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Ratnaparkhi MM, Vyawahare CR, Gandham NR. Hepatitis B virus genotype distribution and mutation patterns: Insights and clinical implications for hepatitis B virus positive patients. World J Exp Med 2025; 15:102395. [DOI: 10.5493/wjem.v15.i2.102395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 01/05/2025] [Accepted: 01/14/2025] [Indexed: 04/16/2025] Open
Abstract
Hepatitis B virus (HBV) infection is still a major worldwide health concern, contributing to chronic liver disorders like hepatocellular carcinoma (HCC). This review comprehensively analyzes HBV genotype distribution, mutation patterns, and their clinical implications, focusing on diagnostic and therapeutic strategies for HBV-positive patients. The discussion begins with HBV virology, emphasizing its capacity for chronic hepatitis and its association with severe liver complications, notably HCC. Understanding HBV genotypes (A-J) and their distinct geographic distributions is crucial, as genotype variations influence disease progression and treatment responses. Genotypes like C are particularly linked to heightened HCC risk, highlighting the need for genotype-specific management strategies. The genomic structure of HBV, consisting of four open reading frames (ORFs) encoding essential viral proteins, is detailed, with emphasis on mutations within these ORFs influenced by host immune responses and antiviral therapies. These mutations contribute to viral resistance and virulence, impacting treatment outcomes through alterations in viral replication dynamics. Clinical implications are explored through genotype-specific impacts on disease outcomes and treatment approaches. Genotype and mutation analysis guide personalized treatment regimens, optimizing therapeutic efficacy while minimizing adverse effects and preventing drug resistance. Diagnostic molecular techniques such as polymerase chain reaction and sequencing are pivotal in genotype and mutation detection, facilitating tailored treatment decisions.
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Affiliation(s)
- Manisha M Ratnaparkhi
- Department of Microbiology, Dr. D. Y. Patil Medical College, Hospital and Research Centre and Dr. D. Y. Patil Vidyapeeth, Pune 411018, Mahārāshtra, India
| | - Chanda R Vyawahare
- Department of Microbiology, Dr. D. Y. Patil Medical College, Hospital and Research Centre and Dr. D. Y. Patil Vidyapeeth, Pune 411018, Mahārāshtra, India
| | - Nageswari R Gandham
- Department of Microbiology, Dr. D. Y. Patil Medical College, Hospital and Research Centre and Dr. D. Y. Patil Vidyapeeth, Pune 411018, Mahārāshtra, India
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Luo C, Ma C, Xu G, Lu C, Ma J, Huang Y, Nie L, Yu C, Xia Y, Liu Z, Zhu Y, Liu S. Hepatitis B surface antigen hijacks TANK-binding kinase 1 to suppress type I interferon and induce early autophagy. Cell Death Dis 2025; 16:304. [PMID: 40234418 PMCID: PMC12000394 DOI: 10.1038/s41419-025-07605-0] [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: 07/16/2024] [Revised: 03/19/2025] [Accepted: 03/27/2025] [Indexed: 04/17/2025]
Abstract
There are close links between innate immunity and autophagy. However, the crosstalk between innate immunity and autophagy in host cells infected with hepatitis B virus (HBV) remains unclear. Here, we reported that HBsAg suppressed type I interferon production and induced the accumulation of autophagosomes. HBsAg boosted TANK-binding kinase 1 (TBK1) phosphorylation and depressed interferon regulatory factor 3 (IRF3) phosphorylation ex vivo and in vivo. Mechanistic studies showed that HBsAg interaction with the kinase domain (KD) of TBK1 augmented its dimerization but disrupted TBK1-IRF3 complexes. Using the TBK1 inhibitor, BX795, we discovered that HBsAg-enhanced TBK1 dimerization, promoting sequestosome-1 (p62) phosphorylation, was necessary for HBV-induced autophagy and HBV replication. Moreover, HBsAg blocked autophagosome-lysosome fusion by inhibiting the synaptosomal-associated protein 29 (SNAP29) promoter. Notably, liver tissues from HBsAg transgenic mice or chronic HBV patients revealed that IFNβ signaling was inhibited and incomplete autophagy was induced. These findings suggest a novel mechanism by which HBsAg targets TBK1 to inhibit type I interferon and induce early autophagy, possibly leading to persistent HBV infection. Molecular mechanisms of HBsAg suppression of the IFNβ signaling pathway and triggering of early autophagy. HBsAg targets the kinase domain of TBK1, thereby disrupting the TBK1-IRF3 complex and inhibiting type I interferon production. On the other hand, HBsAg enhances TBK1 dimerization and phosphorylation, which upregulates the phosphorylation of p62 to induce p62-mediated autophagy. Furthermore, HBV infection causes the accumulation of autophagosomes. This is achieved by HBsAg suppressing the SNAP29 promoter activity, which blocks autophagosome-lysosome fusion.
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Affiliation(s)
- Chuanjin Luo
- State Key Laboratory of Virology, Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, China
| | - Caijiao Ma
- State Key Laboratory of Virology, Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, China
| | - Gang Xu
- State Key Laboratory of Virology, Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, China
| | - Chengbo Lu
- State Key Laboratory of Virology, Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, China
| | - June Ma
- Department of Clinical Laboratory, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yu Huang
- State Key Laboratory of Virology, Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, China
| | - Longyu Nie
- State Key Laboratory of Virology, Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, China
| | - Chen Yu
- State Key Laboratory of Virology, Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, China
| | - Yongfang Xia
- State Key Laboratory of Virology, Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, China
| | - Zhiqiang Liu
- State Key Laboratory of Virology, Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, China
| | - Ying Zhu
- State Key Laboratory of Virology, Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, China.
| | - Shi Liu
- State Key Laboratory of Virology, Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, China.
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Yamagishi N, Ando N, Yoshimasa T, Toda S, Sobata R, Goto N, Matsubayashi K, Satake M, Tani Y. The first case of transfusion-transmitted hepatitis B virus genotype I in Japan. Transfusion 2025; 65:773-778. [PMID: 40025815 PMCID: PMC12005574 DOI: 10.1111/trf.18186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 02/13/2025] [Accepted: 02/14/2025] [Indexed: 03/04/2025]
Abstract
BACKGROUND In Japan, the risk of transfusion-transmitted hepatitis B virus (TT-HBV) infection has been reduced since 2014 by implementing individual donation nucleic acid amplification testing (ID-NAT). CASE REPORT A male repeat blood donor in his 20s converted positive for HBV DNA and hepatitis B surface antigen. Red cell concentrate from his previous donation had been transfused into a woman in her 70s. Her serum showed HBV DNA positivity 62 days after transfusion. HBV genome sequences across two regions were shown to be identical in the donor and recipient. The HBV full-length genome sequence from the donor belonged to nonindigenous subgenotype I1. It contained double mutations A1762T and G1764A, which are associated with hepatocellular carcinoma development. The donor had no history of traveling abroad within 126 days prior to the index donation, so he was probably infected with HBV in Japan. DISCUSSION Including this case, nine cases of TT-HBV from eight blood donations have been detected in Japan since the introduction of ID-NAT. Seven of the eight TT-HBV-related donations had HBV subgenotypes that were exotic to Japan. Exotic HBV strains spreading in Japan pose a risk of TT-HBV owing to ongoing acute HBV infection with these strains.
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Affiliation(s)
- Naoji Yamagishi
- Central Blood Institute, Blood Service HeadquartersJapanese Red Cross SocietyTokyoJapan
| | - Naoko Ando
- Central Blood Institute, Blood Service HeadquartersJapanese Red Cross SocietyTokyoJapan
| | - Takashi Yoshimasa
- Central Blood Institute, Blood Service HeadquartersJapanese Red Cross SocietyTokyoJapan
| | - Shizuho Toda
- Central Blood Institute, Blood Service HeadquartersJapanese Red Cross SocietyTokyoJapan
| | - Rieko Sobata
- Central Blood Institute, Blood Service HeadquartersJapanese Red Cross SocietyTokyoJapan
| | - Naoko Goto
- Blood Service HeadquartersJapanese Red Cross SocietyTokyoJapan
| | - Keiji Matsubayashi
- Central Blood Institute, Blood Service HeadquartersJapanese Red Cross SocietyTokyoJapan
| | - Masahiro Satake
- Blood Service HeadquartersJapanese Red Cross SocietyTokyoJapan
| | - Yoshihiko Tani
- Central Blood Institute, Blood Service HeadquartersJapanese Red Cross SocietyTokyoJapan
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Hales LT, Mountford SJ, Takawy M, Colledge D, Maher B, Shortt J, Thompson PE, Greenall SA, Warner N. VHL-independent degradation of hepatitis B virus e antigen (HBeAg) by VHL-binding chimeric small molecules. RSC Med Chem 2025:d5md00118h. [PMID: 40276592 PMCID: PMC12017376 DOI: 10.1039/d5md00118h] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Accepted: 03/22/2025] [Indexed: 04/26/2025] Open
Abstract
Hepatitis B virus (HBV) is a leading cause of liver cancer worldwide, with current treatment options unable to provide lasting efficacy against chronic infection. A key viral protein, HBV e antigen (HBeAg), plays an important role in suppressing the cellular and humoral immune response during infection and its loss is a precursor to clearance of chronic HBV infection. Its structural similarity to capsid forming HBV core protein antigen (HBcAg) makes it an intriguing, yet understudied target for pharmaceutical intervention. Recently, targeted protein degradation has been successfully applied against several viral proteins. This work investigates the targeting of HBeAg using heterobifunctional degraders derived from reported HBcAg ligands known to interact with HBeAg. Multiple compounds designed to recruit the VHL E3 ligase were found to be capable of reducing recombinant HBeAg protein levels in a HiBiT reporter assay system. Surprisingly, this decrease was found to be independent of VHL recruitment but driven by structural motifs of the VHL recruiting ligand, VH032. Virological assessment of these compounds against wildtype virus revealed an equipotent capability to reduce secreted HBeAg compared to the parental inhibitor, however increased efficacy was observed against an inhibitor resistant strain. Together, this work provides an initial description of the feasibility of converting HBV capsid-targeting ligands into degraders and provides evidence that such degraders may harbour improved activity against mutated forms of target which are resistant to parental compounds.
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Affiliation(s)
- Liam T Hales
- Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University Parkville 3052 Australia
| | - Simon J Mountford
- Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University Parkville 3052 Australia
| | - Mina Takawy
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital at The Peter Doherty, Institute for Infection and Immunity Melbourne 3000 Australia
| | - Danni Colledge
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital at The Peter Doherty, Institute for Infection and Immunity Melbourne 3000 Australia
| | - Belinda Maher
- Blood Cancer Therapeutics Laboratory, Department of Medicine, School of Clinical Sciences at Monash Health, Monash University Clayton 3168 Australia
- Monash Haematology, Monash Health Clayton 3168 Australia
| | - Jake Shortt
- Blood Cancer Therapeutics Laboratory, Department of Medicine, School of Clinical Sciences at Monash Health, Monash University Clayton 3168 Australia
- Monash Haematology, Monash Health Clayton 3168 Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne Parkville 3010 Australia
| | - Philip E Thompson
- Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University Parkville 3052 Australia
| | - Sam A Greenall
- Blood Cancer Therapeutics Laboratory, Department of Medicine, School of Clinical Sciences at Monash Health, Monash University Clayton 3168 Australia
| | - Nadia Warner
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital at The Peter Doherty, Institute for Infection and Immunity Melbourne 3000 Australia
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Chiang CM, Lin YJ, Liu WC, Chou TC, Tsai CH, Chang TT, Wu IC. HBV Recurrence Detected by HBV-Related Serum Markers and Immune Escape Mutations in Chronic Hepatitis B Patients Following Liver Transplantation. J Med Virol 2025; 97:e70306. [PMID: 40108993 DOI: 10.1002/jmv.70306] [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: 07/09/2024] [Revised: 03/01/2025] [Accepted: 03/09/2025] [Indexed: 03/22/2025]
Abstract
The posttransplantation recurrence rate of hepatitis B virus (HBV) infection in patients with chronic hepatitis B (CHB) is underestimated and linked with unfavorable outcomes. We investigated HBV recurrence by serum assays in patients with CHB following liver transplantation. We enrolled patients with CHB who underwent liver transplantation between March 2001 and July 2021 to participate in cross-sectional testing for HBV-related serum markers, including biochemical analysis for HBsAg and hepatitis B core-related antigen (HBcrAg) and real-time RT-PCR/PCR for HBV RNA and HBV DNA, in 2022. HBV recurrence in this study was defined as positive results of at least one posttransplantation HBV-related serum markers. Next-generation sequencing was performed for those with posttransplantation virological breakthroughs. Ninety-six patients with CHB who underwent liver transplantation were enrolled. Among 84 patients who received grafts negative for HBsAg, 41 (48.8%) exhibited HBV recurrence, and they tested positive for either HBsAg or HBcrAg, or both. High-risk patients, identified using a risk stratification model, had a higher likelihood of recurrence than low-risk patients (odds ratio: 2.59, 95% confidence interval: 1.06-6.35, p = 0.038). In 51 patients who tested negative for HBsAg after receiving HBsAg-negative grafts, 8 (15.7%) had positive HBcrAg, indicating occult HBV infection (OBI). We identified immune escape mutations and altered N-glycosylation patterns on the surface protein in patients experiencing virological breakthroughs following lamivudine resistance. HBsAg plus HBcrAg levels can be used to detect posttransplantation HBV recurrence. The OBI prevalence was higher in patients transplanted with HBsAg-negative liver grafts compared to blood donors, vaccinated young population, and community-based populations reported in literatures, possibly because of immune escape mutations or altered N-glycosylation patterns of surface proteins.
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Affiliation(s)
- Chien-Ming Chiang
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yih-Jyh Lin
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Wen-Chun Liu
- Department of Nursing, National Tainan Junior College of Nursing, Tainan, Taiwan
| | - Tsung-Ching Chou
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chih-Hsuan Tsai
- Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Ting-Tsung Chang
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - I-Chin Wu
- Medical Department, Ministry of Health and Welfare Hengchun Tourism Hospital, Pingtung, Taiwan
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6
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Lehky M, Moonian T, Michel T, Junker D, Müsken M, Strömpl J, Nübling P, Neumann F, Krumbholz A, Krause G, Schneiderhan‐Marra N, van den Heuvel J, Strengert M. A novel method for recombinant mammalian-expressed S-HBsAg virus-like particle production for assembly status analysis and improved anti-HBs serology. Protein Sci 2025; 34:e5251. [PMID: 39660966 PMCID: PMC11633054 DOI: 10.1002/pro.5251] [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: 06/11/2024] [Revised: 10/19/2024] [Accepted: 11/25/2024] [Indexed: 12/12/2024]
Abstract
The Hepatitis B surface antigen (HBsAg) as the only lipid-associated envelope protein of the Hepatitis B virus (HBV) acts as cellular attachment and entry mediator of HBV making it the main target of neutralizing antibodies to provide HBV immunity after infection or vaccination. Despite its central role in inducing protective immunity, there is however a surprising lack of comparative studies examining different HBsAgs and their ability to detect anti-HBs antibodies. On the contrary, various time-consuming complex HBsAg production protocols have been established, which result in structurally and functionally insufficiently characterized HBsAg. Here, we present an easy-to-perform, streamlined and robust method for recombinant S-HBsAg virus-like particle (VLP) production by transient expression in mammalian cells and purification from the cell lysate with the aim of displaying uniform antigenic epitopes on the surface to improve serological detection of anti-HBs antibodies. We not only compare assembly status and particle composition by transmission electron microscopy and mass photometry of our S-HBsAg and of commonly used HBsAg reference samples, but also assess their antigenic quality and functional suitability for anti-HBs antibody detection to identify the best performing sample for serological screenings. While we found that serum-isolated and recombinant HBsAg VLPs are assembled differently, our S-HBsAg VLPs detected anti-HBs antibodies with the highest sensitivity and specificity in multiplex serology when compared to yeast or serum HBsAg making it the most suitable antigen for analysis of HBV immunity through anti-HBs serostatus.
