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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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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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Hepatitis B Virus Infection in Vaccinated Children and Adolescents with HBsAg-positive Parents: Is Routine Vaccination Sufficient? HEALTH SCOPE 2022. [DOI: 10.5812/jhealthscope.120505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background: Hepatitis B virus (HBV) is a severe public health problem in Iran. This study was conducted to investigate the intrafamilial transmission of HBV in vaccinated children whose one or both parents were positive for hepatitis B surface antigen (HBsAg). Methods: In a study with retrospective cohort design, 110 exposed cases with HBsAg-positive parent(s) were compared with 110 unexposed controls of the same sex and age groups. The participants were directly asked about demographic characteristics, medical history, and vaccinations. Blood samples were collected and analyzed for HBV infection markers using the ELIZA method. Results: Overall, 1.8% HBsAg (P = 0.15) and 13.6% hepatitis B core antibody (HBcAb) (P < 0.0001) positivity rates were detected in the exposed group. The hepatitis B surface antibody titer (HBsAb) showed that 34.5% of cases and 56.3% of controls had HBsAb levels > 10 IU/L. There was a significant difference in the protective HBsAb level between the two groups (P < 0.0001). There were significant associations between HBsAb level and gender in the exposed group and decreased HBsAb levels and age. Conclusions: The high rate of positive HBcAb and HBsAg and decreasing HBsAb levels with age in this study indicate that routine childhood vaccination programs are inadequate in preventing HBV transmission and vaccine routes changing or further booster vaccination is essential. Effective case finding in vaccinated children with HBsAg-positive parents, intradermal vaccination, and hepatitis B immunoglobulin in newborns with HBsAg-positive fathers are suggested.
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Goto R, Kosai-Fujimoto Y, Yagi S, Kobayashi T, Akamatsu N, Shimamura T, Imura S, Ogiso S, Mizuno S, Takatsuki M, Fukuhara T, Kanto T, Eguchi S, Yanaga K, Ogura Y, Fukumoto T, Shimada M, Hasegawa K, Ohdan H, Uemoto S, Soejima Y, Ikegami T, Yoshizumi T, Taketomi A, Maehara Y. De novo hepatocellular carcinoma in living donor liver grafts: A Japanese multicenter experience. Hepatol Res 2020; 50:1365-1374. [PMID: 32860719 DOI: 10.1111/hepr.13565] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 07/29/2020] [Accepted: 08/14/2020] [Indexed: 12/24/2022]
Abstract
AIM Direct-acting antivirals for hepatitis C virus have reduced the decompensation risk. Immunosuppressants for transplantation raise the risk of occurrence of de novo malignancies. We assessed the probabilities of and risk factors for de novo hepatocellular carcinoma (HCC) development post-living donor liver transplantation (LDLT). METHODS We retrospectively evaluated the data of developed HCC in a graft including metastatic HCC post-LDLT from 2779 adult cases collected from nine major liver transplantation centers in Japan. RESULTS Of 2779 LDLT adult recipients, 34 (1.2%) developed HCCs in their grafts. Of 34, five HCCs appeared to be de novo because of a longer period to tumor detection (9.7 [6.4-15.4] years) and no HCC within the native liver of the two recipients. The donor origin of three of five de novo HCCs was confirmed using microsatellite analysis in resected tissue. Primary disease of all five was hepatitis C virus-related cirrhosis, of which two were treated with direct-acting antivirals. Four of five developed HCC de novo in the hepatitis B core antibody-positive grafts. De novo HCCs had favorable prognosis; four of five were cured with complete remission. However, recurrent HCC (n = 29) in the graft had a poorer outcome, especially in patients with neutrophil to lymphocyte ratio scores above 4 (median survival time, 262 [19-463] days). CONCLUSION Analysis of the database from major liver transplantation institutes in Japan revealed that de novo HCCs determined by microsatellite analysis were rarely detected, but the majority were successfully treated. LDLT recipients with higher risks of de novo HCC, including those with hepatitis B core antibody-positive grafts, should be carefully followed by surveillance of the liver graft.
