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1
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Fu MX, Elsharkawy A, Healy B, Jackson C, Bradshaw D, Watkins E, Ushiro-Lumb I, Griffiths J, Neuberger J, Maguire K, Desai M, McDougall N, Priddee N, Barclay ST, Blackmore S, Simmonds P, Irving WL, Harvala H. Occult hepatitis B virus infection: risk for a blood supply, but how about individuals' health? EClinicalMedicine 2025; 81:103095. [PMID: 39975699 PMCID: PMC11836515 DOI: 10.1016/j.eclinm.2025.103095] [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: 11/24/2024] [Revised: 01/14/2025] [Accepted: 01/20/2025] [Indexed: 02/21/2025] Open
Abstract
The implementation of effective blood donation screening for hepatitis B virus (HBV) anti-core antibodies with highly sensitive molecular HBV DNA detection in low-endemic countries like the United Kingdom has improved blood safety. However, the linkage to care and management for blood donors with occult HBV infection (OBI) is a complex dilemma involving virological, clinical, methodological, and social issues. Limited evidence suggests that OBI may accelerate the progression of liver disease and cancer. The need for a specialist referral for donors identified with OBI carries mixed opinions from blood establishments, hepatologists, and public health. Following extensive multidisciplinary discussions, experts agree upon a need for clear messaging for donors and to consider the oncogenic implications of OBI. Proposals for future studies are identified, and the applicability of the recommendations in low-resource, high-endemic regions is considered, as well as the inclusion of OBI in global hepatitis elimination targets.
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Affiliation(s)
- Michael X. Fu
- Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Ahmed Elsharkawy
- Liver Unit, Queen Elizabeth Hospital Birmingham, NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham, Birmingham, UK
| | - Brendan Healy
- Public Health Wales and Swansea Bay University Health Board, Swansea, UK
| | - Celia Jackson
- West of Scotland Specialist Virology Centre, Glasgow, UK
| | - Daniel Bradshaw
- Virus Reference Department, UK Health Security Agency, London, UK
| | - Emma Watkins
- Clinical Services, NHS Blood and Transplant, Birmingham, UK
| | | | | | - James Neuberger
- Liver Unit, Queen Elizabeth Hospital Birmingham, NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham, Birmingham, UK
| | | | - Monica Desai
- Blood Safety, UK Health Security Agency, London, UK
| | | | - Nicole Priddee
- Donor Services Division, Scottish National Blood Transfusion Service, Edinburgh, UK
| | | | | | - Peter Simmonds
- Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - William L. Irving
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, University of Nottingham, Nottingham, UK
| | - Heli Harvala
- Microbiology Services, NHS Blood and Transplant, Colindale, UK
- Radcliffe Department of Medicine, University of Oxford, Oxford, UK
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2
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Huang C, Zhang H, Wang J, Li J, Liu Q, Zong Q, Zhang Y, Wang Q, Zhou Q. Preliminary analysis of the role of small hepatitis B surface proteins mutations in the pathogenesis of occult hepatitis B infection via the endoplasmic reticulum stress-induced UPR-ERAD pathway. Open Life Sci 2025; 20:20220951. [PMID: 39926475 PMCID: PMC11806202 DOI: 10.1515/biol-2022-0951] [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: 04/14/2024] [Revised: 07/04/2024] [Accepted: 07/30/2024] [Indexed: 02/11/2025] Open
Abstract
A growing body of evidence has shown that hepatitis B surface antigen (HBsAg) mutations can influence the occurrence of occult hepatitis B infection (OBI), particularly amino acid substitutions in small hepatitis B surface proteins (SHBs). The mechanistic basis for these results, however, remains unclear. This study was designed to explore the potential impact and mechanisms of OBI-related SHBs mutations on serum HBsAg. Huh7 and HepG2 cells were transfected with plasmids encoding wild-type (WT) or OBI-related SHB mutation-containing sequences, after which a chemiluminescence approach was used to detect HBsAg levels in cell culture supernatants. Western blotting was further used to assess HBsAg and endoplasmic reticulum stress (ERS)-related protein levels in lysates prepared from these cells, while the localization of HBsAg within cells was assessed via immunofluorescent staining. Cells transfected with OBI-related SHB mutation-encoding plasmids exhibited lower supernatant HBsAg levels than cells transfected with WT plasmids. Intracellular and extracellular HBsAg levels in these mutant plasmid-transfected cells were lower relative to those for WT plasmid-transfected cells, and HBsAg accumulation within the ER was detected via immunofluorescent staining in cells transfected with OBI-related SHB mutation-encoding plasmids, ERS-related protein content was also significantly increased in mutant plasmid-transfected cells as compared to those in the WT group. These results suggest that proteins harboring OBI-related mutations may tend to accumulate in the ER, thereby triggering an ERS response and impairing the transcription and translation of HBsAg via the activation of the unfolded protein response and ER-associated protein degradation pathway. These effects ultimately reduce the overall assembly of HBV virions in the ER and their associated secretion.
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Affiliation(s)
- Chengrong Huang
- Department of Clinical Laboratory, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
- Department of Clinical Laboratory, Anqing Municipal Hospital, Anqing, 246003, China
| | - Hao Zhang
- Department of Clinical Laboratory, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
| | - Jing Wang
- Department of Clinical Laboratory, Nanjing Jiangning Hospital, Nanjing, 211100, China
| | - Jianfei Li
- Department of Clinical Laboratory, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
| | - Qian Liu
- Department of Clinical Laboratory, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
| | - Qiyin Zong
- Department of Clinical Laboratory, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
| | - Yunyun Zhang
- Department of Clinical Laboratory, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
| | - Qin Wang
- Department of Clinical Laboratory, The Second Affiliated Hospital of Anhui Medical University, 678 Furong Road, Hefei, 230601, China
| | - Qiang Zhou
- Department of Clinical Laboratory, The Second Affiliated Hospital of Anhui Medical University, 678 Furong Road, Hefei, 230601, China
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3
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Park J, Kim DY, Gee HY, Yu HC, Yang JD, Hwang S, Choi Y, Lee JG, Rhu J, Choi D, You YK, Ryu JH, Nah YW, Kim BW, Kim DS, Cho JY, Group TKOTR(KOTRYS. Genome-Wide Association Study to Identify Genetic Factors Linked to HBV Reactivation Following Liver Transplantation in HBV-Infected Patients. Int J Mol Sci 2024; 26:259. [PMID: 39796114 PMCID: PMC11719695 DOI: 10.3390/ijms26010259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Revised: 12/19/2024] [Accepted: 12/23/2024] [Indexed: 01/13/2025] Open
Abstract
This study utilized a genome-wide association study (GWAS) to investigate the genetic variations linked to the risk of hepatitis B virus (HBV) reactivation in patients who have undergone liver transplantation (LT), aiming to enhance understanding and improve clinical outcomes. Genotyping performed on a selected patients from the Korean Organ Transplantation Registry (KOTRY) data using high-throughput platforms with the Axiom Korea Biobank array 1.1. The discovery cohort included 21 patients who experienced HBV reactivation (cases) and 888 patients without HBV reactivation (controls) following LT. The replication cohort consisted of 5 patients with HBV reactivation (cases) and 312 patients without HBV reactivation (controls) after LT. Additive logistic regression analysis was conducted using PLINK software ver 1.9, with adjustments for age and gender. The GWAS findings from the discovery cohort were validated using the replication cohort. The GWAS identified several single-nucleotide polymorphisms (SNPs) in the RGL1, CDCA7L, and AQP9 genes that were significantly linked to HBV reactivation after LT, with genome-wide significance thresholds set at p < 10-7. Down-regulation of RGL1 cDNAs was observed in primary duck hepatocytes infected with duck HBV. Overexpression of CDCA7L was found to promote hepatocellular carcinoma cell proliferation and colony formation, whereas knocking down CDCA7L inhibited these processes. Additionally, the absence of AQP9 triggered immune and inflammatory responses, leading to mild and scattered liver cell pyroptosis, accompanied by compensatory liver cell proliferation. This study provides critical insights into the genetic factors influencing HBV reactivation after LT, identifying significant associations with SNPs in RGL1, CDCA7L, and AQP9. These findings hold promise for developing predictive biomarkers and personalized management strategies to improve outcomes for HBV-infected LT recipients.
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Affiliation(s)
- Joonhong Park
- Department of Laboratory Medicine, Jeonbuk National University College of Medicine and Hospital, Jeonju 54907, Republic of Korea;
- Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju 54907, Republic of Korea;
| | - Dong Yun Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea;
| | - Heon Yung Gee
- Department of Pharmacology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Hee Chul Yu
- Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju 54907, Republic of Korea;
- Department of Surgery, Jeonbuk National University College of Medicine and Hospital, Jeonju 54907, Republic of Korea
| | - Jae Do Yang
- Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju 54907, Republic of Korea;
- Department of Surgery, Jeonbuk National University College of Medicine and Hospital, Jeonju 54907, Republic of Korea
| | - Shin Hwang
- Department of Surgery, Asan Medical Center, College of Medicine University of Ulsan, Seoul 05505, Republic of Korea;
| | - YoungRok Choi
- Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, Republic of Korea;
| | - Jae Geun Lee
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul 03722, Republic of Korea;
| | - Jinsoo Rhu
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea;
| | - Donglak Choi
- Department of Surgery, Daegu Catholic University School of Medicine, Daegu 42472, Republic of Korea;
| | - Young Kyoung You
- Department of Surgery, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea;
| | - Je Ho Ryu
- Department of Surgery, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea;
| | - Yang Won Nah
- Department of Surgery, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 44033, Republic of Korea;
| | - Bong-Wan Kim
- Department of Hepato-Biliary-Pancreatic Surgery, Ajou University School of Medicine, Suwon 16499, Republic of Korea;
| | - Dong-Sik Kim
- Department of Surgery, Korea University College of Medicine, Seoul 02841, Republic of Korea;
| | - Jai Young Cho
- Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 13620, Republic of Korea;
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Huang SW, Long H, Huang JQ. Surveillance Following Hepatitis B Surface Antigen Loss: An Issue Requiring Attention. Pathogens 2024; 14:8. [PMID: 39860969 PMCID: PMC11768139 DOI: 10.3390/pathogens14010008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 12/25/2024] [Accepted: 12/27/2024] [Indexed: 01/27/2025] Open
Abstract
Due to the lack of agents that directly target covalently closed circular DNA and integrated HBV DNA in hepatocytes, achieving a complete cure for chronic hepatitis B (CHB) remains challenging. The latest guidelines recommend (hepatitis B surface antigen) HBsAg loss as the ideal treatment target for improving liver function, histopathology, and long-term prognosis. However, even after HBsAg loss, hepatitis B virus can persist, with a risk of recurrence, reactivation, cirrhosis, and hepatocellular carcinoma. Therefore, follow-up and surveillance are still necessary. With increasing treatment options available for achieving HBsAg loss in patients with CHB, developing effective surveillance strategies has become crucial. Recent studies on outcomes following HBsAg loss provide new insights for refining current surveillance strategies, though further improvement is needed through long-term observation and follow-up.
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Affiliation(s)
- Shuai-Wen Huang
- Department of General Practice, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China;
- Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China;
- Department of Nutrition, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China
| | - Hong Long
- Department of General Practice, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China;
| | - Jia-Quan Huang
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China;
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5
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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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6
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Anderson M, Phinius BB, Phakedi BK, Mudanga M, Bhebhe LN, Tlhabano GN, Motshosi P, Ratsoma T, Baruti K, Mpebe G, Choga WT, Marlink R, Glebe D, Blackard JT, Moyo S, Kramvis A, Gaseitsiwe S. Persistence and risk factors of occult hepatitis B virus infections among antiretroviral therapy-naïve people living with HIV in Botswana. Front Microbiol 2024; 15:1342862. [PMID: 38784816 PMCID: PMC11112038 DOI: 10.3389/fmicb.2024.1342862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 04/22/2024] [Indexed: 05/25/2024] Open
Abstract
Aim This study aimed to determine the kinetics of occult hepatitis B virus infections (OBI) among people with HIV (PWH). Methods The study used archived plasma samples from longitudinal HIV natural history studies. We identified new OBI cases and assessed risk factors for OBI using Cox proportional hazards regression analysis. Results At baseline, 8 of 382 [(2.1%) (95% CI: 1.06-4.1)] samples tested positive for hepatitis B surface antigen (HBsAg+). Of the 374 HBsAg-negative samples, 76 had sufficient sample volume for HBV DNA screening. OBI positivity (OBI+) at baseline was reported in 11 of 76 [14.7 95% CI (8.3-24.1)] HBsAg-negative (HBsAg-) participants. Baseline HBsAg-negative samples with sufficient follow-up samples (n = 90) were used for analysis of newly identified OBI cases. Participants contributed 129.74 person-years to the study and were followed for a median of 1.02 years (IQR: 1.00-2.00). Cumulatively, there were 34 newly identified OBI cases from the 90 participants, at the rate of 26.2/100 person-years (95% CI: 18.7-36.7). Newly identified OBI cases were more common among men than women (61.1% vs. 31.9%) and among participants with CD4+ T-cell counts ≤450 cells/mL (p-value = 0.02). Most of the newly identified OBI cases [55.9% (19/34)] were possible reactivations as they were previously HBV core antibody positive. Conclusion There was a high rate of newly identified OBI among young PWH in Botswana, especially in men and in participants with lower CD4+ T-cell counts. OBI screening in PWH should be considered because of the risk of transmission, possible reactivation, and risk factors for the development of chronic liver disease, including hepatocellular carcinoma.