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Affiliation(s)
- Michael Lehky
- Department of Structure and Function of ProteinsHelmholtz Centre for Infection ResearchBraunschweigGermany
| | - Tashveen Moonian
- Department of EpidemiologyHelmholtz Centre for Infection ResearchBraunschweigGermany
| | - Tanja Michel
- Department of Multiplex ImmunoassaysNMI Natural and Medical Sciences Institute at the University of TübingenReutlingenGermany
| | - Daniel Junker
- Department of Multiplex ImmunoassaysNMI Natural and Medical Sciences Institute at the University of TübingenReutlingenGermany
| | - Mathias Müsken
- Central Facility for MicroscopyHelmholtz Centre for Infection ResearchBraunschweigGermany
| | - Julia Strömpl
- Department of EpidemiologyHelmholtz Centre for Infection ResearchBraunschweigGermany
| | - Patrick Nübling
- Department of EpidemiologyHelmholtz Centre for Infection ResearchBraunschweigGermany
| | | | - Andi Krumbholz
- Laboratory Dr. Krause and Colleagues MVZ GmbHKielGermany
- Institute for Infection MedicineKiel University and University Hospital Schleswig‐HolsteinKielGermany
| | - Gérard Krause
- Department of EpidemiologyHelmholtz Centre for Infection ResearchBraunschweigGermany
- German Centre for Infection Research (DZIF)Braunschweig‐HannoverGermany
- TWINCORE, Centre for Experimental and Clinical Infection ResearchA Joint Venture of Hannover Medical School and the Helmholtz Centre for Infection ResearchHannoverGermany
| | - Nicole Schneiderhan‐Marra
- Department of Multiplex ImmunoassaysNMI Natural and Medical Sciences Institute at the University of TübingenReutlingenGermany
| | - Joop van den Heuvel
- Department of Structure and Function of ProteinsHelmholtz Centre for Infection ResearchBraunschweigGermany
| | - Monika Strengert
- Department of EpidemiologyHelmholtz Centre for Infection ResearchBraunschweigGermany
- TWINCORE, Centre for Experimental and Clinical Infection ResearchA Joint Venture of Hannover Medical School and the Helmholtz Centre for Infection ResearchHannoverGermany
- Department of Virus‐based TechnologiesFraunhofer Institute for Interfacial Engineering and Biotechnology IGBBiberach an der RißGermany
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Pondé RADA, Amorim GDSP. Exchanges in the 'a' determinant of the hepatitis B virus surface antigen revisited. Virology 2024; 599:110184. [PMID: 39127000 DOI: 10.1016/j.virol.2024.110184] [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: 04/16/2024] [Revised: 07/02/2024] [Accepted: 07/17/2024] [Indexed: 08/12/2024]
Abstract
The hepatitis B virus surface antigen's (HBsAg) 'a' determinant comprises a sequence of amino acid residues located in the major hydrophilic region of the S protein, whose exchanges are closely associated with compromising the antigenicity and immunogenicity of that antigen. The HBsAg is generally present in the bloodstream of individuals with acute or chronic hepatitis B virus (HBV) infection. It is classically known as the HBV infection marker, and is therefore the first marker to be investigated in the laboratory in the clinical hypothesis of infection by this agent. One of the factors that compromises the HBsAg detection in the bloodstream by the assays adopted in serological screening in both clinical contexts is the loss of S protein antigenicity. This can occur due to mutations that emerge in the HBV genome regions that encode the S protein, especially for its immunodominant region - the 'a' determinant. These mutations can induce exchanges of amino acid residues in the S protein's primary structure, altering its tertiary structure and the antigenic conformation, which may not be recognized by anti-HBs antibodies, compromising the infection diagnosis. In addition, these exchanges can render ineffective the anti-HBs antibodies action acquired by vaccination, compromise the effectiveness of the chronically HBV infected patient's treatment, and also the HBsAg immunogenicity, by promoting its retention within the cell. In this review, the residues exchange that alter the S protein's structure is revisited, as well as the mechanisms that lead to the HBsAg antigenicity loss, and the clinical, laboratory and epidemiological consequences of this phenomenon.
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Affiliation(s)
- Robério Amorim de Almeida Pondé
- Secretaria de Estado da Saúde -SES/Superintendência de Vigilância Em Saúde-SUVISA/GO, Gerência de Vigilância Epidemiológica de Doenças Transmissíveis-GVEDT/Coordenação de Análises e Pesquisas-CAP, Goiânia, Goiás, Brazil; Laboratory of Human Virology, Institute of Tropical Pathology and Public Health, Federal University of Goiás, Goiânia, Goiás, Brazil.
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Yang X, Wang H, Yu C. The Mechanism of APOBEC3B in Hepatitis B Virus Infection and HBV Related Hepatocellular Carcinoma Progression, Therapeutic and Prognostic Potential. Infect Drug Resist 2024; 17:4477-4486. [PMID: 39435460 PMCID: PMC11492903 DOI: 10.2147/idr.s484265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 10/11/2024] [Indexed: 10/23/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors globally. Prominent factors include chronic hepatitis B (CHB) and chronic hepatitis C (CHC) virus infections, exposure to aflatoxin, alcohol abuse, diabetes, and obesity. The prevalence of hepatitis B (HBV) is substantial, and the significant proportion of asymptomatic carriers heightens the challenge in diagnosing and treating hepatocellular carcinoma (HCC), necessitating further and more comprehensive research. Apolipoprotein B mRNA editing catalytic polypeptide (APOBEC) family members are single-stranded DNA cytidine deaminases that can restrict viral replication. The APOBEC-related mutation pattern constitutes a primary characteristic of somatic mutations in various cancer types such as lung, breast, bladder, head and neck, cervix, and ovary. Symptoms in the early stages of HCC are often subtle and nonspecific, posing challenges in treatment and monitoring. Furthermore, this article primarily focuses on the established specific mechanism of action of the APOBEC3B (A3B) gene in the onset and progression of HBV-related HCC (HBV-HCC) through stimulating mutations in HBV, activating Interleukin-6 (IL-6) and promoting reactive oxygen species(ROS) production, while also exploring the potential for A3B to serve as a therapeutic target and prognostic indicator in HBV-HCC.
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Affiliation(s)
- Xiaochen Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China
| | - Huanqiu Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China
| | - Chengbo Yu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China
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9
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Kim HS, Kim JS, Kim JM, Han JW, Lee SK, Nam H, Sung PS, Kwon JH, Bae SH, Choi JY, Yoon SK, Jang JW. Differential HBV replicative markers and covalently closed circular DNA transcription in immune-active chronic hepatitis B with and without HBeAg. Liver Int 2024; 44:2753-2762. [PMID: 39073214 DOI: 10.1111/liv.16032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 05/29/2024] [Accepted: 06/26/2024] [Indexed: 07/30/2024]
Abstract
BACKGROUND AND AIMS Molecular processes driving immune-active chronic hepatitis B (CHB) with and without hepatitis B e antigen (HBeAg) remain incompletely understood. This study aimed to investigate expression profiles of serum and intrahepatic HBV markers and replicative activity of HBV in CHB patients with or without HBeAg. METHODS This study recruited 111 untreated immune-active CHB (60 HBeAg-positive and 51 HBeAg-negative) patients and quantified intrahepatic covalently closed circular DNA (cccDNA), pre-genomic RNA (pgRNA), total HBV DNA (tDNA), and replicative intermediates as well as serum HBV markers (HBV DNA, hepatitis B surface antigen, hepatitis B core-related antigen). Correlations between HBV markers and clinico-virological factors influencing expression levels of HBV markers were analysed. RESULTS Levels of all serum markers and intrahepatic cccDNA/tDNA as well as cccDNA transcriptional activity and virion productivity were significantly reduced in HBeAg-negative patients compared to those in HBeAg-positive patients. Additionally, correlations between intrahepatic cccDNA/pgRNA and serum markers were impaired in HBeAg-negative individuals. Aminotransferase levels were positively correlated with cccDNA transcriptional activity in HBeAg-positive patients, but not in HBeAg-negative patients. Notably, among HBeAg-positive patients, there was a progressive decline in pgRNA level, transcriptional activity, and serum HBV markers as liver fibrosis advanced, which was not observed in HBeAg-negative patients. CONCLUSIONS HBeAg loss is correlated with diminished intrahepatic HBV reservoirs and cccDNA transcription, leading to decreased serum HBV marker levels. Circulating HBV markers are not reliable indicators of intrahepatic HBV replicative activity for HBeAg-negative patients. Our findings reveal distinct disease phenotypes between immune-active CHB with and without HBeAg, highlighting the need to establish optimal surrogate biomarkers that can accurately mirror intrahepatic viral activity to aid in decision-making for antiviral therapy for immune-active CHB.
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Affiliation(s)
- Hye Seon Kim
- The Catholic University Liver Research Center, Collage of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Department of Biomedicine & Health Sciences, Graduate School, The Catholic University of Korea, Seoul, Republic of Korea
- Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jin Seoub Kim
- The Catholic University Liver Research Center, Collage of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Department of Biomedicine & Health Sciences, Graduate School, The Catholic University of Korea, Seoul, Republic of Korea
- Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Ji Min Kim
- The Catholic University Liver Research Center, Collage of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Department of Biomedicine & Health Sciences, Graduate School, The Catholic University of Korea, Seoul, Republic of Korea
- Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Ji Won Han
- The Catholic University Liver Research Center, Collage of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Soon Kyu Lee
- The Catholic University Liver Research Center, Collage of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Heechul Nam
- The Catholic University Liver Research Center, Collage of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Pil Soo Sung
- The Catholic University Liver Research Center, Collage of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jung Hyun Kwon
- The Catholic University Liver Research Center, Collage of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Si Hyun Bae
- The Catholic University Liver Research Center, Collage of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jong Young Choi
- The Catholic University Liver Research Center, Collage of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Seung Kew Yoon
- The Catholic University Liver Research Center, Collage of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jeong Won Jang
- The Catholic University Liver Research Center, Collage of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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10
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Bucio-Ortiz L, Enriquez-Navarro K, Maldonado-Rodríguez A, Torres-Flores JM, Cevallos AM, Salcedo M, Lira R. Occult Hepatitis B Virus Infection in Hepatic Diseases and Its Significance for the WHO's Elimination Plan of Viral Hepatitis. Pathogens 2024; 13:662. [PMID: 39204261 PMCID: PMC11357063 DOI: 10.3390/pathogens13080662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 07/30/2024] [Accepted: 08/02/2024] [Indexed: 09/03/2024] Open
Abstract
Liver damage can progress through different stages, resulting in cirrhosis or hepatocellular carcinoma (HCC), conditions that are often associated with viral infections. Globally, 42% and 21% of cirrhosis cases correlate with HBV and HCV, respectively. In the Americas, the prevalence ranges from 1% to 44%. The WHO has the goal to eliminate viral hepatitis, but it is important to consider occult HBV infection (OBI), a clinical condition characterized by the presence of HBV genomes despite negative surface antigen tests. This review aims to provide an overview of recent data on OBI, focusing on its role in the development of hepatic diseases and its significance in the WHO Viral Hepatitis Elimination Plan. Specific HBV gene mutations have been linked to HCC and other liver diseases. Factors related to the interactions between OBI and mutated viral proteins, which induce endoplasmic reticulum stress and oxidative DNA damage, and the potential role of HBV integration sites (such as the TERT promoter) have been identified in HCC/OBI patients. Health initiatives for OBI research in Latin American countries are crucial to achieving the WHO's goal of eradicating viral hepatitis by 2030, given the difficulty in diagnosing OBI and its unclear association with hepatic diseases.
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Affiliation(s)
- Leticia Bucio-Ortiz
- Medicina y Carcinogénesis Experimental, Universidad Autónoma Metropolitana Iztapalapa, Ciudad de Mexico 09340, Mexico; (L.B.-O.); (K.E.-N.)
| | - Karina Enriquez-Navarro
- Medicina y Carcinogénesis Experimental, Universidad Autónoma Metropolitana Iztapalapa, Ciudad de Mexico 09340, Mexico; (L.B.-O.); (K.E.-N.)
- Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias, UMAE Hospital de Pediatría, CMN Siglo XXI, Instituto Mexicano del Seguro Social (IMSS), Ciudad de Mexico 06720, Mexico;
| | - Angélica Maldonado-Rodríguez
- Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias, UMAE Hospital de Pediatría, CMN Siglo XXI, Instituto Mexicano del Seguro Social (IMSS), Ciudad de Mexico 06720, Mexico;
| | - Jesús Miguel Torres-Flores
- Laboratorio Nacional de Vacunología y Virus Tropicales, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Ciudad de Mexico 11350, Mexico;
| | - Ana María Cevallos
- Departamento de Biología Molecular y Biotecnología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de Mexico, Ciudad de Mexico 04510, Mexico;
| | - Mauricio Salcedo
- Unidad de Investigación Biomédica Oncológica Genómica, Hospital de Gineco Pediatría 3-A, Instituto Mexicano del Seguro Social, Órgano de Operación Administrativa Desconcentrada (OOAD) Cd Mx Norte, Ciudad de Mexico 07760, Mexico;
| | - Rosalia Lira
- Unidad de Investigación Biomédica Oncológica Genómica, Hospital de Gineco Pediatría 3-A, Instituto Mexicano del Seguro Social, Órgano de Operación Administrativa Desconcentrada (OOAD) Cd Mx Norte, Ciudad de Mexico 07760, Mexico;
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11
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Adachi E, Sedohara A, Arizono K, Takahashi K, Otani A, Kanno Y, Saito M, Koga M, Yotsuyanagi H. Hepatitis B Virus Reactivation after Switch to Cabotegravir/Rilpivirine in Patient with Low Hepatitis B Surface Antibody. Emerg Infect Dis 2024; 30:1668-1671. [PMID: 39043430 PMCID: PMC11286062 DOI: 10.3201/eid3008.240019] [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: 07/25/2024] Open
Abstract
A patient in Japan with HIV began antiretroviral therapy because of acute hepatitis B virus (HBV) 15 years ago, with low hepatitis B surface antibody, and experienced breakthrough HBV reactivation 4 months after switching from bictegravir/emtricitabine/tenofovir alafenamide to cabotegravir/rilpivirine. An immune escape mutation, E164V, was identified in the isolated HBV DNA.
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12
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Sasaki T, Kakisaka K, Miyasaka A, Nishiya M, Yanagawa N, Kuroda H, Matsumoto T, Takahashi M, Okamoto H. Spontaneous reactivation of hepatitis B virus with multiple novel mutations in an elderly patient with resolved hepatitis B virus infection. Clin J Gastroenterol 2024; 17:683-690. [PMID: 38748198 DOI: 10.1007/s12328-024-01984-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 05/05/2024] [Indexed: 07/11/2024]
Abstract
Spontaneous reactivation of the Hepatitis B virus (HBV) is rare in individuals with previously resolved infections. This report presents the case of a 71 year-old Japanese woman who experienced HBV reactivation without any prior immunosuppressive therapy or chemotherapy. Before the onset of liver injury, the patient was negative for hepatitis B surface antigen (HBsAg) but positive for hepatitis B surface antibody. She subsequently developed liver injury, with the reappearance of HBsAg and HBV DNA. The patient was successfully treated with tenofovir alafenamide, and prednisolone. Full-genome sequencing of HBV revealed subgenotype B1 without hepatitis B e-negative mutations in the precore and core promoter regions and 12 amino acid alterations in the pre-S1/S, P, and X genes. Notably, the S gene mutations D144A and K160N, which alter the antigenicity of HBsAg and potentially contribute to its reactivation, were identified. This case emphasizes the importance of vigilance for spontaneous reactivation of resolved HBV, highlighting the need for comprehensive genomic analysis to understand the associated virological intricacies.
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Affiliation(s)
- Tokio Sasaki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Iwate, 028-3694, Japan.
| | - Keisuke Kakisaka
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Iwate, 028-3694, Japan
| | - Akio Miyasaka
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Iwate, 028-3694, Japan
| | - Masao Nishiya
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Iwate, 028-3694, Japan
| | - Naoki Yanagawa
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Iwate, 028-3694, Japan
| | - Hidekatsu Kuroda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Iwate, 028-3694, Japan
| | - Takayuki Matsumoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Iwate, 028-3694, Japan
| | - Masaharu Takahashi
- Division of Virology, Department of Infection and Immunity, School of Medicine, Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan
| | - Hiroaki Okamoto
- Division of Virology, Department of Infection and Immunity, School of Medicine, Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan
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13
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Savaliya BP, Shekouhi R, Mubarak F, Manaise HK, Jimenez PB, Kowkabany G, Popp RA, Popp K, Gabriel E. Risk of hepatitis B virus reactivation in cancer patients undergoing treatment with tyrosine kinase-inhibitors. World J Gastroenterol 2024; 30:3052-3058. [PMID: 38983963 PMCID: PMC11230056 DOI: 10.3748/wjg.v30.i24.3052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 05/10/2024] [Accepted: 05/30/2024] [Indexed: 06/25/2024] Open
Abstract
This editorial commented on an article in the World Journal of Gastroenterology titled "Risks of Reactivation of Hepatitis B Virus in Oncological Patients Using Tyrosine Kinase-Inhibitors: Case Report and Literature Analysis" by Colapietro et al. In this editorial, we focused on providing a more comprehensive exploration of hepatitis B virus reactivation (HBVr) associated with the usage of tyrosine kinase inhibitors (TKIs). It includes insights into the mechanisms underlying HBV reactivation, the temporal relationship between TKIs and HBV reactivation, and preventive measures. The aim is to understand the need for nucleos(t)ide analogs (NAT) and serial blood tests for early recognition of reactivation and acute liver injury, along with management strategies. TKIs are considered to be an intermediate (1%-10%) of HBVr. Current guidelines stipulate that patients receiving therapy with high or moderate risks of reactivation or recent cancer diagnosis must have at least tested hepatitis B surface antigen, anti-hepatitis B core antigen (HBc), and anti-hepatitis B surface antibody. Anti-HBc screening in highly endemic areas means people with negative tests should be vaccinated against HBV. Nucleoside or nucleotide analogs (NAs) like entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF) form the basis of HBV reactivation prophylaxis and treatment during immunosuppression. Conversely, lamivudine, telbivudine, and adefovir are generally discouraged due to their reduced antiviral efficacy and higher risk of fostering drug-resistant viral strains. However, these less effective NAs may still be utilized in cases where ETV, TDF, and TAF are not feasible treatment options.
