosch
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, France
- University of Lyon, Université Claude-Bernard (UCBL), Lyon, France
| | | | - Barbara Testoni
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, France
- University of Lyon, Université Claude-Bernard (UCBL), Lyon, France
| | - Fabien Zoulim
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, France
- University of Lyon, Université Claude-Bernard (UCBL), Lyon, France
- Hospices Civils de Lyon (HCL), Lyon, France
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5
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Pan C, Gish R, Jacobson IM, Hu KQ, Wedemeyer H, Martin P. Diagnosis and Management of Hepatitis Delta Virus Infection. Dig Dis Sci 2023; 68:3237-3248. [PMID: 37338616 PMCID: PMC10374831 DOI: 10.1007/s10620-023-07960-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 04/24/2023] [Indexed: 06/21/2023]
Abstract
Hepatitis D virus (HDV) depends on hepatitis B virus (HBV) to enter and exit hepatocytes and to replicate. Despite this dependency, HDV can cause severe liver disease. HDV accelerates liver fibrosis, increases the risk of hepatocellular carcinoma, and hastens hepatic decompensation compared to chronic HBV monoinfection. The Chronic Liver Disease Foundation (CLDF) formed an expert panel to publish updated guidelines on the testing, diagnosis, and management of hepatitis delta virus. The panel group performed network data review on the transmission, epidemiology, natural history, and disease sequelae of acute and chronic HDV infection. Based on current available evidence, we provide recommendations for screening, testing, diagnosis, and treatment of hepatitis D infection and review upcoming novel agents that may expand treatment options. The CLDF recommends universal HDV screening for all patients who are Hepatitis B surface antigen-positive. Initial screening should be with an assay to detect antibodies generated against HDV (anti-HDV). Patients who are positive for anti-HDV IgG antibodies should then undergo quantitative HDV RNA testing. We also provide an algorithm that describes CLDF recommendations on the screening, diagnosis, testing, and initial management of Hepatitis D infection.
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Affiliation(s)
- Calvin Pan
- Guangzhou Eighth People’s Hospital, Guangzhou Medical University, Guangzhou, China
- Gastroenterology and Hepatology, NYU Langone Health, NYU Grossman School of Medicine, New York, USA
| | - Robert Gish
- Robert G. Gish Consultants, LLC, 6022 La Jolla Mesa Dr, La Jolla, CA 92037-7814 USA
- Medical Director Hepatitis B Foundation, Doylestown, PA USA
| | - Ira M. Jacobson
- NYU Langone Gastroenterology Associates, 240 East 38Th Street, 23Rd Floor, New York, NY 10016 USA
| | - Ke-Qin Hu
- University of California, Irvine, 101 The City Dr S, Building 22C, Room 1503, Orange, CA 92868 USA
| | - Heiner Wedemeyer
- Clinic for Gastroenterology, Hepatology and Endocrinology Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Paul Martin
- University of Miami Miller School of Medicine, 1500 NW 12 AVE., E Tower #1101, Miami, FL 33136 USA
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6
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Hershkovich L, Shekhtman L, Bazinet M, Pântea V, Placinta G, Cotler SJ, Vaillant A, Dahari H. Rapid monophasic HBsAg decline during nucleic-acid polymer-based therapy predicts functional cure. Hepatol Commun 2023; 7:e0205. [PMID: 37458583 PMCID: PMC10351942 DOI: 10.1097/hc9.0000000000000205] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 04/13/2023] [Indexed: 07/20/2023] Open
Abstract
BACKGROUND AND AIMS Analyzing the interplay among serum HBV DNA, HBsAg, anti-HBs, and alanine aminotransferase (ALT) during nucleic-acid polymer (NAP)-based therapy for chronic hepatitis B provides a unique opportunity to identify kinetic patterns associated with functional cure. METHODS All participants with HBeAg-negative chronic HBV infection in the REP 401 study (NCT02565719) first received 24 weeks of tenofovir-disoproxil-fumarate (TDF) monotherapy. The early triple therapy group (n = 20) next received 48 weeks of TDF+pegylated interferon-α2a (pegIFN)+NAPs. In contrast, the delayed triple therapy group (n = 20) next received 24 weeks of TDF+pegIFN before 48 weeks of triple therapy. Three participants discontinued treatment and were excluded. Functional cure (HBsAg and HBV DNA not detectable with normal ALT) was assessed at 48 weeks post-treatment. Different kinetic phases were defined by at least a 2-fold change in slope. A single-phase decline was categorized as monophasic, and 2-phase declines were categorized as biphasic. RESULTS Fourteen (35%) participants achieved a functional cure. HBV DNA remained below or near undetectable for all participants by the end of TDF monotherapy and during subsequent combination therapies. Three HBsAg kinetic patterns were found in both the early and delayed groups, nonresponders (n = 4 and n = 4), monophasic (n = 11 and n = 11), and biphasic (n = 4 and n = 3), respectively. All participants who achieved a functional cure had a monophasic HBsAg kinetic pattern during triple therapy. Among participants with a monophasic HBsAg decline, those who had a functional cure had a shorter median time to HBsAg loss of 21 (interquartile range=11) weeks compared with those who did not achieve functional cure [median: 27 (7) weeks] (p = 0.012). CONCLUSIONS Functional cure was associated with a rapid monophasic HBsAg decline during NAP-based therapy. A nonmonophasic HBsAg kinetic pattern had a 100% negative predictive value (NPV) for a functional cure.
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Affiliation(s)
- Leeor Hershkovich
- Program for Experimental & Theoretical Modeling, Department of Medicine, Division of Hepatology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois, USA
| | - Louis Shekhtman
- Program for Experimental & Theoretical Modeling, Department of Medicine, Division of Hepatology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois, USA
- Network Science Institute, Northeastern University, Boston, Massachusetts, USA
| | | | - Victor Pântea
- Department of Infectious Diseases, Nicolae Testemiţanu, State University of Medicine and Pharmacy, Chişinău, Republic of Moldova
| | - Gheorge Placinta
- Department of Infectious Diseases, Nicolae Testemiţanu, State University of Medicine and Pharmacy, Chişinău, Republic of Moldova
| | - Scott J. Cotler
- Program for Experimental & Theoretical Modeling, Department of Medicine, Division of Hepatology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois, USA
| | | | - Harel Dahari
- Program for Experimental & Theoretical Modeling, Department of Medicine, Division of Hepatology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois, USA
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7
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Hadinejad F, Morad H, Jahanshahi M, Zarrabi A, Pazoki-Toroudi H, Mostafavi E. A Novel Vision of Reinforcing Nanofibrous Masks with Metal Nanoparticles: Antiviral Mechanisms Investigation. ADVANCED FIBER MATERIALS 2023; 5:1-45. [PMID: 37361103 PMCID: PMC10088653 DOI: 10.1007/s42765-023-00275-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 02/13/2023] [Indexed: 06/28/2023]
Abstract
Prevention of spreading viral respiratory disease, especially in case of a pandemic such as coronavirus disease of 2019 (COVID-19), has been proved impossible without considering obligatory face mask-wearing protocols for both healthy and contaminated populations. The widespread application of face masks for long hours and almost everywhere increases the risks of bacterial growth in the warm and humid environment inside the mask. On the other hand, in the absence of antiviral agents on the surface of the mask, the virus may have a chance to stay alive and be carried to different places or even put the wearers at risk of contamination when touching or disposing the masks. In this article, the antiviral activity and mechanism of action of some of the potent metal and metal oxide nanoparticles in the role of promising virucidal agents have been reviewed, and incorporation of them in an electrospun nanofibrous structure has been considered an applicable method for the fabrication of innovative respiratory protecting materials with upgraded safety levels. Graphical Abstract
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Affiliation(s)
- Farinaz Hadinejad
- Nanotechnology Research Institute, Faculty of Chemical Engineering, Babol Noushirvani University of Technology, Babol, 4714873113 Iran
| | - Hamed Morad
- Department of Pharmaceutics and Pharmaceutical Nanotechnology, School of Pharmacy, Iran University of Medical Sciences, Tehran, 1475886973 Iran
- Ramsar Campus, Mazandaran University of Medical Sciences, Ramsar, 4691710001 Iran
| | - Mohsen Jahanshahi
- Nanotechnology Research Institute, Faculty of Chemical Engineering, Babol Noushirvani University of Technology, Babol, 4714873113 Iran
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul, 34396 Turkey
| | - Hamidreza Pazoki-Toroudi
- Physiology Research Center, Faculty of Medicine, Iran University of Medical Sciences, Tehran, 1449614535 Iran
- Department of Physiology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, 1449614535 Iran
| | - Ebrahim Mostafavi
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305 USA
- Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305 USA
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8
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Papatheodoridi M, Papatheodoridis GV. State-of-the-art and emerging antivirals for chronic hepatitis B infection. Expert Opin Pharmacother 2022; 23:1999-2012. [DOI: 10.1080/14656566.2022.2144219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Margarita Papatheodoridi
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, General Hospital of Athens “Laiko”, Athens, Greece
| | - George V. Papatheodoridis
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, General Hospital of Athens “Laiko”, Athens, Greece
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9
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Vaillant A. Oligonucleotide-Based Therapies for Chronic HBV Infection: A Primer on Biochemistry, Mechanisms and Antiviral Effects. Viruses 2022; 14:v14092052. [PMID: 36146858 PMCID: PMC9502277 DOI: 10.3390/v14092052] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 09/08/2022] [Accepted: 09/08/2022] [Indexed: 11/21/2022] Open
Abstract
Three types of oligonucleotide-based medicines are under clinical development for the treatment of chronic HBV infection. Antisense oligonucleotides (ASOs) and synthetic interfering RNA (siRNA) are designed to degrade HBV mRNA, and nucleic acid polymers (NAPs) stop the assembly and secretion of HBV subviral particles. Extensive clinical development of ASOs and siRNA for a variety of liver diseases has established a solid understanding of their pharmacodynamics, accumulation in different tissue types in the liver, pharmacological effects, off-target effects and how chemical modifications and delivery approaches affect these parameters. These effects are highly conserved for all ASO and siRNA used in human studies to date. The clinical assessment of several ASO and siRNA compounds in chronic HBV infection in recent years is complicated by the different delivery approaches used. Moreover, these assessments have not considered the large clinical database of ASO/siRNA function in other liver diseases and known off target effects in other viral infections. The goal of this review is to summarize the current understanding of ASO/siRNA/NAP pharmacology and integrate these concepts into current clinical results for these compounds in the treatment of chronic HBV infection.
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Affiliation(s)
- Andrew Vaillant
- Replicor Inc., 6100 Royalmount Avenue, Montreal, QC H4P 2R2, Canada
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10
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Suresh M, Menne S. Recent Drug Development in the Woodchuck Model of Chronic Hepatitis B. Viruses 2022; 14:v14081711. [PMID: 36016334 PMCID: PMC9416195 DOI: 10.3390/v14081711] [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: 06/17/2022] [Revised: 07/22/2022] [Accepted: 07/31/2022] [Indexed: 11/24/2022] Open
Abstract
Infection with hepatitis B virus (HBV) is responsible for the increasing global hepatitis burden, with an estimated 296 million people being carriers and living with the risk of developing chronic liver disease and cancer. While the current treatment options for chronic hepatitis B (CHB), including oral nucleos(t)ide analogs and systemic interferon-alpha, are deemed suboptimal, the path to finding an ultimate cure for this viral disease is rather challenging. The lack of suitable laboratory animal models that support HBV infection and associated liver disease progression is one of the major hurdles in antiviral drug development. For more than four decades, experimental infection of the Eastern woodchuck with woodchuck hepatitis virus has been applied for studying the immunopathogenesis of HBV and developing new antiviral therapeutics against CHB. There are several advantages to this animal model that are beneficial for performing both basic and translational HBV research. Previous review articles have focused on the value of this animal model in regard to HBV replication, pathogenesis, and immune response. In this article, we review studies of drug development and preclinical evaluation of direct-acting antivirals, immunomodulators, therapeutic vaccines, and inhibitors of viral entry, gene expression, and antigen release in the woodchuck model of CHB since 2014 until today and discuss their significance for clinical trials in patients.