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Affiliation(s)
- Motswedi Anderson
- Research Laboratory, Botswana Harvard Health Partnership, Gaborone, Botswana
| | - Bonolo B. Phinius
- Research Laboratory, Botswana Harvard Health Partnership, Gaborone, Botswana
- School of Allied Health Professions, Faculty of Health Sciences, University of Botswana, Gaborone, Botswana
| | | | - Mbatshi Mudanga
- Botswana – University of Maryland School of Medicine Health Initiative, Gaborone, Botswana
| | - Lynnette N. Bhebhe
- Research Laboratory, Botswana Harvard Health Partnership, Gaborone, Botswana
| | - Girlie N. Tlhabano
- Research Laboratory, Botswana Harvard Health Partnership, Gaborone, Botswana
| | - Patience Motshosi
- Research Laboratory, Botswana Harvard Health Partnership, Gaborone, Botswana
| | - Tsholofelo Ratsoma
- Research Laboratory, Botswana Harvard Health Partnership, Gaborone, Botswana
| | - Kabo Baruti
- Research Laboratory, Botswana Harvard Health Partnership, Gaborone, Botswana
- Department of Biological Sciences, Faculty of Science, University of Botswana, Gaborone, Botswana
| | - Gorata Mpebe
- Research Laboratory, Botswana Harvard Health Partnership, Gaborone, Botswana
| | - Wonderful T. Choga
- Research Laboratory, Botswana Harvard Health Partnership, Gaborone, Botswana
- School of Allied Health Professions, Faculty of Health Sciences, University of Botswana, Gaborone, Botswana
| | - Richard Marlink
- Research Laboratory, Botswana Harvard Health Partnership, Gaborone, Botswana
- Rutgers Global Health Institute, Rutgers University, New Brunswick, NJ, United States
| | - Dieter Glebe
- Institute of Medical Virology, National Reference Centre for Hepatitis B Viruses and Hepatitis D Viruses, Justus Liebig University of Giessen, Giessen, Germany
| | - Jason T. Blackard
- Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Sikhulile Moyo
- Research Laboratory, Botswana Harvard Health Partnership, Gaborone, Botswana
- School of Allied Health Professions, Faculty of Health Sciences, University of Botswana, Gaborone, Botswana
- Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, United States
- Division of Medical Virology, Faculty of Medicine and Health Sciences, University of Stellenbosch, Cape Town, South Africa
- School of Health Systems and Public Health, University of Pretoria, Pretoria, South Africa
| | - Anna Kramvis
- Hepatitis Virus Diversity Research Unit, Department of Internal Medicine, School of Clinical Medicine, University of the Witwatersrand, Johannesburg, South Africa
| | - Simani Gaseitsiwe
- Research Laboratory, Botswana Harvard Health Partnership, Gaborone, Botswana
- Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, United States
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7
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Maqsood Q, Sumrin A, Iqbal M, Younas S, Hussain N, Mahnoor M, Wajid A. Hepatitis C virus/Hepatitis B virus coinfection: Current prospectives. Antivir Ther 2023; 28:13596535231189643. [PMID: 37489502 DOI: 10.1177/13596535231189643] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/26/2023]
Abstract
In endemic areas, hepatitis C virus (HCV)/hepatitis B virus (HBV) coinfection is common, and patients with coinfection have a higher risk of developing liver disease such as hepatocellular carcinoma, liver fibrosis and cirrhosis. In such cases, HCV predominates, and HBV replication is suppressed by HCV. HCV core proteins and interferons that are activated by HCV are responsible for the suppression of HBV. Immunosuppression is also seen in patients with HCV and HBV coinfections. A decrease in HCV-neutralizing antibody response and circulation of Th1-like Tfh cells is observed in patients with HCV and HBV coinfection. Both viruses interacted in the liver, and treatment of HCV/HBV coinfection is genotype-based and complex due to the interaction of both viruses. In HCV-dominant cases, direct-acting antiviral drugs and peg interferon plus ribavirin are used for the treatment, with continuous monitoring of AST and ALT. HBV-dominant cases are less common and are treated with peg interferon and nucleoside nucleotide analogues with monitoring of AST and ALT. The SVR rate in HCV-HBV coinfection is higher than that in monoinfection when treated with direct-acting antiviral drugs. But there is a risk of reactivation of HBV during and after therapy. The rate of reactivation is lower in patients treated with direct-acting antiviral drugs as compared to those treated with peg interferon plus ribavirin. Biomarkers of HBV such as HBcrAg, HBV DNA and HBVpg RNA are not effective in the prediction of HBV reactivation; only the hepatitis B surface antigen titre can be used as a biomarker for HBV reactivation. HCV can also be reactive, but this is found in very rare cases in which HBV is present and is treated first.
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Affiliation(s)
- Quratulain Maqsood
- Centre for Applied Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Aleena Sumrin
- Centre for Applied Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Maryam Iqbal
- Centre for Applied Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Saima Younas
- Centre for Applied Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Nazim Hussain
- Centre for Applied Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Muhammada Mahnoor
- Department of Rehabilitation Science, The University of Lahore, Lahore, Pakistan
| | - Abdul Wajid
- Department of Biotechnology, Balochistan University of Information Technology, Engineering and Management Science, Quetta, Pakistan
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8
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Osasona OG, Oguntoye T, Eromon P, Abdulkareem L, Arowosaye AO, Ariyo OE, George UE, Yusuf M, Adewumi OM, Happi C, Folarin OA. Atypical serologic profiles of hepatitis B virus infection across clinical cohorts of patients in Southwestern Nigeria. J Immunoassay Immunochem 2023; 44:176-191. [PMID: 36681932 DOI: 10.1080/15321819.2023.2168556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Hepatitis B virus (HBV) infection follows a natural course of events predicted by a dynamic interaction between viral antigen and the host immune system, which forms the basis for HBV serological diagnosis. These interactions may deviate from the typical serologic patterns. This study investigates the types of atypical HBV serologic profiles (AHBSP) across clinical cohorts of patients with HBV infection in southwestern Nigeria. This is a cross-sectional, hospital-based, multi-centered study. Patients' sera were analyzed for HBsAg, anti-HBs, HBeAg, anti-HBe, anti-HBc IgM, and anti-HBc IgG by ELISA from 279 study participants attending selected gastroenterology clinics between August 2019 and December 2020. The prevalence of atypical HBV serologic profiles was 27% (n = 76). The mean age of patients was 35.7 ± 11.2 years. The gender distribution involved 183 females (65.6%) and 96 males (34.4%). Across clinical cohorts of patients with atypical serologic profiles, HBeAg Negative, anti-HBe positive with detectable HBV DNA had the highest prevalence of 21% followed by isolated anti-HBc antibody positive, HBsAg negative and detectable HBV DNA, 5%. The atypical serologic profiles, HBeAg positive, HBsAg negative with detectable HBV DNA and concurrent anti-HBs with HBsAg, had the lowest prevalence, 0.4%, respectively. This study identified the considerable presence of atypical HBV serologic profiles across clinical cohorts of HBV infection in southwestern Nigeria.
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Affiliation(s)
| | - Tosin Oguntoye
- Department of Medicine, Federal Teaching Hospital Ido- Ekiti, Federal Teaching Hospital Ido-Ekiti, Ido Ekiti, Nigeria
| | - Philomena Eromon
- African Center of Excellence for Genomics of Infectious diseases Redeemer's University, Redeemer's University Ede, Ede, Nigeria
| | - Lukman Abdulkareem
- Department of Medicine, University of Abuja Teaching Hospital, Gwagwalada, Nigeria
| | | | - Olumuyiwa Elijah Ariyo
- Department of Medicine, Federal Teaching Hospital Ido- Ekiti, Federal Teaching Hospital Ido-Ekiti, Ido Ekiti, Nigeria
| | - Uwem Etop George
- Department of Biological Sciences, Redeemer's University, Osun, Nigeria
| | - Musa Yusuf
- Department of Medicine, Federal Teaching Hospital Ido- Ekiti, Federal Teaching Hospital Ido-Ekiti, Ido Ekiti, Nigeria
| | | | - Christian Happi
- African Centre of Excellence for Genomics of Infectious Diseases, Department of Biological Sciences, Redeemers University, Ede, Nigeria
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9
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Zhu M, Wang H, Lou T, Xiong P, Zhang J, Li L, Sun Y, Wu Y. Current treatment of chronic hepatitis B: Clinical aspects and future directions. Front Microbiol 2022; 13:975584. [PMID: 36160238 PMCID: PMC9493448 DOI: 10.3389/fmicb.2022.975584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 07/26/2022] [Indexed: 11/23/2022] Open
Abstract
Hepatitis B virus (HBV) infection is a public health threat worldwide, and there is no direct treatment yet available. In the event of infection, patients may present liver cirrhosis and cancer, which threaten the patients’ health globally, especially in the Asia-Pacific region and China. In 2019, Chinese hepatopathologists updated the 2015 Guidelines for the Prevention and Treatment of Chronic Hepatitis B as the clinical reference. The other versions formulated by the American Association for the Study of Liver Diseases (2018 AASLD guidelines) (AASLD, 2018), European Association for the Study of the Liver (2017 EASL guidelines) (EASL, 2017), and Asian-Pacific Association for the Study of the Liver (2015 APASL guidelines) (APASL, 2015) also provide clinical guidance. However, there are still some issues that need to be addressed. In the present study, the following aspects will be introduced successively: (1) Who should be treated in the general population according to the guidelines; (2) Treatment of specific populations infected with HBV; (3) Controversial issues in clinical practice; (4) Perspective.
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Affiliation(s)
- Minmin Zhu
- The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
| | - Hui Wang
- The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
| | - Tao Lou
- The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
| | - Pian Xiong
- The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
| | - Jiebing Zhang
- The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
| | - Lele Li
- The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
| | - Yuchao Sun
- The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
- International Institutes of Medicine, Zhejiang University, Jinhua, China
| | - Yingping Wu
- The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Jinhua, China
- International Institutes of Medicine, Zhejiang University, Jinhua, China
- *Correspondence: Yingping Wu,
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10
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Saitta C, Caruso A, Maimone S, Filomia R, Cacciola I, Caccamo G, Franzè MS, Pitrone C, Alibrandi A, Gaeta M, Mandraffino G, Squadrito G, Raimondo G. Antibody to hepatitis B virus core antigen positivity is a predictor of non-alcoholic fatty liver disease severity. Intern Emerg Med 2022; 17:1609-1616. [PMID: 35332431 DOI: 10.1007/s11739-022-02971-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 03/08/2022] [Indexed: 12/16/2022]
Abstract
Insufficient information is available about co-factors favoring the progression of non-alcoholic fatty liver disease (NAFLD) toward cirrhosis. We aimed to evaluate the impact of a limited alcohol intake and of occult hepatitis B virus (HBV) infection (OBI) on the severity of NAFLD. Three-hundred-seventy-four alcohol non-abusers and HBV surface antigen negative NAFLD patients (223 males; mean age 55.4 years), consecutively admitted to the outpatients clinic of a referral liver unit from January 1st, 2018 to December 31st, 2019, were studied. Anti-HBV core antigen antibody [(anti-HBc), a surrogate marker of OBI] was assessed in all patients. Patients were distinguished between teetotal and moderate alcohol consumers (intake of less than 30 g and 20 g if males or females, respectively). Liver fibrosis was non-invasively assessed by FIB-4 and transient elastography. Uni- and multivariate analyses were performed to identify predictors of advanced fibrosis. Patients had a mean BMI of 28.5 kg/m2, and the majority presented metabolic and cardio-vascular comorbidities [258 patients (69%) had insulin resistance/diabetes, 249 (66.6%) dyslipidemia, 200 (53.5%) arterial hypertension]. Multivariate analysis showed that anti-HBc positivity (p = 0.046, OR 2.153) was a factor associated with advanced fibrosis at FIB-4 score testing, whereas moderate alcohol intake was not associated with severe NAFLD both at FIB-4 and transient elastography evaluations. The study showed that a moderate alcohol intake has no impact on NAFLD severity and suggested that OBI might negatively affect the NAFLD outcome.
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Affiliation(s)
- Carlo Saitta
- Division of Medicine and Hepatology, University Hospital of Messina, Messina, Italy.
- Division of Medicine and Hepatology, Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria, 1, 98124, Messina, Italy.
| | - Alessia Caruso
- Division of Medicine and Hepatology, University Hospital of Messina, Messina, Italy
- Division of Medicine and Hepatology, Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria, 1, 98124, Messina, Italy
| | - Sergio Maimone
- Division of Medicine and Hepatology, University Hospital of Messina, Messina, Italy
| | - Roberto Filomia
- Division of Medicine and Hepatology, University Hospital of Messina, Messina, Italy
| | - Irene Cacciola
- Division of Medicine and Hepatology, University Hospital of Messina, Messina, Italy
- Division of Medicine and Hepatology, Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria, 1, 98124, Messina, Italy
| | - Gaia Caccamo
- Division of Medicine and Hepatology, University Hospital of Messina, Messina, Italy
| | - Maria Stella Franzè
- Division of Medicine and Hepatology, University Hospital of Messina, Messina, Italy
- Division of Medicine and Hepatology, Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria, 1, 98124, Messina, Italy
| | - Concetta Pitrone
- Division of Medicine and Hepatology, University Hospital of Messina, Messina, Italy
- Division of Medicine and Hepatology, Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria, 1, 98124, Messina, Italy
| | - Angela Alibrandi
- Division of Statistical and Mathematical Sciences, Department of Economics, University of Messina, Messina, Italy
| | - Michele Gaeta
- Division of Diagnostic Imaging, Department of Biomedical and Dental Sciences and of Morphologic and Functional Imaging, University of Messina, Messina, Italy
| | - Giuseppe Mandraffino
- Division of Medicine and Hepatology, Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria, 1, 98124, Messina, Italy
- Division of Internal Medicine, University Hospital of Messina, Messina, Italy
| | - Giovanni Squadrito
- Division of Medicine and Hepatology, Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria, 1, 98124, Messina, Italy
- Division of Internal Medicine, University Hospital of Messina, Messina, Italy
| | - Giovanni Raimondo
- Division of Medicine and Hepatology, University Hospital of Messina, Messina, Italy
- Division of Medicine and Hepatology, Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria, 1, 98124, Messina, Italy
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11
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Xie WY, Sun C, He H, Deng C, Sheng Y. Estimates of the prevalence of occult HBV infection in Asia: a systematic review and meta-analysis. Infect Dis (Lond) 2022; 54:881-896. [PMID: 36047593 DOI: 10.1080/23744235.2022.2115126] [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] [Indexed: 11/05/2022] Open
Abstract
PURPOSE Occult Hepatitis B virus infection (OBI) is of great significance to the transmission of Hepatitis B virus (HBV) and the evolution of the patient's clinical outcome. We conducted a systematic review and meta-analysis to estimate the prevalence of OBI in Asia. METHODS Literature search was conducted in PubMed, Cochrane Library database, Web of Science and Embase with the keywords of 'Hepatitis B virus', 'occult infection', 'prevalence'. 70 studies were included in the meta-analysis. Meta-analysis was performed using random-effects models to calculate the pooled prevalence of OBI and 95% confidence interval (CI). The data were analyzed in R 4.1.2. RESULTS The overall prevalence of OBI was 4% (95%CI: 0.03-0.06) in Asia. Subgroup analysis based on geographic region showed a prevalence of 3% (95%CI 0.02-0.06) in East Asia, 9% (95%CI 0.05-0.15) in West Asia, 3% (95%CI 0.01-0.11) in Southern Asia and 9% (95%CI 0.05-0.15) in Southeast Asia. Subgroup analysis demonstrated a prevalence of 1% (95%CI 0.00-0.02) in general population, 5% (95%CI: 0.03-0.08) in high-risk population, 9% (95%CI: 0.03-0.22) in the human immunodeficiency virus (HIV)-infected patient, 18% (95%CI: 0.09-0.32) in the hepatopathy patients. CONCLUSION Based on the meta-analysis of the prevalence of OBI in different populations, we concluded that the prevalence of OBI in the high-risk population, hepatopathy patients, and HIV-infected patients was higher than that in the general population. A systematic review showed that OBI was associated with disease progression and prognosis. Therefore, these populations should be routinely screened for OBI and promptly intervened to avoid promoting disease progression.