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Affiliation(s)
- Ryoichi Goto
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Yukiko Kosai-Fujimoto
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shintaro Yagi
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Tsuyoshi Kobayashi
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Nobuhisa Akamatsu
- Division of Artificial Organ and Transplantation, Department of Surgery, University of Tokyo, Tokyo, Japan
| | - Tsuyoshi Shimamura
- Division of Organ Transplantation, Hokkaido University Hospital, Sapporo, Japan
| | - Satoru Imura
- Department of Surgery, Tokushima University, Tokushima, Japan
| | - Satoshi Ogiso
- Department of Transplantation Surgery, Nagoya University Hospital, Nagoya, Japan
| | - Shugo Mizuno
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Mie, Japan
| | - Mitsuhisa Takatsuki
- Department of Surgery, Nagasaki University, Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Takasuke Fukuhara
- Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Tatsuya Kanto
- National Center for Global Health and Medicine Research Center for Hepatitis and Immunology, Ichikawa, Japan
| | - Susumu Eguchi
- Department of Surgery, Nagasaki University, Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Katsuhiko Yanaga
- Department of Surgery, Jikei University School of Medicine, Tokyo, Japan
| | - Yasuhiro Ogura
- Department of Transplantation Surgery, Nagoya University Hospital, Nagoya, Japan
| | - Takumi Fukumoto
- Department of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Mitsuo Shimada
- Department of Surgery, Tokushima University, Tokushima, Japan
| | - Kiyoshi Hasegawa
- Division of Artificial Organ and Transplantation, Department of Surgery, University of Tokyo, Tokyo, Japan
| | - Hideki Ohdan
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Shinji Uemoto
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yuji Soejima
- Department of Surgery, Shinshu University School of Medicine, Matsumoto, Japan
| | - Toru Ikegami
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tomoharu Yoshizumi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Akinobu Taketomi
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Yoshihiko Maehara
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Kyushu Central Hospital of the Mutual Aid Association of Public School Teachers, Fukuoka, Japan
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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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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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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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Cho J, Lee SS, Choi YS, Jeon Y, Chung JW, Baeg JY, Si WK, Jang ES, Kim JW, Jeong SH. Occult hepatitis B virus infection is not associated with disease progression of chronic hepatitis C virus infection. World J Gastroenterol 2016; 22:9427-9436. [PMID: 27895431 PMCID: PMC5107707 DOI: 10.3748/wjg.v22.i42.9427] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Revised: 08/18/2016] [Accepted: 09/06/2016] [Indexed: 02/07/2023] Open
Abstract
AIM To clarify the prevalence of occult hepatitis B virus (HBV) infection (OBI) and the association between OBI and liver disease progression, defined as development of liver cirrhosis or hepatocellular carcinoma (HCC), worsening of Child-Pugh class, or mortality in cases of chronic hepatitis C virus (HCV) infection.
METHODS This prospective cohort study enrolled 174 patients with chronic HCV infection (chronic hepatitis, n = 83; cirrhosis, n = 47; HCC, n = 44), and evaluated disease progression during a mean follow-up of 38.7 mo. OBI was defined as HBV DNA positivity in 2 or more different viral genomic regions by nested polymerase chain reaction using 4 sets of primers in the S, C, P and X open reading frame of the HBV genome.
RESULTS The overall OBI prevalence in chronic HCV patients at enrollment was 18.4%, with 16.9%, 25.5% and 13.6% in the chronic hepatitis C, liver cirrhosis and HCC groups, respectively (P = 0.845). During follow-up, 52 patients showed disease progression, which was independently associated with aspartate aminotransferase > 40 IU/L, Child-Pugh score and sustained virologic response (SVR), but not with OBI positivity. In 136 patients who were not in the SVR state during the study period, OBI positivity was associated with neither disease progression, nor HCC development.
CONCLUSION The prevalence of OBI in chronic HCV patients was 18.4%, and OBI was not associated with disease progression in South Koreans.
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Coppola N, Onorato L, Sagnelli C, Sagnelli E, Angelillo IF. Association between anti-HBc positivity and hepatocellular carcinoma in HBsAg-negative subjects with chronic liver disease: A meta-analysis. Medicine (Baltimore) 2016; 95:e4311. [PMID: 27472708 PMCID: PMC5265845 DOI: 10.1097/md.0000000000004311] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2016] [Revised: 05/19/2016] [Accepted: 06/28/2016] [Indexed: 02/07/2023] Open
Abstract
A meta-analysis was performed to ascertain to what extent hepatitis B surface antigen (HBsAg)-negative/anti-hepatitis B core (anti-HBc)-positive subjects with chronic liver disease are at a higher risk of developing hepatocellular carcinoma (HCC) than the anti-HBc-negative.All studies included had to fulfill the following characteristics and inclusion criteria: they investigated the relationship between HBsAg-negative/anti-HBc-positive serology and the occurrence of HCC, whether a case-control or cohort study, they provided relative risk (RR) or odds ratios (ORs) and 95% confidence intervals (CIs), were available as a full text written in English, and were published and indexed up to April 2015.Twenty-six original studies met the inclusion criteria, allowing a meta-analysis on 44,553 patients. The risk of HCC among the 9986 anti-HBc-positive subjects was 67% higher than in the 34,567 anti-HBc-negative (95% CI = 1.44-1.95, P < 0.0001). The results were similar when groups of patients with a different stage of liver disease (patients with chronic liver disease, patients with cirrhosis), with different ethnicity (Asian and non-Asian) and etiology (HCV and non-HCV) were considered. The risk of HCC was significantly higher in the 651 anti-HBs/anti-HBc-positive patients (RR = 1.36; 95% CI = 1.17-1.58, P = 0.03) and in the 595 anti-HBs-negative/anti-HBc-positive subjects (RR = 2.15; 95% CI = 1.58-2.92, P < 0.0001) than in the 1242 anti-HBs/anti-HBc negative. However, the RR from 8 studies indicated that the risk of HCC was 35% lower among the anti-HBs/anti-HBc-positive subjects compared to the anti-HBs-negative/anti-HBc-positive (RR = 0.65; 95% CI = 0.52-0.8, P < 0.0001).This meta-analysis shows that in HBsAg-negative subjects with chronic liver disease, anti-HBc positivity is strongly associated with the presence of HCC, an association observed in all subgroups according to the stage of the disease, etiology, and ethnicity.