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11
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Bazinet M, Anderson M, Pântea V, Placinta G, Moscalu I, Cebotarescu V, Cojuhari L, Jimbei P, Iarovoi L, Smesnoi V, Musteata T, Jucov A, Dittmer U, Gersch J, Holzmayer V, Kuhns M, Cloherty G, Vaillant A. HBsAg isoform dynamics during NAP-based therapy of HBeAg-negative chronic HBV and HBV/HDV infection. Hepatol Commun 2022; 6:1870-1880. [PMID: 35368148 PMCID: PMC9315123 DOI: 10.1002/hep4.1951] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 02/15/2022] [Accepted: 03/03/2022] [Indexed: 12/11/2022] Open
Abstract
Nucleic acid polymers block the assembly of hepatitis B virus (HBV) subviral particles, effectively preventing hepatitis B surface antigen (HBsAg) replenishment in the circulation. Nucleic acid polymer (NAP)-based combination therapy of HBV infection or HBV/hepatitis D virus (HDV) co-infection is accompanied by HBsAg clearance and seroconversion, HDV-RNA clearance in co-infection, and persistent functional cure of HBV (HBsAg < 0.05 IU/ml, HBV-DNA target not dected, normal alanine aminotransferase) and persistent clearance of HDV RNA. An analysis of HBsAg isoform changes during quantitative HBsAg declines (qHBsAg), and subsequent treatment-free follow-up in the REP 301/REP 301-LTF (HBV/HDV) and REP 401 (HBV) studies was conducted. HBsAg isoforms were analyzed from frozen serum samples using Abbott Research Use Only assays for HBsAg isoforms (large [L], medium [M], and total [T]). The relative change over time in small HBsAg relative to the other isoforms was inferred by the change in the ratio over time of T-HBsAg to M-HBsAg. HBsAg isoform declines followed qHBsAg declines in all participants. No HBsAg isoforms were detectable in any participants with functional cure. HBsAg declines > 2 log10 IU/ml from baseline were correlated with selective clearance of S-HBsAg in 39 of 42 participants. Selective S-HBsAg decline was absent in 9 of 10 participants with HBsAg decline < 2 log10 IU/ml from baseline. Mild qHBsAg rebound during follow-up <10 IU/ml consisted mostly of S-HBsAg and M-HBsAg and not accompanied by significant covalently closed circular DNA activity. Conclusion: The faster observed declines in S-HBsAg indicate the selective clearance of subviral particles from the circulation, consistent with previous mechanistic studies on NAPs. Trace HBsAg rebound in the absence of HBV DNA may reflect HBsAg derived from integrated HBV DNA and not rebound of viral infection.
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Affiliation(s)
| | | | - Victor Pântea
- Department of Infectious DiseasesNicolae Testemiţanu State University of Medicine and PharmacyChișinăuRepublic of Moldova
| | - Gheorghe Placinta
- Department of Infectious DiseasesNicolae Testemiţanu State University of Medicine and PharmacyChișinăuRepublic of Moldova
| | - Iurie Moscalu
- ARENSIA Exploratory MedicineRepublican Clinical HospitalChișinăuRepublic of Moldova
| | - Valentin Cebotarescu
- Department of Infectious DiseasesNicolae Testemiţanu State University of Medicine and PharmacyChișinăuRepublic of Moldova
| | - Lilia Cojuhari
- Department of Infectious DiseasesNicolae Testemiţanu State University of Medicine and PharmacyChișinăuRepublic of Moldova
| | - Pavlina Jimbei
- Toma Ciorbǎ Infectious Clinical HospitalChișinăuRepublic of Moldova
| | - Liviu Iarovoi
- Department of Infectious DiseasesNicolae Testemiţanu State University of Medicine and PharmacyChișinăuRepublic of Moldova
| | | | - Tatina Musteata
- Toma Ciorbǎ Infectious Clinical HospitalChișinăuRepublic of Moldova
| | - Alina Jucov
- Department of Infectious DiseasesNicolae Testemiţanu State University of Medicine and PharmacyChișinăuRepublic of Moldova.,ARENSIA Exploratory MedicineRepublican Clinical HospitalChișinăuRepublic of Moldova
| | - Ulf Dittmer
- Institute for VirologyUniversity of Duisburg-EssenEssenGermany
| | | | | | - Mary Kuhns
- Abbott DiagnosticsAbbott ParkIllinoisUSA
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12
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Editorial: In vitro mechanistic evaluation of nucleic acid polymers: A cautionary tale. MOLECULAR THERAPY. NUCLEIC ACIDS 2022; 28:168-174. [PMID: 35402067 PMCID: PMC8956958 DOI: 10.1016/j.omtn.2022.03.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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13
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Akbari A, Bigham A, Rahimkhoei V, Sharifi S, Jabbari E. Antiviral Polymers: A Review. Polymers (Basel) 2022; 14:1634. [PMID: 35566804 PMCID: PMC9101550 DOI: 10.3390/polym14091634] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 04/10/2022] [Accepted: 04/11/2022] [Indexed: 11/22/2022] Open
Abstract
Polymers, due to their high molecular weight, tunable architecture, functionality, and buffering effect for endosomal escape, possess unique properties as a carrier or prophylactic agent in preventing pandemic outbreak of new viruses. Polymers are used as a carrier to reduce the minimum required dose, bioavailability, and therapeutic effectiveness of antiviral agents. Polymers are also used as multifunctional nanomaterials to, directly or indirectly, inhibit viral infections. Multifunctional polymers can interact directly with envelope glycoproteins on the viral surface to block fusion and entry of the virus in the host cell. Polymers can indirectly mobilize the immune system by activating macrophages and natural killer cells against the invading virus. This review covers natural and synthetic polymers that possess antiviral activity, their mechanism of action, and the effect of material properties like chemical composition, molecular weight, functional groups, and charge density on antiviral activity. Natural polymers like carrageenan, chitosan, fucoidan, and phosphorothioate oligonucleotides, and synthetic polymers like dendrimers and sialylated polymers are reviewed. This review discusses the steps in the viral replication cycle from binding to cell surface receptors to viral-cell fusion, replication, assembly, and release of the virus from the host cell that antiviral polymers interfere with to block viral infections.
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Affiliation(s)
- Ali Akbari
- Solid Tumor Research Center, Research Institute for Cellular and Molecular Medicine, Urmia University of Medical Sciences, Urmia 57147, Iran; (A.A.); (V.R.)
| | - Ashkan Bigham
- Institute of Polymers, Composites and Biomaterials—National Research Council (IPCB-CNR), Viale J.F. Kennedy 54—Mostra d’Oltremare Pad. 20, 80125 Naples, Italy;
| | - Vahid Rahimkhoei
- Solid Tumor Research Center, Research Institute for Cellular and Molecular Medicine, Urmia University of Medical Sciences, Urmia 57147, Iran; (A.A.); (V.R.)
| | - Sina Sharifi
- Disruptive Technology Laboratory, Massachusetts Eye and Ear and Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA 02115, USA;
| | - Esmaiel Jabbari
- Biomaterials and Tissue Engineering Laboratory, Department of Chemical Engineering, University of South Carolina, Columbia, SC 29208, USA
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14
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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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15
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Elazar M, Glenn JS. Combination of Novel Therapies for HDV. Viruses 2022; 14:v14020268. [PMID: 35215860 PMCID: PMC8877160 DOI: 10.3390/v14020268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 01/16/2022] [Accepted: 01/21/2022] [Indexed: 11/16/2022] Open
Abstract
Treatment options for HDV have been limited to interferon alfa-based therapies with its poor efficacy to side effects ratio. Several novel therapies have now advanced into the clinic. As they each have a different mechanism of action, there is the potential for combination therapy. Here we review how studying the HDV life cycle has led to the development of these novel therapies, the key developments leading to, and the details of, the first combination study of novel anti-HDV therapies, and suggest what additional combinations of novel therapies can be anticipated as we enter this exciting new area of HDV treatments.
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Affiliation(s)
- Menashe Elazar
- Division of Gastroenterology and Hepatology, Department of Medicine-Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA;
| | - Jeffrey S. Glenn
- Division of Gastroenterology and Hepatology, Department of Medicine-Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA;
- Palo Alto Veterans Administration, Palo Alto, CA 94305, USA
- Correspondence:
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16
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Khan IW, Dad Ullah MU, Choudhry M, Ali MJ, Ali MA, Lam SLK, Shah PA, Kaur SP, Lau DTY. Novel Therapies of Hepatitis B and D. Microorganisms 2021; 9:2607. [PMID: 34946209 PMCID: PMC8707465 DOI: 10.3390/microorganisms9122607] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 12/03/2021] [Accepted: 12/07/2021] [Indexed: 02/05/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a global public health issue and is a major cause of cirrhosis and hepatocellular carcinoma (HCC). Hepatitis D virus (HDV) requires the hepatitis B surface antigen (HBsAg) to replicate. The eradication of HBV, therefore, can also cure HDV. The current therapies for chronic hepatitis B and D are suboptimal and cannot definitely cure the viruses. In order to achieve functional or complete cure of these infections, novel therapeutic agents that target the various sites of the viral replicative cycle are necessary. Furthermore, novel immunomodulatory agents are also essential to achieve viral clearance. Many of these new promising compounds such as entry inhibitors, covalently closed circular DNA (cccDNA) inhibitors, small interfering RNAs (siRNAs), capsid assembly modulators and nucleic acid polymers are in various stages of clinical developments. In this review article, we provided a comprehensive overview of the structure and lifecycle of HBV, the limitations of the current therapies and a summary of the novel therapeutic agents for both HDV and HBV infection.
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Affiliation(s)
- Iman Waheed Khan
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA; (I.W.K.); (M.U.D.U.); (M.C.); (M.J.A.); (M.A.A.); (S.P.K.)
| | - Mati Ullah Dad Ullah
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA; (I.W.K.); (M.U.D.U.); (M.C.); (M.J.A.); (M.A.A.); (S.P.K.)
| | - Mina Choudhry
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA; (I.W.K.); (M.U.D.U.); (M.C.); (M.J.A.); (M.A.A.); (S.P.K.)
| | - Mukarram Jamat Ali
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA; (I.W.K.); (M.U.D.U.); (M.C.); (M.J.A.); (M.A.A.); (S.P.K.)
| | - Muhammad Ashar Ali
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA; (I.W.K.); (M.U.D.U.); (M.C.); (M.J.A.); (M.A.A.); (S.P.K.)
| | - Sam L. K. Lam
- Liver Center, Department of Medicine, Department of Pharmacy, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA;
| | - Pir Ahmad Shah
- Department of Internal Medicine, University of Texas, San Antonio, TX 78229, USA;
| | - Satinder Pal Kaur
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA; (I.W.K.); (M.U.D.U.); (M.C.); (M.J.A.); (M.A.A.); (S.P.K.)
| | - Daryl T. Y. Lau
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA; (I.W.K.); (M.U.D.U.); (M.C.); (M.J.A.); (M.A.A.); (S.P.K.)