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Affiliation(s)
- Bansi P Savaliya
- Department of Surgery, Medical Academy Named after SI Georgievsky of Vernadsky Crimean Federal University, Simferopol 295015, Crimea, Russia
| | - Ramin Shekouhi
- Division of Plastic and Reconstructive Surgery, Department of Surgery, University of Florida, Gainesville, FL 32608, United States
| | - Fatima Mubarak
- Department of Surgery, Aga Khan University, Karachi 74800, Sindh, Pakistan
| | - Harsheen K Manaise
- Department of Surgery, Government Medical College and Hospital, Chandigarh 160030, Punjab, India
| | - Paola Berrios Jimenez
- Department of Surgery, University of Puerto Rico School of Medicine, San Juan 00921, Puerto Rico
| | - Gabrielle Kowkabany
- Department of Chemical and Biological Engineering, University of Alabama, Tuscaloosa, AL 35487, United States
| | - Reed A Popp
- Department of Surgery, University of Florida College of Medicine, Gainesville, FL 32610, United States
| | - Kyle Popp
- Department of Surgery, Florida State University, Tallahassee, FL 32306, United States
| | - Emmanuel Gabriel
- Department of Surgery, Mayo Clinic, Jacksonville, FL 32224, United States
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Ali MJ, Shah PA, Rehman KU, Kaur S, Holzmayer V, Cloherty GA, Kuhns MC, Lau DTY. Immune-Escape Mutations Are Prevalent among Patients with a Coexistence of HBsAg and Anti-HBs in a Tertiary Liver Center in the United States. Viruses 2024; 16:713. [PMID: 38793596 PMCID: PMC11125813 DOI: 10.3390/v16050713] [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: 03/21/2024] [Revised: 04/21/2024] [Accepted: 04/27/2024] [Indexed: 05/26/2024] Open
Abstract
The concurrent seropositivity of HBsAg and anti-HBs has been described among patients with chronic hepatitis B (CHB), but its prevalence is variable. HBV S-gene mutations can affect the antigenicity of HBsAg. Patients with mutations in the 'α' determinant region of the S gene can develop severe HBV reactivation under immunosuppression. In this study at a tertiary liver center in the United States, we evaluated the frequency and virological characteristics of the HBsAg mutations among CHB patients with the presence of both HBsAg and anti-HBs. In this cohort, 45 (2.1%) of 2178 patients were identified to have a coexistence of HBsAg and anti-HBs, and 24 had available sera for the genome analysis of the Pre-S1, Pre-S2, and S regions. The frequency of mutations in the S gene was significantly higher among those older than 50 years (mean 8.5 vs. 5.4 mutations per subject, p = 0.03). Twelve patients (50%) had mutations in the 'α' determinant region of the S gene. Mutations at amino acid position 126 were most common in eight subjects. Three had a mutation at position 133. Only one patient had a mutation at position 145-the classic vaccine-escape mutation. Despite the universal HBV vaccination program, the vaccine-escape mutant is rare in our cohort of predominantly Asian patients.
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Affiliation(s)
- Mukarram Jamat Ali
- Liver Center, Division of Gastroenterology and Hepatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (M.J.A.); (P.A.S.); (K.U.R.); (S.K.)
- Howard University Hospital, Howard University College of Medicine, Washington, DC 20060, USA
| | - Pir Ahmed Shah
- Liver Center, Division of Gastroenterology and Hepatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (M.J.A.); (P.A.S.); (K.U.R.); (S.K.)
| | - Khalil Ur Rehman
- Liver Center, Division of Gastroenterology and Hepatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (M.J.A.); (P.A.S.); (K.U.R.); (S.K.)
| | - Satinder Kaur
- Liver Center, Division of Gastroenterology and Hepatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (M.J.A.); (P.A.S.); (K.U.R.); (S.K.)
| | - Vera Holzmayer
- Abbott Diagnostics Division, Abbott Laboratories, Abbott Park, IL 60064, USA; (V.H.); (G.A.C.); (M.C.K.)
| | - Gavin A. Cloherty
- Abbott Diagnostics Division, Abbott Laboratories, Abbott Park, IL 60064, USA; (V.H.); (G.A.C.); (M.C.K.)
| | - Mary C. Kuhns
- Abbott Diagnostics Division, Abbott Laboratories, Abbott Park, IL 60064, USA; (V.H.); (G.A.C.); (M.C.K.)
| | - Daryl T. Y. Lau
- Liver Center, Division of Gastroenterology and Hepatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (M.J.A.); (P.A.S.); (K.U.R.); (S.K.)
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15
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Sedohara A, Takahashi K, Arai K, Arizono K, Tuvshinjargal K, Saito M, Nakahara F, Tsutsumi T, Ikeuchi K, Adachi E, Yotsuyanagi H. Characterization of mutations in hepatitis B virus DNA isolated from Japanese HBsAg-positive blood donors in 2021 and 2022. Arch Virol 2024; 169:103. [PMID: 38632180 PMCID: PMC11023964 DOI: 10.1007/s00705-024-06016-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 02/04/2024] [Indexed: 04/19/2024]
Abstract
Missense mutations in certain small envelope proteins diminish the efficacy of antibodies. Consequently, tracking the incidence and types of vaccine-escape mutations (VEMs) was crucial both before and after the introduction of universal hepatitis B vaccination in Japan in 2016. In this study, we isolated hepatitis B virus (HBV) DNA from 58 of 169 hepatitis B surface antigen (HBsAg)-positive blood samples from Japanese blood donors and determined the nucleotide sequence encoding the small envelope protein. DNA from six (10%) of the samples had VEMs, but no missense mutations, such as G145R, were detected. Complete HBV genome sequences were obtained from 29 of the 58 samples; the viral genotype was A1 in one (3%), A2 in three (10%), B1 in nine (31%), B2 in five (17%), B4 in one (3%), and C2 in 10 (34%) samples. Tenofovir-resistance mutations were detected in two (7%) samples. In addition, several core promoter mutations, such as 1762A>T and 1764G>A, and a precore nonsense mutation, 1986G>A, which are risk factors for HBV-related chronic liver disease, were detected. These findings provide a baseline for future research and highlight the importance of ongoing monitoring of VEMs and drug resistance mutations in HBV DNA from HBsAg-positive blood donors without HBV antibodies.
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Affiliation(s)
- Ayako Sedohara
- Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
| | - Kazuaki Takahashi
- Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Keiko Arai
- Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Kotaro Arizono
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
| | - Khulan Tuvshinjargal
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
| | - Makoto Saito
- Department of Infectious Disease and Applied Immunology, IMSUT Hospital of The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Fumio Nakahara
- Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
- Division of Regenerative Medicine, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan
| | - Takeya Tsutsumi
- Department of Infectious Disease and Applied Immunology, IMSUT Hospital of The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
- Department of Infectious Diseases, Faculty of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kazuhiko Ikeuchi
- Department of Infectious Disease and Applied Immunology, IMSUT Hospital of The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Eisuke Adachi
- Department of Infectious Disease and Applied Immunology, IMSUT Hospital of The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Hiroshi Yotsuyanagi
- Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
- Department of Infectious Disease and Applied Immunology, IMSUT Hospital of The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
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16
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Hossain MG, Islam M, Araf Y, Paul SK, Akter S, Khan MK, Ahmed MU, Khan S, Akbar SMF, Debnath CR. Comprehensive analysis of antigenic variations and genomic properties of hepatitis B virus in clinical samples in the mid-north east region of Bangladesh. INFECTION, GENETICS AND EVOLUTION : JOURNAL OF MOLECULAR EPIDEMIOLOGY AND EVOLUTIONARY GENETICS IN INFECTIOUS DISEASES 2024; 119:105572. [PMID: 38367678 DOI: 10.1016/j.meegid.2024.105572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 02/12/2024] [Accepted: 02/13/2024] [Indexed: 02/19/2024]
Abstract
This investigation delineates an exhaustive analysis of the clinical, immunological, and genomic landscapes of hepatitis B virus (HBV) infection across a cohort of 22 verified patients. The demographic analysis unveiled a pronounced male bias (77.27%), with patient ages spanning 20 to 85 years and durations of illness ranging from 10 days to 4 years. Predominant clinical manifestations included fever, fatigue, anorexia, abdominal discomfort, and arthralgia, alongside observed co-morbidities such as chronic renal disorders and hepatocellular carcinoma. Antigenic profiling of the HBV envelope proteins elucidated significant heterogeneity among the infected subjects, particularly highlighted by discordances in the detection capabilities of small and large HBsAg assays, suggesting antigenic diversity. Quantitative assessment of viral loads unveiled a broad spectrum, accompanied by atypical HBeAg reactivity patterns, challenging the reliability of existing serological markers. Correlative studies between viral burden and antigenicity of the envelope proteins unearthed phenomena indicative of diagnostic evasion. Notably, samples demonstrating robust viral replication were paradoxically undetectable by the large HBsAg ELISA kit, advocating for more sophisticated diagnostic methodologies. Genotypic examination of three HBV isolates classified them as genotype D (D2), with phylogenetic alignment to strains from various global origins. Mutational profiling identified pivotal mutations within the basic core promoter and preS2/S1 regions, associated with an augmented risk of hepatocellular carcinoma. Further, mutations discerned in the small HBsAg and RT/overlap regions were recognized as contributors to vaccine and/or diagnostic escape mechanisms. In summation, this scholarly discourse elucidates the intricate interplay of clinical presentations, antigenic diversity, and genomic attributes in HBV infection, accentuating the imperative for ongoing investigative endeavors to refine diagnostic and therapeutic modalities.
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Affiliation(s)
- Md Golzar Hossain
- Department of Microbiology and Hygiene, Bangladesh Agricultural University, Mymensingh 2202, Bangladesh.
| | - Mahfuz Islam
- Department of Microbiology, Mymensingh Medical College, Mymensingh, Bangladesh
| | - Yusha Araf
- Department of Microbiology and Hygiene, Bangladesh Agricultural University, Mymensingh 2202, Bangladesh
| | - Shyamal Kumar Paul
- Department of Microbiology, Mymensingh Medical College, Mymensingh, Bangladesh
| | - Sharmin Akter
- Department of Physiology, Bangladesh Agricultural University, Mymensingh 2202, Bangladesh
| | | | - Muzahed Uddin Ahmed
- Department of Medicine, Bangladesh Agricultural University, Mymensingh 2202, Bangladesh
| | - Sakirul Khan
- Research Center for Global and Local Infectious Diseases, Oita University, Oita, Japan; Department of Microbiology, Faculty of Medicine, Oita University, Oita, Japan
| | - Sheikh Mohammad Fazle Akbar
- Research Center for Global and Local Infectious Diseases, Oita University, Oita, Japan; Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan; Miyakawa Memorial Research Foundation, Tokyo, Japan
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17
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Leontari M, Mousavere I, Fousekis FS, Kalampoki A, Baltayiannis G. Occult Hepatitis B Infection among Blood Donors in Northwestern Greece. MAEDICA 2024; 19:17-22. [PMID: 38736917 PMCID: PMC11079725 DOI: 10.26574/maedica.2024.19.1.17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/26/2024]
Abstract
Background: Occult hepatitis B virus infection (OBI) is characterized by the presence of HBV DNA in individuals who test negative for hepatitis B surface antigen (HBsAg). It poses diagnostic challenges and contributes to chronic liver diseases. Understanding its epidemiology, pathogenesis and clinical outcomes remains essential. This study aimed to assess the prevalence and characteristics of OBI in Northwestern Greece. Methods:Serum samples were prospectively collected from 702 blood donors at the University Hospital of Ioannina, Greece, between February 2018 and September 2022. The investigation focused on the presence of hepatitis B virus (HBV) markers, utilizing the Abbott Architect HBsAg and HBcAb HB Qualitative II kit for the detection of HBsAg and anti-HBc, respectively. Further analysis was conducted on serum samples from individuals who tested negative for HBsAg but positive for anti-HBc, employing polymerase chain reaction (PCR) to detect HBV-DNA. In instances of OBI, sequencing and mutation analysis of the HBV pre-S/S gene were carried out for comprehensive characterization. Results:Screening revealed 56 cases (7.9%) with active HBV infection (HBsAg positive) and identified 144 cases (20.5%) indicative of past HBV infection (HBsAg negative, anti-HBc positive). Additionally, a prevalence of 5.4% (38/702) of OBI was detected. Among these, 36 cases exhibited a low HBV DNA load of less than 225 IU/mL. Notably, one OBI patient was co-infected with HIV. Furthermore, two cases of OBI with high HBV-DNA levels exceeding 200,000 IU/ml were detected. Sequencing analysis unveiled S- and pre-S mutations in four cases of OBI, including both instances with elevated HBV-DNA levels. Conclusion:In a region with a high proportion of immigrants from countries where HBV is endemic, a high prevalence of HBV infection and occult HBV infection (OBI) has been detected. Furthermore, mutations in the S gene were found to be associated with cases of OBI with high levels of HBV-DNA. However, additional research is needed to validate the results and understand the clinical relevance of specific OBI mutations for disease progression and treatment efficacy.
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Affiliation(s)
- Maria Leontari
- Department of Internal Medicine, University Hospital of Ioannina, Ioannina, Greece
| | - Ioanna Mousavere
- Department of Gastroenterology, University Hospital of Ioannina, Ioannina, Greece
| | - Fotios S Fousekis
- Department of Gastroenterology, University Hospital of Ioannina, Ioannina, Greece
| | - Aikaterini Kalampoki
- Department of Internal Medicine, University Hospital of Ioannina, Ioannina, Greece
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18
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Leontari M, Mousavere I, Fousekis FS, Kalampoki A, Baltayiannis G. Occult Hepatitis B Infection among Blood Donors in Northwestern Greece. MAEDICA 2024; 19:17-22. [PMID: 38736917 PMCID: PMC11079725 DOI: 10.26574/maedica.2024.19.11.17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 05/14/2024]
Abstract
Background: Occult hepatitis B virus infection (OBI) is characterized by the presence of HBV DNA in individuals who test negative for hepatitis B surface antigen (HBsAg). It poses diagnostic challenges and contributes to chronic liver diseases. Understanding its epidemiology, pathogenesis and clinical outcomes remains essential. This study aimed to assess the prevalence and characteristics of OBI in Northwestern Greece. Methods:Serum samples were prospectively collected from 702 blood donors at the University Hospital of Ioannina, Greece, between February 2018 and September 2022. The investigation focused on the presence of hepatitis B virus (HBV) markers, utilizing the Abbott Architect HBsAg and HBcAb HB Qualitative II kit for the detection of HBsAg and anti-HBc, respectively. Further analysis was conducted on serum samples from individuals who tested negative for HBsAg but positive for anti-HBc, employing polymerase chain reaction (PCR) to detect HBV-DNA. In instances of OBI, sequencing and mutation analysis of the HBV pre-S/S gene were carried out for comprehensive characterization. Results:Screening revealed 56 cases (7.9%) with active HBV infection (HBsAg positive) and identified 144 cases (20.5%) indicative of past HBV infection (HBsAg negative, anti-HBc positive). Additionally, a prevalence of 5.4% (38/702) of OBI was detected. Among these, 36 cases exhibited a low HBV DNA load of less than 225 IU/mL. Notably, one OBI patient was co-infected with HIV. Furthermore, two cases of OBI with high HBV-DNA levels exceeding 200,000 IU/ml were detected. Sequencing analysis unveiled S- and pre-S mutations in four cases of OBI, including both instances with elevated HBV-DNA levels. Conclusion:In a region with a high proportion of immigrants from countries where HBV is endemic, a high prevalence of HBV infection and occult HBV infection (OBI) has been detected. Furthermore, mutations in the S gene were found to be associated with cases of OBI with high levels of HBV-DNA. However, additional research is needed to validate the results and understand the clinical relevance of specific OBI mutations for disease progression and treatment efficacy.