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Affiliation(s)
- Nicola Coppola
- Department of Mental Health and Public Medicine, Section of Infectious Diseases
| | - Lorenzo Onorato
- Department of Mental Health and Public Medicine, Section of Infectious Diseases
| | - Caterina Sagnelli
- Department of Clinical and Experimental Medicine and Surgery “F. Magrassi e A. Lanzara”
| | | | - Italo F. Angelillo
- Department of Experimental Medicine, Second University of Naples, Naples, Italy
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11
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Coppola N, Onorato L, Pisaturo M, Macera M, Sagnelli C, Martini S, Sagnelli E. Role of occult hepatitis B virus infection in chronic hepatitis C. World J Gastroenterol 2015; 21:11931-11940. [PMID: 26576082 PMCID: PMC4641115 DOI: 10.3748/wjg.v21.i42.11931] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2015] [Revised: 06/28/2015] [Accepted: 09/14/2015] [Indexed: 02/06/2023] Open
Abstract
The development of sensitive assays to detect small amounts of hepatitis B virus (HBV) DNA has favored the identification of occult hepatitis B infection (OBI), a virological condition characterized by a low level of HBV replication with detectable levels of HBV DNA in liver tissue but an absence of detectable surface antigen of HBV (HBsAg) in serum. The gold standard to diagnose OBI is the detection of HBV DNA in the hepatocytes by highly sensitive and specific techniques, a diagnostic procedure requiring liver tissue to be tested and the use of non-standardized non-commercially available techniques. Consequently, in everyday clinical practice, the detection of anti-hepatitis B core antibody (anti-HBc) in serum of HBsAg-negative subjects is used as a surrogate marker to identify patients with OBI. In patients with chronic hepatitis C (CHC), OBI has been identified in nearly one-third of these cases. Considerable data suggest that OBI favors the increase of liver damage and the development of hepatocellular carcinoma (HCC) in patients with CHC. The data from other studies, however, indicate no influence of OBI on the natural history of CHC, particularly regarding the risk of developing HCC.
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12
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Kwak MS, Kim YJ. Occult hepatitis B virus infection. World J Hepatol 2014; 6:860-869. [PMID: 25544873 PMCID: PMC4269905 DOI: 10.4254/wjh.v6.i12.860] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2014] [Revised: 09/23/2014] [Accepted: 10/29/2014] [Indexed: 02/06/2023] Open
Abstract
Occult hepatitis B virus (HBV) infection (OBI) refers to the presence of HBV DNA in the absence of detectable hepatitis B surface antigen. Since OBI was first described in the late 1970s, there has been increasing interest in this topic. The prevalence of OBI varies according to the different endemicity of HBV infection, cohort characteristics, and sensitivity and specificity of the methods used for detection. Although the exact mechanism of OBI has not been proved, intra-hepatic persistence of viral covalently closed circular DNA under the host’s strong immune suppression of HBV replication and gene expression seems to be a cause. OBI has important clinical significance in several conditions. First, OBI can be transmitted through transfusion, organ transplantation including orthotopic liver transplantation, or hemodialysis. Donor screening before blood transfusion, prophylaxis for high-risk organ transplantation recipients, and dialysis-specific infection-control programs should be considered to reduce the risk of transmission. Second, OBI may reactivate and cause acute hepatitis in immunocompromised patients or those receiving chemotherapy. Close HBV DNA monitoring and timely antiviral treatment can prevent HBV reactivation and consequent clinical deterioration. Third, OBI may contribute to the progression of hepatic fibrosis in patients with chronic liver disease including hepatitis C. Finally, OBI seems to be a risk factor for hepatocellular carcinoma by its direct proto-oncogenic effect and by indirectly causing persistent hepatic inflammation and fibrosis. However, this needs further investigation. We review published reports in the literature to gain an overview of the status of OBI and emphasize the clinical importance of OBI.