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17
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Bazinet M, Anderson M, Pântea V, Placinta G, Moscalu I, Cebotarescu V, Cojuhari L, Jimbei P, Iarovoi L, Smesnoi V, Musteata T, Jucov A, Dittmer U, Gersch J, Holzmayer V, Kuhns M, Cloherty G, Vaillant A. Analysis of HBsAg Immunocomplexes and cccDNA Activity During and Persisting After NAP-Based Therapy. Hepatol Commun 2021; 5:1873-1887. [PMID: 34558823 PMCID: PMC8557319 DOI: 10.1002/hep4.1767] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 04/28/2021] [Accepted: 05/04/2021] [Indexed: 02/06/2023] Open
Abstract
Therapy with nucleic acid polymers (NAPs), tenofovir disoproxil fumarate (TDF), and pegylated interferon (pegIFN) achieve high rates of HBsAg loss/seroconversion and functional cure in chronic hepatitis B virus (HBV) infection. The role of hepatitis B surface antigen (HBsAg) seroconversion and inactivation of covalently closed circular DNA (cccDNA) in establishing functional cure were examined. Archived serum from the REP 401 study was analyzed using the Abbott ARCHITECT HBsAg NEXT assay (Chicago, IL), Abbott research use-only assays for HBsAg immune complexes (HBsAg ICs), circulating HBV RNA, and the Fujirebio assay for hepatitis B core-related antigen (HBcrAg; Malvern, PA). HBsAg became < 0.005 IU/mL in 23 participants during NAP exposure, which persisted in all participants with functional cure. HBsAg IC declined during lead-in TDF monotherapy and correlated with minor declines in HBsAg. Following the addition of NAPs and pegIFN, minor HBsAg IC increases (n = 13) or flares (n = 2) during therapy were not correlated with HBsAg decline, hepatitis B surface antibody (anti-HBs) titers, or alanine aminotransferase. HBsAg IC universally declined during follow-up in participants with virologic control or functional cure. Universal declines in HBV RNA and HBcrAg during TDF monotherapy continued with NAP + pegIFN regardless of therapeutic outcome. At the end of therapy, HBV RNA was undetectable in only 5 of 14 participants with functional cure but became undetectable after removal of therapy in all participants with functional cure. Undetectable HBV RNA at the end of therapy in 5 participants was followed by relapse to virologic control or viral rebound. Conclusion: Anti-HBs-independent mechanisms contribute to HBsAg clearance during NAP therapy. Inactivation of cccDNA does not predict functional cure following NAP-based therapy; however, functional cure is accompanied by persistent inactivation of cccDNA. Persistent HBsAg loss with functional cure may also reflect reduction/clearance of integrated HBV DNA. Clinicaltrials.org number NCT02565719.
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Affiliation(s)
| | | | - Victor Pântea
- Department of Infectious DiseasesNicolae Testemiţanu State University of Medicine and PharmacyChișinăuRepublic of Moldova
| | - Gheorghe Placinta
- Department of Infectious DiseasesNicolae Testemiţanu State University of Medicine and PharmacyChișinăuRepublic of Moldova
| | - Iurie Moscalu
- ARENSIA Exploratory MedicineRepublican Clinical HospitalChișinăuRepublic of Moldova
| | - Valentin Cebotarescu
- Department of Infectious DiseasesNicolae Testemiţanu State University of Medicine and PharmacyChișinăuRepublic of Moldova
| | - Lilia Cojuhari
- Department of Infectious DiseasesNicolae Testemiţanu State University of Medicine and PharmacyChișinăuRepublic of Moldova
| | - Pavlina Jimbei
- Toma Ciorbǎ Infectious Clinical HospitalChișinăuRepublic of Moldova
| | - Liviu Iarovoi
- Department of Infectious DiseasesNicolae Testemiţanu State University of Medicine and PharmacyChișinăuRepublic of Moldova
| | | | - Tatina Musteata
- Toma Ciorbǎ Infectious Clinical HospitalChișinăuRepublic of Moldova
| | - Alina Jucov
- Department of Infectious DiseasesNicolae Testemiţanu State University of Medicine and PharmacyChișinăuRepublic of Moldova.,ARENSIA Exploratory MedicineRepublican Clinical HospitalChișinăuRepublic of Moldova
| | - Ulf Dittmer
- Institute for VirologyUniversity of Duisburg-EssenEssenGermany
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18
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Bartoli A, Gabrielli F, Tassi A, Cursaro C, Pinelli A, Andreone P. Treatments for HBV: A Glimpse into the Future. Viruses 2021; 13:1767. [PMID: 34578347 PMCID: PMC8473442 DOI: 10.3390/v13091767] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 08/17/2021] [Accepted: 08/24/2021] [Indexed: 12/16/2022] Open
Abstract
The hepatitis B virus is responsible for most of the chronic liver disease and liver cancer worldwide. As actual therapeutic strategies have had little success in eradicating the virus from hepatocytes, and as lifelong treatment is often required, new drugs targeting the various phases of the hepatitis B virus (HBV) lifecycle are currently under investigation. In this review, we provide an overview of potential future treatments for HBV.
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Affiliation(s)
- Alessandra Bartoli
- Department of Medical and Surgical Sciences, Division of Internal Medicine, Maternal-Infantile and Adult, University of Modena and Reggio Emilia, 41126 Modena, Italy; (A.B.); (F.G.); (A.T.); (C.C.); (A.P.)
- Postgraduate School of Allergy and Clinical Immunology, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Filippo Gabrielli
- Department of Medical and Surgical Sciences, Division of Internal Medicine, Maternal-Infantile and Adult, University of Modena and Reggio Emilia, 41126 Modena, Italy; (A.B.); (F.G.); (A.T.); (C.C.); (A.P.)
- Postgraduate School of Internal Medicine, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Andrea Tassi
- Department of Medical and Surgical Sciences, Division of Internal Medicine, Maternal-Infantile and Adult, University of Modena and Reggio Emilia, 41126 Modena, Italy; (A.B.); (F.G.); (A.T.); (C.C.); (A.P.)
- Postgraduate School of Internal Medicine, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Carmela Cursaro
- Department of Medical and Surgical Sciences, Division of Internal Medicine, Maternal-Infantile and Adult, University of Modena and Reggio Emilia, 41126 Modena, Italy; (A.B.); (F.G.); (A.T.); (C.C.); (A.P.)
| | - Ambra Pinelli
- Department of Medical and Surgical Sciences, Division of Internal Medicine, Maternal-Infantile and Adult, University of Modena and Reggio Emilia, 41126 Modena, Italy; (A.B.); (F.G.); (A.T.); (C.C.); (A.P.)
- Postgraduate School of Allergy and Clinical Immunology, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Pietro Andreone
- Department of Medical and Surgical Sciences, Division of Internal Medicine, Maternal-Infantile and Adult, University of Modena and Reggio Emilia, 41126 Modena, Italy; (A.B.); (F.G.); (A.T.); (C.C.); (A.P.)
- Postgraduate School of Allergy and Clinical Immunology, University of Modena and Reggio Emilia, 41126 Modena, Italy
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19
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Yang S, Zeng W, Zhang J, Lu F, Chang J, Guo JT. Restoration of a functional antiviral immune response to chronic HBV infection by reducing viral antigen load: if not sufficient, is it necessary? Emerg Microbes Infect 2021; 10:1545-1554. [PMID: 34227927 PMCID: PMC8354158 DOI: 10.1080/22221751.2021.1952851] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
The prolonged viral antigen stimulation is the driving force for the development of immune tolerance to chronic hepatitis B virus (HBV) infection. The sustained reduction of viral proteins may allow for the recovery and efficient activation of HBV-specific T and B cells by immune-stimulating agents, checkpoint blockades and/or therapeutic vaccinations. Recently, several therapeutic approaches have been shown to significantly reduce intrahepatic viral proteins and/or circulating HBV surface antigen (HBsAg) with variable impacts on the host antiviral immune responses in animal models or human clinical trials. It remains to be further investigated whether reduction of viral protein expression or induction of intrahepatic viral protein degradation is more efficacious to break the immune tolerance to chronic HBV infection. It is also of great interest to know if the accelerated clearance of circulating HBsAg by antibodies has a long-term immunological impact on HBV infection and disease progression. Although it is clear that removal of antigen stimulation alone is not sufficient to induce the functional recovery of exhausted T and B cells, accumulating evidence suggests that the reduction of viral antigen load appears to facilitate the therapeutic activation of functional antiviral immunity in chronic HBV carriers. Based on a systematic review of the findings in animal models and clinical studies, the research directions toward discovery and development of more efficacious therapeutic approaches to reinvigorate HBV-specific adaptive immune function and achieve the durable control of chronic HBV infection, i.e. a functional cure, in the vast majority of treated patients are discussed.
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Affiliation(s)
- Sisi Yang
- Baruch S. Blumberg Institute, Doylestown, PA, USA.,Huashan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Wanjia Zeng
- Peking University Health Science Center, Beijing, People's Republic of China
| | - Jiming Zhang
- Huashan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Fengmin Lu
- Peking University Health Science Center, Beijing, People's Republic of China
| | | | - Ju-Tao Guo
- Baruch S. Blumberg Institute, Doylestown, PA, USA
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20
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Niro GA, Ferro A, Cicerchia F, Brascugli I, Durazzo M. Hepatitis delta virus: From infection to new therapeutic strategies. World J Gastroenterol 2021; 27:3530-3542. [PMID: 34239267 PMCID: PMC8240063 DOI: 10.3748/wjg.v27.i24.3530] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 04/07/2021] [Accepted: 05/27/2021] [Indexed: 02/06/2023] Open
Abstract
The hepatitis delta virus (HDV) is a small RNA virus that encodes a single protein and which requires the hepatitis B virus (HBV)-encoded hepatitis B surface antigen (HBsAg) for its assembly and transmission. HBV/HDV co-infections exist worldwide and show a higher prevalence among selected groups of HBV-infected populations, specifically intravenous drug users, practitioners of high-risk sexual behaviours, and patients with cirrhosis and hepatocellular carcinoma. The chronic form of HDV-related hepatitis is usually severe and rapidly progressive. Patterns of the viral infection itself, including the status of co-infection or super-infection, virus genotypes (both for HBV and HDV), and persistence of the virus’ replication, influence the outcome of the accompanying and manifested liver disease. Unfortunately, disease severity is burdened by the lack of an effective cure for either virus type. For decades, the main treatment option has been interferon, administered as mono-therapy or in combination with nucleos(t)ide analogues. While its efficacy has been reported for different doses, durations and courses, only a minority of patients achieve a sustained response, which is the foundation of eventual improvement in related liver fibrosis. The need for an efficient therapeutic alternative remains. Research efforts towards this end have led to new treatment options that target specific steps in the HDV life cycle; the most promising among these are myrcludex B, which inhibits virus entry into hepatocytes, lonafarnib, which inhibits farnesylation of the viral-encoded L-HDAg large hepatitis D antigen, and REP-2139, which interferes with HBsAg release and assembly.