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Affiliation(s)
- Maria Leontari
- Department of Internal Medicine, University Hospital of Ioannina, Ioannina, Greece
| | - Ioanna Mousavere
- Department of Gastroenterology, University Hospital of Ioannina, Ioannina, Greece
| | - Fotios S Fousekis
- Department of Gastroenterology, University Hospital of Ioannina, Ioannina, Greece
| | - Aikaterini Kalampoki
- Department of Internal Medicine, University Hospital of Ioannina, Ioannina, Greece
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D’Avila H, Lima CNR, Rampinelli PG, Mateus LCO, de Sousa Silva RV, Correa JR, de Almeida PE. Lipid Metabolism Modulation during SARS-CoV-2 Infection: A Spotlight on Extracellular Vesicles and Therapeutic Prospects. Int J Mol Sci 2024; 25:640. [PMID: 38203811 PMCID: PMC10778989 DOI: 10.3390/ijms25010640] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 12/05/2023] [Accepted: 12/12/2023] [Indexed: 01/12/2024] Open
Abstract
Extracellular vesicles (EVs) have a significant impact on the pathophysiological processes associated with various diseases such as tumors, inflammation, and infection. They exhibit molecular, biochemical, and entry control characteristics similar to viral infections. Viruses, on the other hand, depend on host metabolic machineries to fulfill their biosynthetic requirements. Due to potential advantages such as biocompatibility, biodegradation, and efficient immune activation, EVs have emerged as potential therapeutic targets against the SARS-CoV-2 infection. Studies on COVID-19 patients have shown that they frequently have dysregulated lipid profiles, which are associated with an increased risk of severe repercussions. Lipid droplets (LDs) serve as organelles with significant roles in lipid metabolism and energy homeostasis as well as having a wide range of functions in infections. The down-modulation of lipids, such as sphingolipid ceramide and eicosanoids, or of the transcriptional factors involved in lipogenesis seem to inhibit the viral multiplication, suggesting their involvement in the virus replication and pathogenesis as well as highlighting their potential as targets for drug development. Hence, this review focuses on the role of modulation of lipid metabolism and EVs in the mechanism of immune system evasion during SARS-CoV-2 infection and explores the therapeutic potential of EVs as well as application for delivering therapeutic substances to mitigate viral infections.
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Affiliation(s)
- Heloisa D’Avila
- Cell Biology Laboratory, Department of Biology, Federal University of Juiz de Fora, Juiz de Fora 36036-900, Brazil; (H.D.); (P.G.R.); (L.C.O.M.); (R.V.d.S.S.)
| | | | - Pollianne Garbero Rampinelli
- Cell Biology Laboratory, Department of Biology, Federal University of Juiz de Fora, Juiz de Fora 36036-900, Brazil; (H.D.); (P.G.R.); (L.C.O.M.); (R.V.d.S.S.)
| | - Laiza Camila Oliveira Mateus
- Cell Biology Laboratory, Department of Biology, Federal University of Juiz de Fora, Juiz de Fora 36036-900, Brazil; (H.D.); (P.G.R.); (L.C.O.M.); (R.V.d.S.S.)
| | - Renata Vieira de Sousa Silva
- Cell Biology Laboratory, Department of Biology, Federal University of Juiz de Fora, Juiz de Fora 36036-900, Brazil; (H.D.); (P.G.R.); (L.C.O.M.); (R.V.d.S.S.)
| | - José Raimundo Correa
- Laboratory of Microscopy and Microanalysis, University of Brasília, Brasília 70910-900, Brazil;
| | - Patrícia Elaine de Almeida
- Cell Biology Laboratory, Department of Biology, Federal University of Juiz de Fora, Juiz de Fora 36036-900, Brazil; (H.D.); (P.G.R.); (L.C.O.M.); (R.V.d.S.S.)
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Lazarevic I, Banko A, Miljanovic D, Cupic M. Hepatitis B Surface Antigen Isoforms: Their Clinical Implications, Utilisation in Diagnosis, Prevention and New Antiviral Strategies. Pathogens 2024; 13:46. [PMID: 38251353 PMCID: PMC10818932 DOI: 10.3390/pathogens13010046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Revised: 12/27/2023] [Accepted: 01/02/2024] [Indexed: 01/23/2024] Open
Abstract
The hepatitis B surface antigen (HBsAg) is a multifunctional glycoprotein composed of large (LHB), middle (MHB), and small (SHB) subunits. HBsAg isoforms have numerous biological functions during HBV infection-from initial and specific viral attachment to the hepatocytes to initiating chronic infection with their immunomodulatory properties. The genetic variability of HBsAg isoforms may play a role in several HBV-related liver phases and clinical manifestations, from occult hepatitis and viral reactivation upon immunosuppression to fulminant hepatitis and hepatocellular carcinoma (HCC). Their immunogenic properties make them a major target for developing HBV vaccines, and in recent years they have been recognised as valuable targets for new therapeutic approaches. Initial research has already shown promising results in utilising HBsAg isoforms instead of quantitative HBsAg for correctly evaluating chronic infection phases and predicting functional cures. The ratio between surface components was shown to indicate specific outcomes of HBV and HDV infections. Thus, besides traditional HBsAg detection and quantitation, HBsAg isoform quantitation can become a useful non-invasive biomarker for assessing chronically infected patients. This review summarises the current knowledge of HBsAg isoforms, their potential usefulness and aspects deserving further research.
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Affiliation(s)
- Ivana Lazarevic
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (A.B.); (D.M.); (M.C.)
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Bubonja-Šonje M, Peruč D, Abram M, Mohar-Vitezić B. Prevalence of occult hepatitis B virus infection and characterisation of hepatitis B surface antigen mutants among adults in western Croatia. Ann Hepatol 2024; 29:101156. [PMID: 37758118 DOI: 10.1016/j.aohep.2023.101156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Revised: 07/27/2023] [Accepted: 09/11/2023] [Indexed: 10/03/2023]
Abstract
INTRODUCTION AND OBJECTIVES Occult hepatitis B virus (HBV) infection (OBI) is characterised by low levels of hepatitis B virus (HBV) DNA in the blood/liver of patients with negative hepatitis B surface antigen (HBsAg). This study aimed to determine the OBI prevalence and virological characteristics (viral genotypes and HBsAg mutants) in patients with an "anti-HBc only" serological profile. MATERIALS AND METHODS A total of 24 900 serum samples were routinely screened for hepatitis B markers over a five-year period. All anti-HBc-positive/HBsAg-negative/anti-HBs-negative sera were selected and analysed for the presence of HBV DNA. Mutational analyses of the HBs gene and polymerase gene sequences were performed. RESULTS 1749 (7.02%) sera were anti-HBc positive, and 113 (0.45%) sera had an "anti-HBc only" serological profile (HBsAg/anti-HBs negative). HBV DNA was detected in 12/113 (10.61%) "anti-HBc only" positive sera, representing 0.048% of all routinely tested samples. Due to extremely low viremia, HBV genome was successfully sequenced in only two sera where subgenotype D3 was confirmed. Mutational analyses of the S gene revealed multiple missense mutations. In addition to the M133I, Y134F, and G145R mutations, already associated with diagnostic escape, we also found nine novel OBI-related S-gene mutations - S136Y, F158L, K160N, E164G, S167L, A168V, L175S, S210I and F212C. CONCLUSIONS We detected multiple known and novel S gene mutations in 2/12 (16.6%) OBI cases, nevertheless, further studies are required to determine their role in the pathogenesis of OBI. Understanding the frequencies of clinically relevant HBV mutations may contribute to improvement of diagnostic protocols.
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Affiliation(s)
- Marina Bubonja-Šonje
- Department of Microbiology and Parasitology, Faculty of Medicine, University of Rijeka, Braće Branchetta 20, Rijeka 51000, Croatia; Department of Clinical Microbiology, Clinical Hospital Centre Rijeka, Krešimirova 42, Rijeka 51000, Croatia.
| | - Dolores Peruč
- Department of Microbiology and Parasitology, Faculty of Medicine, University of Rijeka, Braće Branchetta 20, Rijeka 51000, Croatia; Department of Clinical Microbiology, Teaching Institute of Public Health of Primorsko-Goranska County, Krešimirova 52a, Rijeka, Croatia
| | - Maja Abram
- Department of Microbiology and Parasitology, Faculty of Medicine, University of Rijeka, Braće Branchetta 20, Rijeka 51000, Croatia; Department of Clinical Microbiology, Clinical Hospital Centre Rijeka, Krešimirova 42, Rijeka 51000, Croatia
| | - Bojana Mohar-Vitezić
- Department of Microbiology and Parasitology, Faculty of Medicine, University of Rijeka, Braće Branchetta 20, Rijeka 51000, Croatia; Department of Clinical Microbiology, Clinical Hospital Centre Rijeka, Krešimirova 42, Rijeka 51000, Croatia
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Osasona OG, Oguntoye OO, Arowosaye AO, Abdulkareem LO, Adewumi MO, Happi C, Folarin O. Patterns of hepatitis b virus immune escape and pol/rt mutations across clinical cohorts of patients with genotypes a, e and occult hepatitis b infection in Nigeria: A multi-centre study. Virulence 2023; 14:2218076. [PMID: 37262110 DOI: 10.1080/21505594.2023.2218076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 03/27/2023] [Accepted: 05/20/2023] [Indexed: 06/03/2023] Open
Abstract
Hepatitis B virus (HBV) immune escape and Pol/RT mutations account for HBV immunoprophylactic, therapeutic, and diagnostic failure globally. Little is known about circulating HBV immune escape and Pol/RT mutants in Nigeria. This study focused on narrowing the knowledge gap of the pattern and prevalence of the HBV mutants across clinical cohorts of infected patients in southwestern Nigeria. Ninety-five enrollees were purposively recruited across clinical cohorts of HBV-infected patients with HBsAg or anti-HBc positive serological outcome and occult HBV infection. Total DNA was extracted from patients' sera. HBV S and Pol gene-specific nested PCR amplification was carried out. The amplicons were further sequenced for serotypic, genotypic, phylogenetic, and mutational analysis. HBV S and Pol genes were amplified in 60 (63.2%) and 19 (20%) of HBV isolates, respectively. All the sixty HBV S gene and 14 of 19 Pol gene sequences were exploitable. The ayw4 serotype was predominant (95%) while ayw1 serotype was identified in 5% of isolates. Genotype E predominates in 95% of sequences, while genotype A, sub-genotype A3 was observed in 5%. Prevalence of HBV IEMs in the "a" determinant region was 29%. Commonest HBV IEM was S113T followed by G145A and D144E. The Pol/RT mutations rtV214A and rtI163V among others were identified in this study. This study provided data on the occurrence of existing and new HBV IEMs and Pol gene mutations in Nigeria.
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Affiliation(s)
- Oluwadamilola G Osasona
- African Centre of Excellence for the Genomics of Infectious Diseases, Redeemers University, Ede, Nigeria
| | | | - Abiola O Arowosaye
- Department of Virology, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | - Lukman O Abdulkareem
- Department of Internal Medicine, University of Abuja Teaching Hospital, Gwagwalada, Abuja, Nigeria
| | - Moses O Adewumi
- Department of Virology, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | - Christian Happi
- African Centre of Excellence for the Genomics of Infectious Diseases, Redeemers University, Ede, Nigeria
| | - Onikepe Folarin
- African Centre of Excellence for the Genomics of Infectious Diseases, Redeemers University, Ede, Nigeria
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Jose-Abrego A, Roman S, Rebello Pinho JR, Gomes-Gouvêa MS, Panduro A. High Frequency of Antiviral Resistance Mutations in HBV Genotypes A2 and H: Multidrug Resistance Strains in Mexico. J Clin Transl Hepatol 2023; 11:1023-1034. [PMID: 37577226 PMCID: PMC10412697 DOI: 10.14218/jcth.2022.00135s] [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: 11/30/2022] [Revised: 04/04/2023] [Accepted: 04/18/2023] [Indexed: 07/03/2023] Open
Abstract
Background and Aims Lamivudine (3TC), telbivudine (LdT), entecavir (ETV), adefovir (ADF), and tenofovir (TFV) are drugs used to treat hepatitis B virus (HBV) infection, but specific mutations allow some viruses to become resistant to antiviral drugs or to acquire immune escape capacities. These mutations have not been thoroughly investigated in Mexico. This study aimed to estimate the prevalence of HBV antiviral resistance and escape mutations. Methods This cross-sectional study analyzed 158 samples. HBV DNA was extracted, amplified, and sequenced in serum samples using the spin column method, PCR assay, and Sanger's sequencing, respectively. HBV genotypes were determined, and HBV mutations were tested using the Geno2pheno tool. Results Overall, 68.4% (108/158) of HBV patients were infected with genotype H, followed by G (11.4%, 18/158), A2 (10.8%, 17/158), F1b (6.9.0%, 11/158), D (1.9%, 3/158), and E (0.6%, 1/158), and 5.1% (8/158) had evidence of recombination. The prevalence of resistance mutations was 8.2% (13/158) and the most common combined mutation was rt180M+rt204V. Notably, we found the combinations rt180M+rt204V+rt173L (n=2) and rt180M+rt204V+rt202G (n=1) that confer multidrug resistance to 3TC, LdT, and ETV. Resistance mutations were found in genotypes A2 (11.8%, 2/17), and H (10.2%, 11/108), and escape mutations were detected in HBV genotypes A2 (11.8%, 2/17), H (10.2%, 11/108), F1b (9.1%, 1/11) and G (5.6%, 1/18). Conclusions The highest prevalence of antiviral resistance mutations or escape mutations was detected in HBV genotypes A2 and H. The earliest cases of HBV multidrug resistance were detected in Mexico.
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Affiliation(s)
- Alexis Jose-Abrego
- Department of Genomic Medicine in Hepatology, Civil Hospital of Guadalajara, “Fray Antonio Alcalde,” Guadalajara, Jalisco, Mexico
- Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, Mexico
| | - Sonia Roman
- Department of Genomic Medicine in Hepatology, Civil Hospital of Guadalajara, “Fray Antonio Alcalde,” Guadalajara, Jalisco, Mexico
- Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, Mexico
| | - João Renato Rebello Pinho
- LIM07, Department of Gastroenterology, University of São Paulo, São Paulo, Brazil
- Hospital Israelita Albert Einstein, São Paulo, Brazil
| | | | - Arturo Panduro
- Department of Genomic Medicine in Hepatology, Civil Hospital of Guadalajara, “Fray Antonio Alcalde,” Guadalajara, Jalisco, Mexico
- Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, Mexico
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Sirilert S, Khamrin P, Kumthip K, Malasao R, Maneekarn N, Tongsong T. Possible Association between Genetic Diversity of Hepatitis B Virus and Its Effect on the Detection Rate of Hepatitis B Virus DNA in the Placenta and Fetus. Viruses 2023; 15:1729. [PMID: 37632070 PMCID: PMC10458115 DOI: 10.3390/v15081729] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 08/10/2023] [Accepted: 08/10/2023] [Indexed: 08/27/2023] Open
Abstract
Background: The prevalence of HBV infection and HBV genotypes varies from country to country, and the role of HBV genotypes in the presence of HBV in the placenta and fetus has never been explored. This study was conducted to (1) identify HBV genotypes, and their frequencies, that infected Northern Thai pregnant women; (2) evaluate the association between HBV genotypes and the detection rate of HBV DNA in the placenta and fetus; (3) evaluate the association between specific mutations of the HBV genome and HBV DNA detection in placental tissue; and (4) identify the mutation of the HBV genome that might occur between maternal blood, placenta, and cord blood. Methods: Stored samples of the maternal blood, placental tissue, and cord blood that were collected from 145 HBsAg-positive pregnant Thai women were analyzed to identify HBV DNA. Results: Approximately 25% of infected mothers had fetal HBV DNA detection, including cases with concomitant HBV DNA detection in the placenta (77.3%). A total of 11.7% of cases with placental detection had no HBV DNA detection in the maternal blood, indicating that the placenta could be a site of HBV accumulation. Of the 31 HBV-positive blood samples detected by nested PCR, the detected strains were subgenotype C1 (77.4%), subgenotype B9 (9.7%), and subgenotype C2, B2, B4, and recombinant B4/C2 (3.2% for each). Genotype B had a trend in increased risk of placental HBV DNA detection compared to genotype C, with a relative risk of 1.40 (95% CI: 1.07-1.84). No specific point mutation had a significant effect on HBV DNA detection in placental tissue. Mutation of C454T tended to enhance HBV DNA detection in placental tissue, whereas T400A tended to have a lower detection rate. No mutation was detected in different sample types collected from the same cases. Conclusions: HBV DNA detection in the fetus was identified in approximately 25% of HBV-positive mothers, associated with the presence of HBV in the placenta in most cases. The placenta could possibly be a site of HBV accumulation. Subgenotype C1 was the most common subgenotype, followed by subgenotype B9. HBV genotype B possibly had a higher trend in intrauterine detection than HBV genotype C. Mutation is unlikely to occur during intrauterine exposure.