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Affiliation(s)
- Wen Yangyang Xie
- Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Changfeng Sun
- Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Infection & Immunity Laboratory, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Hongyan He
- Experimental Teaching Center, School of Public Health of Southwest Medical University, Luzhou, China
| | - Cunliang Deng
- Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yunjian Sheng
- Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Infection & Immunity Laboratory, The Affiliated Hospital of Southwest Medical University, Luzhou, China
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12
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Saitta C, Pollicino T, Raimondo G. Occult Hepatitis B Virus Infection: An Update. Viruses 2022; 14:v14071504. [PMID: 35891484 PMCID: PMC9318873 DOI: 10.3390/v14071504] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Revised: 06/28/2022] [Accepted: 06/29/2022] [Indexed: 11/16/2022] Open
Abstract
Occult hepatitis B virus (HBV) infection (OBI) refers to a condition in which replication-competent viral DNA is present in the liver (with detectable or undetectable HBV DNA in the serum) of individuals testing negative for the HBV surface antigen (HBsAg). In this peculiar phase of HBV infection, the covalently closed circular DNA (cccDNA) is in a low state of replication. Many advances have been made in clarifying the mechanisms involved in such a suppression of viral activity, which seems to be mainly related to the host's immune control and epigenetic factors. OBI is diffused worldwide, but its prevalence is highly variable among patient populations. This depends on different geographic areas, risk factors for parenteral infections, and assays used for HBsAg and HBV DNA detection. OBI has an impact in several clinical contexts: (a) it can be transmitted, causing a classic form of hepatitis B, through blood transfusion or liver transplantation; (b) it may reactivate in the case of immunosuppression, leading to the possible development of even fulminant hepatitis; (c) it may accelerate the progression of chronic liver disease due to different causes toward cirrhosis; (d) it maintains the pro-oncogenic properties of the "overt" infection, favoring the development of hepatocellular carcinoma.
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Affiliation(s)
- Carlo Saitta
- Division of Medicine and Hepatology, University Hospital of Messina, 98124 Messina, Italy;
- Department of Clinical and Experimental Medicine, University of Messina, 98124 Messina, Italy
| | - Teresa Pollicino
- Department of Human Pathology, University Hospital of Messina, 98124 Messina, Italy;
| | - Giovanni Raimondo
- Division of Medicine and Hepatology, University Hospital of Messina, 98124 Messina, Italy;
- Department of Clinical and Experimental Medicine, University of Messina, 98124 Messina, Italy
- Correspondence: ; Tel.: +39-(0)-902212392
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13
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Çakal B, Çavuş B, Atasoy A, Poda M, Bulakçi M, Güllüoğlu M, Demirci M, Şener LT, Altunok D, Arslan AB, Akyüz F. What is the clinical impact of occult HBV infections and anti-HBc positivity in patients with chronic hepatitis C? Microbiol Immunol 2022; 66:386-393. [PMID: 35661243 DOI: 10.1111/1348-0421.13012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 05/20/2022] [Accepted: 06/01/2022] [Indexed: 11/29/2022]
Abstract
Occult hepatitis B infection (OBI) is defined by the persistence of the hepatitis B virus (HBV) genome in the liver of individuals testing negative for hepatitis B surface antigen (HBsAg). Hepatitis B core antibody (anti-HBc) is the serological marker that indicates HBV exposure. The impact of anti-HBc and OBI on patients with chronic hepatitis C remains unclear. The aim of the present study was to determine the prevalence of anti-HBc and OBI and to evaluate their impact on the clinical and pathological outcomes of patients with chronic hepatitis C. The study included 59 HBsAg-negative chronic hepatitis C patients who underwent a liver parenchymal biopsy. The presence of HBV DNA was investigated using an in-house nested PCR method. OBI was detected in 16 (27.1%) of the 59 cases and also in 10 (62.5%) of 22 (37.3%) anti-HBc-positive patients. None of the patients had positive serum HBV DNA. OBI was associated with the presence of anti-HBV antibodies (p<0.05). There was also an association between anti-HBc positivity and the activity grades and fibrosis stages of the liver and also a prevalence of liver steatosis (p<0.05). Positive anti-HBc results may predict OBI and also be associated with the progression of liver injury in HBsAg-negative patients with chronic hepatitis C. Therefore, it is suggested that patients with chronic hepatitis C should be screened for anti-HBc positivity, and anti-HBc-positive patients should be carefully evaluated for disease progression. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Bülent Çakal
- Department of Medical Microbiology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Bilger Çavuş
- Division of Gastroenterohepatology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Alp Atasoy
- Division of Gastroenterohepatology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Mehveş Poda
- Department of Genetics, Aziz Sancar Institute for Experimental Medical Research, Istanbul University, Istanbul, Turkey
| | - Mesut Bulakçi
- Department of Radiology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Mine Güllüoğlu
- Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Mehmet Demirci
- Department of Medical Microbiology, Faculty of Medicine, Kirklareli University, Kirklareli, Turkey
| | - Leyla Türker Şener
- Department of Biophysics Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Damla Altunok
- Division of Gastroenterohepatology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | | | - Filiz Akyüz
- Division of Gastroenterohepatology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
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14
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Franzè MS, Pollicino T, Raimondo G, Squadrito G. Occult hepatitis B virus infection in hepatitis C virus negative chronic liver diseases. Liver Int 2022; 42:963-972. [PMID: 35246933 PMCID: PMC9310828 DOI: 10.1111/liv.15233] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 01/09/2022] [Accepted: 02/16/2022] [Indexed: 01/26/2023]
Abstract
Data concerning the prevalence of hepatitis B virus (HBV) occult infection (OBI) varies greatly in the different studies according to the sensitivity and specificity of the diagnostic approaches and the HBV prevalence in the different populations examined. The clinical implications of OBI are still debated. While the impact of OBI in HBV transmission as well as in HBV reactivation under immunosuppression are well established, the role of OBI in liver disease and hepatocellular carcinoma (HCC) development are still not definitively elucidated. It has been hypothesized that OBI might contribute to worsening the liver disease course when other causes of liver damage co-exist. Furthermore, much evidence suggests a role of OBI in the hepato-carcinogenesis processes through both indirect and direct oncogenic mechanisms that might favour HCC development. Data on the OBI clinical implications mainly come from studies performed in patients with hepatitis C virus (HCV) infection. However, HCV prevalence has dramatically fallen in the past years also because of the advent of specific and highly effective direct acting antivirals, with a consequent abrupt change of the worldwide scenario of chronic liver disease. Information about OBI prevalence and possible clinical impact in non-HCV-related liver disease are fragmentary, and the objective of this review is to critically summarize the available data in this field.
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Affiliation(s)
- Maria Stella Franzè
- Department of Clinical and Experimental MedicineMessina UniversityMessinaItaly
- Division of Medicine and HepatologyMessina University HospitalMessinaItaly
| | - Teresa Pollicino
- Department of Human PathologyMessina UniversityMessinaItaly
- Division of Advanced Diagnostic LaboratoriesMessina University HospitalMessinaItaly
| | - Giovanni Raimondo
- Department of Clinical and Experimental MedicineMessina UniversityMessinaItaly
- Division of Medicine and HepatologyMessina University HospitalMessinaItaly
| | - Giovanni Squadrito
- Department of Clinical and Experimental MedicineMessina UniversityMessinaItaly
- Division of Internal MedicineMessina University HospitalMessinaItaly
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15
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Beykaso G, Mulu A, Giday M, Berhe N, Selamu M, Hailu D, Teklehaymanot T. Occult Hepatitis B Virus Infection and Its Risks of Cryptic Transmission in Southern Ethiopia. Infect Drug Resist 2022; 15:619-630. [PMID: 35241914 PMCID: PMC8886027 DOI: 10.2147/idr.s344668] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 02/07/2022] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND The detection of hepatitis B virus surface antigen (HBsAg) in serum remains the mainstay in diagnosing and screening of hepatitis B virus (HBV) in most developing countries. The absence of HBsAg in the blood may not indicate the absence of circulating HBV and might be infectious. Thus, this study aimed to estimate the burden and its cryptic transmission risks of occult hepatitis B infection (OBI) among HBsAg negative healthy individuals in Southern Ethiopia. METHODS A community-based cross-sectional study was conducted from September 2020 to January 2021. Serum samples were collected and assayed for HBsAg and HBV core antibody (anti-HBc) seromarkers using enzyme-linked immunosorbent assay (ELISA). In anti-HBc positive samples, HBV DNA was detected using real-time polymerase chain reaction (RT-PCR). Data were entered into Epi-Data version 3.1, cleaned, and analyzed using SPSS version 21.0. Descriptive and logistic regression analyses were employed. Statistical significance was decided at p < 0.05. RESULTS A total of 346 were individuals included in this study; 34 (9.8%) were tested positive for HBsAg. The rest 312 (90.2%) negatively tested were further assayed for anti-HBc, and 115 (36.7%) were found positive implying previous exposure to HBV, and 21 (18.3%) out of 115 anti-HBc positives had HBV DNA signifying OBI. The HBV DNA concentration below 200 IU/mL was 85.7%. A high rate of OBI was observed among individuals who had multiple sexual contacts, a family history of hepatitis, and tattooing. CONCLUSION In this study, the prevalence of OBI is high. This indicates the burden of HBV is considerable since screening is exclusively dependent on HBsAg which will not eliminate the possibility of residual cryptic transmission through blood donation, organ transplantation, perinatal transmission, and other contacts. Our results demonstrate that nucleic acid-based testing (NAT) should be an essential part of screening to prevent missing OBI.
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Affiliation(s)
- Gizachew Beykaso
- Aklilu Lemma Institute of Pathobiology, Department of Molecular Biology and Immunology, Addis Ababa University, Addis Ababa, Ethiopia
- College of Medicine and Health Sciences, Department of Public Health, Wachemo University, Hossana, Ethiopia
| | - Andargachew Mulu
- Armauer Hansen Research Institute, Department of Virology, Addis Ababa, Ethiopia
| | - Mirutse Giday
- Aklilu Lemma Institute of Pathobiology, Department of Molecular Biology and Immunology, Addis Ababa University, Addis Ababa, Ethiopia
| | - Nega Berhe
- Aklilu Lemma Institute of Pathobiology, Department of Molecular Biology and Immunology, Addis Ababa University, Addis Ababa, Ethiopia
| | - Markos Selamu
- College of Medicine and Health Sciences, Department of Public Health, Wachemo University, Hossana, Ethiopia
| | - Dawit Hailu
- Armauer Hansen Research Institute, Department of Virology, Addis Ababa, Ethiopia
| | - Tilahun Teklehaymanot
- Aklilu Lemma Institute of Pathobiology, Department of Molecular Biology and Immunology, Addis Ababa University, Addis Ababa, Ethiopia
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16
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de Faria AC, Correa BHM, Faria LC, Vidigal PVT, Xavier MAP, Ferrari TCA. Occult hepatitis B virus infection in patients with chronic liver disease of different etiology in a Brazilian referral center: comparison of two different hepatitis B virus deoxyribonucleic acid amplification protocols: a cross-sectional study. SAO PAULO MED J 2022; 141:e2022147. [PMID: 36169566 PMCID: PMC10065104 DOI: 10.1590/1516-3180.2022.0147.r1.12072022] [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: 03/24/2022] [Accepted: 07/12/2022] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Occult hepatitis B virus infection (OBI) is defined as the presence of hepatitis B virus (HBV) deoxyribonucleic acid (DNA) in the liver of individuals with undetectable hepatitis B virus surface antigen (HBsAg) in the serum. The actual prevalence of OBI and its clinical relevance are not yet fully understood. OBJECTIVE To evaluate the prevalence of HBV DNA in liver biopsies of HBsAg-negative patients with chronic liver disease of different etiologies in a referral center in Brazil and compare two different HBV DNA amplification protocols to detect HBV. DESIGN AND SETTING This cross-sectional observational study was conducted at the Liver Outpatient Clinic, Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil, between January 2016 and December 2019. METHODS HBV DNA was investigated in 104 liver biopsy samples from individuals with chronic liver disease of different etiologies, in whom HBsAg was undetectable in serum by nested-polymerase chain reaction (nested-PCR), using two different protocols. RESULTS OBI, diagnosed by detecting HBV DNA using both protocols, was detected in 6.7% of the 104 individuals investigated. Both protocols showed a good reliability. CONCLUSION In addition to the differences in the prevalence of HBV infection in different regions, variations in the polymerase chain reaction technique used for HBV DNA amplification may be responsible for the large variations in the prevalence of OBI identified in different studies. There is a need for better standardization of the diagnostic methods used to diagnose this entity.