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Affiliation(s)
- Grazia A Niro
- Department of Gastroenterology, IRCCS Casa Sollievo della Sofferenza Hospital Foundation, San Giovanni Rotondo 71013, Italy
| | - Arianna Ferro
- Department of Medical Sciences, University of Turin, Turin 10126, Italy
| | | | | | - Marilena Durazzo
- Department of Medical Sciences, University of Turin, Turin 10126, Italy
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21
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Vaillant A. HBsAg, Subviral Particles, and Their Clearance in Establishing a Functional Cure of Chronic Hepatitis B Virus Infection. ACS Infect Dis 2021; 7:1351-1368. [PMID: 33302622 DOI: 10.1021/acsinfecdis.0c00638] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
In diverse viral infections, the production of excess viral particles containing only viral glycoproteins (subviral particles or SVP) is commonly observed and is a commonly evolved mechanism for immune evasion. In hepatitis B virus (HBV) infection, spherical particles contain the hepatitis B surface antigen, outnumber infectious virus 10 000-100 000 to 1, and have diverse inhibitory effects on the innate and adaptive immune response, playing a major role in the chronic nature of HBV infection. The current goal of therapies in development for HBV infection is a clinical outcome called functional cure, which signals a persistent and effective immune control of the infection. Although removal of spherical SVP (and the HBsAg they carry) is an important milestone in achieving functional cure, this outcome is rarely achieved with current therapies due to distinct mechanisms for assembly, secretion, and persistence of SVP, which are poorly targeted by direct acting antivirals or immunotherapies. In this Review, the current understanding of the distinct mechanisms involved in the production and persistence of spherical SVP in chronic HBV infection and their immunoinhibitory activity will be reviewed as well as current therapies in development with the goal of clearing spherical SVP and achieving functional cure.
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Affiliation(s)
- Andrew Vaillant
- Replicor Inc., 6100 Royalmount Avenue, Montreal, Quebec H8Y 3E6, Canada
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22
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Huang X, Xu W, Li M, Zhang P, Zhang YS, Ding J, Chen X. Antiviral biomaterials. MATTER 2021; 4:1892-1918. [DOI: 10.1016/j.matt.2021.03.016] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/14/2025]
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23
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Bazinet M, Pântea V, Placinta G, Moscalu I, Cebotarescu V, Cojuhari L, Jimbei P, Iarovoi L, Smesnoi V, Musteata T, Jucov A, Dittmer U, Krawczyk A, Vaillant A. Benefit of transaminase elevations in establishing functional cure of HBV infection during nap-based combination therapy. J Viral Hepat 2021; 28:817-825. [PMID: 33556206 DOI: 10.1111/jvh.13483] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 01/18/2021] [Indexed: 12/12/2022]
Abstract
Treatment of HBV infection with nucleic acid polymers and pegIFN is accompanied by transaminase elevations in 95% of participants. HBV viral rebound, partial cure (HBV DNA < 2000 IU/mL, normal ALT) or functional cure (HBV DNA target not detected, HBsAg <LLOQ, normal ALT) occurred in 27%, 38% and 35% of participants. Correlations between ALT, AST and GGT elevations, virologic baseline, response during therapy and HBV therapeutic outcome were investigated. A retrospective analysis of all 40 participants in the REP 401 study (NCT02565719) included maxima and area under the curve for ALT, AST and GGT, baseline virology, HBsAg and anti-HBs response and HBV therapeutic outcomes. ALT, AST and GGT elevations were asymptomatic, independent of baseline virologic status and anti-HBs response but correlated with HBsAg reduction ≥3 log10 from baseline. Functional cure was associated with significantly lower HBsAg during the nadir of ALT flares versus viral rebound or partial cure. ALT elevations >3X ULN while HBsAg was <1 IU/mL occurred in 3/11 (27%), 11/15 (74%) and 14/14 (100%) of participants experiencing viral rebound, partial or functional cure. ALT elevation >3X ULN during HBsAg <1 IU/mL and <10 IU/mL were the best predictors of partial and functional cure. In conclusion, elevations in ALT, AST or GGT while HBsAg <10 IU/ml during therapy with REP 2139 + pegIFN are associated with partial and functional cure. More potent HBsAg reduction during flare nadir is associated with the establishment of functional cure, suggesting a critical role for HBsAg-specific immunity to achieve this outcome. These on-therapy milestones may have similar positive prognostic value with other combination therapies.
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Affiliation(s)
| | - Victor Pântea
- Department of Infectious Diseases, Nicolae Testemiţanu State University of Medicine and Pharmacy, Chișinău, Republic of Moldova
| | - Gheorghe Placinta
- Department of Infectious Diseases, Nicolae Testemiţanu State University of Medicine and Pharmacy, Chișinău, Republic of Moldova
| | - Iurie Moscalu
- ARENSIA Exploratory Medicine, Republican Clinical Hospital Chișinău, Moldova
| | - Valentin Cebotarescu
- Department of Infectious Diseases, Nicolae Testemiţanu State University of Medicine and Pharmacy, Chișinău, Republic of Moldova
| | - Lilia Cojuhari
- Department of Infectious Diseases, Nicolae Testemiţanu State University of Medicine and Pharmacy, Chișinău, Republic of Moldova
| | - Pavlina Jimbei
- Toma Ciorbă Infectious Clinical Hospital, Chișinău, Republic of Moldova
| | - Liviu Iarovoi
- Department of Infectious Diseases, Nicolae Testemiţanu State University of Medicine and Pharmacy, Chișinău, Republic of Moldova
| | - Valentina Smesnoi
- Toma Ciorbă Infectious Clinical Hospital, Chișinău, Republic of Moldova
| | - Tatiana Musteata
- Toma Ciorbă Infectious Clinical Hospital, Chișinău, Republic of Moldova
| | - Alina Jucov
- Department of Infectious Diseases, Nicolae Testemiţanu State University of Medicine and Pharmacy, Chișinău, Republic of Moldova.,ARENSIA Exploratory Medicine, Republican Clinical Hospital Chișinău, Moldova
| | - Ulf Dittmer
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Adalbert Krawczyk
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.,Department of Infectious Diseases, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
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24
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Maepa MB, Bloom K, Ely A, Arbuthnot P. Hepatitis B virus: promising drug targets and therapeutic implications. Expert Opin Ther Targets 2021; 25:451-466. [PMID: 33843412 DOI: 10.1080/14728222.2021.1915990] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Introduction: Current therapy for infection with hepatitis B virus (HBV) rarely clears the virus, and viremia commonly resurges following treatment withdrawal. To prevent serious complications of the infection, research has been aimed at identifying new viral and host targets that can be exploited to inactivate HBV replication.Areas covered: This paper reviews the use of these new molecular targets to advance anti-HBV therapy. Emphasis is on appraising data from pre-clinical and early clinical studies described in journal articles published during the past 10 years and available from PubMed.Expert opinion: The wide range of viral and host factors that can be targeted to disable HBV is impressive and improved insight into HBV molecular biology continues to provide the basis for new drug design. In addition to candidate therapies that have direct or indirect actions on HBV covalently closed circular DNA (cccDNA), compounds that inhibit HBsAg secretion, viral entry, destabilize viral RNA and effect enhanced immune responses to HBV show promise. Preclinical and clinical evaluation of drug candidates, as well as investigating use of treatment combinations, are encouraging. The field is poised at an interesting stage and indications are that reliably achieving functional cure from HBV infection is a tangible goal.
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Affiliation(s)
- Mohube Betty Maepa
- School of Pathology, Faculty of Health Sciences, Wits/SAMRC Antiviral Gene Therapy Research Unit, University of the Witwatersrand, Johannesburg, South Africa
| | - Kristie Bloom
- School of Pathology, Faculty of Health Sciences, Wits/SAMRC Antiviral Gene Therapy Research Unit, University of the Witwatersrand, Johannesburg, South Africa
| | - Abdullah Ely
- School of Pathology, Faculty of Health Sciences, Wits/SAMRC Antiviral Gene Therapy Research Unit, University of the Witwatersrand, Johannesburg, South Africa
| | - Patrick Arbuthnot
- School of Pathology, Faculty of Health Sciences, Wits/SAMRC Antiviral Gene Therapy Research Unit, University of the Witwatersrand, Johannesburg, South Africa
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25
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Bazinet M, Pântea V, Cebotarescu V, Cojuhari L, Jimbei P, Anderson M, Gersch J, Holzmayer V, Elsner C, Krawczyk A, Kuhns MC, Cloherty G, Dittmer U, Vaillant A. Persistent Control of Hepatitis B Virus and Hepatitis Delta Virus Infection Following REP 2139-Ca and Pegylated Interferon Therapy in Chronic Hepatitis B Virus/Hepatitis Delta Virus Coinfection. Hepatol Commun 2021; 5:189-202. [PMID: 33553968 PMCID: PMC7850315 DOI: 10.1002/hep4.1633] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 10/08/2020] [Accepted: 10/13/2020] [Indexed: 02/04/2023] Open
Abstract
The nucleic acid polymer REP 2139 inhibits assembly/secretion of hepatitis B virus (HBV) subviral particles. Previously, REP 2139-Ca and pegylated interferon (pegIFN) in HBV/hepatitis delta virus (HDV) coinfection achieved high rates of HDV RNA and hepatitis B surface antigen (HBsAg) loss/seroconversion in the REP 301 study (NCT02233075). The REP 301-LTF study (NCT02876419) examined safety and efficacy during 3.5 years of follow-up. In the current study, participants completing therapy in the REP 301 study were followed for 3.5 years. Primary outcomes were safety and tolerability, and secondary outcomes were HDV functional cure (HDV RNA target not detected [TND], normal alanine aminotransferase [ALT]), HBV virologic control (HBV DNA ≤2,000 IU/mL, normal ALT), HBV functional cure (HBV DNA TND; HBsAg <0.05 IU/mL, normal ALT), and HBsAg seroconversion. Supplemental analysis included high-sensitivity HBsAg (Abbott ARCHITECT HBsAg NEXT), HBV pregenomic RNA (pgRNA), HBsAg/hepatitis B surface antibody (anti-HBs) immune complexes (HBsAg ICs), and hepatitis B core-related antigen (HBcrAg). Asymptomatic grade 1-2 ALT elevations occurred in 2 participants accompanying viral rebound; no other safety or tolerability issues were observed. During therapy and follow-up, HBsAg reductions to <0.05 IU/mL were also <0.005 IU/mL. HBsAg ICs declined in 7 of 11 participants during REP 2139-Ca monotherapy and in 10 of 11 participants during follow-up. HDV functional cure persisted in 7 of 11 participants; HBV virologic control persisted in 3 and functional cure (with HBsAg seroconversion) persisted in 4 of these participants. Functional cure of HBV was accompanied by HBV pgRNA TND and HBcrAg <lower limit of quantitation. Conclusion: REP 2139-Ca + pegIFN is not associated with long-term safety or tolerability issues. The establishment of HDV functional cure and HBV virologic control/functional cure and HBsAg seroconversion are durable over 3.5 years and may reflect removal of integrated HBV DNA from the liver. Further investigation is warranted in larger studies.