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Jang JY, Park EJ. [Occult hepatitis B virus infection in chronic hepatitis C]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2014; 62:154-9. [PMID: 24077625 DOI: 10.4166/kjg.2013.62.3.154] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Occult HBV infection is defined as the presence of HBV DNA in the liver (with or without detectable or undetectable HBV DNA in the serum) of individuals testing negative for HBsAg. Studies on occult HBV infection in hepatitis C patients have reported highly variable prevalence, because the prevalence of occult HBV infection varies depending on the hepatitis B risk factors and methodological approaches. The most reliable diagnostic approach for detecting occult HBV detection is through examination of liver DNA extracts. HCV has been suspected to strongly suppress HBV replication up to the point where it may be directly responsible for occult HBV infection development. However, more data are needed to arrive at a definitive conclusion regarding the role of HCV in inducing occult HBV infection. Occult HBV infection in chronic hepatitis C patients is a complex biological entity with possible relevant clinical implications. Influence of occult HBV infection on the clinical outcomes of chronic hepatitis C may be considered negative. However, recent studies have shown that occult HBV infection could be associated with the development of hepatocellular carcinoma and contribute to the worsening of the course of chronic liver disease over time in chronic hepatitis C patients. Nevertheless, the possible role of occult HBV infection in chronic hepatitis C is still unresolved and no firm conclusion has been made up until now. It still remains unclear how occult HBV infection affects the treatment of chronic hepatitis C. Therefore, in order to resolve current controversies and understand the pathogenic role and clinical impacts of occult HBV infection in chronic hepatitis C patients, well-designed clinical studies are needed.
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Affiliation(s)
- Jae Young Jang
- Institution for Digestive Research, Digestive Disease Center, Department of Internal Medicine, Soonchunhyang University College of Medicine, Seoul, Korea
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Pollicino T, Saitta C. Occult hepatitis B virus and hepatocellular carcinoma. World J Gastroenterol 2014; 20:5951-5961. [PMID: 24876718 PMCID: PMC4033435 DOI: 10.3748/wjg.v20.i20.5951] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 01/15/2014] [Accepted: 04/16/2014] [Indexed: 02/06/2023] Open
Abstract
Occult hepatitis B virus (HBV) infection (OBI) is a challenging pathobiological and clinical issue that has been widely debated for several decades. By definition, OBI is characterized by the persistence of HBV DNA in the liver tissue (and in some cases also in the serum) in the absence of circulating HBV surface antigen (HBsAg). Many epidemiological and molecular studies have indicated that OBI is an important risk factor for hepatocellular carcinoma (HCC) development. OBI may exert direct pro-oncogenic effects through the activation of the same oncogenic mechanisms that are activated in the course of an HBsAg-positive infection. Indeed, in OBI as in HBV-positive infection, HBV DNA can persist in the hepatocytes both integrated into the host genome as well as free episome, and may maintain the capacity to produce proteins-mainly X protein and truncated preS-S protein - provided with potential transforming properties. Furthermore, OBI may indirectly favor HCC development. It has been shown that the persistence of very low viral replicative activity during OBI may induce mild liver necro-inflammation continuing for life, and substantial clinical evidence indicates that OBI can accelerate the progression of liver disease towards cirrhosis that is considered the most important risk factor for HCC development.
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Hai H, Tamori A, Kawada N. Role of hepatitis B virus DNA integration in human hepatocarcinogenesis. World J Gastroenterol 2014; 20:6236-6243. [PMID: 24876744 PMCID: PMC4033461 DOI: 10.3748/wjg.v20.i20.6236] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2013] [Revised: 12/14/2013] [Accepted: 01/14/2014] [Indexed: 02/06/2023] Open
Abstract
Liver cancer ranks sixth in cancer incidence, and is the third leading cause of cancer-related deaths worldwide. Hepatocellular carcinoma (HCC) is the most common type of liver cancer, which arises from hepatocytes and accounts for approximately 70%-85% of cases. Hepatitis B virus (HBV) frequently causes liver inflammation, hepatic damage and subsequent cirrhosis. Integrated viral DNA is found in 85%-90% of HBV-related HCCs. Its presence in tumors from non-cirrhotic livers of children or young adults further supports the role of viral DNA integration in hepatocarcinogenesis. Integration of subgenomic HBV DNA fragments into different locations within the host DNA is a significant feature of chronic HBV infection. Integration has two potential consequences: (1) the host genome becomes altered ("cis" effect); and (2) the HBV genome becomes altered ("trans" effect). The cis effect includes insertional mutagenesis, which can potentially disrupt host gene function or alter host gene regulation. Tumor progression is frequently associated with rearrangement and partial gain or loss of both viral and host sequences. However, the role of integrated HBV DNA in hepatocarcinogenesis remains controversial. Modern technology has provided a new paradigm to further our understanding of disease mechanisms. This review summarizes the role of HBV DNA integration in human carcinogenesis.