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Affiliation(s)
- Alessandra Coutinho de Faria
- MD, MSc. Physician, Department of Internal Medicine, Faculty of
Medicine, Hospital das Clínicas, Universidade Federal de Minas Gerais (UFMG),
Belo Horizonte (MG), Brazil
| | - Bernardo Henrique Mendes Correa
- Research Associate, Undergraduate Student, Department of
Internal Medicine, Faculty of Medicine, Universidade Federal de Minas Gerais
(UFMG), Belo Horizonte (MG), Brazil
| | - Luciana Costa Faria
- MD, PhD. Professor Associate, Department of Internal Medicine,
Faculty of Medicine, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte
(MG), Brazil
| | - Paula Vieira Teixeira Vidigal
- MD, PhD. Professor Associate, Department of Pathological
Anatomy and Forensic Medicine, Faculty of Medicine, Universidade Federal de
Minas Gerais (UFMG), Belo Horizonte (MG), Brazil
| | - Marcelo Antônio Pascoal Xavier
- MD, PhD. Professor, Department of Pathological Anatomy and
Forensic Medicine, Faculty of Medicine, Universidade Federal de Minas Gerais
(UFMG), Belo Horizonte (MG), Brazil
| | - Teresa Cristina Abreu Ferrari
- MD, PhD. Professor, Department of Internal Medicine, Faculty of
Medicine, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte (MG),
Brazil
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17
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Grattagliano I, Rossi A, Marconi E, Lapi F, Cricelli C. Determinants of HCV-related complications in Italian primary care patients. Liver Int 2021; 41:2857-2865. [PMID: 34268863 DOI: 10.1111/liv.15017] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 06/01/2021] [Accepted: 07/05/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIMS This study aimed to assess the demographic and clinical determinants of liver complications in Hepatitis C virus (HCV)-positive patients in primary care setting. METHODS Using the Health Search database, we selected a cohort of patients aged ≥14 diagnosed with HCV between 2002 and 2017. Patients were followed up until the occurrence of cirrhosis and other disease progressions such as oesophageal varices, hepatocellular carcinoma and/or liver transplantation. The candidate determinants for the risk of HCV-related complications included sex, age, smoking status, liver fibrosis (measured by fibrosis 4 index [FIB-4]), infections by the human immunodeficiency virus (HIV), hepatitis B virus (HBV), other forms of hepatitis, abuse of alcohol or illicit substances or drugs, obesity, metabolic syndrome, diabetes mellitus and renal disease. Cox regression was used to test the association between candidate determinants and the outcome. RESULTS The cohort included 8299 HCV-positive patients (50.93% men) with an overall prevalence rate equal to 0.61%. At least one HCV-related complication was found in 12.2% of patients, with a mean time-to-event equal to 8.1 year. Along with male sex and advanced age, a FIB-4 greater than 3.25 and the presence of diabetes were associated with a greater risk of HCV-related complications. CONCLUSION Our study shows that patients with certain demographics and clinical characteristics are more prone to incur in HCV-related complications. The knowledge and early identification of these determinants by GPs may result in reducing disease progression and related healthcare costs through a closer monitoring.
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Affiliation(s)
| | - Alessandro Rossi
- Italian College of General Practitioners and Primary Care, Florence, Italy
| | - Ettore Marconi
- Health Search, Italian College of General Practitioners and Primary Care, Florence, Italy
| | - Francesco Lapi
- Health Search, Italian College of General Practitioners and Primary Care, Florence, Italy
| | - Claudio Cricelli
- Italian College of General Practitioners and Primary Care, Florence, Italy
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18
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Liu Y. Some concerns about "PDCD1 and IFNL4 genetic variants and risk of developing hepatitis C virus-related diseases". Liver Int 2021; 41:1154. [PMID: 33058503 DOI: 10.1111/liv.14702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 10/07/2020] [Indexed: 02/13/2023]
Affiliation(s)
- Yanqing Liu
- Department of Clinical Laboratory, Ningbo First Hospital, Ningbo, Zhejiang, China
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19
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Pak K, Ordway S, Torres D. Occult HBV Infection: A Case Series at a Military Treatment Facility. Mil Med 2021; 185:e795-e798. [PMID: 31681958 DOI: 10.1093/milmed/usz379] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 09/08/2019] [Accepted: 09/10/2019] [Indexed: 01/04/2023] Open
Abstract
Occult HBV infection (OBI) is defined as the presence of detectable hepatitis B virus (HBV) DNA in HBV surface antigen (HBsAg) negative individuals. Rarely, OBI is attributed to mutant HBV that cannot be detected by commercial assays, but most cases occur in the setting of chronic hepatitis B, particularly infection with wild-type viruses associated with strong HBV suppression. OBI is a high-risk diagnosis as it is associated with multiple complications: HBV reactivation in immunocompromised states, transmission of HBV, progression of liver disease, and hepatocellular carcinoma. The diagnosis is also easy to overlook, as the negative HBsAg in such cases can be falsely reassuring. This case series describes four male patients (mean age 51) who were diagnosed with OBI in the same military treatment facility between February 2018 and October 2018. Two of the four patients were active duty service members at the time of diagnosis. These patients had variable clinical presentations and outcomes. This case series illustrates the clinical significance of OBI and the importance of screening for OBI in HBsAg negative patients with signs of chronic or severe hepatic inflammation. It also prompts an intriguing question regarding the prevalence of both HBV and OBI in the United States military and whether or not routine screening for HBV should be implemented in this population. Further study is warranted to determine if adding HBV core antibody to a universally employed screening regimen would be beneficial.
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Affiliation(s)
- Kevin Pak
- Department of Internal Medicine, WRNMMC, 8901 Rockville Pike, Bethesda, MD 20889
| | - Sarah Ordway
- Division of Gastroenterology, Department of Internal Medicine, WRNMMC, 8901 Rockville Pike, Bethesda, MD 20889
| | - Dawn Torres
- Division of Gastroenterology, Department of Internal Medicine, WRNMMC, 8901 Rockville Pike, Bethesda, MD 20889
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20
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Cheng X, Uchida T, Xia Y, Umarova R, Liu CJ, Chen PJ, Gaggar A, Suri V, Mücke MM, Vermehren J, Zeuzem S, Teraoka Y, Osawa M, Aikata H, Tsuji K, Mori N, Hige S, Karino Y, Imamura M, Chayama K, Liang TJ. Diminished hepatic IFN response following HCV clearance triggers HBV reactivation in coinfection. J Clin Invest 2021; 130:3205-3220. [PMID: 32163375 DOI: 10.1172/jci135616] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 03/05/2020] [Indexed: 12/12/2022] Open
Abstract
In patients with HBV and HCV coinfection, HBV reactivation leading to severe hepatitis has been reported with the use of direct-acting antivirals (DAAs) to treat HCV infection. Here we studied the molecular mechanisms behind this viral interaction. In coinfected cell culture and humanized mice, HBV replication was suppressed by HCV coinfection. In vitro, HBV suppression was attenuated when interferon (IFN) signaling was blocked. In vivo, HBV viremia, after initial suppression by HCV superinfection, rebounded following HCV clearance by DAA treatment that was accompanied by a reduced hepatic IFN response. Using blood samples of coinfected patients, IFN-stimulated gene products including C-X-C motif chemokine 10 (CXCL10), C-C motif chemokine ligand 5 (CCL5), and alanine aminotransferase (ALT) were identified to have predictive value for HBV reactivation after HCV clearance. Taken together, our data suggest that HBV reactivation is a result of diminished hepatic IFN response following HCV clearance and identify serologic markers that can predict HBV reactivation in DAA-treated HBV-HCV-coinfected persons.
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Affiliation(s)
- Xiaoming Cheng
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
| | - Takuro Uchida
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA.,Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yuchen Xia
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
| | - Regina Umarova
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
| | - Chun-Jen Liu
- Graduate Institute of Clinical Medicine, Hepatitis Research Center and Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Pei-Jer Chen
- Graduate Institute of Clinical Medicine, Hepatitis Research Center and Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Anuj Gaggar
- Gilead Sciences, Foster City, California, USA
| | | | - Marcus M Mücke
- Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt, Germany
| | - Johannes Vermehren
- Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt, Germany
| | - Stefan Zeuzem
- Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt, Germany
| | - Yuji Teraoka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Mitsutaka Osawa
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Keiji Tsuji
- Department of Gastroenterology, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Hiroshima, Japan
| | - Nami Mori
- Department of Gastroenterology, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Hiroshima, Japan
| | - Shuhei Hige
- Department of Hepatology, Sapporo Kosei General Hospital, Sapporo, Japan
| | - Yoshiyasu Karino
- Department of Hepatology, Sapporo Kosei General Hospital, Sapporo, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - T Jake Liang
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
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21
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Reply. Clin Gastroenterol Hepatol 2021; 19:408-409. [PMID: 33451513 DOI: 10.1016/j.cgh.2020.03.058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 03/25/2020] [Accepted: 03/26/2020] [Indexed: 02/07/2023]
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22
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Occult Hepatitis B Infection in Recent Immigrants to Italy: Occult B Infection in Immigrants. J Community Health 2021; 45:357-362. [PMID: 31555924 DOI: 10.1007/s10900-019-00746-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
This study determined the prevalence and clinical features of occult hepatitis B infection (OBI) in a population of recent immigrants to Italy. Two hundred-five immigrants were tested for HBV-infection and were classified as seropositive-OBI or false-OBI. Biochemical/virological activities and imaging diagnostics were determined in anti-HBc-positive subjects. Among the tested subjects, 39.0% were anti-HBc-positive/HBsAg-negative; 11.2% had persistently normal ALT levels with mild detectable HBV-DNA, seropositive-OBI; 6.2% had slightly elevated ALT and positive serum HBV-DNA with a mean level of viral load: 3275 copies/mL-false-OBI. The total prevalence of OBI was 6.8%; 4.4% were seropositive-OBI and 2.4% were false-OBI. Diagnosis by echo-tomography was achieved in 35.7% OBI subjects with alterations of the hepatic echo-texture. We found a moderate prevalence of occult hepatitis B-infection in immigrants. Frequently, these subjects present false-OBI.
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Ribeiro CRDA, de Almeida NAA, Martinelli KG, Pires MA, Mello CEB, Barros JJ, de Paula VS. Cytokine profile during occult hepatitis B virus infection in chronic hepatitis C patients. Virol J 2021; 18:15. [PMID: 33435966 PMCID: PMC7802259 DOI: 10.1186/s12985-021-01487-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 01/02/2021] [Indexed: 12/19/2022] Open
Abstract
Background The hepatitis B virus (HBV) is one of the leading causes of acute, chronic and occult hepatitis (OBI) representing a serious public health threat. Cytokines are known to be important chemical mediators that regulate the differentiation, proliferation and function of immune cells. Accumulating evidence indicate that the inadequate immune responses are responsible for HBV persistency. The aim of this study were to investigate the cytokines IFN-γ, TNF-α, IL-2, IL-4, IL-6, IL-10 and IL-17A in patients with OBI and verify if there is an association between the levels of these cytokines with the determination of clinical courses during HBV occult infection. Methods 114 patients with chronic hepatitis C were investigated through serological and molecular tests, the OBI coinfected patients were subjected to the test for cytokines using the commercial human CBA kit. As controls, ten healthy donors with no history of liver disease and 10 chronic HBV monoinfected patients of similar age to OBI patients were selected. Results Among 114 HCV patients investigated, 11 individuals had occult hepatitis B. The levels of cytokines were heterogeneous between the groups, most of the cytokines showed higher levels of production detection among OBI/HCV individuals when compared to control group and HBV monoinfected pacients. We found a high level of IL-17A in the HBV monoinfected group, high levels of TNF-α, IL-10, IL-6, IL-4 and IL-2 in OBI/HCV patients. Conclusion These cytokines could be involved in the persistence of HBV DNA in hepatocytes triggers a constant immune response, inducing continuous liver inflammation, which can accelerate liver damage and favor the development of liver cirrhosis in other chronic liver diseases.
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Affiliation(s)
- Camilla Rodrigues de Almeida Ribeiro
- Laboratory of Molecular Virology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, 4365, Brasil Av., Manguinhos, Rio de Janeiro, RJ, 21040-360, Brazil
| | - Nathalia Alves Araújo de Almeida
- Laboratory of Molecular Virology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, 4365, Brasil Av., Manguinhos, Rio de Janeiro, RJ, 21040-360, Brazil
| | | | - Marcia Amendola Pires
- Gaffrée and Guinle Universitary Hospital, Ambulatory of Liver Disease, Rio de Janeiro State Federal University/UniRio, Rio de Janeiro, Brazil
| | - Carlos Eduardo Brandao Mello
- Gaffrée and Guinle Universitary Hospital, Ambulatory of Liver Disease, Rio de Janeiro State Federal University/UniRio, Rio de Janeiro, Brazil
| | - José J Barros
- Laboratory of Molecular Virology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, 4365, Brasil Av., Manguinhos, Rio de Janeiro, RJ, 21040-360, Brazil.
| | - Vanessa Salete de Paula
- Laboratory of Molecular Virology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, 4365, Brasil Av., Manguinhos, Rio de Janeiro, RJ, 21040-360, Brazil
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24
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Tseng TC, Liu CJ. Occult Hepatitis B Infection. HEPATITIS B VIRUS AND LIVER DISEASE 2021:411-425. [DOI: 10.1007/978-981-16-3615-8_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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25
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Pisaturo M, Onorato L, Russo A, Coppola N. Prevalence of occult HBV infection in Western countries. J Med Virol 2020; 92:2917-2929. [PMID: 32275083 DOI: 10.1002/jmv.25867] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 03/19/2020] [Indexed: 12/11/2022]
Abstract
Due to a lack of standardized tests, it is difficult to obtain prevalence data and define the real impact of occult HBV infection (OBI) in Western countries. The present review article addresses the prevalence of OBI, defined as presence of hepatitis B virus (HBV) DNA in liver tissue or plasma in HBsAg-negative subjects, in Western countries. This varies in different studies according to the different methodologies used (based on serology vs virology), to the sample analyzed for the diagnosis (liver tissue vs plasma), to the different populations studied, to the different geographical variations in the HBV spread, to the host characteristics (age, gender, risk factors for acquiring HBV infection) and to the presence of other parenteral infections (hepatitis C virus and/or human immunodeficiency virus [HIV] infections). Considering the different liver diseases analyzed, that is in patients with cryptogenic cirrhosis or advanced liver fibrosis, the prevalence of OBI ranges 4% to 38%. Considering the different populations studied, in the case of parenteral blood exposure it is about 45%, in patients with chronic hepatitis C it is estimated at about 52%, in HIV-infected patients it ranges from 0% to 45%, in blood donors from 0% to 22.7% and in hemodialysis patients it ranges from 0% to 54%. In conclusion, OBI is a virological entity to be considered when performing the patient's evaluation for immunosuppressive diseases, liver pathologies, or for blood transfusions. Knowing the prevalence and clinical impact of OBI will allow better patient management.