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Affiliation(s)
| | - Victor Pântea
- Department of Infectious DiseasesNicolae Testemiţanu State University of Medicine and PharmacyChișinăuRepublic of Moldova
| | - Valentin Cebotarescu
- Department of Infectious DiseasesNicolae Testemiţanu State University of Medicine and PharmacyChișinăuRepublic of Moldova
| | - Lilia Cojuhari
- Department of Infectious DiseasesNicolae Testemiţanu State University of Medicine and PharmacyChișinăuRepublic of Moldova
| | - Pavlina Jimbei
- Toma Ciorbă Infectious Clinical HospitalChișinăuRepublic of Moldova
| | | | | | | | - Carina Elsner
- Institute for VirologyUniversity Hospital EssenUniversity of Duisburg-EssenEssenGermany
| | - Adalbert Krawczyk
- Institute for VirologyUniversity Hospital EssenUniversity of Duisburg-EssenEssenGermany.,Department of Infectious DiseasesUniversity Hospital EssenUniversity of Duisburg-EssenEssenGermany
| | | | | | - Ulf Dittmer
- Institute for VirologyUniversity Hospital EssenUniversity of Duisburg-EssenEssenGermany
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26
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Alexopoulou A, Vasilieva L, Karayiannis P. New Approaches to the Treatment of Chronic Hepatitis B. J Clin Med 2020; 9:jcm9103187. [PMID: 33019573 PMCID: PMC7601587 DOI: 10.3390/jcm9103187] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 09/26/2020] [Accepted: 09/28/2020] [Indexed: 02/07/2023] Open
Abstract
The currently recommended treatment for chronic hepatitis B virus (HBV) infection achieves only viral suppression whilst on therapy, but rarely hepatitis B surface antigen (HBsAg) loss. The ultimate therapeutic endpoint is the combination of HBsAg loss, inhibition of new hepatocyte infection, elimination of the covalently closed circular DNA (cccDNA) pool, and restoration of immune function in order to achieve virus control. This review concentrates on new antiviral drugs that target different stages of the HBV life cycle (direct acting antivirals) and others that enhance both innate and adaptive immunity against HBV (immunotherapy). Drugs that block HBV hepatocyte entry, compounds that silence or deplete the cccDNA pool, others that affect core assembly, agents that degrade RNase-H, interfering RNA molecules, and nucleic acid polymers are likely interventions in the viral life cycle. In the immunotherapy category, molecules that activate the innate immune response such as Toll-like-receptors, Retinoic acid Inducible Gene-1 (RIG-1) and stimulator of interferon genes (STING) agonists or checkpoint inhibitors, and modulation of the adaptive immunity by therapeutic vaccines, vector-based vaccines, or adoptive transfer of genetically-engineered T cells aim towards the restoration of T cell function. Future therapeutic trends would likely be a combination of one or more of the aforementioned drugs that target the viral life cycle and at least one immunomodulator.
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Affiliation(s)
- Alexandra Alexopoulou
- Department of Medicine, Medical School, National & Kapodistrian University of Athens, Hippokration General Hospital, 11527 Athens, Greece;
- Correspondence: ; Tel.: +30-2132-088-178; Fax: +30-2107-706-871
| | - Larisa Vasilieva
- Department of Medicine, Medical School, National & Kapodistrian University of Athens, Hippokration General Hospital, 11527 Athens, Greece;
| | - Peter Karayiannis
- Department of Basic and Clinical Sciences, Medical School, University of Nicosia, Engomi, CY-1700 Nicosia, Cyprus;
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27
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Rybicka M, Bielawski KP. Recent Advances in Understanding, Diagnosing, and Treating Hepatitis B Virus Infection. Microorganisms 2020; 8:E1416. [PMID: 32942584 PMCID: PMC7565763 DOI: 10.3390/microorganisms8091416] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 09/08/2020] [Accepted: 09/11/2020] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection affects 292 million people worldwide and is associated with a broad range of clinical manifestations including cirrhosis, liver failure, and hepatocellular carcinoma (HCC). Despite the availability of an effective vaccine HBV still causes nearly 900,000 deaths every year. Current treatment options keep HBV under control, but they do not offer a cure as they cannot completely clear HBV from infected hepatocytes. The recent development of reliable cell culture systems allowed for a better understanding of the host and viral mechanisms affecting HBV replication and persistence. Recent advances into the understanding of HBV biology, new potential diagnostic markers of hepatitis B infection, as well as novel antivirals targeting different steps in the HBV replication cycle are summarized in this review article.
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Affiliation(s)
- Magda Rybicka
- Department of Molecular Diagnostics, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Abrahama 58, 80-307 Gdansk, Poland;
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28
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Boulon R, Blanchet M, Lemasson M, Vaillant A, Labonté P. Characterization of the antiviral effects of REP 2139 on the HBV lifecycle in vitro. Antiviral Res 2020; 183:104853. [PMID: 32585322 DOI: 10.1016/j.antiviral.2020.104853] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 05/22/2020] [Accepted: 06/11/2020] [Indexed: 12/18/2022]
Abstract
During hepatitis B virus (HBV) infection, HBV subviral particles (SVP) are produced in large excess in comparison to infectious virions and account for the major source of HBV surface antigen (HBsAg) in the blood. This abundant circulating HBsAg has been postulated to promote HBV chronicity by inducing immune exhaustion against HBsAg. Nucleic acid polymers (NAPs) such as REP 2139 display promising antiviral activity against both HBV and hepatitis Delta virus (HDV) in clinical trials. REP 2139 is accompanied by clearance of HBsAg from blood with concomitant reappearance of anti-HBsAg antibodies. To decipher the mechanism-of-action of NAPs, a recently developed cell-based assay in human HepG2.2.15 cells was used (Blanchet et al., 2019). This assay recapitulates the HBsAg secretion inhibition observed in treated patients. In the present study, we analysed the antiviral effect of REP 2139 on the HBV lifecycle. Importantly, we confirm here the potent inhibitory activity of the compound on HBsAg secretion, and report minor or no effect on other viral markers such as intracellular DNA and RNA, and HBeAg or Dane particle secretion. Notably, intracellular HBsAg accumulation is prevented by proteasomal and lysosomal degradation.
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Affiliation(s)
| | - Matthieu Blanchet
- INRS-Institut Armand Frappier, Laval, H7V 1B7, Canada; Replicor Inc. Montréal, H4P 2R2, Canada
| | - Matthieu Lemasson
- Institut National de La Transfusion Sanguine, CNRS-INSERM U1134, Paris, 75739, France
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29
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Spyrou E, Smith CI, Ghany MG. Hepatitis B: Current Status of Therapy and Future Therapies. Gastroenterol Clin North Am 2020; 49:215-238. [PMID: 32389360 PMCID: PMC7444867 DOI: 10.1016/j.gtc.2020.01.003] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Despite the availability of a protective vaccine for over 3 decades, the number of persons with chronic hepatitis B virus (HBV) infection remains high. These persons are at risk for cirrhosis and hepatocellular carcinoma. Current treatment is effective at inhibiting viral replication and reducing complications of chronic HBV infection, but is not curative. There is a need for novel, finite therapy that can cure chronic HBV infection. Several agents are in early-phase development and can be broadly viewed as agents that target the virus directly or indirectly or the host immune response. This article highlights key developments in antiviral/immunomodulatory therapy, the rationale for these approaches, and possible therapeutic regimens.
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Affiliation(s)
- Elias Spyrou
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Washington, DC, USA,Nazih Zuhdi Transplant Institute, INTEGRIS Baptist Medical Center, Oklahoma City, OK, USA
| | - Coleman I. Smith
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Washington, DC, USA
| | - Marc G. Ghany
- Liver Diseases Branch, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
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30
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Abstract
Chronic hepatitis B (CHB) is a widespread global infection and a leading cause of hepatocellular carcinoma and liver failure. Current approaches to treat CHB involve the suppression of viral replication with either interferon or nucleos(t)ide analog therapy, but neither of these approaches can reliably induce viral eradication, immunologic control or long-lived viral suppression in the absence of continued therapy. In this update, we explore the major obstacles of CHB cure and review new therapeutic strategies and drug candidates.
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Affiliation(s)
- Lydia Tang
- Division of Clinical Care & Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Program in Oncology, University of Maryland Marlene & Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA
| | - Shyam Kottilil
- Division of Clinical Care & Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Program in Oncology, University of Maryland Marlene & Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA
| | - Eleanor Wilson
- Division of Clinical Care & Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Program in Oncology, University of Maryland Marlene & Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA
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31
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David G, Fogeron ML, Montserret R, Lecoq L, Page A, Delolme F, Nassal M, Böckmann A. Phosphorylation and Alternative Translation on Wheat Germ Cell-Free Protein Synthesis of the DHBV Large Envelope Protein. Front Mol Biosci 2019; 6:138. [PMID: 31850370 PMCID: PMC6902406 DOI: 10.3389/fmolb.2019.00138] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Accepted: 11/18/2019] [Indexed: 12/13/2022] Open
Abstract
Wheat-germ cell-free protein synthesis (WG-CFPS) is a potent platform for the high-yield production of proteins. It is especially of interest for difficult-to-express eukaryotic proteins, such as toxic and transmembrane proteins, and presents an important tool in high-throughput protein screening. Until recently, an assumed drawback of WG-CFPS was a reduced capacity for post-translational modifications. Meanwhile, phosphorylation has been observed in WG-CFPS; yet, authenticity of the respective phosphorylation sites remained unclear. Here we show that a viral membrane protein, the duck hepatitis B virus (DHBV) large envelope protein (DHBs L), produced by WG-CFPS, is phosphorylated upon translation at the same sites as DHBs L produced during DHBV infection of primary hepatocytes. Furthermore, we show that alternative translation initiation of the L protein, previously identified in virus-producing hepatic cells, occurs on WG-CFPS as well. Together, these findings further strengthen the high potential of WG-CFPS to include the reproduction of specific modifications proteins experience in vivo.
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Affiliation(s)
- Guillaume David
- Institut de Biologie et Chimie des Protéines, MMSB, Labex Ecofect, UMR 5086 CNRS, Université de Lyon, Lyon, France
| | - Marie-Laure Fogeron
- Institut de Biologie et Chimie des Protéines, MMSB, Labex Ecofect, UMR 5086 CNRS, Université de Lyon, Lyon, France
| | - Roland Montserret
- Institut de Biologie et Chimie des Protéines, MMSB, Labex Ecofect, UMR 5086 CNRS, Université de Lyon, Lyon, France
| | - Lauriane Lecoq
- Institut de Biologie et Chimie des Protéines, MMSB, Labex Ecofect, UMR 5086 CNRS, Université de Lyon, Lyon, France
| | - Adeline Page
- Protein Science Facility, SFR BioSciences CNRS UMS3444, Inserm US8, UCBL, ENS de Lyon, Lyon, France
| | - Frédéric Delolme
- Protein Science Facility, SFR BioSciences CNRS UMS3444, Inserm US8, UCBL, ENS de Lyon, Lyon, France
| | - Michael Nassal
- Internal Medicine II/Molecular Biology, University Hospital Freiburg, Freiburg, Germany
| | - Anja Böckmann
- Institut de Biologie et Chimie des Protéines, MMSB, Labex Ecofect, UMR 5086 CNRS, Université de Lyon, Lyon, France
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32
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Usman Z, Mijočević H, Karimzadeh H, Däumer M, Al-Mathab M, Bazinet M, Frishman D, Vaillant A, Roggendorf M. Kinetics of hepatitis B surface antigen quasispecies during REP 2139-Ca therapy in HBeAg-positive chronic HBV infection. J Viral Hepat 2019; 26:1454-1464. [PMID: 31323705 DOI: 10.1111/jvh.13180] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Accepted: 06/22/2019] [Indexed: 12/18/2022]
Abstract
Chronic HBV infection results in various clinical manifestations due to different levels of immune response. In recent years, hepatitis B treatment has improved by long-term administration of nucleos(t)ide analogues (NUCs) and peg-interferon. Nucleic acid polymers (NAPs; REP 2139-Ca and REP 2139-Mg) are new antiviral drugs that block the assembly of subviral particles, thus preventing the release of HBsAg and allowing its clearance and restoration of functional control of infection when combined with various immunotherapies. In the REP 102 study (NCT02646189), 9 of 12 patients showed substantial reduction of HBsAg and seroconversion to anti-HBs in response to REP 2139-Ca, whereas 3 of 12 patients did not show responses (>1 log reduction of HBsAg and HBV DNA from baseline). We characterized the dynamic changes of HBV quasispecies (QS) within the major hydrophilic region (MHR) of the 'pre-S/S' open reading frame including the 'a' determinant in responders and nonresponders of the REP 102 study and four untreated matched controls. HBV QS complexity at baseline varied slightly between responders and nonresponders (P = .28). However, these responders showed significant decline in viral complexity (P = .001) as REP 2139-Ca therapy progressed but no significant change in complexity was observed among the nonresponders (P = .99). The MHR mutations were more frequently observed in responders than in nonresponders and matched controls. No mutations were observed in 'a' determinant of major QS population which may interfere with the detection of HBsAg by diagnostic assays. No specific mutations were found within the MHR which could explain patients' poor HBsAg response during REP 2139-Ca therapy.