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Huang X, Hollinger FB. Occult hepatitis B virus infection and hepatocellular carcinoma: a systematic review. J Viral Hepat 2014; 21:153-62. [PMID: 24438677 DOI: 10.1111/jvh.12222] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2013] [Accepted: 12/08/2013] [Indexed: 12/13/2022]
Abstract
Occult hepatitis B (OHB) infection has been reported to play an important role in the development of hepatocellular carcinoma (HCC). In this systematic review, a significantly higher prevalence of OHB was observed in patients with HCC in the presence or absence of HCV infection when compared with control populations without HCC. Correspondingly, among adequately designed prospective studies, the cumulative probability of developing HCC was significantly greater among patients with OHB than among HBV DNA-negative patients in the presence or absence of HCV infection. Study design, inclusion criteria, treatment options, methodology and potential confounding variables were evaluated, and immunopathogenic mechanisms that could be involved in OHB as a risk factor in HCC were reviewed. From this analysis, we conclude that although OHB is an independent risk factor in HCC development in anti-HCV-negative patients, a synergistic or additive role in the occurrence of HCC in HCV-coinfected patients is more problematic due to the HCC risk attributable to HCV alone, especially in patients with advanced fibrosis and cirrhosis.
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Affiliation(s)
- X Huang
- Department of Blood Transfusion, The General Hospital of Jinan Military Command, Jinan, China
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Reddy A, May E, Ehrinpreis M, Mutchnick M. Latent hepatitis B is a risk factor for hepatocellular carcinoma in patients with chronic hepatitis C. World J Gastroenterol 2013; 19:9328-9333. [PMID: 24409059 PMCID: PMC3882405 DOI: 10.3748/wjg.v19.i48.9328] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2013] [Accepted: 09/05/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the potential association between hepatocellular carcinoma (HCC) in patients with chronic hepatitis C (CHC), cirrhosis and latent hepatitis B (LHB) infection, defined as the absence of detectable serum hepatitis B surface antigen (HBsAg) and the presence of hepatitis B core antibody (HBcAb).
METHODS: This retrospective analysis is comprised of 185 cirrhotic patients with HCC who were hepatitis C virus antibody (HCV Ab) (+) and HBsAg(-) at Wayne State University between 1999 and 2008. From these, 108 patients had HCV polymerase chain reaction confirmation of viremia while the remaining (77) were considered to have CHC on the basis of a positive HCV Ab and the absence of any other cause of liver disease. Controls were drawn from our institutional database from the same time period and consisted of 356 HBsAg(-) age, race and gender matched patients with HCV RNA-confirmed CHC and without evidence of HCC. A subgroup of controls included 118 matched patients with liver cirrhosis. χ2 test and t test were used for data analysis.
RESULTS: Seventy-seven percent of patients in all 3 groups were African Americans. Patients with HCC had a significantly higher body mass index (P = 0.03), a higher rate of co-infection with human immunodeficiency virus (HIV) (P = 0.05) and a higher prevalence of alcohol abuse (P = 0.03) than the controls. More patients with HCC had LHB than controls (78% vs 39%, P = 0.01). Sixty three percent of patients with HCC were both hepatitis B surface antigen (HBsAb)(-) and HBcAb(+) compared to 23% of controls (P < 0.01). When compared to cirrhotic controls, the frequency of HBcAb(+) remained higher in patients with HCC (78% vs 45%, P = 0.02). Patients with HCC were more likely to be both HBsAb(-) and HBcAb(+) than the cirrhotic controls (63% vs 28%, P = 0.01). Although not statistically significant, 100% of CHC and HIV co-infected patients with HCC (n = 11) were HBcAb(+) when compared to controls (44%; n = 9).
CONCLUSION: These data suggest that LHB occurs at a significantly increased frequency in patients with CHC and HCC than in patients with CHC without HCC.