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Affiliation(s)
- Sirinart Sirilert
- Department of Obstetrics and Gynecology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand;
| | - Pattara Khamrin
- Department of Microbiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; (P.K.); (K.K.); (N.M.)
| | - Kattareeya Kumthip
- Department of Microbiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; (P.K.); (K.K.); (N.M.)
| | - Rungnapa Malasao
- Department of Community Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand;
| | - Niwat Maneekarn
- Department of Microbiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; (P.K.); (K.K.); (N.M.)
| | - Theera Tongsong
- Department of Obstetrics and Gynecology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand;
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Pondé RADA. Unusual serological profile in hepatitis B virus (HBV) infection associated with a probable clinical case of acute exacerbation of pre-existing chronic HBV infection. Mol Biol Rep 2023; 50:6435-6443. [PMID: 37326752 DOI: 10.1007/s11033-023-08546-7] [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: 03/28/2023] [Accepted: 05/22/2023] [Indexed: 06/17/2023]
Abstract
BACKGROUND Acute or chronic HBV infection in an individual can be laboratory characterized according to the serological profile of the viral markers in the bloodstream, and the dynamics monitoring of these markers is necessary to assess the disorder course and the infection outcome. However, under certain circumstances unusual or atypical serological profiles may be observed in both acute and chronic HBV infection. They are considered as such because they do not properly characterize the form or infection clinical phase or because they seem inconsistent, considering the viral markers dynamics in both clinical contexts. This manuscript comprises the analysis of an unusual serological profile in HBV infection. METHODS AND RESULTS This clinical-laboratory study, had as reference a patient who presented clinical profile suggestive of acute HBV infection after recent exposure, whose laboratory data were initially compatible with this clinical presentation. However, the serological profile analysis and its monitoring demonstrated unusual pattern of viral markers expression, which has been observed in several clinical contexts, and is often associated a number of agent- or host-related factors. CONCLUSION The serological profile analyzed here, associated with the biochemical markers serum levels found, is indicative of active chronic infection, consequence of viral reactivation. This finding suggests that in the event of unusual serological profiles in HBV infection, if the influence of agent- or host-related factors is not properly considered and neither the viral markers dynamics properly analyzed, there may be mistake in the infection clinical diagnosis, especially when the patient's clinical and epidemiological history is unknown.
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Affiliation(s)
- Robério Amorim de Almeida Pondé
- Secretaria de Estado da Saúde -SES/Superintendência de Vigilância em Saúde-SUVISA/GO, Gerência de Vigilância Epidemiológica de Doenças Transmissíveis-GVEDT/Coordenação de Análises e Pesquisas-CAP, Goiânia, Brazil.
- Laboratory of Human Virology, Institute of Tropical Pathology and Public Health, Federal University of Goiás, Goiânia, Goiás, Brazil.
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Balde T, Ostankova YV, Boumbaly S, Naidenova EV, Zueva EB, Serikova EN, Valutite DE, Schemelev AN, Davydenko VS, Esaulenko EV, Totolian AA. [Frequency of drug resistance and immune escape mutations in the hepatitis B virus genome detected in pregnant women in the Republic of Guinea]. Vopr Virusol 2023; 68:228-241. [PMID: 37436414 DOI: 10.36233/0507-4088-175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Indexed: 07/13/2023]
Abstract
The aim of the work is to assess the prevalence of hepatitis B virus drug resistance mutations and immune escape mutations in pregnant women in the Republic of Guinea. MATERIALS AND METHODS Blood plasma samples obtained from 480 pregnant women from different regions of the Republic of Guinea with laboratory-confirmed viral hepatitis B were studied. Nucleotide sequences for genotype identification and mutation detection were obtained using nested-PCR followed by Sanger sequencing, based on overlapping pairs of primers spanning the complete genome of the virus. RESULTS AND DISCUSSION In the examined group, the viral genotype E was the most prevalent (92.92%) compared with subgenotypes A1 (1.67%), A3 (1.46%), D1 (0.63%), D2 (1.04%) and D3 (2.29%). Among the examined HBV-infected pregnant women, 188 (39.17%) had undetectable HBsAg. Drug resistance mutations were detected in 33 individuals, which amounted to 6.88%. The following mutations were found: S78T (27.27%), L80I (24.24%), S202I (15.15%), M204I/V (42.42%). The presence of polymorphic variants not described as drug resistant has also been shown in positions associated with the development of drug resistance to tenofovir, lamivudine, telbivudine and entecavir (L80F, S202I, M204R). When analyzing the MHR and the region of a determinant, mutations were detected in 318 (66.25%) of pregnant women. In 172 of them, which amounted to 54.09%, multiple mutations were found. The amino acid substitutions in 13 positions associated with HBsAg-negative hepatitis B and/or potentially affecting HBsAg antigenicity were identified. CONCLUSION The high prevalence of immune escape and drug resistance mutations potentially associated with false-negative result of HBsAg screening, prophylaxis failure, and virological failure of therapy that has been identified among treatment naive pregnant women imposes a serious problem.
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Affiliation(s)
- T Balde
- Research Institute of Applied Biology of Guinea
| | | | - S Boumbaly
- Research Institute of Applied Biology of Guinea
- Centre International de Recherche sur les Infections Tropicales en Guinée
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Abbasfard Z, Kasraian L, Farhadi A, Jowkar Z, Amiri Zadeh Fard S, Nejabat N, Kargar M, Rastegari B, Zarghampoor F, Behzad-Behbahani A. Detection of Hepatitis B Virus Genome with Mutations Outside the Major Hydrophilic Region in the Surface Antigen Isolated from Patients with Coexisting HBsAg and Anti-HBs. HEPATITIS MONTHLY 2023; 23. [DOI: 10.5812/hepatmon-131307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Revised: 03/25/2023] [Accepted: 03/27/2023] [Indexed: 04/06/2025]
Abstract
Background: The leading cause of mutations in the hepatitis B virus (HBV) genome is the high rate of nucleotide misincorporation during reverse transcription. Most mutations were found within the “a” determinant of the S gene’s major hydrophilic region (MHR). They resulted in escape mutants due to amino acid changes in the MHR. However, mutations outside the MHR can also trigger escape mutants. Objectives: This study focused on further molecular studies on the MHR of genotype D of HBV DNA isolated from patients with chronic HBV infection, together with the coexistence of hepatitis B surface antigen (HBsAg) and hepatitis B surface antibodies (anti-HBs) in their serum samples. Methods: In this study, serum samples from 83 patients with chronic HBV infection were analyzed by serological and immunological tests for the concurrence of HBsAg and anti-HBs. In addition, the mutation in the HBV DNA was assessed by nucleotide sequencing of S genes within, upstream, and downstream of the MHR. Results: Among 83 patients with chronic HBV infection, the coexistence of HBsAg and anti-HBs were detected in 11 (13.25%) individuals. Mutations in eight amino acids of seven samples analyzed for nucleotide sequencing were observed at 27 different sites in three locations, namely upstream, within, and downstream of the MHR. The mutations affected the structure of the epitope and the appearance of an escape mutant. Conclusions: The results indicated that mutations downstream and upstream of the MHR play a role in the coexistence of HBsAg and anti-HBs in patients with chronic HBV infection.
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Molecular and Genetic Characterization of Hepatitis B Virus (HBV) among Saudi Chronically HBV-Infected Individuals. Viruses 2023; 15:v15020458. [PMID: 36851671 PMCID: PMC9964524 DOI: 10.3390/v15020458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 01/31/2023] [Accepted: 01/31/2023] [Indexed: 02/10/2023] Open
Abstract
The study aimed to characterize the genotype and subgenotypes of HBV circulating in Saudi Arabia, the presence of clinically relevant mutations possibly associated with resistance to antivirals or immune escape phenomena, and the possible impact of mutations in the structural characteristics of HBV polymerase. Plasma samples from 12 Saudi Arabian HBV-infected patients were analyzed using an in-house PCR method and direct sequencing. Saudi patients were infected with mainly subgenotype D1. A number of mutations in the RT gene (correlated to antiviral resistance) and within and outside the major hydrophilic region of the S gene (claimed to influence immunogenicity and be related to immune escape) were observed in almost all patients. Furthermore, the presence of mutations in the S region caused a change in the tertiary structure of the protein compared with the consensus region. Clinical manifestations of HBV infection may change dramatically as a result of viral and host factors: the study of mutations and protein-associated cofactors might define possible aspects relevant for the natural and therapeutic history of HBV infection.
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Shen C, Jiang X, Li M, Luo Y. Hepatitis Virus and Hepatocellular Carcinoma: Recent Advances. Cancers (Basel) 2023; 15:533. [PMID: 36672482 PMCID: PMC9856776 DOI: 10.3390/cancers15020533] [Citation(s) in RCA: 58] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Revised: 01/08/2023] [Accepted: 01/13/2023] [Indexed: 01/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC) remains a global health challenge, causing 600,000 deaths each year. Infectious factors, including hepatitis B virus (HBV), hepatitis C virus (HCV) and hepatitis D virus (HDV), have long been considered the major risk factors for the development and progression of HCC. These pathogens induce hepatocyte transformation through a variety of mechanisms, including insertional mutations caused by viral gene integration, epigenetic changes, and the induction of long-term immune dysfunction. The discovery of these mechanisms, while advancing our understanding of the disease, also provides targets for new diagnostic and therapeutic approaches. In addition, the discovery and research of chronic HEV infection over the past decade indicate that this common hepatitis virus also seems to have the potential to induce HCC. In this review, we provide an overview of recent studies on the link between hepatitis virus and HCC, as well as new diagnostic and therapeutic approaches to HCC based on these findings. Finally, we also discuss the potential relationship between HEV and HCC. In conclusion, these associations will further optimize the diagnosis and treatment of infection-associated HCC and call for better management policies.
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Affiliation(s)
| | | | - Mei Li
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yao Luo
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
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Low Risk of Occult Hepatitis B Infection among Vietnamese Blood Donors. Pathogens 2022; 11:pathogens11121524. [PMID: 36558858 PMCID: PMC9786887 DOI: 10.3390/pathogens11121524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 12/08/2022] [Accepted: 12/09/2022] [Indexed: 12/15/2022] Open
Abstract
Occult hepatitis B infection (OBI) is characterized by the presence of low levels of hepatitis B virus (HBV) DNA and undetectable HBsAg in the blood. The prevalence of OBI in blood donors in Asia ranges from 0.013% (China) to 10.9% (Laos), with no data available from Vietnam so far. We aimed to investigate the prevalence of OBI among Vietnamese blood donors. A total of 623 (114 women and 509 men) HBsAg-negative blood donors were screened for anti-HBc and anti-HBs by ELISA assays. In addition, DNA from sera was isolated and nested PCR was performed for the HBV surface gene (S); a fragment of the S gene was then sequenced in positive samples. The results revealed that 39% (n = 242) of blood donors were positive for anti-HBc, and 70% (n = 434) were positive for anti-HBs, with 36% (n = 223) being positive for both anti-HBc and anti-HBs. In addition, 3% of blood donors (n = 19) were positive for anti-HBc only, and 34% (n = 211) had only anti-HBs as serological marker. A total of 27% (n = 170) were seronegative for any marker. Two of the blood donors (0.3%) were OBI-positive and sequencing revealed that HBV sequences belonged to HBV genotype B, which is the predominant genotype in Vietnam.
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Villano U, Mataj E, Dorrucci M, Farchi F, Pirone C, Valdarchi C, Equestre M, Madonna E, Bruni R, Pisani G, Martina A, Simeoni M, Iaiani G, Ciccozzi M, Ciccaglione AR, Conti F, Ceccarelli F, Lo Presti A. Molecular Characterization of Hepatitis B Virus Infection in a Patient with Cutaneous Lupus Erythematosus. Diagnostics (Basel) 2022; 12:2866. [PMID: 36428926 PMCID: PMC9689093 DOI: 10.3390/diagnostics12112866] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 10/28/2022] [Accepted: 10/31/2022] [Indexed: 11/22/2022] Open
Abstract
Hepatitis B virus (HBV) infection is a serious global health problem. Patients with autoimmune diseases, such as Lupus Erythematosus, are exposed to a higher risk of acquiring infections. In this study, a molecular characterization, genomic investigation of the Hepatitis B virus, polymerase (P) and surface (S) genes, from a patient affected by Cutaneous Lupus Erythematosus (CLE), was presented. Viral DNA was extracted from 200 μL of serum, and the HBV-DNA was amplified by real-time polymerase chain reaction (PCR) with the Platinum Taq DNA Polymerase. The PCR products were purified and sequencing reactions were performed. A phylogenetic analysis was performed through maximum likelihood and Bayesian approaches. The HBV CLE isolate was classified as sub-genotype D3 and related to other Italian HBV D3 genomes, and some from foreign countries. No drug resistant mutations were identified. One mutation (a.a. 168 M) was located in the last part of the major hydrophilic region (MHR) of the surface antigen (HBsAg). Moreover, three sites (351G, 526Y, 578C) in the polymerase were exclusively present in the CLE patient. The mutations identified exclusively in the HBsAg of our CLE patient may have been selected because of the Lupus autoantibodies, which are characteristic in the Lupus autoimmune disease, using a possible molecular mimicry mechanism.
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Affiliation(s)
- Umbertina Villano
- Department of Infectious Diseases, Istituto Superiore di Sanità, 00161 Rome, Italy
| | - Elida Mataj
- Instituti i Shendetit Publik (ISHP), Alessander Moisiu No. 80, Tirane, Albania
| | - Maria Dorrucci
- Department of Infectious Diseases, Istituto Superiore di Sanità, 00161 Rome, Italy
| | - Francesca Farchi
- Department of Infectious Diseases, Istituto Superiore di Sanità, 00161 Rome, Italy
| | - Carmelo Pirone
- Lupus Clinic, Rheumatology, Dipartimento di Scienze Cliniche, Internistiche, Anestesiologiche e Cardiovascolari, Sapienza Università, 00185 Rome, Italy
| | - Catia Valdarchi
- Department of Infectious Diseases, Istituto Superiore di Sanità, 00161 Rome, Italy
| | - Michele Equestre
- Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, 00161 Rome, Italy
| | - Elisabetta Madonna
- Department of Infectious Diseases, Istituto Superiore di Sanità, 00161 Rome, Italy
| | - Roberto Bruni
- Department of Infectious Diseases, Istituto Superiore di Sanità, 00161 Rome, Italy
| | - Giulio Pisani
- Center for Immunobiological Research and Evaluation, National Institute of Health, 00161 Rome, Italy
| | - Antonio Martina
- Center for Immunobiological Research and Evaluation, National Institute of Health, 00161 Rome, Italy
| | - Matteo Simeoni
- Center for Immunobiological Research and Evaluation, National Institute of Health, 00161 Rome, Italy
| | - Giancarlo Iaiani
- Department of Tropical and Infectious Diseases, Aou Policlinico Umberto I, 00185 Rome, Italy
| | - Massimo Ciccozzi
- Unit of Medical Statistics and Molecular Epidemiology, University Campus Bio-Medico of Rome, 00128 Rome, Italy
| | | | - Fabrizio Conti
- Lupus Clinic, Rheumatology, Dipartimento di Scienze Cliniche, Internistiche, Anestesiologiche e Cardiovascolari, Sapienza Università, 00185 Rome, Italy
| | - Fulvia Ceccarelli
- Lupus Clinic, Rheumatology, Dipartimento di Scienze Cliniche, Internistiche, Anestesiologiche e Cardiovascolari, Sapienza Università, 00185 Rome, Italy
| | - Alessandra Lo Presti
- Department of Infectious Diseases, Istituto Superiore di Sanità, 00161 Rome, Italy
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Mirzaee R, Nemati F, Mirzaee M, Golkaran B, Khorasani A, Rashedi N, Asgarhalvaei F, Savoji MA, Mahdavi M. PPD in HBsAg vaccine formulation suppressed IFN-γ and IL-4 cytokine responses and induced long-lived humoral immune responses: Results from 220-day monitoring of specific IgG responses. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2022; 25:1326-1333. [PMID: 36474577 PMCID: PMC9699948 DOI: 10.22038/ijbms.2022.61941.13710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 10/09/2022] [Indexed: 01/25/2023]
Abstract
OBJECTIVES Here, immune responses and long-lived IgG responses of HBsAg-Alum, HBsAg-MF59, as well as HBsAg-MF59 were compared when formulated with PPD. MATERIALS AND METHODS BALB/c mice were vaccinated subcutaneously three times with a two-week -interval. Then, specific IgG, long-lived IgG responses up to 220 days, and IgG1/IgG2a isotypes, and IFN-γ and IL-4 on spleen cell culture supernatant were assessed using ELISA. RESULTS IFN-γ cytokine response between MF59- and Alum-adjuvanted vaccines did not show a significant difference. HBsAg-Alum revealed an increase in IL-4 cytokine versus HBsAg-MF59 at borderline (P=0.0553). In addition, HBsAg-MF59+PPD 10 µg showed a significant decrease in IL-4 and IFN-γ cytokines versus HBsAg-MF59. Furthermore, HBsAg-MF59+PPD10 µg showed a significant increase in the IL-2/IL-4 ratio versus HBsAg-MF59 (P=0.0339). Specific IgG antibody showed a significant increase in HBsAg-MF59, as compared with HBsAg-Alum. Furthermore, HBsAg-MF59 plus PPD showed a significant increase in IgG responses versus HBsAg-MF59 and HBsAg-Alum groups. Long-lived IgG responses showed a significant increase in HBsAgMF59 versus HBsAg-Alum group and PPD in the HBsAg-MF59 vaccine formulation, resulting in a significant increase in IgG responses versus HBsAg-MF59 group. In addition, HBsAg-MF59 plus PPD suppressed IgG1 response versus HBsAg-Alum. However, HBsAg-MF59 showed a significant increase in IgG2α versus the HBsAg-Alum group (P=0.0190). Immunization with HBsAg-MF59+PPD (10 µg) showed a significant increase versus the HBsAg-MF59 group (P=0.0040). IgG2a/IgG1 ratio in HBsAg-MF59+PPD1µg and HBsAg-MF59+PPD10 µg groups showed a significant increase versus HBsAg-MF59 groups (P<0.0345). CONCLUSION PPD leads to a more potent long-lived IgG responses in the HBsAg vaccine, highlighting its potential as a component of a complex adjuvant.