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Affiliation(s)
- Zainab Usman
- Department of Bioinformatics, Technische Universität München, Wissenschaftszentrum Weihenstephan, Freising, Germany
| | - Hrvoje Mijočević
- Institute of Virology, Technische Universität München, Munich, Germany
| | - Hadi Karimzadeh
- Institute of Virology, Technische Universität München, Munich, Germany.,Department of Medicine II, University Hospital Munich-Grosshadern, Munich, Germany
| | - Martin Däumer
- Institute of Immunology and Genetics, Kaiserslautern, Germany
| | - Mamun Al-Mathab
- Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | | | - Dmitrij Frishman
- Department of Bioinformatics, Technische Universität München, Wissenschaftszentrum Weihenstephan, Freising, Germany.,Laboratory of Bioinformatics, RASA research center, St Petersburg State Polytechnical University, Saint Petersburg, Russia
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33
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Shah PA, Choudhry S, Reyes KJC, Lau DTY. An update on the management of chronic hepatitis D. Gastroenterol Rep (Oxf) 2019; 7:396-402. [PMID: 32494363 PMCID: PMC7249531 DOI: 10.1093/gastro/goz052] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2019] [Revised: 07/19/2019] [Accepted: 08/23/2019] [Indexed: 02/07/2023] Open
Abstract
Hepatitis D virus (HDV) infection is associated with severe liver-related morbidity and mortality. The prevalence of HDV is rising especially among people who abuse drugs and immigrants from endemic areas. Reliable diagnostic assays with enhanced sensitivity and specificity are essential for screening at-risk populations. Until recently, interferon has been the only treatment for hepatitis D. Its efficacy is, however, limited and it is associated with significant side effects. A number of novel antiviral agents that target various stages of the HDV life cycle show promising results. They are currently in different phases of clinical development. This review focuses on the changing epidemiology, novel therapeutic agents, and updated management of chronic hepatitis delta.
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Affiliation(s)
- Pir Ahmad Shah
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Saad Choudhry
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Karen J Campoverde Reyes
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.,Neuroendocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Daryl T Y Lau
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
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34
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Gilman C, Heller T, Koh C. Chronic hepatitis delta: A state-of-the-art review and new therapies. World J Gastroenterol 2019; 25:4580-4597. [PMID: 31528088 PMCID: PMC6718034 DOI: 10.3748/wjg.v25.i32.4580] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Revised: 07/03/2019] [Accepted: 07/19/2019] [Indexed: 02/06/2023] Open
Abstract
Chronic delta hepatitis is the most severe form of viral hepatitis affecting nearly 65 million people worldwide. Individuals with this devastating illness are at higher risk for developing cirrhosis and hepatocellular carcinoma. Delta virus is a defective RNA virus that requires hepatitis B surface antigen for propagation in humans. Infection can occur in the form of a co-infection with hepatitis B, which can be self-limiting, vs superinfection in a patient with established hepatitis B infection, which often leads to chronicity in majority of cases. Current noninvasive tools to assess for advanced liver disease have limited utility in delta hepatitis. Guidelines recommend treatment with pegylated interferon, but this is limited to patients with compensated disease and is efficacious in about 30% of those treated. Due to limited treatment options, novel agents are being investigated and include entry, assembly and export inhibitors of viral particles in addition to stimulators of the host immune response. Future clinical trials should take into consideration the interaction of hepatitis B and hepatitis D as suppression of one virus can lead to the activation of the other. Also, surrogate markers of treatment efficacy have been proposed.
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MESH Headings
- Antiviral Agents/pharmacology
- Antiviral Agents/therapeutic use
- Coinfection/drug therapy
- Coinfection/epidemiology
- Coinfection/virology
- Drug Therapy, Combination/methods
- Global Burden of Disease
- Hepatitis B Surface Antigens/immunology
- Hepatitis B Surface Antigens/metabolism
- Hepatitis B virus/immunology
- Hepatitis B virus/pathogenicity
- Hepatitis B, Chronic/drug therapy
- Hepatitis B, Chronic/epidemiology
- Hepatitis B, Chronic/virology
- Hepatitis D, Chronic/drug therapy
- Hepatitis D, Chronic/epidemiology
- Hepatitis D, Chronic/virology
- Hepatitis Delta Virus/immunology
- Hepatitis Delta Virus/pathogenicity
- Humans
- Interferon-alpha/pharmacology
- Interferon-alpha/therapeutic use
- Lipopeptides/pharmacology
- Lipopeptides/therapeutic use
- Organic Anion Transporters, Sodium-Dependent/antagonists & inhibitors
- Organic Anion Transporters, Sodium-Dependent/metabolism
- Piperidines/pharmacology
- Piperidines/therapeutic use
- Pyridines/pharmacology
- Pyridines/therapeutic use
- Randomized Controlled Trials as Topic
- Review Literature as Topic
- Superinfection/drug therapy
- Superinfection/epidemiology
- Superinfection/virology
- Symporters/antagonists & inhibitors
- Symporters/metabolism
- Therapies, Investigational/methods
- Treatment Outcome
- Virus Assembly/drug effects
- Virus Internalization/drug effects
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Affiliation(s)
- Christy Gilman
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, United States
| | - Theo Heller
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, United States
| | - Christopher Koh
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, United States
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Abstract
Chronic hepatitis D (CHD) results from an infection with the hepatitis B virus and hepatitis D virus (HDV). CHD is the most severe form of human viral hepatitis. Current treatment options consist of interferon alfa, which is effective only in a minority of patients. Study of HDV molecular virology has resulted in new approaches entering clinical trials, with phase-3 studies the most advanced. These include the entry inhibitor bulevirtide, the nucleic acid polymer REP 2139-Ca, the farnesyltransferase inhibitor lonafarnib, and pegylated interferon lambda. This article summarizes the available data on these emerging therapeutics.
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Affiliation(s)
- Christopher Koh
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Ben L. Da
- Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Jeffrey S. Glenn
- Departments of Medicine and Microbiology & Immunology, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
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36
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Vaillant A. REP 2139: Antiviral Mechanisms and Applications in Achieving Functional Control of HBV and HDV Infection. ACS Infect Dis 2019; 5:675-687. [PMID: 30199230 DOI: 10.1021/acsinfecdis.8b00156] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Nucleic acid polymers (NAPs) are broad spectrum antiviral agents whose antiviral activity in hepatitis B virus (HBV) infection is derived from their ability to block the release of the hepatitis B virus surface antigen (HBsAg). This pharmacological activity blocks replenishment of HBsAg in the circulation, allowing host mediated clearance. This effect has important clinical significance as the clearance of circulating HBsAg dramatically potentiates the ability of immunotherapies to restore functional control of HBV infection which persists after antiviral therapy is removed. These effects are reproducible in preclinical evaluations and in several clinical trials that have evaluated the activity of the lead NAP, REP 2139, in monotherapy and in combination with immunotherapy in hepatitis B e antigen (HBeAg) negative and HBeAg positive HBV infection and also in HBeAg negative HBV/hepatitis D virus (HDV) coinfection. These antiviral effects of REP 2139 are achieved in the absence of any direct immunostimulatory effect in the liver and also without any discernible direct interaction with viral components. The search for the host protein interaction with NAPs that drives their antiviral effects is ongoing, and the interaction targeted by REP 2139 within infected cells has not yet been elucidated. This article provides an updated review of available data on the effects of REP 2139 in HBV and HDV infection and the ability of REP 2139-based combination therapy to achieve functional control of HBV and HDV infection in patients.
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Affiliation(s)
- Andrew Vaillant
- Replicor Inc., 6100 Royalmount Avenue, Montreal, Quebec H4P 2R2, Canada
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37
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Yurdaydin C, Abbas Z, Buti M, Cornberg M, Esteban R, Etzion O, Gane EJ, Gish RG, Glenn JS, Hamid S, Heller T, Koh C, Lampertico P, Lurie Y, Manns M, Parana R, Rizzetto M, Urban S, Wedemeyer H. Treating chronic hepatitis delta: The need for surrogate markers of treatment efficacy. J Hepatol 2019; 70:1008-1015. [PMID: 30982526 DOI: 10.1016/j.jhep.2018.12.022] [Citation(s) in RCA: 80] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 12/18/2018] [Accepted: 12/20/2018] [Indexed: 12/11/2022]
Abstract
Chronic hepatitis delta represents the most severe form of chronic viral hepatitis. The current treatment of hepatitis delta virus (HDV) infection consists of the use of interferons and is largely unsatisfactory. Several new compounds are currently in development for the treatment of HDV infection. However, surrogate markers that can be used to develop clinical endpoints in HDV infection are not well defined. In the current manuscript, we aimed to evaluate the existing data on treatment of HDV infection and to suggest treatment goals (possible "trial endpoints") that could be used across different clinical trials.