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Taha SE, El-Hady SA, Ahmed TM, Ahmed IZ. Detection of occult HBV infection by nested PCR assay among chronic hepatitis C patients with and without hepatocellular carcinoma. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2013. [DOI: 10.1016/j.ejmhg.2013.06.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
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Squadrito G, Cacciola I, Alibrandi A, Pollicino T, Raimondo G. Impact of occult hepatitis B virus infection on the outcome of chronic hepatitis C. J Hepatol 2013; 59:696-700. [PMID: 23751755 DOI: 10.1016/j.jhep.2013.05.043] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2012] [Revised: 05/08/2013] [Accepted: 05/31/2013] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIMS Occult hepatitis B virus infection (OBI) frequently occurs in patients with hepatitis C virus (HCV) related chronic hepatitis (CHC), but the influence of OBI on the CHC outcome is still uncertain. This observational cohort study evaluated the clinical evolution of CHC patients according to their OBI status. METHODS From 1991 to 2000, 326 hepatitis B surface antigen negative CHC patients were tested for OBI by the analysis of liver biopsy DNA extracts. A total of 128/326 cases (39.2%) tested OBI positive and 198/326 (60.8%) OBI negative. Ninety-four of 326 patients (37 OBI positive, 57 OBI negative) were followed-up for a median time of 11 years (range 5-19 years). During the follow-up, 79/94 patients underwent anti-HCV treatments and 25 [corrected] achieved a sustained virological response that occurred independently of their OBI status RESULTS Eighteen patients (13/37 OBI positive, 5/57 OBI negative, p < 0.01) developed hepatocellular carcinoma (HCC). Among the 76 non-HCC individuals, 15 subjects (8/24 OBI positive, 7/52 OBI negative, p < 0.05) developed advanced forms of cirrhosis. Eighteen patients died during follow-up and 2 underwent liver transplantation. OBI positive individuals had a cumulative survival rate significantly shorter than OBI negative individuals (p = 0.003). Liver-related deaths were more frequently found in OBI positive than OBI negative patients (12/37 OBI positive vs. 6/57 OBI negative patients respectively, p < 0.01). Finally, non-response to anti-HCV therapy was significantly associated with lower survival (p = 0.02). CONCLUSIONS Among CHC patients, occult HBV co-infected individuals are a category at high risk of progression toward cirrhosis, HCC development, and lower survival.
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Affiliation(s)
- Giovanni Squadrito
- Division of Clinical and Molecular Hepatology, University of Messina, Messina, Italy; Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
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Nishikawa H, Osaki Y. Clinical significance of occult hepatitis B infection in progression of liver disease and carcinogenesis. J Cancer 2013; 4:473-80. [PMID: 23901347 PMCID: PMC3726709 DOI: 10.7150/jca.6609] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2013] [Accepted: 07/05/2013] [Indexed: 01/04/2023] Open
Abstract
Occult hepatitis B infection (OBI) is defined as long-lasting persistence of hepatitis B virus (HBV) DNA in the liver of patients with hepatitis B surface antigen (HBsAg)-negative status, with or without serological markers of previous exposure (antibodies to HBsAg and/or to hepatitis B core antigen). Over the past two decades, significant progress has been made in understanding OBI and its clinical implications. OBI as a cause of chronic liver disease in patients with HBsAg-negative status is becoming an important disease entity. In conditions of immunocompetence, OBI is inoffensive in itself and detection of HBV DNA in the liver does not always indicate active hepatitis. However, when other factors that cause liver damage, such as hepatitis C virus infection, obesity and alcohol abuse are present, the minimal lesions produced by the immunological response to OBI might worsen the clinical course of the underlying liver disease. Several lines of evidence suggest that OBI is associated with progression of liver fibrosis and the development of hepatocellular carcinoma in patients with chronic liver disease. The major interest in OBI is primarily associated with the growing, widely discussed evidence of its clinical impact. The aim of this review is to highlight recent data for OBI, with a major focus on disease progression or carcinogenesis in patients with chronic liver disease.
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Affiliation(s)
- Hiroki Nishikawa
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
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Odhiambo R, Chhatwal J, Ferrante SA, El Khoury A, Elbasha E. Economic Evaluation of Boceprevir for the Treatment of Patients with Genotype 1 Chronic Hepatitis C Virus Infection in Hungary. JOURNAL OF HEALTH ECONOMICS AND OUTCOMES RESEARCH 2013; 1:62-82. [PMID: 37664146 PMCID: PMC10471397 DOI: 10.36469/9854] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/05/2023]
Abstract
Background: Recent international, randomized, placebo-controlled clinical trials (SPRINT-2; RESPOND-2) demonstrated that the triple combination of peginterferon (PEG), ribavirin (RBV) and boceprevir (BOC) was more efficacious than the standard dual therapy of PEG and RBV in treatment of patients chronically infected with genotype 1 hepatitis C virus (HCV) infection. The objective of this study was to evaluate the cost-effectiveness of triple therapy in both treatment-naive and treatment-experienced patients in Hungary. Methods: A Markov model was developed to evaluate the long-term clinical benefits and the costeffectiveness of the triple therapy from the Hungarian payer perspective. Model states were fibrosis (F0-F4, defined using METAVIR fibrosis scores), decompensated cirrhosis (DC), hepatocellular carcinoma (HCC), liver transplantation (LT), and liver-related deaths (LD). Efficacy was estimated from SPRINT-2 and RESPOND-2 studies. Disease progression rates and health state utilities used in the model were obtained from published studies. Estimates of probability of liver transplantation and cost were based on an analysis of the Hungarian Sick Fund database. All cost and benefits were discounted at 5% per year. Results: Compared to dual therapy, triple therapy was projected to increase the life expectancy by 0.98 and 2.42 life years and increase the quality-adjusted life years (QALY) by 0.59 and 1.13 in treatment-naive and treatment-experienced patients, respectively. The corresponding incremental cost-effectiveness ratios were HUF7,747,962 (€26,717) and HUF5,888,240 (€20,304) per QALY. The lifetime incidence of severe liver disease events (DC, HCC, LT, LD) were projected to decrease by 45% and 61% in treatment-naïve and treatment-experienced patients treated with triple therapy groups in comparison with PEG-RBV treatment. Conclusion: The addition of boceprevir to standard therapy for the treatment of patients with genotype 1 chronic HCV infection in Hungary is projected to be cost-effective using a commonly used willingness to pay threshold of HUF 8.46 million (3 times gross domestic product per capita).