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Affiliation(s)
- Rayhaneh Mirzaee
- Department of Biotechnology, Faculty of Advanced Sciences & Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Fahimeh Nemati
- Department of Biotechnology, Faculty of Advanced Sciences & Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mina Mirzaee
- Department of Microbiology, Faculty of Advanced Sciences & Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Bahareh Golkaran
- Department of Microbiology, Faculty of Advanced Sciences & Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Akbar Khorasani
- Department of FMD vaccine, Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization (AREEO), Karaj, Iran
| | - Niloufar Rashedi
- Department of Biology, Faculty of basic science, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Fatemeh Asgarhalvaei
- Department of Microbiology, Faculty of Advanced Sciences & Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mohammad Ali Savoji
- Department of Microbiology, Faculty of Advanced Sciences & Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mehdi Mahdavi
- Advanced Therapy Medicinal Product (ATMP) Department, Breast Cancer Research Center, Motamed Cancer Institute, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran,Recombinant Vaccine Research Center, Tehran University of Medical Sciences, Tehran, Iran ,Immunotherapy Group, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran ,Department of Immunology, Pasteur Institute of Iran, Tehran, Iran,Corresponding author: Mehdi Mahdavi. ATMP Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, P.O. BOX: 15179/64311, Tehran, Iran. NO.146, South Gandi Ave, Vanak Sq. Tehran, Iran. Recombinant Vaccine Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran. 16 Azar St. Tehran 14174. Iran. Tel/Fax: +98-21-88203915;
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Belaiba Z, Ayouni K, Gdoura M, Kammoun Rebai W, Touzi H, Sadraoui A, Hammemi W, Yacoubi L, Abdelati S, Hamzaoui L, Msaddak Azzouz M, Chouikha A, Triki H. Whole genome analysis of hepatitis B virus before and during long-term therapy in chronic infected patients: Molecular characterization, impact on treatment and liver disease progression. Front Microbiol 2022; 13:1020147. [PMID: 36325017 PMCID: PMC9618822 DOI: 10.3389/fmicb.2022.1020147] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Accepted: 09/15/2022] [Indexed: 07/23/2023] Open
Abstract
Hepatitis B virus (HBV) infection remains a serious public health concern worldwide despite the availability of an efficient vaccine and the major improvements in antiviral treatments. The aim of the present study is to analyze the mutational profile of the HBV whole genome in ETV non-responder chronic HBV patients, in order to investigate antiviral drug resistance, immune escape, and liver disease progression to Liver Cirrhosis (LC) or Hepatocellular Carcinoma (HCC). Blood samples were collected from five chronic hepatitis B patients. For each patient, two plasma samples were collected, before and during the treatment. Whole genome sequencing was performed using Sanger technology. Phylogenetic analysis comparing the studied sequences with reference ones was used for genotyping. The mutational profile was analyzed by comparison with the reference sequence M32138. Genotyping showed that the studied strains belong to subgenotypes D1, D7, and D8. The mutational analysis showed high genetic variability. In the RT region of the polymerase gene, 28 amino acid (aa) mutations were detected. The most significant mutations were the pattern rtL180M + rtS202G + rtM204V, which confer treatment resistance. In the S gene, 35 mutations were detected namely sP120T, sT126S, sG130R, sY134F, sS193L, sI195M, and sL216stop were previously described to lead to vaccine, immunotherapy, and/or diagnosis escape. In the C gene, 34 mutations were found. In particular, cG1764A, cC1766G/T, cT1768A, and cC1773T in the BCP; cG1896A and cG1899A in the precore region and cT12S, cE64D, cA80T, and cP130Q in the core region were associated with disease progression to LC and/or HCC. Other mutations were associated with viral replication increase including cT1753V, cG1764A/T, cC1766G/T, cT1768A, and cC1788G in the BCP as well as cG1896A and cG1899A in the precore region. In the X gene, 30 aa substitutions were detected, of which substitutions xT36D, xP46S, xA47T, xI88F, xA102V, xI127T, xK130M, xV131I, and xF132Y were previously described to lead to LC and/or HCC disease progression. In conclusion, our results show high genetic variability in the long-term treatment of chronic HBV patients causing several effects. This could contribute to guiding national efforts to optimize relevant HBV treatment management in order to achieve the global hepatitis elimination goal by 2030.
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Affiliation(s)
- Zeineb Belaiba
- Laboratory of Clinical Virology, WHO Reference Laboratory for Poliomyelitis and Measles in the Eastern Mediterranean Region, Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
- Research Laboratory “Virus, Vectors and Hosts: One Health Approach and Technological Innovation for a Better Health,” LR20IPT02, Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
| | - Kaouther Ayouni
- Laboratory of Clinical Virology, WHO Reference Laboratory for Poliomyelitis and Measles in the Eastern Mediterranean Region, Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
- Research Laboratory “Virus, Vectors and Hosts: One Health Approach and Technological Innovation for a Better Health,” LR20IPT02, Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
| | - Mariem Gdoura
- Laboratory of Clinical Virology, WHO Reference Laboratory for Poliomyelitis and Measles in the Eastern Mediterranean Region, Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
- Research Laboratory “Virus, Vectors and Hosts: One Health Approach and Technological Innovation for a Better Health,” LR20IPT02, Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
| | - Wafa Kammoun Rebai
- Laboratory of Biomedical Genomics and Oncogenetics (LR16IPT05), Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
| | - Henda Touzi
- Laboratory of Clinical Virology, WHO Reference Laboratory for Poliomyelitis and Measles in the Eastern Mediterranean Region, Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
| | - Amel Sadraoui
- Laboratory of Clinical Virology, WHO Reference Laboratory for Poliomyelitis and Measles in the Eastern Mediterranean Region, Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
| | - Walid Hammemi
- Laboratory of Clinical Virology, WHO Reference Laboratory for Poliomyelitis and Measles in the Eastern Mediterranean Region, Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
| | - Lamia Yacoubi
- Laboratory of Clinical Virology, WHO Reference Laboratory for Poliomyelitis and Measles in the Eastern Mediterranean Region, Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
| | - Salwa Abdelati
- Department of Gastroenterology, Polyclinic of CNSS, Sousse, Tunisia
| | - Lamine Hamzaoui
- Department of Gastroenterology, Hospital of Tahar Maamouri, Nabeul, Tunisia
| | | | - Anissa Chouikha
- Laboratory of Clinical Virology, WHO Reference Laboratory for Poliomyelitis and Measles in the Eastern Mediterranean Region, Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
- Research Laboratory “Virus, Vectors and Hosts: One Health Approach and Technological Innovation for a Better Health,” LR20IPT02, Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
| | - Henda Triki
- Laboratory of Clinical Virology, WHO Reference Laboratory for Poliomyelitis and Measles in the Eastern Mediterranean Region, Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
- Research Laboratory “Virus, Vectors and Hosts: One Health Approach and Technological Innovation for a Better Health,” LR20IPT02, Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
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Establishing an In Vitro System to Assess How Specific Antibodies Drive the Evolution of Foot-and-Mouth Disease Virus. Viruses 2022; 14:v14081820. [PMID: 36016442 PMCID: PMC9412381 DOI: 10.3390/v14081820] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 08/16/2022] [Accepted: 08/17/2022] [Indexed: 11/16/2022] Open
Abstract
Viruses can evolve to respond to immune pressures conferred by specific antibodies generated after vaccination and/or infection. In this study, an in vitro system was developed to investigate the impact of serum-neutralising antibodies upon the evolution of a foot-and-mouth disease virus (FMDV) isolate. The presence of sub-neutralising dilutions of specific antisera delayed the onset of virus-induced cytopathic effect (CPE) by up to 44 h compared to the untreated control cultures. Continued virus passage with sub-neutralising dilutions of these sera resulted in a decrease in time to complete CPE, suggesting that FMDV in these cultures adapted to escape immune pressure. These phenotypic changes were associated with three separate consensus-level non-synonymous mutations that accrued in the viral RNA-encoding amino acids at positions VP266, VP280 and VP1155, corresponding to known epitope sites. High-throughput sequencing also identified further nucleotide substitutions within the regions encoding the leader (Lpro), VP4, VP2 and VP3 proteins. While association of the later mutations with the adaptation to immune pressure must be further verified, these results highlight the multiple routes by which FMDV populations can escape neutralising antibodies and support the application of a simple in vitro approach to assess the impact of the humoral immune system on the evolution of FMDV and potentially other viruses.
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AbdelMassih A, Sedky A, Shalaby A, Shalaby AF, Yasser A, Mohyeldin A, Amin B, Saleheen B, Osman D, Samuel E, Abdelfatah E, Albustami E, ElGhamry F, Khaled H, Amr H, Gaber H, Makhlouf I, Abdeldayem J, El-Beialy JW, Milad K, El Sharkawi L, Abosenna L, Safi MG, AbdelKareem M, Gaber M, Elkady M, Ihab M, AbdelRaouf N, Khaled R, Shalata R, Mahgoub R, Jamal S, El Hawary SED, ElRashidy S, El Shorbagy S, Gerges T, Kassem Y, Magdy Y, Omar Y, Shokry Y, Kamel A, Hozaien R, El-Husseiny N, El Shershaby M. From HIV to COVID-19, Molecular mechanisms of pathogens' trade-off and persistence in the community, potential targets for new drug development. BULLETIN OF THE NATIONAL RESEARCH CENTRE 2022; 46:194. [PMID: 35818410 PMCID: PMC9258762 DOI: 10.1186/s42269-022-00879-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 06/22/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND On the staggering emergence of the Omicron variant, numerous questions arose about the evolution of virulence and transmissibility in microbes. MAIN BODY OF THE ABSTRACT The trade-off hypothesis has long speculated the exchange of virulence for the sake of superior transmissibility in a wide array of pathogens. While this certainly applies to the case of the Omicron variant, along with influenza virus, various reports have been allocated for an array of pathogens such as human immunodeficiency virus (HIV), malaria, hepatitis B virus (HBV) and tuberculosis (TB). The latter abide to another form of trade-off, the invasion-persistence trade-off. In this study, we aim to explore the molecular mechanisms and mutations of different obligate intracellular pathogens that attenuated their more morbid characters, virulence in acute infections and invasion in chronic infections. SHORT CONCLUSION Recognizing the mutations that attenuate the most morbid characters of pathogens such as virulence or persistence can help in tailoring new therapies for such pathogens. Targeting macrophage tropism of HIV by carbohydrate-binding agents, or targeting the TMPRSS2 receptors to prevent pulmonary infiltrates of COVID-19 is an example of how important is to recognize such genetic mechanisms.
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Affiliation(s)
- Antoine AbdelMassih
- Pediatric Department, Pediatric Cardiology Unit, Faculty of Medicine, Cairo University Children Hospital, Cairo University, Kasr Al Ainy Street, Cairo, 12411 Egypt
| | - Abrar Sedky
- Internship Research Program (Research Accessibility Team), Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Ahmed Shalaby
- Internship Research Program (Research Accessibility Team), Faculty of Medicine, Cairo University, Cairo, Egypt
| | - AlAmira-Fawzia Shalaby
- Internship Research Program (Research Accessibility Team), Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Alia Yasser
- Internship Research Program (Research Accessibility Team), Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Aya Mohyeldin
- Internship Research Program (Research Accessibility Team), Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Basma Amin
- Internship Research Program (Research Accessibility Team), Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Basma Saleheen
- Internship Research Program (Research Accessibility Team), Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Dina Osman
- Internship Research Program (Research Accessibility Team), Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Elaria Samuel
- Internship Research Program (Research Accessibility Team), Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Emmy Abdelfatah
- Internship Research Program (Research Accessibility Team), Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Eveen Albustami
- Internship Research Program (Research Accessibility Team), Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Farida ElGhamry
- Internship Research Program (Research Accessibility Team), Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Habiba Khaled
- Internship Research Program (Research Accessibility Team), Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Hana Amr
- Internship Research Program (Research Accessibility Team), Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Hanya Gaber
- Internship Research Program (Research Accessibility Team), Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Ismail Makhlouf
- Internship Research Program (Research Accessibility Team), Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Janna Abdeldayem
- Internship Research Program (Research Accessibility Team), Faculty of Medicine, Cairo University, Cairo, Egypt
| | | | - Karim Milad
- Internship Research Program (Research Accessibility Team), Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Laila El Sharkawi
- Internship Research Program (Research Accessibility Team), Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Lina Abosenna
- Internship Research Program (Research Accessibility Team), Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Madonna G. Safi
- Internship Research Program (Research Accessibility Team), Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mariam AbdelKareem
- Internship Research Program (Research Accessibility Team), Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Marwa Gaber
- Internship Research Program (Research Accessibility Team), Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mirna Elkady
- Internship Research Program (Research Accessibility Team), Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mohamed Ihab
- Internship Research Program (Research Accessibility Team), Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Nora AbdelRaouf
- Internship Research Program (Research Accessibility Team), Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Rawan Khaled
- Internship Research Program (Research Accessibility Team), Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Reem Shalata
- Internship Research Program (Research Accessibility Team), Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Rudayna Mahgoub
- Internship Research Program (Research Accessibility Team), Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Sarah Jamal
- Internship Research Program (Research Accessibility Team), Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Seif El-Din El Hawary
- Internship Research Program (Research Accessibility Team), Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Shady ElRashidy
- Internship Research Program (Research Accessibility Team), Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Sherouk El Shorbagy
- Internship Research Program (Research Accessibility Team), Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Tony Gerges
- Internship Research Program (Research Accessibility Team), Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Yara Kassem
- Internship Research Program (Research Accessibility Team), Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Yasmeen Magdy
- Internship Research Program (Research Accessibility Team), Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Yasmin Omar
- Internship Research Program (Research Accessibility Team), Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Yasmine Shokry
- Internship Research Program (Research Accessibility Team), Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Aya Kamel
- Internship Research Program (Research Accessibility Team), Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Rafeef Hozaien
- Internship Research Program (Research Accessibility Team), Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Nadine El-Husseiny
- Faculty of Dentistry, Cairo University, Cairo, Egypt
- Pixagon Graphic Design Agency, Cairo, Egypt
| | - Meryam El Shershaby
- Internship Research Program (Research Accessibility Team), Faculty of Medicine, Cairo University, Cairo, Egypt
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Association of Pre-S/S and Polymerase Mutations with Acute and Chronic Hepatitis B Virus Infections in Patients from Rio de Janeiro, Brazil. Viruses 2022; 14:v14071375. [PMID: 35891356 PMCID: PMC9315576 DOI: 10.3390/v14071375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Revised: 06/10/2022] [Accepted: 06/16/2022] [Indexed: 02/01/2023] Open
Abstract
Several hepatitis B virus (HBV)-related factors, including the viral load, genotype, and genomic mutations, have been linked to the development of liver diseases. Therefore, in this study we aimed to investigate the influence of HBV genetic variability during acute and chronic infection phases. A real-time nested PCR was used to detect HBV DNA in all samples (acute, n = 22; chronic, n = 49). All samples were sequenced for phylogenetic and mutation analyses. Genotype A, sub-genotype A1, was the most common genotype in the study population. A total of 190 mutations were found in the pre-S/S gene area and the acute profile revealed a greater number of nucleotide mutations (p < 0.05). However, both profiles contained nucleotide mutations linked to immune escape and an increased risk of hepatocellular carcinomas (acute, A7T; chronic, A7Q). Furthermore, 17 amino acid substitutions were identified in the viral polymerase region, including the drug resistance mutations lamivudine and entecavir (rtL180M), with statistically significant differences between the mutant and wild type strains. Owing to the natural occurrence of these mutations, it is important to screen for resistance mutations before beginning therapy.
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Gherlan GS. Occult hepatitis B - the result of the host immune response interaction with different genomic expressions of the virus. World J Clin Cases 2022; 10:5518-5530. [PMID: 35979101 PMCID: PMC9258381 DOI: 10.12998/wjcc.v10.i17.5518] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 01/30/2022] [Accepted: 04/04/2022] [Indexed: 02/06/2023] Open
Abstract
With over 40 years of history, occult hepatitis B infection (OBI) continues to remain an important and challenging public health problem. Defined as the presence of replication-competent hepatitis B virus (HBV) DNA (i.e., episomal HBV covalently closed circular DNA) in the liver and/or HBV DNA in the blood of people who test negative for hepatitis B surface antigen (HBsAg) in currently available assays, OBI is currently diagnosed using polymerase chain reaction (PCR) and real-time PCR assays. However, all efforts should be made to exclude a false negative HBsAg in order to completely follow the definition of OBI. In recent years, significant advances have been made in understanding the HBV lifecycle and the molecular mechanisms that lead to the persistence of the virus in the occult form. These factors are mainly related to the host immune system and, to a smaller proportion, to the virus. Both innate and adaptive immune responses are important in HBV infection management, and epigenetic changes driven by host mechanisms (acetylation, methylation, and microRNA implication) are added to such actions. Although greater genetic variability in the S gene of HBV isolated from OBIs was found compared with overt infection, the mechanisms of OBI are not mainly viral mutations.