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Affiliation(s)
- Cihan Yurdaydin
- Department of Gastroenterology, Ankara University, Ankara, and Department of Internal Medicine, Koc University, Istanbul, Turkey.
| | - Zaigham Abbas
- Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
| | - Maria Buti
- Liver Unit, Hospital Universitario Vall d'Hebron and Ciber-ehd, Instituto Carlos III, Barcelona, Spain
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Rafael Esteban
- Liver Unit, Hospital Universitario Vall d'Hebron and Ciber-ehd, Instituto Carlos III, Barcelona, Spain
| | - Ohad Etzion
- Institute of Gastroenterology and Liver Diseases Soroka University Medical Center Faculty of Health Sciences, Ben-Gurion University of the Negev, Beersheba, Israel
| | | | - Robert G Gish
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Stanford, CA, USA
| | - Jeffrey S Glenn
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Stanford, CA, USA
| | - Saeed Hamid
- Aga Khan University Hospital, Department of Medicine, Karachi, Pakistan
| | - Theo Heller
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Christopher Koh
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Pietro Lampertico
- CRC "A. M. e A. Migliavacca", Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - Yoav Lurie
- Central Virology Laboratory, Ministry of Health, Chaim Sheba Medical Center, Tel - Hashomer, 52621 Ramat Gan, Israel
| | - Michael Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Raymundo Parana
- Hepatology Centre of the University Hospital Professor Edgar Santos, Federal University of Bahia, Salvador, Brazil
| | - Mario Rizzetto
- Department of Gastroenterology, University of Turin, Turin, Italy
| | - Stephan Urban
- Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology and Hepatology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany
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Mijočević H, Karimzadeh H, Seebach J, Usman Z, Al-Mahtab M, Bazinet M, Vaillant A, Roggendorf M. Variants of hepatitis B virus surface antigen observed during therapy with nucleic acid polymer REP 2139-Ca have no influence on treatment outcome and its detection by diagnostic assays. J Viral Hepat 2019; 26:485-495. [PMID: 30450662 DOI: 10.1111/jvh.13044] [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: 06/26/2018] [Accepted: 10/15/2018] [Indexed: 12/23/2022]
Abstract
The treatment of patients suffering from HBeAg-positive chronic hepatitis B with REP 2139-Ca resulted in potent reductions in HBsAg and HBV DNA, seroconversion to anti-HBs and the establishment of functional control of infection. In this cohort of 12 patients, we investigated whether differences between HBsAg sequences might explain the lack of response to REP 2139-Ca observed in 3 of 12 patients. We also assessed if the reduction or complete loss of HBsAg in serum observed during therapy were caused by mutations in the "a" determinant preventing the detection of HBsAg by standard diagnostic assays. The complete pre-S/S open reading frame (ORF) was sequenced and pre-S1, pre-S2 and S amino acid sequences were analysed. We found no major differences between pre-S1, pre-S2 and S sequences in responders and nonresponders correlated with low reduction in HBsAg. In addition, we found no mutations in the "a" determinant that would significantly affect the reactivity of HBsAg in diagnostic assays. These results demonstrate that the amino acid sequence of complete pre-S/S ORF has no direct influence on response to REP 2139-Ca therapy.
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Affiliation(s)
- Hrvoje Mijočević
- Institute of Virology, Technische Universität München, Munich, Germany
| | - Hadi Karimzadeh
- Institute of Virology, Technische Universität München, Munich, Germany.,Department of Medicine II, University Hospital Munich-Grosshadern, Munich, Germany
| | - Judith Seebach
- Institute of Virology, Technische Universität München, Munich, Germany
| | - Zainab Usman
- Department of Bioinformatics, Wissenschaftszentrum Weihenstephan, Technische Universität München, Freising, Germany
| | - Mamun Al-Mahtab
- Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
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Blanchet M, Sinnathamby V, Vaillant A, Labonté P. Inhibition of HBsAg secretion by nucleic acid polymers in HepG2.2.15 cells. Antiviral Res 2019; 164:97-105. [PMID: 30771404 DOI: 10.1016/j.antiviral.2019.02.009] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 02/08/2019] [Accepted: 02/12/2019] [Indexed: 02/07/2023]
Abstract
More than 290 million people have chronic HBV infection and are at risk of developing cirrhosis and hepatocellular carcinoma. HBV subviral particles are produced in large excess over virions in infected patients and are the primary source of HBsAg, which is postulated to be important in allowing HBV to chronically persist by interfering with immune function. Nucleic acid polymers (NAPs) have been shown to result in clearance of HBsAg from the blood in pre-clinical and clinical studies. In this study, we show for the first time the recapitulation of NAP- induced inhibition of secretion of HBsAg in vitro using the human HepG2.2.15 cell line. With the restoration of endosomal release of NAPs in vitro using the UNC7938 compound, NAPs were observed to selectively impair the secretion of HBsAg without any intracellular HBsAg accumulation. Additionally, the structure-activity relationship of NAPs for this antiviral activity is similar to that previously reported in other infectious diseases and identifies an exposed hydrophobic protein domain as the target interface for this antiviral effect. The presented in vitro model, the first one to be based on a human derived cell line that constitutively expresses HBV, is a very promising tool for the identification of the host proteins(s) targeted by NAPs.
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Affiliation(s)
- Matthieu Blanchet
- Replicor.inc, Montréal, Canada; INRS-Institut Armand-Frappier, Institut National de la Recherche Scientifique, Laval, Canada
| | - Vigigah Sinnathamby
- INRS-Institut Armand-Frappier, Institut National de la Recherche Scientifique, Laval, Canada
| | | | - Patrick Labonté
- INRS-Institut Armand-Frappier, Institut National de la Recherche Scientifique, Laval, Canada.
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40
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Koh C, Heller T, Glenn JS. Pathogenesis of and New Therapies for Hepatitis D. Gastroenterology 2019; 156:461-476.e1. [PMID: 30342879 PMCID: PMC6340762 DOI: 10.1053/j.gastro.2018.09.058] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Revised: 09/21/2018] [Accepted: 09/25/2018] [Indexed: 12/13/2022]
Abstract
Hepatitis delta virus (HDV) infection of humans was first reported in 1977, and now it is now estimated that 15-20 million people are infected worldwide. Infection with HDV can be an acute or chronic process that occurs only in patients with an hepatitis B virus infection. Chronic HDV infection commonly results in the most rapidly progressive form of viral hepatitis; it is the chronic viral infection that is most likely to lead to cirrhosis, and it is associated with an increased risk of hepatocellular carcinoma. HDV infection is the only chronic human hepatitis virus infection without a therapy approved by the US Food and Drug Administration. Peginterferon alfa is the only recommended therapy, but it produces unsatisfactory results. We review therapeutic agents in development, designed to disrupt the HDV life cycle, that might benefit patients with this devastating disease.
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Affiliation(s)
- Christopher Koh
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
| | - Theo Heller
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Jeffrey S. Glenn
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California, USA
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41
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Orekondy N, Kallwitz ER. A Brief Update on the Management of Hepatitis Delta. Curr Gastroenterol Rep 2018; 20:60. [PMID: 30547237 DOI: 10.1007/s11894-018-0666-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Affiliation(s)
- Nayantara Orekondy
- Loyola University Medical Center, 2160 S First Ave., Maywood, IL, 60153, USA
| | - Eric R Kallwitz
- Loyola University Medical Center, 2160 S First Ave., Maywood, IL, 60153, USA.
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Farci P, Anna Niro G. Current and Future Management of Chronic Hepatitis D. Gastroenterol Hepatol (N Y) 2018; 14:342-351. [PMID: 30166948 PMCID: PMC6111511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Hepatitis D virus (HDV) is a defective RNA virus that requires the hepatitis B surface antigen (HBsAg) of the hepatitis B virus (HBV) for its assembly, release, and transmission. HDV is highly pathogenic, causing the least common, but most severe, form of chronic viral hepatitis at all ages. Although significant advances have been made in the treatment of chronic viral hepatitis, targeting HDV remains a major challenge because of the unconventional nature of this virus and the severity of its disease. The virus contains a ribonucleoprotein complex formed by the RNA genome with a single structural protein, delta antigen (HDAg), which exists in 2 forms (small and large HDAg) and is coated by HBsAg. Farnesylation of the large HDAg is essential for anchoring the ribonucleoprotein to HBsAg for the assembly of virion particles. HDV enters into hepatocytes by using the HBV receptor, the sodium taurocholate cotransporting polypeptide (NTCP). Unlike other RNA viruses, HDV does not encode its own polymerase but exploits the host RNA polymerase II for replication. Thus, in contrast to HBV and hepatitis C virus, which possess virus-specific enzymes that can be targeted by specific inhibitors, the lack of a virus-specific polymerase makes HDV a particularly challenging therapeutic target. Treatment of hepatitis D remains unsatisfactory, and interferon-α has been the only approved drug over the past 30 years. This article examines the unconventional nature of HDV, the current management of chronic hepatitis D, and how new insights from the HDV life cycle have led to the development of 3 novel classes of drugs (NTCP receptor inhibitors, farnesyltransferase inhibitors, and nucleic acid polymers) that are currently under clinical evaluation.
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Affiliation(s)
- Patrizia Farci
- Dr Farci is chief of the Hepatic Pathogenesis Section of the Laboratory of Infectious Diseases at the National Institute of Allergy and Infectious Diseases in the National Institutes of Health in Bethesda, Maryland
- Dr Niro is a senior staff clinician in the Gastroenterology Unit at IRCCS Casa Sollievo Sofferenza Hospital in San Giovanni Rotondo, Foggia, Italy
| | - Grazia Anna Niro
- Dr Farci is chief of the Hepatic Pathogenesis Section of the Laboratory of Infectious Diseases at the National Institute of Allergy and Infectious Diseases in the National Institutes of Health in Bethesda, Maryland
- Dr Niro is a senior staff clinician in the Gastroenterology Unit at IRCCS Casa Sollievo Sofferenza Hospital in San Giovanni Rotondo, Foggia, Italy
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43
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Quinet J, Jamard C, Burtin M, Lemasson M, Guerret S, Sureau C, Vaillant A, Cova L. Nucleic acid polymer REP 2139 and nucleos(T)ide analogues act synergistically against chronic hepadnaviral infection in vivo in Pekin ducks. Hepatology 2018; 67:2127-2140. [PMID: 29251788 PMCID: PMC6001552 DOI: 10.1002/hep.29737] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 11/24/2017] [Accepted: 12/12/2017] [Indexed: 12/18/2022]
Abstract
Nucleic acid polymer (NAP) REP 2139 treatment was shown to block the release of viral surface antigen in duck HBV (DHBV)-infected ducks and in patients with chronic HBV or HBV/hepatitis D virus infection. In this preclinical study, a combination therapy consisting of REP 2139 with tenofovir disoproxil fumarate (TDF) and entecavir (ETV) was evaluated in vivo in the chronic DHBV infection model. DHBV-infected duck groups were treated as follows: normal saline (control); REP 2139 TDF; REP 2139 + TDF; and REP 2139 + TDF + ETV. After 4 weeks of treatment, all animals were followed for 8 weeks. Serum DHBsAg and anti-DHBsAg antibodies were monitored by enzyme-linked immunosorbent assay and viremia by qPCR. Total viral DNA and covalently closed circular DNA (cccDNA) were quantified in autopsy liver samples by qPCR. Intrahepatic DHBsAg was assessed at the end of follow-up by immunohistochemistry. On-treatment reduction of serum DHBsAg and viremia was more rapid when REP 2139 was combined with TDF or TDF and ETV, and, in contrast to TDF monotherapy, no viral rebound was observed after treatment cessation. Importantly, combination therapy resulted in a significant decrease in intrahepatic viral DNA (>3 log) and cccDNA (>2 log), which were tightly correlated with the clearance of DHBsAg in the liver. CONCLUSION Synergistic antiviral effects were observed when REP 2139 was combined with TDF or TDF + ETV leading to control of infection in blood and liver, associated with intrahepatic viral surface antigen elimination that persisted after treatment withdrawal. Our findings suggest the potential of developing such combination therapy for treatment of chronically infected patients in the absence of pegylated interferon. (Hepatology 2018;67:2127-2140).