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Affiliation(s)
- Mariantonietta Pisaturo
- Department of Mental Health and Public Medicine-Infectious Diseases Unit, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Lorenzo Onorato
- Department of Mental Health and Public Medicine-Infectious Diseases Unit, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Antonio Russo
- Department of Mental Health and Public Medicine-Infectious Diseases Unit, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Nicola Coppola
- Department of Mental Health and Public Medicine-Infectious Diseases Unit, University of Campania Luigi Vanvitelli, Naples, Italy
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26
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Occult hepatitis B infection and hepatocellular carcinoma: Epidemiology, virology, hepatocarcinogenesis and clinical significance. J Hepatol 2020; 73:952-964. [PMID: 32504662 DOI: 10.1016/j.jhep.2020.05.042] [Citation(s) in RCA: 132] [Impact Index Per Article: 26.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 05/21/2020] [Accepted: 05/25/2020] [Indexed: 12/12/2022]
Abstract
Occult hepatitis B infection (OBI) refers to a condition where replication-competent HBV DNA is present in the liver, with or without HBV DNA in the blood, in individuals with serum HBsAg negativity assessed by currently available assays. The episomal covalently closed circular DNA (cccDNA) in OBI is in a low replicative state. Viral gene expression is mediated by epigenetic control of HBV transcription, including the HBV CpG island methylation pathway and post-translational modification of cccDNA-bound histone, with a different pattern from patients with chronic HBV infection. The prevalence of OBI varies tremendously across patient populations owing to numerous factors, such as geographic location, assay characteristics, host immune response, coinfection with other viruses, and vaccination status. Apart from the risk of viral reactivation upon immunosuppression and the risk of transmission of HBV, OBI has been implicated in hepatocellular carcinoma (HCC) development in patients with chronic HCV infection, those with cryptogenic or known liver disease, and in patients with HBsAg seroclearance after chronic HBV infection. An increasing number of prospective studies and meta-analyses have reported a higher incidence of HCC in patients with HCV and OBI, as well as more advanced tumour histological grades and earlier age of HCC diagnosis, compared with patients without OBI. The proposed pathogenetic mechanisms of OBI-related HCC include the influence of HBV DNA integration on the hepatocyte cell cycle, the production of pro-oncogenic proteins (HBx protein and mutated surface proteins), and persistent low-grade necroinflammation (contributing to the development of fibrosis and cirrhosis). There remain uncertainties about exactly how, and in what order, these mechanisms drive the development of tumours in patients with OBI.
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27
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Raimondo G, Saitta C, Lombardo D, Giraudi PJ, Rosso N, Ieni A, Lazzara S, Palmisano S, Bonazza D, Alibrandi A, Navarra G, Tiribelli C, Pollicino T. Occult hepatitis B virus infection predicts non-alcoholic steatohepatitis in severely obese individuals from Italy. Liver Int 2020; 40:1601-1609. [PMID: 32329579 DOI: 10.1111/liv.14473] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 04/04/2020] [Accepted: 04/06/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Obesity is associated with non-alcoholic fatty liver (NAFL), which may progress towards non-alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). Occult hepatitis B virus infection (OBI) may contribute to hepatic damage in patients with chronic liver disease of different aetiologies (eg HCV, alcohol). However, information on the prevalence and clinical impact of OBI in obese individuals is lacking. The aims of this study were to investigate NASH prevalence and risk factors in obese people who underwent bariatric surgery. METHODS Two-hundred and twenty-six subjects (160 females; mean age 42.9 years ±10.8 SD) without evidence of any further cause of liver disease consecutively underwent bariatric surgery in two Italian liver centers. During surgery, all patients underwent liver biopsy for histological evaluation and molecular studies. Liver DNA extracts were tested for PNPLA3, TM6SF2, MBOAT7, IRGM polymorphisms and for OBI. Univariate and multivariate analyses were used to identify predictors of NASH. RESULTS Histology showed NASH in 115 (50.9%) and NAFL in 111 cases (49.1%). Twenty-nine/226 (12.8%) cases had OBI, 24 (82.8%) of whom had NASH and 5 (17.2%) NAFL, whereas among the 197 OBI-negative cases, 91 (46.2%) had NASH and 106 (53.8%) NAFL (P = .0002). Multivariate analysis showed that older age (P = .03, OR 1.034), alanine aminotransferase values (P = .005, OR 1.023), insulin resistance/diabetes (P = .02, OR 2.257), TM6SF2 polymorphism (P = .04, OR 3.168) and OBI (P = .004, OR 5.503) were independent predictors of NASH. CONCLUSION NASH is highly prevalent in obese individuals undergoing bariatric surgery. OBI is one of the strongest risk factors of NASH in these patients.
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Affiliation(s)
- Giovanni Raimondo
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.,Unit of Clinical and Molecular Hepatology, University Hospital of Messina, Messina, Italy
| | - Carlo Saitta
- Unit of Clinical and Molecular Hepatology, University Hospital of Messina, Messina, Italy
| | - Daniele Lombardo
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Pablo J Giraudi
- Italian Liver Foundation, Liver Study Centre, Trieste, Italy
| | - Natalia Rosso
- Italian Liver Foundation, Liver Study Centre, Trieste, Italy
| | - Antonio Ieni
- Department of Human Pathology, University of Messina, Messina, Italy.,Unit of Pathology, University Hospital of Messina, Messina, Italy
| | - Salvatore Lazzara
- Department of Human Pathology, University of Messina, Messina, Italy.,Unit of Oncological Surgery, University Hospital of Messina, Messina, Italy
| | - Silvia Palmisano
- Italian Liver Foundation, Liver Study Centre, Trieste, Italy.,Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - Deborah Bonazza
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - Angela Alibrandi
- Department of Economics, Unit of Statistical and Mathematical Sciences, University of Messina, Messina, Italy
| | - Giuseppe Navarra
- Department of Human Pathology, University of Messina, Messina, Italy.,Unit of Oncological Surgery, University Hospital of Messina, Messina, Italy
| | | | - Teresa Pollicino
- Unit of Clinical and Molecular Hepatology, University Hospital of Messina, Messina, Italy.,Department of Human Pathology, University of Messina, Messina, Italy
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Zarębska-Michaluk D, Flisiak R, Flisiak-Jackiewicz M. Management of hepatitis B and hepatitis C coinfection: an expert review. Expert Rev Anti Infect Ther 2020; 18:1033-1044. [PMID: 32579414 DOI: 10.1080/14787210.2020.1776112] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections share common routes of transmission. HBV/HCV coinfection can lead to interactions affecting mechanisms of infection and therapy. AREAS COVERED In the review, we present epidemiology of HBV/HCV coinfection and current therapeutic options for both viruses. The possibility of drug-drug interactions during the treatment of coinfected patients is discussed. However, the major part of the review is dedicated to interactions between viruses and risk of HBV reactivation during HCV treatment with direct-acting antivirals (DAA). Finally, we analyze available international and national guidelines for the management of HBV reactivations related to DAA administration. EXPERT OPINION The most important international societies' guidelines include comments on HBV/HCV coinfection, but due to their inconsistency we present a proposal of management for HBV/HCV coinfected patients focusing mostly on HBV reactivation in patients treated for HCV. We provide some advice that should be considered in future guidelines for the management of HBV/HCV coinfection.
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Affiliation(s)
| | - Robert Flisiak
- Department of Infectious Diseases and Hepatology, Medical University of Białystok , 15-540, Białystok, Poland
| | - Marta Flisiak-Jackiewicz
- Department of Pediatrics, Gastroenterology, Hepatology, Nutrition and Allergology, Medical University of Bialystok , 15-247, Bialystok, Poland
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29
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Hedayati-Moghaddam MR, Soltanian H, Behzadifar M. Occult Hepatitis B Virus Infection Prevalence Among Different Populations of Iran: A Systematic Review and Meta-Analysis. HEPATITIS MONTHLY 2020; 20. [DOI: 10.5812/hepatmon.101722] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 05/13/2020] [Accepted: 05/15/2020] [Indexed: 08/30/2023]
Abstract
Context: Various frequency rates of occult hepatitis B virus infection (OBI) are reported from different parts of Iran. This systematic review and meta-analysis aimed to characterize the OBI epidemiology in Iran and estimate the pooled prevalence among different populations. Evidence Acquisition: Nine international and Persian electronic databases, as well as some conference proceedings, were searched. Original cross-sectional studies up to December 2018 were included if they investigated the prevalence of OBI by the detection of serum hepatitis B virus surface antigen and hepatitis B virus nucleic acid in at least 30 samples selected with any sampling methods. Comprehensive meta-analysis software was used to analyze the data, and Cochran’s Q-test and I-square statistics were applied to assess the heterogeneity. Meta-regression analysis was performed to assess the impact of the year of study on the OBI frequency. A P value < 0.05 was considered as the level of significance. Results: Of 412 citations found in electronic sources and 35 relevant citations added by searching the gray literature, 83 non-duplicated non-overlapping studies were evaluated. A total of 55 documents comprising 14,485 individuals from 16 provinces met the inclusion criteria and were used in the analysis. The prevalence of OBI considerably varied in different parts of the country with the highest prevalence (63.1%) reported among the HIV-positive population in Fars province. The rates of the OBI prevalence were estimated at 0.06% (95% CI: 0.02 - 0.16%) among blood donors (BDs) regardless of their anti-HBc status, 7.90% (95% CI: 4.33 - 13.99%) among anti-HBc positive BDs, 2.49% (95% CI: 1.2 - 4.81%) among hemodialysis (HD) patients, 4.44% (95% CI: 1.56 - 12.02%) among HIV-positive patients, and 7.76% (95% CI: 4.57 - 12.86%) among HCV-positive patients. No significant trends were observed in OBI prevalence rates among different groups over time (P > 0.05). Conclusions: This review revealed high rates of OBI prevalence among high-risk populations in Iran. It is strongly suggested that occult hepatitis B be investigated among populations with a high chance of its occurrence in our country.
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30
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Positive Hepatitis B Core Antibody Is Associated With Cirrhosis and Hepatocellular Carcinoma in Nonalcoholic Fatty Liver Disease. Am J Gastroenterol 2020; 115:867-875. [PMID: 32149781 DOI: 10.14309/ajg.0000000000000588] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Previous exposure to hepatitis B virus (HBV) may increase the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C. We aim to study the impact of previous HBV infection on the severity and outcomes of patients with nonalcoholic fatty liver disease (NAFLD). METHODS This was a multicenter study of 489 patients with biopsy-proven NAFLD and 69 patients with NAFLD-related or cryptogenic HCC. Antihepatitis B core antibody (anti-HBc) was used to detect the previous HBV infection. RESULTS In the biopsy cohort, positive anti-HBc was associated with lower steatosis grade but higher fibrosis stage. 18.8% and 7.5% of patients with positive and negative anti-HBc had cirrhosis, respectively (P < 0.001). The association between anti-HBc and cirrhosis remained significant after adjusting for age and metabolic factors (adjusted odds ratio 2.232; 95% confidence interval, 1.202-4.147). At a mean follow-up of 6.2 years, patients with positive anti-HBc had a higher incidence of HCC or cirrhotic complications (6.5% vs 2.2%; P = 0.039). Among patients with NAFLD-related or cryptogenic HCC, 73.9% had positive anti-HBc. None of the patients had positive serum HBV DNA. By contrast, antihepatitis B surface antibody did not correlate with histological severity. DISCUSSION Positive anti-HBc is associated with cirrhosis and possibly HCC and cirrhotic complications in patients with NAFLD. Because a significant proportion of NAFLD-related HCC may develop in noncirrhotic patients, future studies should define the role of anti-HBc in selecting noncirrhotic patients with NAFLD for HCC surveillance.
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Bhatia M, Gupta E, Choudhary MC, Jindal A, Sarin SK. Evaluation of impact of occult hepatitis B infection in chronic HCV-infected patients: A retrospective cohort study. J Lab Physicians 2020; 10:304-308. [PMID: 30078967 PMCID: PMC6052820 DOI: 10.4103/jlp.jlp_12_18] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
CONTEXT Occult hepatitis B infection (OBI) may contribute to liver damage and variable therapeutic response in patients with chronic hepatitis C (CHC) infection. AIMS To study the prevalence of OBI and to evaluate its impact and/or that of anti-HBc total seropositivity on clinical outcomes and response to directly acting antiviral (DAA) therapy in CHC-infected patients. SETTINGS AND DESIGN A retrospective cohort study was conducted in a tertiary care liver hospital from January to May 2017. SUBJECTS AND METHODS Eighty HBsAg-negative CHC patients who were initiated on DAA therapy were retrospectively included. Archived pretreatment baseline plasma samples were retrieved and tested for quantitative HBV DNA, anti-HBs, and anti-HBc total antibodies. HCV RNA, genotype, clinical, biochemical and histopathological parameters & treatment response data were obtained from the hospital information system. STATISTICAL ANALYSIS USED Comparison of continuous variables was done by Mann-Whitney and Kruskal-Wallis tests and categorical variables by Fisher's exact test or Pearson's Chi-square test. RESULTS Prevalence of OBI was 1.25%. Anti-HBc total positivity was seen in 25% patients. Based on anti-HBc total status, patients were categorized into two groups namely Group 1 (anti-HBc positive) and Group 2 (anti-HBc negative). Group 1 patients were further categorized into three subgroups based on signal/cutoff (S/Co) of HBc total antibody semi-quantitative values. HBc total antibody levels did not influence the severity of CHC disease. Comparative evaluation of parameters such as median log10 baseline RNA (P = 0.929 and 0.464), median alanine aminotransferase (ALT 0) (P = 0.519 and 0.449), ALT at 12 weeks (P = 0.875 and 0.594), sustained virological response (SVR) at 12 weeks (P = 0.405 and 0.263) and SVR at 24 weeks (P = 0.265 and 0.625) between Groups 1 and 2 and among three categories within Group 1, respectively, were not found to be statistically significant. CONCLUSIONS Very low prevalence of OBI was seen in CHC patients. HBc total antibody levels did not influence clinical outcome and response to DAA therapy in this cohort.
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Affiliation(s)
- Mohit Bhatia
- Department of Clinical Virology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Ekta Gupta
- Department of Clinical Virology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Manish C Choudhary
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Ankur Jindal
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
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Khiangte B, Kothakota SR, Sasidharan M, Kareem H, Nair AK, Kumar VV, Kanala JR, Kumar PC. Hepatitis B Reactivation in Liver Transplant Recipients With Hepatitis B Virus Core Antibody Positive Grafts: a Retrospective Study. J Clin Exp Hepatol 2020; 10:548-554. [PMID: 33311891 PMCID: PMC7719971 DOI: 10.1016/j.jceh.2020.05.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 05/01/2020] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Liver grafts from hepatitis B core antibody (anti-HBc) positive donors increase the risk of hepatitis B virus (HBV) reactivation in recipients due to posttransplant immunosuppressive therapy. AIM AND OBJECTIVE to study the HBV reactivation in liver transplant recipients with anti-HBc-positive donors. METHODS This was a retrospective study. Liver transplant recipients who received grafts from anti-HBc-positive donors between January 2013 and December 2017 were included in analysis. Hospital records of all subjects for a 2-year posttransplantation period were studied to observe reactivation of hepatitis B. As per our institute protocol, prophylaxis for HBV was given to subjects with either positive hepatitis B surface antigens or hepatitis B surface antibody (anti-HBs) titre <100 mIU/ml, after transplantation with anti-HBc-positive donor grafts. Recipients with anti-HBs titre >100 mIU/mL were exempted from prophylaxis and kept on regular monitoring for HBV markers. RESULTS Of 85 liver transplant recipients, 20 subjects who received anti-HBc-positive grafts were included in analysis. The mean age of the study population was 46 years (range 2-68 years). The most common aetiology of cirrhosis in our study population was cryptogenic followed by ethanol. Among the study population, 16 (80%) transplant recipients had anti-HBs titre less than 100 mu/ml and 4 (20%) subjects had anti-HBs > 100 miu/ml. HBV reactivation occurred in 6 (30%) subjects. Reactivation was seen even in those who received HBV prophylaxis, while none of the subjects with anti-HBs titre >100 miu/ml developed HBV reactivation despite absence of prophylaxis. CONCLUSION HBV reactivation can occur even in the presence of target anti-HBs titre (i.e. >10 miu/ml) and HBV prophylaxis during postliver transplantation. However, HBV reactivation is not seen in recipients with anti-HBs titre of >100 miu/ml.