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Affiliation(s)
- George Sebastian Gherlan
- Department of Infectious Diseases, “Carol Davila” University of Medicine and Pharmacy, Bucharest 030303, Romania
- Department of Infectious Diseases, “Dr. Victor Babes” Hospital of Infectious and Tropical Diseases, Bucharest 030303, Romania
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Asai A, Hirai S, Yokohama K, Nishikawa T, Nishikawa H, Higuchi K. Effect of an Electronic Alert System on Hepatitis B Virus Reactivation in Patients Receiving Immunosuppressive Drug Therapy. J Clin Med 2022; 11:jcm11092446. [PMID: 35566572 PMCID: PMC9104084 DOI: 10.3390/jcm11092446] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 04/19/2022] [Accepted: 04/23/2022] [Indexed: 02/04/2023] Open
Abstract
Hepatitis B virus (HBV) reactivation (HBVr) can occur in patients receiving immunosuppressive drug therapies, causing significant morbidity and mortality. Although the guidelines for HBVr have been proposed by several academic societies, some providers do not follow them, resulting in HBVr and death. As HBV-DNA levels increase before liver enzyme levels do, we previously constructed an electronic alert system that recommends the measurement of HBV-DNA. Here, we investigated whether this alert system improves the HBV-DNA measurement rate and elicits responses according to guidelines. A total of 5329 patients were divided into two groups, before and after the introduction of the alert system, and the HBV-DNA measurement rates in both groups were compared. Because of the introduction of the alert system, the HBV-DNA measurement rate among HBsAg-negative patients with anti-HBs and/or anti-HBc before immunosuppressive drug therapy improved significantly. The HBV-DNA monitoring rate within 3 months also improved significantly (p = 0.0034) in HBV-remission phase patients. HBVr was detected immediately, and the affected patients were treated with nucleotide analogs before severe hepatitis onset. The introduction of the alert system for HBVr improved the HBV-DNA measurement rates in patients receiving immunosuppressive drug therapy, leading to the rapid treatment of patients with HBVr.
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Affiliation(s)
- Akira Asai
- The Second Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki 569-8686, Japan; (K.Y.); (T.N.); (H.N.); (K.H.)
- Correspondence: ; Tel.: +81-(726)-83-1221
| | - Saho Hirai
- Faculty of Medicine, Osaka Medical and Pharmaceutical University, Takatsuki 569-8686, Japan;
| | - Keisuke Yokohama
- The Second Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki 569-8686, Japan; (K.Y.); (T.N.); (H.N.); (K.H.)
| | - Tomohiro Nishikawa
- The Second Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki 569-8686, Japan; (K.Y.); (T.N.); (H.N.); (K.H.)
| | - Hiroki Nishikawa
- The Second Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki 569-8686, Japan; (K.Y.); (T.N.); (H.N.); (K.H.)
| | - Kazuhide Higuchi
- The Second Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki 569-8686, Japan; (K.Y.); (T.N.); (H.N.); (K.H.)
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Teng W, Chang TT, Yang HI, Peng CY, Su CW, Su TH, Hu TH, Yu ML, Yang HC, Wu JC. Risk scores to predict HCC and the benefits of antiviral therapy for CHB patients in gray zone of treatment guidelines. Hepatol Int 2021; 15:1421-1430. [PMID: 34741723 DOI: 10.1007/s12072-021-10263-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 10/18/2021] [Indexed: 11/26/2022]
Abstract
BACKGROUNDS ALT ≥ 80 U/L and HBV DNA ≥ 2000 IU/ml are treatment criteria of APASL guidelines for chronic hepatitis B (CHB) patients. The need of antiviral therapy for patients in gray zone (ALT < 80 U/L or HBV DNA < 2000 IU/ml) is controversial. This study aimed to develop a scoring system to predict hepatocellular carcinoma (HCC) and evaluate the benefit of antiviral therapy in these patients. METHODS Seven hundred and forty-nine patients were analyzed. Significant variables were weighted to develop a scoring system for HCC prediction. The area under receiver operating curves (AUROC) were estimated and validated by REVEAL-HBV cohort (n = 3527). RESULTS Older age (p < 0.001), male sex (p = 0.036), family history of HCC (p = 0.002) and HBV DNA ≥ 2000 IU/ml (p = 0.045) were independently associated with HCC. A 14-point risk score system predicts 3 and 5-years HCC risk to be 0.866 and 0.868 of AUROC, respectively in the derivation cohort; 0.821 and 0.820, in the REVEAL-HBV cohort. The cumulative HCC incidence was higher in the high risk (score ≥ 8) group both in derivation and validation cohorts (p < 0.001). Patients with antiviral therapy had lower HCC incidence compared to those without (p = 0.016). Of note, antiviral therapy significantly decreased HCC in the high risk group (p = 0.005), but not in the low risk group (p = 0.705). CONCLUSIONS A risk scoring system is established and validated. Of CHB patients in gray zone of APASL guidelines, those with risk scores ≥ 8 had higher risk of HCC, but the risk could be significantly reduced by antiviral therapy.
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Affiliation(s)
- Wei Teng
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, Republic of China
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan, Republic of China
| | - Ting-Tsung Chang
- Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan, Republic of China
| | - Hwai-I Yang
- Genomics Research Center, Academia Sinica, Taipei, Taiwan, Republic of China
| | - Cheng-Yuan Peng
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan, Republic of China
| | - Chien-Wei Su
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China
| | - Tung-Hung Su
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan, Republic of China
| | - Tsung-Hui Hu
- Department of Gastroenterology and Hepatology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan, Republic of China
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, Republic of China
| | - Hung-Chih Yang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan, Republic of China
| | - Jaw-Ching Wu
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, Republic of China.
- Translational Research Division, Medical Research Department, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China.
- Cancer Progression Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan, Republic of China.
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Abstract
Hepatitis B virus (HBV) can hide in the liver in the form of covalently closed circular DNA. When the body’s immunity changes, HBV reactivation (HBV-R) can occur. The risk of HBV-R is determined by the complex interaction among virological factors, medication factors and host factors. However, many patients do not know that they are infected with HBV, and doctors often do not invest enough time to systematically evaluate the patient’s HBV-R risk factors before immunosuppressive treatment. Therefore, HBV clinical screening should be vigorously promoted to achieve early detection and early prevention for patients with high risk of HBV-R. The mechanism, clinical features, risk factors, HBV-R under different disease etiologies, prevention and treatment of HBV-R were summarized to improve the in-depth understanding and awareness.
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Affiliation(s)
- Wei Huang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy & Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Lingyao Du
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy & Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy & Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, 610041, China
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Caviglia GP, Zorzi A, Rizzetto M, Mirandola M, Olivero A, Carolo G. Hepatitis B Virus Reactivation upon Immunosuppression: Is There a Role for Hepatitis B Core-Related Antigen in Patients with Immune-Escape Mutants? A Case Report. Diagnostics (Basel) 2021; 11:diagnostics11122185. [PMID: 34943420 PMCID: PMC8700299 DOI: 10.3390/diagnostics11122185] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 11/21/2021] [Accepted: 11/23/2021] [Indexed: 01/06/2023] Open
Abstract
The reactivation of hepatitis B virus (HBVr) in patients undergoing pharmacological immunosuppression is a potentially fatal clinical event that may occur in patients with overt or occult HBV infection. The risk of HBVr is mainly determined by the type of immunosuppressive therapy and the HBV serologic profile, with a higher risk in patients positive for the hepatitis B surface antigen (HBsAg), and a lower risk in HBsAg-negative/antibodies to core antigen-positive subjects. Notably, a considerable proportion of patients experiencing HBVr showed a high degree of variability of the HBV S gene, possibly leading to immune escape mutants. These mutations, usually in the “a-determinant” of the HBsAg, can cause diagnostic problems and consequently hamper the appropriate management strategy of patients at risk of HBVr. Here, we describe a case of HBVr in a patient with a diagnosis of chronic myeloid leukemia and a previous history of kidney transplant, providing evidence of the potential usefulness of hepatitis B core-related antigen measurement in patients with HBV immune-escape mutants at risk of viral reactivation.
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Affiliation(s)
- Gian Paolo Caviglia
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy;
- Correspondence: (G.P.C.); (A.O.); Tel.: +39-011-6333532 (G.P.C.)
| | - Antonella Zorzi
- Virology and Microbiology Unit, Department of Pathology and Diagnostics, Verona University Hospital, 37126 Verona, Italy;
| | - Mario Rizzetto
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy;
| | - Massimo Mirandola
- Infectious Diseases Section, Department of Diagnostics and Public Health, University of Verona, 37134 Verona, Italy; (M.M.); (G.C.)
| | - Antonella Olivero
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy;
- Correspondence: (G.P.C.); (A.O.); Tel.: +39-011-6333532 (G.P.C.)
| | - Giada Carolo
- Infectious Diseases Section, Department of Diagnostics and Public Health, University of Verona, 37134 Verona, Italy; (M.M.); (G.C.)
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Jin X, Yan ZH, Lu L, Lu S, Zhang G, Lin W. Peripheral Immune Cells Exhaustion and Functional Impairment in Patients With Chronic Hepatitis B. Front Med (Lausanne) 2021; 8:759292. [PMID: 34782855 PMCID: PMC8589627 DOI: 10.3389/fmed.2021.759292] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 09/17/2021] [Indexed: 12/30/2022] Open
Abstract
After infection of hepatitis B virus (HBV), the virus induces a variety of immune disorders in the host, leading to immune escape and, finally, the chronicity of the disease. This study investigated immune cell defects and functional impairment in patients with chronic hepatitis B (CHB). We analyzed the percentage, function, and phenotypes of various immune cell subpopulations in the peripheral blood along with the concentrations of cytokines in the plasma. We compared the results between patients with CHB and healthy individuals. It was found that in patients with CHB, the cell function was impaired and, there was increased expression of inhibitory receptors, such as NKG2A and PD-1 in both NK and T cells. The impairment of function was mainly in cytokine secretion, and the cytotoxicity was not significantly diminished. We also found that the proportion of dendritic cells (DC) decreased and regulatory B cells (Breg) increased in CHB. In addition, the Breg cells were negatively correlated with T cell cytokine and positively correlated with ALT and HBV viral load. Taken together, various disorders and functional impairments were found in the immune cells of peripheral blood in CHB patients, especially NK and T cells. These cells showed exhaustion and the increase of regulatory B cells may be one of the reasons for this phenomenon.
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Affiliation(s)
- Xin Jin
- Department of Clinical Laboratory, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Zhi-Han Yan
- Department of Hepatology, Wuxi Fifth People's Hospital, Wuxi, China
| | - Lingna Lu
- Department of Clinical Laboratory, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Shengjia Lu
- Department of Infectious Diseases, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Guoping Zhang
- Department of Clinical Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
| | - Wei Lin
- Department of Otolaryngology, Tongde Hospital of Zhejiang Province, Hangzhou, China
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Ghosh S, Chakraborty A, Banerjee S. Persistence of Hepatitis B Virus Infection: A Multi-Faceted Player for Hepatocarcinogenesis. Front Microbiol 2021; 12:678537. [PMID: 34526974 PMCID: PMC8435854 DOI: 10.3389/fmicb.2021.678537] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 07/06/2021] [Indexed: 12/14/2022] Open
Abstract
Hepatitis B virus (HBV) infection has a multi-dimensional effect on the host, which not only alters the dynamics of immune response but also persists in the hepatocytes to predispose oncogenic factors. The virus exists in multiple forms of which the nuclear localized covalently closed circular DNA (cccDNA) is the most stable and the primary reason for viral persistence even after clearance of surface antigen and viral DNA. The second reason is the existence of pregenomic RNA (pgRNA) containing virion particles. On the other hand, the integration of the viral genome in the host chromosome also leads to persistent production of viral proteins along with the chromosomal instabilities. The interferon treatment or administration of nucleot(s)ide analogs leads to reduction in the viral DNA load, but the pgRNA and surface antigen clearance are a slow process and complete loss of serological HBsAg is rare. The prolonged exposure of immune cells to the viral antigens, particularly HBs antigen, in the blood circulation results in T-cell exhaustion, which disrupts immune clearance of the virus and virus-infected cells. In addition, it predisposes immune-tolerant microenvironment, which facilitates the tumor progression. Thus cccDNA, pgRNA, and HBsAg along with the viral DNA could be the therapeutic targets in the early disease stages that may improve the quality of life of chronic hepatitis B patients by impeding the progression of the disease toward hepatocellular carcinoma.
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Affiliation(s)
| | | | - Soma Banerjee
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
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Liang YJ, Teng W, Chen CL, Sun CP, Teng RD, Huang YH, Liang KH, Chen YW, Lin CC, Su CW, Tao MH, Wu JC. Clinical Implications of HBV PreS/S Mutations and the Effects of PreS2 Deletion on Mitochondria, Liver Fibrosis, and Cancer Development. Hepatology 2021; 74:641-655. [PMID: 33675094 DOI: 10.1002/hep.31789] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 01/11/2021] [Accepted: 02/03/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS PreS mutants of HBV have been reported to be associated with HCC. We conducted a longitudinal study of the role of HBV preS mutations in the development of HCC, particularly in patients with chronic hepatitis B (CHB) having low HBV DNA or alanine aminotransferase (ALT) levels, and investigated the effects of secretion-defective preS2 deletion mutant (preS2ΔMT) on hepatocyte damage in vitro and liver fibrosis in vivo. APPROACH AND RESULTS Association of preS mutations with HCC in 343 patients with CHB was evaluated by a retrospective case-control follow-up study. Effects of preS2ΔMT on HBsAg retention, endoplasmic reticulum (ER) stress, calcium accumulation, mitochondrial dysfunction, and liver fibrosis were examined. Multivariate analysis revealed a significant association of preS mutations with HCC (HR, 3.210; 95% CI, 1.072-9.613; P = 0.037) including cases with low HBV DNA or ALT levels (HR, 2.790; 95% CI, 1.133-6.873; P = 0.026). Antiviral therapy reduced HCC risk, including cases with preS mutations. PreS2ΔMT expression promoted HBsAg retention in the ER and unfolded protein response (UPR). Transmission electron microscopic examination, MitoTracker staining, real-time ATP assay, and calcium staining of preS2ΔMT-expressing cells revealed aberrant ER and mitochondrial ultrastructure, reduction of mitochondrial membrane potential and ATP production, and calcium overload. Serum HBV secretion levels were ~100-fold lower in preS2ΔMT-infected humanized Fah-/-/ Rag2-/-/Il2rg-/- triple knockout mice than in wild-type HBV-infected mice. PreS2ΔMT-infected mice displayed up-regulation of UPR and caspase-3 and enhanced liver fibrosis. CONCLUSIONS PreS mutations were significantly associated with HCC development in patients with CHB, including those with low HBV DNA or ALT levels. Antiviral therapy reduced HCC occurrence in patients with CHB, including those with preS mutations. Intracellular accumulation of mutated HBsAg induced or promoted ER stress, calcium overload, mitochondrial dysfunction, impaired energy metabolism, liver fibrosis, and HCC.