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Affiliation(s)
- Jonathan Quinet
- Institut National de Santé et Recherche Médicale (INSERM) U1052LyonFrance
| | - Catherine Jamard
- Institut National de Santé et Recherche Médicale (INSERM) U1052LyonFrance
| | - Madeleine Burtin
- Institut National de Santé et Recherche Médicale (INSERM) U1052LyonFrance
| | | | | | - Camille Sureau
- Institut National de la Transfusion Sanguine (INTS)ParisFrance
| | | | - Lucyna Cova
- Institut National de Santé et Recherche Médicale (INSERM) U1052LyonFrance
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44
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Overcoming immune tolerance in chronic hepatitis B by therapeutic vaccination. Curr Opin Virol 2018; 30:58-67. [PMID: 29751272 DOI: 10.1016/j.coviro.2018.04.003] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Revised: 04/03/2018] [Accepted: 04/18/2018] [Indexed: 12/14/2022]
Abstract
The currently used nucleoside analogs (i.e. entecavir and tenofovir) with high barrier-to-resistance efficiently suppress viral replication, limit inflammation and reduce the sequelae of chronic hepatitis B, but cannot cure the disease and thus have to be applied long-term. Therapeutic vaccination as an approach to cure chronic hepatitis B has shown promising pre-clinical results, nevertheless the proof of its efficacy in clinical trials is still missing. This may be partially due to suboptimal vaccine design. A main obstacle in chronic hepatitis B, however, is the high load of viral antigens expressed and secreted, which has been proposed to cause antigen-specific immune tolerance. Reduction of the viral antigen load is therefore considered a key factor for success of immune-based therapies. Although nucleoside analogs do not reduce viral antigen expression, new antiviral strategies are becoming available. Targeting viral translation by siRNA or targeting release of HBsAg from infected hepatocytes by nucleic acid polymers both reduce the antigen load. They may be considered as pre-treatment for therapeutic vaccination to increase the potential to elicit an HBV-specific immune response able to control and cure chronic HBV infection.
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45
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Recent progress in potential anti-hepatitis B virus agents: Structural and pharmacological perspectives. Eur J Med Chem 2018; 147:205-217. [PMID: 29438889 DOI: 10.1016/j.ejmech.2018.02.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Revised: 01/29/2018] [Accepted: 02/01/2018] [Indexed: 12/13/2022]
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Nucleic Acid Polymers Are Active against Hepatitis Delta Virus Infection In Vitro. J Virol 2018; 92:JVI.01416-17. [PMID: 29212929 DOI: 10.1128/jvi.01416-17] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Accepted: 11/22/2017] [Indexed: 12/14/2022] Open
Abstract
In this study, an in vitro infection model for the hepatitis delta virus (HDV) was used to evaluate the antiviral effects of phosphorothioate nucleic acid polymers (NAPs) and investigate their mechanism of action. The results show that NAPs inhibit HDV infection at concentrations less than 4 μM in cultures of differentiated human hepatoma cells. NAPs were shown to be active at viral entry but inactive postentry on HDV RNA replication. Inhibition was independent of the NAP nucleotide sequence but dependent on both size and amphipathicity of the polymer. NAP antiviral activity was effective against HDV virions bearing the main hepatitis B virus (HBV) immune escape substitutions (D144A and G145R) and was pangenomic with regard to HBV envelope proteins. Furthermore, similar to immobilized heparin, immobilized NAPs could bind HDV particles, suggesting that entry inhibition was due, at least in part, to preventing attachment of the virus to cell surface glycosaminoglycans. The results document NAPs as a novel class of antiviral compounds that can prevent HDV propagation.IMPORTANCE HDV infection causes the most severe form of viral hepatitis in humans and one of the most difficult to cure. Currently, treatments are limited to long-term administration of interferon at high doses, which provide only partial efficacy. There is thus an urgent need for innovative approaches to identify new antiviral against HDV. The significance of our study is in demonstrating that nucleic acid polymers (NAPs) are active against HDV by targeting the envelope of HDV virions. In an in vitro infection assay, NAP activity was recorded at concentrations less than 4 μM in the absence of cell toxicity. Furthermore, the fact that NAPs could block HDV at viral entry suggests their potential to control the spread of HDV in a chronically HBV-infected liver. In addition, NAP anti-HDV activity was pangenomic with regard to HBV envelope proteins and not circumvented by HBsAg substitutions associated with HBV immune escape.
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47
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Bazinet M, Pântea V, Cebotarescu V, Cojuhari L, Jimbei P, Albrecht J, Schmid P, Le Gal F, Gordien E, Krawczyk A, Mijočević H, Karimzadeh H, Roggendorf M, Vaillant A. Safety and efficacy of REP 2139 and pegylated interferon alfa-2a for treatment-naive patients with chronic hepatitis B virus and hepatitis D virus co-infection (REP 301 and REP 301-LTF): a non-randomised, open-label, phase 2 trial. Lancet Gastroenterol Hepatol 2017; 2:877-889. [PMID: 28964701 DOI: 10.1016/s2468-1253(17)30288-1] [Citation(s) in RCA: 188] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2017] [Revised: 08/11/2017] [Accepted: 08/11/2017] [Indexed: 02/06/2023]
Affiliation(s)
| | - Victor Pântea
- Department of Infectious Diseases, State University of Medicine and Pharmacy 'Nicolae Testemitanu', Chișinău, Moldova
| | - Valentin Cebotarescu
- Department of Infectious Diseases, State University of Medicine and Pharmacy 'Nicolae Testemitanu', Chișinău, Moldova
| | - Lilia Cojuhari
- Department of Infectious Diseases, State University of Medicine and Pharmacy 'Nicolae Testemitanu', Chișinău, Moldova
| | - Pavlina Jimbei
- Toma Ciorbă Hospital of Infectious Diseases, Chișinău, Moldova
| | | | - Peter Schmid
- National Genetics Institute, Los Angeles, CA, USA
| | - Frédéric Le Gal
- Laboratoire de Microbiologie Clinique, Centre National de référence des hépatites B, C et Delta, Hôpitaux Universitaires de Paris Seine-Saint-Denis, Université Sorbonne Paris Cité, Paris, France
| | - Emmanuel Gordien
- Laboratoire de Microbiologie Clinique, Centre National de référence des hépatites B, C et Delta, Hôpitaux Universitaires de Paris Seine-Saint-Denis, Université Sorbonne Paris Cité, Paris, France
| | - Adalbert Krawczyk
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Hrvoje Mijočević
- Institute for Virology, Technical University of Munich, Munich, Germany
| | - Hadi Karimzadeh
- Institute for Virology, Technical University of Munich, Munich, Germany
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Schöneweis K, Motter N, Roppert PL, Lu M, Wang B, Roehl I, Glebe D, Yang D, Morrey JD, Roggendorf M, Vaillant A. Activity of nucleic acid polymers in rodent models of HBV infection. Antiviral Res 2017; 149:26-33. [PMID: 29126900 DOI: 10.1016/j.antiviral.2017.10.022] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2017] [Revised: 09/19/2017] [Accepted: 10/27/2017] [Indexed: 12/18/2022]
Abstract
Nucleic acid polymers (NAPs) block the release of HBsAg from infected hepatocytes. These compounds have been previously shown to have the unique ability to eliminate serum surface antigen in DHBV-infected Pekin ducks and achieve multilog reduction of HBsAg or HBsAg loss in patients with chronic HBV infection and HBV/HDV coinfection. In ducks and humans, the blockage of HBsAg release by NAPs occurs by the selective targeting of the assembly and/or secretion of subviral particles (SVPs). The clinically active NAP species REP 2055 and REP 2139 were investigated in other relevant animal models of HBV infection including woodchucks chronically infected with WHV, HBV transgenic mice and HBV infected SCID-Hu mice. The liver accumulation of REP 2139 in woodchucks following subcutaneous administration was examined and was found to be similar to that observed in mice and ducks. However, in woodchucks, NAP treatment was associated with only mild (36-79% relative to baseline) reductions in WHsAg (4/10 animals) after 3-5 weeks of treatment without changes in serum WHV DNA. In HBV infected SCID-Hu mice, REP 2055 treatment was not associated with any reduction of HBsAg, HBeAg or HBV DNA in the serum after 28 days of treatment. In HBV transgenic mice, no reductions in serum HBsAg were observed with REP 2139 with up to 12 weeks of treatment. In conclusion, the antiviral effects of NAPs in DHBV infected ducks and patients with chronic HBV infection were weak or absent in woodchuck and mouse models despite similar liver accumulation of NAPs in all these species, suggesting that the mechanisms of SVP assembly and or secretion present in rodent models differs from that in DHBV and chronic HBV infections.
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Affiliation(s)
- Katrin Schöneweis
- Department of Virology, University of Duisburg-Essen, Essen, Germany
| | - Neil Motter
- Institute for Antiviral Research, Utah State University, Logan, UT, USA
| | - Pia L Roppert
- Institute of Medical Virology, National Reference Centre for Hepatitis B and D Viruses, German Centre for Infection Research (DZIF), Justus Liebig University of Giessen, Giessen, Germany
| | - Mengji Lu
- Department of Virology, University of Duisburg-Essen, Essen, Germany
| | - Baoju Wang
- Department of Infectious Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | | | - Dieter Glebe
- Institute of Medical Virology, National Reference Centre for Hepatitis B and D Viruses, German Centre for Infection Research (DZIF), Justus Liebig University of Giessen, Giessen, Germany
| | - Dongliang Yang
- Department of Infectious Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - John D Morrey
- Institute for Antiviral Research, Utah State University, Logan, UT, USA
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49
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Pei Y, Wang C, Yan SF, Liu G. Correction to Past, Current, and Future Developments of Therapeutic Agents for Treatment of Chronic Hepatitis B Virus Infection. J Med Chem 2017; 60:6766-6767. [PMID: 28613860 DOI: 10.1021/acs.jmedchem.7b00781] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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50
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Lempp FA, Urban S. Hepatitis Delta Virus: Replication Strategy and Upcoming Therapeutic Options for a Neglected Human Pathogen. Viruses 2017; 9:E172. [PMID: 28677645 PMCID: PMC5537664 DOI: 10.3390/v9070172] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Revised: 06/28/2017] [Accepted: 06/29/2017] [Indexed: 12/15/2022] Open
Abstract
The human Hepatitis Delta Virus (HDV) is unique among all viral pathogens. Encoding only one protein (Hepatitis Delta Antigen; HDAg) within its viroid-like self-complementary RNA, HDV constitutes the smallest known virus in the animal kingdom. To disseminate in its host, HDV depends on a helper virus, the human Hepatitis B virus (HBV), which provides the envelope proteins required for HDV assembly. HDV affects an estimated 15-20 million out of the 240 million chronic HBV-carriers and disperses unequally in disparate geographical regions of the world. The disease it causes (chronic Hepatitis D) presents as the most severe form of viral hepatitis, leading to accelerated progression of liver dysfunction including cirrhosis and hepatocellular carcinoma and a high mortality rate. The lack of approved drugs interfering with specific steps of HDV replication poses a high burden for gaining insights into the molecular biology of the virus and, consequently, the development of specific novel medications that resiliently control HDV replication or, in the best case, functionally cure HDV infection or HBV/HDV co-infection. This review summarizes our current knowledge of HBV molecular biology, presents an update on novel cell culture and animal models to study the virus and provides updates on the clinical development of the three developmental drugs Lonafarnib, REP2139-Ca and Myrcludex B.
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Affiliation(s)
- Florian A Lempp
- Department of Infectious Diseases, Molecular Virology, Heidelberg University, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany.
- German Centre for Infection Research (DZIF), Partner Site Heidelberg, 69120 Heidelberg, Germany.
| | - Stephan Urban
- Department of Infectious Diseases, Molecular Virology, Heidelberg University, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany.
- German Centre for Infection Research (DZIF), Partner Site Heidelberg, 69120 Heidelberg, Germany.
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