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Affiliation(s)
| | - Sunil R. Kothakota
- Address for correspondence. Sunil Raviraj K, Senior Resident, Department of Gastroenterology, KIMS hospital, Postal code/ P.O. Box: Anayara PO., Trivandrum, Kerala, 695029, India.
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HBV DNA in the Plasma and Peripheral Blood Mononuclear Cells in Chronic HBV Infected Individuals Who Became HBsAg-Serocleared or Seroconverted. HEPATITIS MONTHLY 2019. [DOI: 10.5812/hepatmon.96014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
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Occult hepatitis B in kidney transplants recipients and donors from Western Mexico. Int J Infect Dis 2019; 91:17-21. [PMID: 31669141 DOI: 10.1016/j.ijid.2019.10.023] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 10/19/2019] [Accepted: 10/21/2019] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Occult hepatitis B virus infection (OBI) is defined as the presence of hepatitis B virus (HBV) DNA in serum and/or liver from HBsAg-negative subjects. Our aim was to determine OBI frequency in serum and genomic DNA in patients undergoing renal transplant and their cognate donors in a selected population from Western Mexico. METHODS Blood samples were obtained from 94 donors and their cognate recipients (188 participants) before kidney transplantation. Identification of HBV DNA was carried-out by nested (S-region) and semi-nested (Pol-region) PCR in both genomic and serum DNA samples from 188 participants at pre-surgical stage and from a subset of 73 recipients at three-month follow-up. RESULTS HBV-DNA was not detected in either genomic or serum DNA samples from recipients or donors prior to transplantation. After three-months of follow-up, 2 out of 73 (2.7%, 95% CI: 0.9-11.9%) recipients were positive to HBV-DNA (Pol-region) in genomic DNA samples using a high sensitivity Taq DNA polymerase. CONCLUSIONS OBI incidence in recipients of kidney transplant may be higher than previously recognized. Detection of HBV-DNA was higher in genomic DNA than in serum samples using a high sensitivity Taq DNA polymerase. To the best of our knowledge, this is the first report regarding this specific topic in Mexicans.
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Hepatitis viruses take advantage of traditional practices to increase the burden of hepatocellular carcinoma in Tunisia. Arch Virol 2019; 165:33-42. [PMID: 31630275 DOI: 10.1007/s00705-019-04440-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2019] [Accepted: 08/26/2019] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is a major public health issue in Africa. In Tunisia, hepatitis B virus (HBV) is known to be an important risk factor for HCC in the south of the country, but the role played by hepatitis C virus (HCV) still remains unclear. The aim of the current case-control study was to identify risk factors for HCC development in the northern part of the country. Clinical and biological data including viral hepatitis status (serological and molecular) and non-infectious risk factors from 73 patients with HCC and 70 control subjects without hepatic diseases were collected. The mean age of the patients was 63 ± 10 years, and the ratio of males to females was 1.1. HCC occurred in cirrhotic liver in 72.0% of the cases. HCV infection was the dominant risk factor (64.3% of cases); the presence of HBV was observed in 53.4% of the cases. Occult hepatitis B and C were implicated, respectively, in 30.1% and 9.6% of the cases. HCV genotype 1b was predominant. Patients originating from western Tunisia formed a homogeneous group, characterized by significantly higher rates of tattoos or scarifications (83%) and HCV infection (80%) than those from other parts of the country. Chronic HCV infection is currently the primary risk factor for HCC in Tunisia; HBV infection remains frequent in its overt or occult infection forms. Traditional esthetic practices apparently contribute to increasing the burden of terminal liver diseases in western Tunisia.
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Tatsuno K, Midorikawa Y, Takayama T, Yamamoto S, Nagae G, Moriyama M, Nakagawa H, Koike K, Moriya K, Aburatani H. Impact of AAV2 and Hepatitis B Virus Integration Into Genome on Development of Hepatocellular Carcinoma in Patients with Prior Hepatitis B Virus Infection. Clin Cancer Res 2019; 25:6217-6227. [PMID: 31320595 DOI: 10.1158/1078-0432.ccr-18-4041] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 04/29/2019] [Accepted: 07/11/2019] [Indexed: 12/31/2022]
Abstract
PURPOSE Hepatitis B viral (HBV) DNA is frequently integrated into the genomes of hepatocellular carcinoma (HCC) in patients with chronic HBV infection (chronic HBV, hereafter), whereas the frequency of HBV integration in patients after the disappearance of HBV (prior HBV, hereafter) has yet to be determined. This study aimed to detect integration of HBV and adeno-associated virus type 2 (AAV2) into the human genome as a possible oncogenic event. EXPERIMENTAL DESIGN Virome capture sequencing was performed, using HCC and liver samples obtained from 243 patients, including 73 with prior HBV without hepatitis C viral (HCV) infection and 81 with chronic HBV. RESULTS Clonal HBV integration events were identified in 11 (15.0%) cases of prior HBV without HCV and 61 (75.3%) cases of chronic HBV (P < 0.001). Several driver genes were commonly targeted by HBV, leading to transcriptional activation of these genes; TERT [four (5.4%) vs. 15 (18.5%)], KMT2B [two (2.7%) vs. five (6.1%)], CCNE1 [zero vs. one (1.2%)], CCNA2 [zero vs. one (1.2%)]. Conversely, CCNE1 and CCNA2 were, respectively, targeted by AAV2 only in prior HBV. In liver samples, HBV genome recurrently integrated into fibrosis-related genes FN1, HS6ST3, KNG1, and ROCK1 in chronic HBV. There was not history of alcohol abuse and 3 patients with a history of nucleoside analogue treatment for HBV in 8 prior HBV with driver gene integration. CONCLUSIONS Despite the seroclearance of hepatitis B surface antigen, HBV or AAV2 integration in prior HBV was not rare; therefore, such patients are at risk of developing HCC.
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Affiliation(s)
- Kenji Tatsuno
- Genome Science Division, RCAST, University of Tokyo, Tokyo, Japan
| | - Yutaka Midorikawa
- Genome Science Division, RCAST, University of Tokyo, Tokyo, Japan. .,Department of Digestive Surgery, Nihon University School of Medicine, Tokyo, Japan
| | - Tadatoshi Takayama
- Department of Digestive Surgery, Nihon University School of Medicine, Tokyo, Japan
| | - Shogo Yamamoto
- Genome Science Division, RCAST, University of Tokyo, Tokyo, Japan
| | - Genta Nagae
- Genome Science Division, RCAST, University of Tokyo, Tokyo, Japan
| | - Mitsuhiko Moriyama
- Department of Gastroenterology and Hepatology, Nihon University School of Medicine, Tokyo, Japan
| | - Hayato Nakagawa
- Department of Gastroenterology, University of Tokyo, Tokyo, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, University of Tokyo, Tokyo, Japan
| | - Kyoji Moriya
- Department of Infectious Diseases, University of Tokyo, Tokyo, Japan
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Midorikawa Y, Takayama T, Nakayama H, Higaki T, Moriguchi M, Moriya K, Kanda T, Matsuoka S, Moriyama M. Prior hepatitis B virus infection as a co-factor of chronic hepatitis C patient survival after resection of hepatocellular carcinoma. BMC Gastroenterol 2019; 19:147. [PMID: 31426746 PMCID: PMC6700986 DOI: 10.1186/s12876-019-1069-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Accepted: 08/15/2019] [Indexed: 02/07/2023] Open
Abstract
Background Prior hepatitis B virus infection (PBI) may increase the risk of developing hepatocellular carcinoma (HCC), but the impact of PBI on clinical outcomes following treatment for HCC remains unknown. The aim of this study was to clarify whether PBI affects clinical outcomes after liver resection for hepatitis C virus (HCV)-related HCC by retrospective cohort study. Methods PBI patients were defined as those negative for hepatitis B surface antigen and positive for anti-hepatitis B core antibody. Surgical outcomes of HCV-related HCC patients with PBI were compared to those without PBI. Survival of patients with non-B non-C HCC with and without PBI were also compared. Results In the HCV group, the median overall survival of 165 patients with PBI was 4.7 years (95% confidence interval [CI], 3.9–5.9), and was significantly shorter compared with 263 patients without PBI (6.6 years [5.3–9.8]; p = 0.015). Conversely, there was no significant difference in recurrence-free survival between the two groups (1.8 years [95% CI, 1.4–2.0] vs 2.0 years [1.7–2.3]; p = 0.205). On Cox proportional hazards regression model, independent factors for overall survival were PBI (hazard ratio 1.38 [95% CI, 1.02–1.87]; p = 0.033), multiple tumors (p = 0.007), tumor size (p = 0.002), and liver cirrhosis (p < 0.001). On the other hand, in the non-B non-C HCC group, both the median overall survival (6.5 years [95% CI, 4.8–7.1]) and recurrence-free survival (2.4 years, [95% CI, 1.5–3.3]) in 104 patients with PBI were not significantly different from those (7.5 years [5.5 − NA; p = 0.932]; and 2.2 years [1.7–2.7; p = 0.983]) in 213 patients without PBI. Conclusions PBI and HCV in conjunction with each other affect the survival of patients that have undergone resection for HCC.
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Affiliation(s)
- Yutaka Midorikawa
- Department of Digestive Surgery, Nihon University School of Medicine, 30-1, Oyaguchikami-cho, Itabashi-ku, Tokyo, 173-8610, Japan.
| | - Tadatoshi Takayama
- Department of Digestive Surgery, Nihon University School of Medicine, 30-1, Oyaguchikami-cho, Itabashi-ku, Tokyo, 173-8610, Japan.
| | - Hisashi Nakayama
- Department of Digestive Surgery, Nihon University School of Medicine, 30-1, Oyaguchikami-cho, Itabashi-ku, Tokyo, 173-8610, Japan
| | - Tokio Higaki
- Department of Digestive Surgery, Nihon University School of Medicine, 30-1, Oyaguchikami-cho, Itabashi-ku, Tokyo, 173-8610, Japan
| | - Masamichi Moriguchi
- Department of Digestive Surgery, Nihon University School of Medicine, 30-1, Oyaguchikami-cho, Itabashi-ku, Tokyo, 173-8610, Japan
| | - Kyoji Moriya
- Department of Infectious Diseases, University of Tokyo Faculty of Medicine, Tokyo, Japan
| | - Tatsuo Kanda
- Department of Gastroenterology and Hepatology, Nihon University School of Medicine, Tokyo, Japan
| | - Shunichi Matsuoka
- Department of Gastroenterology and Hepatology, Nihon University School of Medicine, Tokyo, Japan
| | - Mitsuhiko Moriyama
- Department of Gastroenterology and Hepatology, Nihon University School of Medicine, Tokyo, Japan
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Raimondo G, Locarnini S, Pollicino T, Levrero M, Zoulim F, Lok AS. Update of the statements on biology and clinical impact of occult hepatitis B virus infection. J Hepatol 2019; 71:397-408. [PMID: 31004683 DOI: 10.1016/j.jhep.2019.03.034] [Citation(s) in RCA: 343] [Impact Index Per Article: 57.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 03/20/2019] [Accepted: 03/28/2019] [Indexed: 02/06/2023]
Abstract
In October 2018 a large number of international experts with complementary expertise came together in Taormina to participate in a workshop on occult hepatitis B virus infection (OBI). The objectives of the workshop were to review the existing knowledge on OBI, to identify issues that require further investigation, to highlight both existing controversies and newly emerging perspectives, and ultimately to update the statements previously agreed in 2008. This paper represents the output from the workshop.
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Affiliation(s)
- Giovanni Raimondo
- Division of Clinical and Molecular Hepatology, University of Messina, Messina, Italy; Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
| | - Stephen Locarnini
- Victorian Infectious Diseases Reference Laboratory at the Doherty Institute, Melbourne, Victoria, Australia
| | - Teresa Pollicino
- Division of Clinical and Molecular Hepatology, University of Messina, Messina, Italy; Department of Human Pathology, University of Messina, Messina, Italy
| | - Massimo Levrero
- Cancer Research Center of Lyon, INSERM U1052, Hospices Civils de Lyon, Lyon University, Lyon, France
| | - Fabien Zoulim
- Cancer Research Center of Lyon, INSERM U1052, Hospices Civils de Lyon, Lyon University, Lyon, France
| | - Anna S Lok
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA
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El-Maksoud MA, Habeeb MR, Ghazy HF, Nomir MM, Elalfy H, Abed S, Zaki MES. Clinicopathological study of occult hepatitis B virus infection in hepatitis C virus-associated hepatocellular carcinoma. Eur J Gastroenterol Hepatol 2019; 31:716-722. [PMID: 30870221 DOI: 10.1097/meg.0000000000001388] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Occult hepatitis B virus infection (OBI) frequently occurs in patients with chronic hepatitis C (CHC) infection, but the influence of OBI on CHC outcome is still uncertain. The aim of the present study was to clarify the clinical and pathological characteristics of OBI in CHC-related hepatocellular carcinoma (HCC). PATIENTS AND METHODS DNA was obtained from serum and tumor tissue of patients with hepatitis C virus (HCV)-related HCC with negative HBsAg and from patients with HCV-related liver cirrhosis. HBV-DNA was detected using qPCR. Clinicopathological features were compared between patients with HCC with and without OBI. RESULTS On the basis of positive serum and tissue HBV-DNA typing, the overall frequency of OBI was 50% in patients with HCV-related HCC. HBV genotype D was the most dominant, constituting 35.3% of HCC cases. Almost 80% of patients with OBI had anti-HBc, whereas 20% of patients had no serological markers. Tissue HBV-DNA showed significant association with positive serum HBV-DNA, anti-HBc, and genotype D. There were no clinical differences between patients with HCC with and without OBI; however, patients with OBI tended to be younger. HCC cases with positive OBI were significantly associated with positive anti-HBc antibodies and late histological grades (3-4). Multivariate logistic regression analysis revealed that the presence of OBI was a predictor of more advanced HCC histological grades in patients with HCV infection. CONCLUSION OBI was detected in 50% of HCV-infected patients with HCC. OBI was strongly associated with the presence of anti-HBc antibodies. Patients with HCC with positive OBI were younger and had more advanced HCC histological grades.