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Affiliation(s)
| | - Jagpreet Chhatwal
- Graduate School of Public Health University of Pittsburgh, Pittsburgh, PA, USA
| | | | - Antoine El Khoury
- Graduate School of Public Health University of Pittsburgh, Pittsburgh, PA, USA
| | - Elamin Elbasha
- Graduate School of Public Health University of Pittsburgh, Pittsburgh, PA, USA
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Occult hepatitis B infection in Portuguese patients with chronic hepatitis C liver disease: prevalence and clinical significance. Eur J Gastroenterol Hepatol 2013; 25:142-6. [PMID: 23044809 DOI: 10.1097/meg.0b013e328359fe54] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
INTRODUCTION Occult hepatitis B virus (HBV) infection, defined as the presence of HBV DNA in the liver (with detectable or undetectable HBV DNA in the serum), has been reported in patients with chronic hepatitis C. Some data suggest its association with a more severe liver disease and a worse response to interferon therapy in this subgroup of patients. However, the clinical significance of this condition is still under debate. AIM To determine the prevalence of occult HBV infection and its clinical significance in patients with chronic hepatitis C liver disease. MATERIALS AND METHODS A prospective analysis of consecutive outpatients with chronic hepatitis C who underwent a liver biopsy recruited between January 2008 and June 2011 was carried out. Data included patient's sex and age, source of hepatitis C virus (HCV) infection, HCV genotype and viral load, presence of serologic markers of previous HBV infection, HBV DNA presence in the liver, histologic findings, and response to interferon and ribavirin treatment. HBV DNA and HCV RNA detection were carried out using a sensitive commercially available PCR kit. HBV DNA was tested in liver samples using a nested PCR procedure. RESULTS One hundred patients were included, 73% men, mean age 49 ± 11.9 years. Most patients had a genotype 1, with a high viral load, HCV infection. Of the patients, 33% had HBV serologic markers of past infection. The presence of HBV DNA in liver samples was found in 57% of the patients. No statistically significant difference in the epidemiological, histological, or virological or response to therapy data was found in patients with occult HBV infection. CONCLUSION Occult HBV infection occurred in a high percentage of patients but was not clinically significant.
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Occult Hepatitis B (OBH) in Clinical Settings. HEPATITIS MONTHLY 2012. [DOI: 10.5812/hapatmon.6126] [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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Alavian SM, Miri SM, Hollinger FB, Jazayeri SM. Occult Hepatitis B (OBH) in Clinical Settings. HEPATITIS MONTHLY 2012; 12:e6126. [PMID: 23087749 PMCID: PMC3475016 DOI: 10.5812/hepatmon.6126] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/20/2012] [Revised: 06/20/2012] [Accepted: 07/08/2012] [Indexed: 12/11/2022]
Abstract
CONTEXT Occult hepatitis B (OHB), or persistent HBV DNA in patients who are hepatitis B surface antigen (HBsAg) negative, is a recently recognized entity. In an attempt to summarize the issues, this review presents an overview of the current proposed hypothesis on the clinical relevance and also updates the knowledge on the classification of OHB in different clinical settings. EVIDENCE ACQUISITION OHB COULD BE FOUND IN DIFFERENT POPULATION AND CLINICAL BACKGROUNDS INCLUDING: viral co-infections (with either human immunodeficiency or hepatitis C viruses), HBV chronic carriers, dialysis patients, transplantation settings and certain clinical situations (named in here: special clinical settings) with no apparent distinguishable clinical parameters. RESULTS The exact magnitude, pathogenesis, and clinical relevance of OHB are unclear. Even the possible role exerted by this cryptic infection on liver disease outcome, and hepatocellular carcinoma development remains unknown. CONCLUSIONS Monitoring of Individuals with positive anti-HBc, mass immunization programs and improvement in diagnostic tools seem to be important to control the probability of transmission of HBV through cryptic HBV infection.