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Affiliation(s)
- Yuh-Jin Liang
- Translational Research DivisionMedical Research DepartmentTaipei Veterans General HospitalTaipeiTaiwan, ROC.,Cancer Progression Research CenterNational Yang-Ming UniversityTaipeiTaiwan, ROC
| | - Wei Teng
- Department of Gastroenterology & HepatologyChang Gung Memorial Hospital, Linkou Medical CenterTaoyuanTaiwan, ROC.,Institute of Clinical MedicineNational Yang-Ming UniversityTaipeiTaiwan, ROC
| | - Chih-Li Chen
- School of MedicineCollege of MedicineFu Jen Catholic UniversityTaipeiTaiwan, ROC
| | - Cheng-Pu Sun
- Institute of Biomedical SciencesAcademia SinicaTaipeiTaiwan, ROC
| | - Rui-Dung Teng
- Institute of Clinical MedicineNational Yang-Ming UniversityTaipeiTaiwan, ROC
| | - Yen-Hua Huang
- Center for Systems and Synthetic Biology and Institute of Biomedical InformaticsNational Yang-Ming UniversityTaipeiTaiwan, ROC
| | - Kung-Hao Liang
- Translational Research DivisionMedical Research DepartmentTaipei Veterans General HospitalTaipeiTaiwan, ROC
| | - Yi-Wen Chen
- Translational Research DivisionMedical Research DepartmentTaipei Veterans General HospitalTaipeiTaiwan, ROC
| | - Chung-Chih Lin
- Department of Life Sciences and Institute of Genome SciencesYang-Ming UniversityTaipeiTaiwan, ROC
| | - Chien-Wei Su
- Division of GastroenterologyDepartment of MedicineTaipei Veterans General HospitalTaipeiTaiwan, ROC.,Faculty of MedicineSchool of MedicineNational Yang-Ming UniversityTaipeiTaiwan, ROC
| | - Mi-Hua Tao
- Institute of Biomedical SciencesAcademia SinicaTaipeiTaiwan, ROC
| | - Jaw-Ching Wu
- Translational Research DivisionMedical Research DepartmentTaipei Veterans General HospitalTaipeiTaiwan, ROC.,Cancer Progression Research CenterNational Yang-Ming UniversityTaipeiTaiwan, ROC.,Institute of Clinical MedicineNational Yang-Ming UniversityTaipeiTaiwan, ROC
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Phan NMH, Faddy HM, Flower RL, Dimech WJ, Spann KM, Roulis EV. Low Genetic Diversity of Hepatitis B Virus Surface Gene amongst Australian Blood Donors. Viruses 2021; 13:1275. [PMID: 34208852 PMCID: PMC8310342 DOI: 10.3390/v13071275] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 06/11/2021] [Accepted: 06/25/2021] [Indexed: 12/13/2022] Open
Abstract
Variants in the small surface gene of hepatitis B virus (HBV), which codes for viral surface antigen (HBsAg), can affect the efficacy of HBsAg screening assays and can be associated with occult HBV infection (OBI). This study aimed to characterise the molecular diversity of the HBV small surface gene from HBV-reactive Australian blood donors. HBV isolates from 16 HBsAg-positive Australian blood donors' plasma were sequenced and genotyped by phylogenies of viral coding genes and/or whole genomes. An analysis of the genetic diversity of eight HBV small surface genes from our 16 samples was conducted and compared with HBV sequences from NCBI of 164 international (non-Australian) blood donors. Genotypes A-D were identified in our samples. The region of HBV small surface gene that contained the sequence encoding the 'a' determinant had a greater genetic diversity than the remaining part of the gene. No escape mutants or OBI-related variants were observed in our samples. Variant call analysis revealed two samples with a nucleotide deletion leading to truncation of polymerase and/or large/middle surface amino acid sequences. Overall, we found that HBV small surface gene sequences from Australian donors demonstrated a lower level of genetic diversity than those from non-Australian donor population included in the study.
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Affiliation(s)
- Ngoc Minh Hien Phan
- Faculty of Health, School of Biomedical Sciences, Queensland University of Technology, Kelvin Grove, Queensland 4059, Australia; (H.M.F.); (R.L.F.); (K.M.S.); (E.V.R.)
- Research and Development, Australian Red Cross Lifeblood, Kelvin Grove, Queensland 4059, Australia
| | - Helen M. Faddy
- Faculty of Health, School of Biomedical Sciences, Queensland University of Technology, Kelvin Grove, Queensland 4059, Australia; (H.M.F.); (R.L.F.); (K.M.S.); (E.V.R.)
- Research and Development, Australian Red Cross Lifeblood, Kelvin Grove, Queensland 4059, Australia
- School of Health and Behavioural Sciences, University of Sunshine Coast, Petrie, Queensland 4502, Australia
| | - Robert L. Flower
- Faculty of Health, School of Biomedical Sciences, Queensland University of Technology, Kelvin Grove, Queensland 4059, Australia; (H.M.F.); (R.L.F.); (K.M.S.); (E.V.R.)
- Research and Development, Australian Red Cross Lifeblood, Kelvin Grove, Queensland 4059, Australia
| | - Wayne J. Dimech
- Scientific & Business Relations, National Serology Reference Laboratory, Fitzroy, Victoria 3065, Australia;
| | - Kirsten M. Spann
- Faculty of Health, School of Biomedical Sciences, Queensland University of Technology, Kelvin Grove, Queensland 4059, Australia; (H.M.F.); (R.L.F.); (K.M.S.); (E.V.R.)
| | - Eileen V. Roulis
- Faculty of Health, School of Biomedical Sciences, Queensland University of Technology, Kelvin Grove, Queensland 4059, Australia; (H.M.F.); (R.L.F.); (K.M.S.); (E.V.R.)
- Research and Development, Australian Red Cross Lifeblood, Kelvin Grove, Queensland 4059, Australia
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Detection of Q129H Immune Escape Mutation in Apparently Healthy Hepatitis B Virus Carriers in Southwestern Nigeria. Viruses 2021; 13:v13071273. [PMID: 34210073 PMCID: PMC8310067 DOI: 10.3390/v13071273] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 06/27/2021] [Accepted: 06/27/2021] [Indexed: 12/12/2022] Open
Abstract
As the global effort to eradicate hepatitis B continues, immune escape mutations (IEMs) and drug resistance mutations (DRMs) affecting its diagnosis, treatment, and prevention are compromising this goal. However, knowledge about the prevalence and circulation of these mutations in Nigeria is scarce. Serum samples (n = 199) from apparently healthy prospective blood donors, pregnant women, and individuals presenting with fever in southwestern Nigeria were analyzed for the presence of IEMs and DRMs by means of nested PCR in the HBV S (HBs) and HBV polymerase (Pol) genes, followed by phylogenetic and mutational analyses. In total, 25.1% (n = 50/199) of samples were positive for HBV, as measured by PCR. In 41 samples (20.6%), both fragments could be amplified, whereas the HBs gene and the Pol gene fragment alone were detected in 0.5% (n = 1/199) and 4% (n = 8/199) of samples, respectively. Sequences were successfully obtained for all 42 HBs gene fragments but for only 31/49 Pol gene fragments (totaling 73 sequences from 44 individuals). All sequences were identified as HBV genotype E. IEMs were present in 18.2% (n = 8/44) of the sequences of HBV-positive individuals with available sequences. IEM Q129H was detected in eight out of the 44 (18.2%) HBV isolates sequenced in this study; however, no DRMs were observed. This study confirms the circulation of HBV IEMs and reports the presence of Q129H IEM for the first time in Nigeria. Intensified research on the dynamics of IEM is necessary in order to enhance the elimination of HBV.
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El-Mokhtar MA, Hetta HF, Mekky MA, Abd El-Kareem DM, Ramadan M, Salah M, Mohamed NA, El-Masry EA, Adel S, Sayed IM. Characterization of Antigen Escape Mutations in Chronic HBV-Infected Patients in Upper Egypt. Infect Drug Resist 2021; 14:2419-2427. [PMID: 34234472 PMCID: PMC8254413 DOI: 10.2147/idr.s315299] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Accepted: 05/24/2021] [Indexed: 12/27/2022] Open
Abstract
Background Mutations within the “a” determinant region (position 124–147) that is present in the major hydrophilic region (MHR, position 99–160) of the hepatitis B surface antigen (HBsAg) are associated with vaccine-escape, lack of diagnosis, and failure to hepatitis B immunoglobulin (HBIG) therapy. Data regarding the amino acid changes of “a” determinant region of HBsAg are limited in Egypt. The prevalence and mutations in this region among chronic HBV (CHB)-infected patients in Upper Egypt are not known. Material and Methods Blood samples were collected from HBsAg-positive CHB-infected patients (n=123) admitted to Assiut University Hospitals. Serum samples were screened for HBsAg, HBeAg, anti-HBs and anti-HBe antibodies using commercially available ELISA kits. Viral load was determined by qPCR. In addition, mutational analysis was carried out targeting the HBV surface gene to determine the HBV genotype and vaccine escape mutations. Results Sequencing analysis of HBV DNA revealed that genotype D is the major circulating type (81.3%), followed by genotype E (18.7%). Analysis of the HBV genome revealed that 103/123 (83.7%) patients showed wild-type sequences and 20/123 (16.3%) showed mutations in the HBsAg gene. Mutation in seventeen patients (17/20, 85%) showed only one mutation, and three patients showed two mutations (3/20, 15%) in the “a” determinant region. The observed mutations were T115S (3/20, 15%), P120T/S (3/20, 15%), T126S (1/20, 5%), Q129R (2/20, 10%), M133T (2/20, 10%), S143L (5/20, 25%), D144E/A (3/20, 15%), and G145R/A (4/20, 20%). Mutations in the “a” determinant region were detected in genotype D isolates only. Conclusion We described for the first time the prevalence and characterization of vaccine escape mutants in CHB patients in Upper Egypt. Mutational analysis of the “a” determinant region revealed the presence of a wide spectrum of mutants in the circulating HBV isolates that could be a potential threat to HBV diagnosis, therapy success, and HBV vaccination program in Upper Egypt.
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Affiliation(s)
- Mohamed A El-Mokhtar
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, 71515, Egypt
| | - Helal F Hetta
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, 71515, Egypt
| | - Mohamed A Mekky
- Department of Tropical Medicine and Gastroenterology, Assiut University Hospital, Assiut, Egypt
| | - Doaa M Abd El-Kareem
- Department of Clinical Pathology, Faculty of Medicine Assiut University, Assiut, Egypt
| | - Mohammed Ramadan
- Microbiology and Immunology Department, Faculty of Pharmacy Al-Azhar University-Assiut branch, Assiut, 71526, Egypt
| | - Mohammed Salah
- Microbiology and Immunology Department, Faculty of Pharmacy Port Said University, Port Said, 42526, Egypt
| | - Nahed A Mohamed
- Department of Medical Biochemistry, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Eman A El-Masry
- Microbiology and Immunology Unit, Department of Pathology, College of Medicine, Jouf University, Al-Jouf, Saudi Arabia.,Department of Medical Microbiology and Immunology, College of Medicine, Menoufia University, Menoufia, Egypt
| | - Sara Adel
- Department of Clinical Pathology, Faculty of Medicine, Al-Azhar University, Assiut, 71515, Egypt
| | - Ibrahim M Sayed
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, 71515, Egypt.,Department of Pathology, School of Medicine, University of California, San Diego, CA, 92093, USA
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Troyer Z, Alhusaini N, Tabler CO, Sweet T, de Carvalho KIL, Schlatzer DM, Carias L, King CL, Matreyek K, Tilton JC. Extracellular vesicles carry SARS-CoV-2 spike protein and serve as decoys for neutralizing antibodies. J Extracell Vesicles 2021; 10:e12112. [PMID: 34188786 PMCID: PMC8213968 DOI: 10.1002/jev2.12112] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 05/17/2021] [Accepted: 05/28/2021] [Indexed: 01/05/2023] Open
Abstract
In late 2019, a novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China. SARS-CoV-2 and the disease it causes, coronavirus disease 2019 (COVID-19), spread rapidly and became a global pandemic in early 2020. SARS-CoV-2 spike protein is responsible for viral entry and binds to angiotensin converting enzyme 2 (ACE2) on host cells, making it a major target of the immune system - particularly neutralizing antibodies (nAbs) that are induced by infection or vaccines. Extracellular vesicles (EVs) are small membraned particles constitutively released by cells, including virally-infected cells. EVs and viruses enclosed within lipid membranes share some characteristics: they are small, sub-micron particles and they overlap in cellular biogenesis and egress routes. Given their shared characteristics, we hypothesized that EVs released from spike-expressing cells could carry spike and serve as decoys for anti-spike nAbs, promoting viral infection. Here, using mass spectrometry and nanoscale flow cytometry (NFC) approaches, we demonstrate that SARS-CoV-2 spike protein can be incorporated into EVs. Furthermore, we show that spike-carrying EVs act as decoy targets for convalescent patient serum-derived nAbs, reducing their effectiveness in blocking viral entry. These findings have important implications for the pathogenesis of SARS-CoV-2 infection in vivo and highlight the complex interplay between viruses, extracellular vesicles, and the immune system that occurs during viral infections.
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Affiliation(s)
- Zach Troyer
- Center for Proteomics and BioinformaticsDepartment of NutritionSchool of MedicineCase Western Reserve UniversityClevelandOhioUSA
| | - Najwa Alhusaini
- Center for Proteomics and BioinformaticsDepartment of NutritionSchool of MedicineCase Western Reserve UniversityClevelandOhioUSA
| | - Caroline O. Tabler
- Center for Proteomics and BioinformaticsDepartment of NutritionSchool of MedicineCase Western Reserve UniversityClevelandOhioUSA
| | - Thomas Sweet
- Center for Proteomics and BioinformaticsDepartment of NutritionSchool of MedicineCase Western Reserve UniversityClevelandOhioUSA
| | | | - Daniela M. Schlatzer
- Center for Proteomics and BioinformaticsDepartment of NutritionSchool of MedicineCase Western Reserve UniversityClevelandOhioUSA
| | - Lenore Carias
- Division of General Medical SciencesSchool of MedicineCase Western Reserve UniversityClevelandOhioUSA
| | - Christopher L. King
- Division of General Medical SciencesSchool of MedicineCase Western Reserve UniversityClevelandOhioUSA
| | - Kenneth Matreyek
- Department of PathologySchool of MedicineCase Western Reserve UniversityClevelandOhioUSA
| | - John C. Tilton
- Center for Proteomics and BioinformaticsDepartment of NutritionSchool of MedicineCase Western Reserve UniversityClevelandOhioUSA
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49
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Epidemiological Genetic Study for Novel World Records of Hepatitis B Virus Strains Detected by DNA Sequences in the South of Iraq/Al-Basrah Province. BIONANOSCIENCE 2021. [DOI: 10.1007/s12668-021-00856-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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50
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Hung MH, Tien YC, Chiu YM. Risk factors for losing hepatitis B virus surface antibody in patients with HBV surface antigen negative/surface antibody positive serostatus receiving biologic disease-modifying anti-rheumatic drugs: a nested case-control study. Adv Rheumatol 2021; 61:22. [PMID: 33832541 DOI: 10.1186/s42358-021-00173-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 02/26/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) reactivation consequent to immunosuppressive therapy is an increasingly prevalent problem with serious clinical implications. Treatment with biologic agents conduces to the loss of protective antibody to HBV surface antigen (anti-HBs), which significantly increases the risk of HBV reactivation. Hence, we investigated the risk factors for losing anti-HBs in patients with rheumatic diseases and HBV surface antigen negative/anti-HBs positive (HBsAg-/anti-HBs+) serostatus during treatment with biologic disease-modifying anti-rheumatic drugs (DMARDs). METHODS Using a nested case-control design, we prospectively enrolled patients with rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis/psoriasis, or juvenile idiopathic arthritis, who were treated with biologic DMARDs at Changhua Christian Hospital, Taiwan, from January 2013 to June 2019 and had HBsAg-/anti-HBs+ serostatus; the analytic sample excluded all patients with HBsAg+ or anti-HBs- serostatus. Anti-HBs titers were monitored 6-monthly and cases were defined as anti-HBs < 10 mIU/ml during follow-up. Cases were matched one-to-all with controls with anti-HBs ≥ 10 mIU/ml on the same ascertainment date and equivalent durations of biologic DMARDs treatment (control patients could be resampled and could also become cases during follow-up). Between-group characteristics were compared and risk factors for anti-HBs loss were investigated by conditional logistic regression analyses. RESULTS Among 294 eligible patients, 23 cases were matched with 311 controls. The incidence of anti-HBs loss was ~ 2.7%/person-year during biologic DMARDs treatment. Besides lower baseline anti-HBs titer (risk ratio 0.93, 95% CI 0.89-0.97), cases were significantly more likely than controls to have diabetes mellitus (risk ratio 4.76, 95% CI 1.48-15.30) and chronic kidney disease (risk ratio 14.00, 95% CI 2.22-88.23) in univariate analysis. Risk factors remaining significantly associated with anti-HBs loss in multivariate analysis were lower baseline anti-HBs titer (adjusted risk ratio 0.93, 95% CI 0.88-0.97) and chronic kidney disease (adjusted risk ratio 45.68, 95% CI 2.39-871.5). CONCLUSIONS Besides lower baseline anti-HBs titer, chronic kidney disease also strongly predicts future anti-HBs negativity in patients with HBsAg-/anti-HBs+ serostatus who receive biologic DMARDs to treat rheumatic diseases. Patients with low anti-HBs titer (≤ 100 mIU/ml) and/or chronic kidney disease should be monitored during biologic DMARDs therapy, to enable timely prophylaxis to preempt potential HBV reactivation.
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Affiliation(s)
- Ming-Hui Hung
- Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Changhua Christian Hospital, 135 Nanxiao St., Changhua City, 500-06, Taiwan
| | - Ya-Chih Tien
- Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Changhua Christian Hospital, 135 Nanxiao St., Changhua City, 500-06, Taiwan
| | - Ying-Ming Chiu
- Department of Allergy, Immunology, and Rheumatology, Tungs' Taichung MetroHarbor Hospital, 699, Sec. 8, Taiwan Blvd., Taichung City, 43503, Taiwan.
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