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Affiliation(s)
| | | | | | - Manal M Nomir
- Clinical Pathology Student's Hospital, Mansoura University, Mansoura, Egypt
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Chang JJ, Mohtashemi N, Bhattacharya D. Significance and Management of Isolated Hepatitis B Core Antibody (Anti-HBc) in HIV and HCV: Strategies in the DAA Era. Curr HIV/AIDS Rep 2019; 15:172-181. [PMID: 29572624 DOI: 10.1007/s11904-018-0379-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
PURPOSE OF REVIEW The purpose of this review is to summarize the prevalence and clinical implications of the isolated anti-HBc serologic profile in HIV-infected individuals. We highlight the rare but important issue of HBV reactivation in the setting of HCV therapy and describe an approach to management. RECENT FINDINGS The isolated anti-HBc pattern, a profile that most often indicates past exposure to HBV with waning anti-HBs immunity, is found commonly in HIV-infected individuals, particularly those with HCV. Some large cohort studies demonstrate an association with advanced liver disease, while others do not. Conversely, meta-analyses have found an association between occult HBV infection (a component of the isolated anti-HBc pattern) and advanced liver disease and hepatocellular carcinoma in HIV-uninfected individuals. In HIV-uninfected individuals with anti-HBc positivity, HBV reactivation has been reported in patients receiving HCV therapy. This phenomenon is likely the result of disinhibition of HBV with HCV eradication. In HIV-infected patients, the long-term liver outcomes associated with the isolated anti-HBc pattern remain to be fully elucidated, supporting the need for large cohort studies with longitudinal follow-up. HBV reactivation during HCV DAA therapy has been well-described in HIV-uninfected cohorts and can inform algorithms for the screening and management of the isolated anti-HBc pattern in this population.
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Affiliation(s)
- Jennifer J Chang
- UCLA CARE Center, Division of Infectious Diseases, David Geffen School of Medicine, University of California, Los Angeles, 10833 Le Conte Avenue, 37-121 CHS, Los Angeles, CA, 90095, USA.,Department of Infectious Diseases, Kaiser Permanente at Los Angeles Medical Center, 1505 N. Edgemont St., 2nd Floor, Los Angeles, CA, 90027, USA
| | - Neaka Mohtashemi
- UCLA CARE Center, Division of Infectious Diseases, David Geffen School of Medicine, University of California, Los Angeles, 10833 Le Conte Avenue, 37-121 CHS, Los Angeles, CA, 90095, USA
| | - Debika Bhattacharya
- UCLA CARE Center, Division of Infectious Diseases, David Geffen School of Medicine, University of California, Los Angeles, 10833 Le Conte Avenue, 37-121 CHS, Los Angeles, CA, 90095, USA.
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Musolino C, Cacciola I, Tripodi G, Lombardo D, Raffa G, Alibrandi A, Squadrito G, Raimondo G, Pollicino T. Behaviour of occult HBV infection in HCV-infected patients under treatment with direct-acting antivirals. Antivir Ther 2019; 24:187-192. [PMID: 30628893 DOI: 10.3851/imp3288] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/28/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND There is controversial data on possible occult HBV reactivation in HCV patients successfully treated with direct-acting antivirals (DAA). However, diagnosis of occult HBV infection (OBI) was not performed by gold standard procedures in any study. METHODS By using several highly sensitive assays, we examined serially collected serum samples from 40 HBV-surface-negative DAA-treated HCV patients with OBI identified by testing liver biopsy specimens through nested-PCR technique. Serum samples were obtained at four time points from each patient (at baseline, at 4 weeks after starting, at the end and 12 weeks after stopping therapy) and tested for HBV DNA by nested-PCR and real-time PCR techniques. RESULTS All tested serum samples were negative by both quantitative HBV surface antigen (HBsAg) and HBV core-related antigen assays. 26/40 patients were anti-HBs-positive and in all of them, the amount of this antibody was stable at the four time points evaluated. Serum HBV DNA was detected in 10 samples at baseline, in 6 samples 4 weeks after starting therapy, in 11 samples at the end of therapy and in 21 samples 12 weeks after stopping treatment (P=0.001). Aminotransferase values dropped within the normal levels at week 4 of therapy and persisted normal over time in all cases. CONCLUSIONS A slight increase in the amount of HBV DNA 3 months after stopping DAA therapy was the only parameter showing a possible reappearance of HBV activity in OBI patients cured for a concomitant HCV infection, but it was insufficient to lead toward a virological reactivation capable of inducing liver injury.
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Affiliation(s)
- Cristina Musolino
- Department of Clinical and Experimental Medicine, Division of Clinical and Molecular Hepatology, University Hospital of Messina, Messina, Italy
| | - Irene Cacciola
- Department of Clinical and Experimental Medicine, Division of Clinical and Molecular Hepatology, University Hospital of Messina, Messina, Italy
| | - Gianluca Tripodi
- Department of Clinical and Experimental Medicine, Division of Clinical and Molecular Hepatology, University Hospital of Messina, Messina, Italy
| | - Daniele Lombardo
- Department of Clinical and Experimental Medicine, Division of Clinical and Molecular Hepatology, University Hospital of Messina, Messina, Italy
| | - Giuseppina Raffa
- Department of Clinical and Experimental Medicine, Division of Clinical and Molecular Hepatology, University Hospital of Messina, Messina, Italy
| | | | - Giovanni Squadrito
- Department of Clinical and Experimental Medicine, Division of Clinical and Molecular Hepatology, University Hospital of Messina, Messina, Italy
| | - Giovanni Raimondo
- Department of Clinical and Experimental Medicine, Division of Clinical and Molecular Hepatology, University Hospital of Messina, Messina, Italy
| | - Teresa Pollicino
- Department of Human Pathology, University Hospital of Messina, Messina, Italy
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Yamaji K, Kai K, Komukai S, Koga H, Ide T, Kawaguchi A, Noshiro H, Aishima S. Occult HBV infection status and its impact on surgical outcomes in patients with curative resection for HCV-associated hepatocellular carcinoma. Hepatobiliary Surg Nutr 2018; 7:443-453. [PMID: 30652089 PMCID: PMC6295390 DOI: 10.21037/hbsn.2018.10.01] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Accepted: 10/09/2018] [Indexed: 02/05/2023]
Abstract
BACKGROUND We sought to clarify the prevalence of occult hepatitis B virus (HBV) infection (OBI) and to determine whether OBI affects the surgical outcomes in curatively resected Japanese patients with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). METHODS A total of 257 patients with HCV-related HCC who underwent curative surgical resection were enrolled. All enrolled patients were serologically negative for HBV surface antigen and positive for HCV antibody. DNA was extracted from formalin-fixed paraffin-embedded liver tissue. OBI was determined by the HBV-DNA amplification of at least two different sets of primers by TaqMan real-time polymerase chain reaction. Surgical outcomes were evaluated according to overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS). RESULTS OBI was identified in 15 of the 257 (5.8%) cases. In the multivariate analyses, the factors significantly correlated with OS were BMI >25 (P=0.0416), portal vein invasion (P=0.0065), and multiple tumors (P=0.0064). The only factor significantly correlated with DSS was T-stage (P=0.0275). The factors significantly correlated with DFS were liver fibrosis (P=0.0017) and T-stage (P=0.0001). The status of OBI did not show any significant correlation with OS, DSS or DFS, but a weak association with DSS (P=0.0603) was observed. CONCLUSIONS The prevalence of OBI was 5.8% in 257 cases of HCV-related HCC. Although a weak association between DSS and OBI was observed, and statistical analyses were limited by small number of OBI cases, no significant correlation between OBI and surgical outcomes was detected.
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Affiliation(s)
- Koutaro Yamaji
- Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan
- Department of Pathology & Microbiology, Saga University Faculty of Medicine, Saga 849-8501, Japan
| | - Keita Kai
- Department of Pathology, Saga University Hospital, Saga 849-8501, Japan
| | - Sho Komukai
- Clinical Research Center, Saga University Hospital, Saga 849-8501, Japan
| | - Hiroki Koga
- Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan
| | - Takao Ide
- Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan
| | - Atsushi Kawaguchi
- Center for Comprehensive Community Medicine, Saga University Faculty of Medicine, Saga 849-8501, Japan
| | - Hirokazu Noshiro
- Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan
| | - Shinichi Aishima
- Department of Pathology & Microbiology, Saga University Faculty of Medicine, Saga 849-8501, Japan
- Department of Pathology, Saga University Hospital, Saga 849-8501, Japan
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Mavilia MG, Wu GY. HBV-HCV Coinfection: Viral Interactions, Management, and Viral Reactivation. J Clin Transl Hepatol 2018; 6:296-305. [PMID: 30271742 PMCID: PMC6160312 DOI: 10.14218/jcth.2018.00016] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Revised: 04/25/2018] [Accepted: 05/01/2018] [Indexed: 12/18/2022] Open
Abstract
Hepatitis B virus (HBV) and hepatitis C virus (HCV) coinfection is a complex clinical entity that has an estimated worldwide prevalence of 1-15%. Most clinical studies have shown that progression of disease is faster in HBV-HCV coinfected patients compared to those with monoinfection. Hepatocellular carcinoma development appears to have higher rate in coinfections. Viral replication in coinfected cells is characterized by a dominance of HCV over HBV replication. There are no established guidelines for treatment of HBV-HCV coinfection. Studies on interferon-based therapies and direct-acting antivirals have shown varying levels of efficacy. Clinical reports have indicated that treatment of HCV without suppression of HBV increases the risk for HBV reactivation. In this review, we appraise studies on both direct-acting antivirals and interferon-based therapies to evaluate the efficacy and rates of reactivation with each regimen. Screening for and prevention of coinfection are important to prevent serious HBV reactivations.
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Affiliation(s)
- Marianna G. Mavilia
- Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA
- *Correspondence to: Marianna G. Mavilia, Department of Medicine, University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT 06032, USA. Tel: +1-860-679-2509, Fax: +1-860-679-6582, E-mail:
| | - George Y. Wu
- Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA
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Wang H, Swann R, Thomas E, Innes HA, Valerio H, Hayes PC, Allen S, Barclay ST, Wilks D, Fox R, Bhattacharyya D, Kennedy N, Morris J, Fraser A, Stanley AJ, Gunson R, Mclntyre PG, Hunt A, Hutchinson SJ, Mills PR, Dillon JF. Impact of previous hepatitis B infection on the clinical outcomes from chronic hepatitis C? A population-level analysis. J Viral Hepat 2018; 25:930-938. [PMID: 29577515 DOI: 10.1111/jvh.12897] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Accepted: 02/11/2018] [Indexed: 12/13/2022]
Abstract
Chronic coinfection with hepatitis C virus (HCV) and hepatitis B virus (HBV) is associated with adverse liver outcomes. The clinical impact of previous HBV infection on liver disease in HCV infection is unknown. We aimed at determining any association of previous HBV infection with liver outcomes using antibodies to the hepatitis B core antigen (HBcAb) positivity as a marker of exposure. The Scottish Hepatitis C Clinical Database containing data for all patients attending HCV clinics in participating health boards was linked to the HBV diagnostic registry and mortality data from Information Services Division, Scotland. Survival analyses with competing risks were constructed for time from the first appointment to decompensated cirrhosis, hepatocellular carcinoma (HCC) and liver-related mortality. Records of 8513 chronic HCV patients were included in the analyses (87 HBcAb positive and HBV surface antigen [HBsAg] positive, 1577 HBcAb positive and HBsAg negative, and 6849 HBcAb negative). Multivariate cause-specific proportional hazards models showed previous HBV infection (HBcAb positive and HBsAg negative) significantly increased the risks of decompensated cirrhosis (hazard ratio [HR]: 1.29, 95% CI: 1.01-1.65) and HCC (HR: 1.64, 95% CI: 1.09-2.49), but not liver-related death (HR: 1.02, 95% CI: 0.80-1.30). This is the largest study to date showing an association between previous HBV infection and certain adverse liver outcomes in HCV infection. Our analyses add significantly to evidence which suggests that HBV infection adversely affects liver health despite apparent clearance. This has important implications for HBV vaccination policy and indications for prioritization of HCV therapy.
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Affiliation(s)
- H Wang
- Dundee Epidemiology and Biostatistics Unit, Population Health Sciences, University of Dundee, Dundee, UK
| | - R Swann
- Department of Gastroenterology, Gartnavel General Hospital, NHS Greater Glasgow and Clyde, Glasgow, UK
| | - E Thomas
- Department of Medicine for the Elderly, North Middlesex Hospital, London, UK
| | - H A Innes
- School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, UK
- Health Protection Scotland, Glasgow, UK
| | - H Valerio
- School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, UK
- Health Protection Scotland, Glasgow, UK
| | - P C Hayes
- Liver Transplant Unit, Royal Infirmary Edinburgh, Edinburgh, UK
| | - S Allen
- Department of Infectious Diseases, University Hospital Crosshouse, Kilmarnock, UK
| | - S T Barclay
- Department of Gastroenterology, Glasgow Royal Infirmary, Glasgow, UK
| | - D Wilks
- Department of Infectious Diseases, Western General Hospital, Edinburgh, UK
| | - R Fox
- The Brownlee Centre, Glasgow, UK
| | | | | | - J Morris
- Department of Gastroenterology, Queen Elizabeth University Hospital, Glasgow, UK
| | - A Fraser
- Aberdeen Royal Infirmary, Aberdeen, UK
| | - A J Stanley
- Department of Gastroenterology, Glasgow Royal Infirmary, Glasgow, UK
| | - R Gunson
- West of Scotland Virology Centre, Glasgow Royal Infirmary, Glasgow, UK
| | - P G Mclntyre
- Department of Microbiology, Ninewells Hospital and Medical School, Dundee, UK
| | - A Hunt
- Department of Virology, Aberdeen Royal Infirmary, Aberdeen, UK
| | - S J Hutchinson
- School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, UK
- Health Protection Scotland, Glasgow, UK
| | - P R Mills
- Department of Gastroenterology, Gartnavel General Hospital, NHS Greater Glasgow and Clyde, Glasgow, UK
| | - J F Dillon
- Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, Dundee, UK
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Muto J, Sugiyama M, Shirabe K, Mukaide M, Kirikae-Muto I, Ikegami T, Yoshizumi T, Yamashita YI, Maehara Y, Mizokami M. Frequency and Characteristics of Occult Hepatitis B Infection Among Hepatocellular Carcinoma Patients in Japan. Ann Hepatol 2018; 17:596-603. [PMID: 29893701 DOI: 10.5604/01.3001.0012.0927] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND AIM Occult hepatitis B virus (HBV) infection (OBI) represents a state without detectable hepatitis B surface antigen, but positive for HBV DNA. The correlation between OBI and hepatocellular carcinoma (HCC) carcinogenesis is controversial. We studied the frequency and characteristics of OBI among HCC patients and metastatic liver cancer patients. MATERIAL AND METHODS DNA was obtained from tumor and non-tumor tissues from 75 HCC patients (15 chronic hepatitis B (CHB), 39 chronic hepatitis C (CHC), 21 cryptogenic) and 15 metastatic liver cancer patients who underwent liver resection. HBV DNA and covalentlyclosed circular (ccc) DNA were detected using real-time polymerase chain reaction (PCR), and four HBV DNA regions were detected by nested PCR. Clinicopathological factors were compared between patients with and without OBI. RESULTS HBV DNA was detected in 14 (93.3%) CHB, five (22.7%) cryptogenic and four (10.3%) CHC patients. cccDNA was detected in 12 (80.0%) CHB, three (14.3%) cryptogenic and two (5.1%) CHC patients. All CHB, eight (38.1%) cryptogenic and ten (25.6%) CHC patients tested positive with nested PCR. No metastatic liver cancer patients were positive for any HBV DNA regions. OBI patients had shorter prothrombin times (P = 0.0055), and lower inflammation activity score in non-tumor liver (P = 0.0274). There were no differences in anti-HBV antibodies. CONCLUSIONS OBI was detected in 38% of cryptogenic and 25.6% of CHC patients. There was no correlation between OBI and anti-HBV antibodies, but fewer patients with OBI had high inflammatory activity, suggesting that factors other than inflammation may be involved in HCC carcinogenesis in patients with OBI.
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Affiliation(s)
- Jun Muto
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masaya Sugiyama
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Chiba, Japan
| | - Ken Shirabe
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Motokazu Mukaide
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Chiba, Japan
| | - Ikue Kirikae-Muto
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Chiba, Japan
| | - Toru Ikegami
- Global Health and Medicine, Ichikawa, Chiba, Japan
| | - Tomoharu Yoshizumi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yo-Ichi Yamashita
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshihiko Maehara
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masashi Mizokami
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Chiba, Japan
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46
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Austria A, Wu GY. Occult Hepatitis C Virus Infection: A Review. J Clin Transl Hepatol 2018; 6:155-160. [PMID: 29951360 PMCID: PMC6018308 DOI: 10.14218/jcth.2017.00053] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Revised: 12/26/2017] [Accepted: 01/09/2018] [Indexed: 12/12/2022] Open
Abstract
Occult hepatitis C virus (HCV) infection (OCI), first described in 2004, is defined as the presence of HCV RNA in hepatocytes or peripheral blood mononuclear cells without detectable HCV RNA in the serum. Here, we aimed to review the epidemiology, diagnostic methods, clinical implications and potential management recommendations currently described in the literature, as well as the future directions for investigation of this entity. PubMed and Cochrane databases were searched with combination of the following keywords: "occult", "hepatitis C virus", and "occult HCV infection". There are data to support OCI as a potential culprit in cryptogenic liver disease. There are also consistent data demonstrating the existence of OCI in specific populations, such as dialysis, human immunodeficiency virus-infected and hepatitis B virus-infected patients, and also in the general population. While the gold standard for diagnosis is liver biopsy, examination of peripheral blood mononuclear cells may be a reliable, safer alternative method of diagnosis. Occult HCV infection is likely associated with liver fibrosis and progression of liver disease. Additional studies are required to determine the infectivity of OCI patients, as well as clarify the natural course and specific clinical implications of OCI. Lastly, studies are needed to determine whether treatment of OCI leads to decreased morbidity and/or mortality.
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Affiliation(s)
- Alyssa Austria
- Division of Gastroenterology-Hepatology, Department of Medicine, University of Connecticut Health Center, Farmington, CT 06030, USA
- *Correspondence to: Alyssa Austria, Department of Medicine, University of Connecticut Health Center, 263 Farmington Ave., Farmington, CT 06030, USA. Tel: +1-860-679-4477, Fax: +1-860-679-1025, E-mail:
| | - George Y. Wu
- Division of Gastroenterology-Hepatology, Department of Medicine, University of Connecticut Health Center, Farmington, CT 06030, USA
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Decreasing prevalence of Hepatitis B and absence of Hepatitis C Virus infection in the Warao indigenous population of Venezuela. PLoS One 2018; 13:e0197662. [PMID: 29799873 PMCID: PMC5969771 DOI: 10.1371/journal.pone.0197662] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 05/07/2018] [Indexed: 12/12/2022] Open
Abstract
Prevalence and molecular epidemiology studies for hepatitis B (HBV) and C (HCV) virus are scarce in Warao Amerindians from Venezuela, where an epidemic of human immunodeficiency virus type 1 (HIV-1) has recently been documented. To carry out a molecular epidemiology analysis of hepatitis B (HBV) and C (HCV) virus in Warao individuals from the Delta Amacuro State of Venezuela. A total of 548 sera were tested for serological and molecular markers for HBV and HCV. The prevalence of active infection (presence of HBV surface antigen, HBsAg), exposure to HBV (presence of Antibody to HBV core antigen, anti-HBc) and anti-HCV, was 1.8%, 13% and 0% respectively. HBV exposure was significantly lower in men below 18 years old and also lower than rates previously reported in other Amerindian communities from Venezuela. Thirty one percent (31%, 25/80) of individuals without evidence of HBV infection exhibited anti-HBs titer ≥ 10U.I / ml, being significantly more frequent in individuals younger than 20 years. A higher HBV exposure was observed among HIV-1 positive individuals (33% vs 11%, p <0.005). A high prevalence of occult HBV infection was also observed (5.6%, 11/195). Phylogenetic analysis of S gene and complete HBV genomes showed that F3 is the only circulating subgenotype, different from the F2 subgenotype found in 1991 in this population. These results suggest a recent introduction of subgenotype F3, with a low divergence among the isolates. These results highlight the importance of molecular epidemiology studies for viral control, and support the effectiveness of vaccination in reducing transmission of HBV.
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48
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[Spontaneous remission of HCV infection after autologous stem cell transplantation in a 58-year-old man]. Internist (Berl) 2018; 58:621-625. [PMID: 28235985 DOI: 10.1007/s00108-017-0206-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
We report about a 58-year-old man with a chronic and treatment-naive hepatitis C virus (HCV) infection of genotype 1b, who had undergone autologous stem cell transplantation twice due to multiple myeloma. Subsequently, a high-level viremic reactivation of an occult hepatitis B virus (HBV) infection and also a reverse seroconversion was observed. Furthermore, a sustained spontaneous remission of HCV infection was seen. Antiviral therapy of HBV infection was initiated with tenofovir. Seven months after therapy initiation, the patient acquired an "anti-HBc-only" status. Antiviral therapy with tenofovir is still continued. The patient is in a good clinical condition.
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49
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Coppola N, Onorato L, Iodice V, Starace M, Minichini C, Farella N, Liorre G, Filippini P, Sagnelli E, de Stefano G. Occult HBV infection in HCC and cirrhotic tissue of HBsAg-negative patients: a virological and clinical study. Oncotarget 2018; 7:62706-62714. [PMID: 27486882 PMCID: PMC5308760 DOI: 10.18632/oncotarget.10909] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2016] [Accepted: 06/18/2016] [Indexed: 12/19/2022] Open
Abstract
Aim To evaluate the virological and clinical characteristics of occult HBV infection (OBI) in 68 consecutive HBsAg-negative patients with biopsy-proven cirrhosis and HCC. Methods HBV DNA was sought and sequenced in plasma, HCC tissue and non-HCC liver tissue by PCRs using primers for HBV core, surface and x regions. OBI was identified by the presence of HBV DNA in at least two different PCRs. Results OBI was detected in HCC tissue of 13 (20%) patients and in non-HCC liver tissue of 3 of these 13. OBI was detected in HCC tissue of 54.5% of 11 anti-HBs- negative/anti-HBc-positive patients, in 29.4% of 17 anti-HBs/anti-HBc-positive and in 5% of 40 anti-HBs/anti-HBc-negative (p < 0.0005). The 13 patients with OBI in HCC tissue more frequently than the 55 without showed Child-B or -C cirrhosis (53.9% vs. 5.5%, p < 0.0001) and BCLC-B or -C stages (46.1% vs. 1.8%, p < 0.0001). The pre-S1, pre-S2 and S region sequences in HCC tissue showed amino acid (AA) substitutions (F19L, P24L, S59F, T131I, Q129H) and deletions (in positions 4,8, 17 and 86) in the S region, AA substitutions (T40S, P124K, L54P, G76A, N222T and I273L) in pre-S1 region and AA substitutions in pre-S2 region (P41H and P66L). In the 3 patients showing OBI also in non-HCC liver tissue the S, pre-S1 and pre-S2 sequencing displayed patterns of mutations different. Conclusions The study showed a significant correlation between OBI and the severity of liver damage, several patterns of mutations in the S, pre-S1 and pre-S2 regions in HCC tissue, some at their first description.
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Affiliation(s)
- Nicola Coppola
- Department of Mental Health and Public Medicine, Second University of Naples, Naples, Italy
| | - Lorenzo Onorato
- Department of Mental Health and Public Medicine, Second University of Naples, Naples, Italy
| | - Valentina Iodice
- Department of Mental Health and Public Medicine, Second University of Naples, Naples, Italy.,Ninth Interventional Ultrasound Unit for Infectious Diseases, Cotugno Hospital, Naples, Italy
| | - Mario Starace
- Department of Mental Health and Public Medicine, Second University of Naples, Naples, Italy
| | - Carmine Minichini
- Department of Mental Health and Public Medicine, Second University of Naples, Naples, Italy
| | - Nunzia Farella
- Ninth Interventional Ultrasound Unit for Infectious Diseases, Cotugno Hospital, Naples, Italy
| | - Giulia Liorre
- Ninth Interventional Ultrasound Unit for Infectious Diseases, Cotugno Hospital, Naples, Italy
| | - Pietro Filippini
- Department of Mental Health and Public Medicine, Second University of Naples, Naples, Italy.,Infectious Diseases Unit, Caserta Hospital, Caserta, Italy
| | - Evangelista Sagnelli
- Department of Mental Health and Public Medicine, Second University of Naples, Naples, Italy
| | - Giorgio de Stefano
- Ninth Interventional Ultrasound Unit for Infectious Diseases, Cotugno Hospital, Naples, Italy
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50
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Calvaruso V, Ferraro D, Licata A, Bavetta MG, Petta S, Bronte F, Colomba G, Craxì A, Di Marco V. HBV reactivation in patients with HCV/HBV cirrhosis on treatment with direct-acting antivirals. J Viral Hepat 2018; 25:72-79. [PMID: 28703895 DOI: 10.1111/jvh.12754] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 06/30/2017] [Indexed: 12/12/2022]
Abstract
Anecdotal reports suggest that patients with chronic hepatitis C virus (HCV) hepatitis and overt or occult hepatitis B virus (HBV) coinfection may reactivate HBV when HCV is suppressed or cleared by direct-acting antivirals (DAAs). We assessed the prevalence of overt or previous HBV coinfection and the risk of HBV reactivation in patients with HCV cirrhosis treated with DAAs. This was a retrospective cohort of 104 consecutive patients with HCV cirrhosis treated with DAAs. Serum HCV-RNA and HBV-DNA were tested at weeks 4, 8 and 12 of DAAs therapy and at week 12 of follow-up. At the start of DAAs, eight patients (7.7%) were HBsAg positive/HBeAg negative with undetectable HBV-DNA and low levels of quantitative HBsAg (four on nucleos(t)ide analogues [NUCs] and four inactive carriers), 37 patients (35.6%) had markers of previous HBV infection (25 anti-HBc positive, 12 anti-HBc/anti-HBs positive) and 59 (56.7%) had no evidence of HBV infection. Sixty-seven patients (64.4%) were HCV-RNA negative at week 4 and 98 (94.2%) achieved sustained virological response. All four HBsAg-positive patients treated with NUCs remained HBV-DNA negative, but three of four untreated patients showed an increase in HBV-DNA of 2-3 log without a biochemical flare and achieved HBV-DNA suppression when given NUCs. During or after DAAs, by conventional assay, HBV-DNA remained not detectable in all 37 anti-HBc-positive patients but in three of them (8.1%) HBV-DNA became detectable with a highly sensitive PCR. HBV reactivation is likely to occur in untreated HBV/HCV-coinfected cirrhotic patients when they undergo HCV treatment with DAAs. Pre-emptive therapy with NUCs should be considered in this setting. Anti-HBc-positive patients rarely reactivate HBV without clinical or virological outcomes.
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Affiliation(s)
- V Calvaruso
- Sezione di Gastroenterologia e Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica, Palermo, Italy
| | - D Ferraro
- Sezione di Microbiologia, Dipartimento di Scienze per la Promozione della Salute e Materno-Infantile G. D'Alessandro, University of Palermo, Palermo, Italy
| | - A Licata
- Sezione di Gastroenterologia e Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica, Palermo, Italy
| | - M G Bavetta
- Sezione di Gastroenterologia e Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica, Palermo, Italy
| | - S Petta
- Sezione di Gastroenterologia e Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica, Palermo, Italy
| | - F Bronte
- Sezione di Gastroenterologia e Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica, Palermo, Italy
| | - G Colomba
- Sezione di Microbiologia, Dipartimento di Scienze per la Promozione della Salute e Materno-Infantile G. D'Alessandro, University of Palermo, Palermo, Italy
| | - A Craxì
- Sezione di Gastroenterologia e Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica, Palermo, Italy
| | - V Di Marco
- Sezione di Gastroenterologia e Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica, Palermo, Italy
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