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Affiliation(s)
- Seyed Moayed Alavian
- Baqiyatallah Research Center for Gastroenterology and Liver Disease, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
| | - Seyed Mohammad Miri
- Baqiyatallah Research Center for Gastroenterology and Liver Disease, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
| | | | - Seyed Mohammad Jazayeri
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, IR Iran
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Delfino CM, Berini C, Eirin ME, Malan R, Pedrozo W, Krupp R, Blejer J, Espejo R, Fierro L, Puca A, Oubiña JR, Mathet VL, Biglione MM. New natural variants of hepatitis B virus among Amerindians from Argentina with mainly occult infections. J Clin Virol 2012; 54:174-9. [DOI: 10.1016/j.jcv.2012.02.023] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2011] [Revised: 02/17/2012] [Accepted: 02/25/2012] [Indexed: 12/18/2022]
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Shi Y, Wu YH, Wu W, Zhang WJ, Yang J, Chen Z. Association between occult hepatitis B infection and the risk of hepatocellular carcinoma: a meta-analysis. Liver Int 2012; 32:231-40. [PMID: 21745272 DOI: 10.1111/j.1478-3231.2011.02481.x] [Citation(s) in RCA: 106] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND The association between occult hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC) remains controversial. AIMS We conducted a meta-analysis of prospective studies and retrospective studies to examine whether occult HBV infection increases the risk of HCC. METHODS Two independent reviewers searched databases for eligible studies published in English or Chinese dated from 1966 to 6 April 2010. The odds ratios or the relative risks (RRs) of each study were considered respectively. RESULTS We identified 16 eligible studies. A significantly increased risk of HCC was found in subjects with occult HBV infection in comparison with non-infected controls in both retrospective [OR(unadjusted) =6.08, 95% confidence interval (CI)=3.45-10.72] and prospective studies (RR(adjusted) =2.86, 95% CI=1.59-4.13), and occult HBV increased the risk for HCC in both hepatitis C virus (HCV)-infected populations (summary RR=2.83, 95% CI=1.56-4.10) and in non-infected populations (OR(unadjusted) =10.65, 95% CI=5.94-19.08). A higher prevalence of occult HBV was observed in individuals who were positive for anti-HBs and anti-HBc (OR(unadjusted) =1.81, 95% CI=1.06, 3.09). CONCLUSION Our findings suggest that occult HBV infection was associated with an increased risk of HCC. Occult HBV may serve as a cofactor in the development of HCV-related HCC, and it may also play a direct role in promoting Non-B and Non-C HCC growth. Suggestive evidence indicates that individuals with a concomitant presence of anti-HBs and anti-HBc had an increased risk of occult HBV infection. However, further studies are needed to clarify these observations.
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Affiliation(s)
- Yu Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Thabit AM, Al-Moyed KA, Al-Balushi MS, Hasson SS, Sallam TA. Occult hepatitis B virus among chronic liver disease patients in Yemen. ASIAN PACIFIC JOURNAL OF TROPICAL DISEASE 2012. [DOI: 10.1016/s2222-1808(12)60002-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
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Lok AS, Everhart JE, Di Bisceglie AM, Kim HY, Hussain M, Morgan TR, the HALT-C Trial Group. Occult and previous hepatitis B virus infection are not associated with hepatocellular carcinoma in United States patients with chronic hepatitis C. Hepatology 2011; 54:434-42. [PMID: 21374690 PMCID: PMC3134544 DOI: 10.1002/hep.24257] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
UNLABELLED Previous studies have suggested that prior exposure to hepatitis B virus (HBV) infection may increase the risk of development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C. The aim of this study was to compare the prevalence of previous or occult HBV infection in a cohort of hepatitis B surface antigen-negative patients with histologically advanced chronic hepatitis C in the United States who did or did not develop HCC. Stored sera from 91 patients with HCC and 182 matched controls who participated in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial were tested for hepatitis B core antibody (anti-HBc), hepatitis B surface antibody, and HBV DNA. Frozen liver samples from 28 HCC cases and 55 controls were tested for HBV DNA by way of real-time polymerase chain reaction. Anti-HBc (as a marker of previous HBV infection) was present in the serum of 41.8% HCC cases and 45.6% controls (P=0.54); anti-HBc alone was present in 16.5% of HCC cases and 24.7% of controls. HBV DNA was detected in the serum of only one control subject and no patients with HCC. HBV DNA (as a marker of occult HBV infection) was detected in the livers of 10.7% of HCC cases and 23.6% of controls (P=0.18). CONCLUSION Although almost half the patients in the HALT-C Trial had serological evidence of previous HBV infection, there was no difference in prevalence of anti-HBc in serum or HBV DNA in liver between patients who did or did not develop HCC. In the United States, neither previous nor occult HBV infection is an important factor in HCC development among patients with advanced chronic hepatitis C.
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Affiliation(s)
- Anna S. Lok
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI
| | - James E. Everhart
- Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD
| | - Adrian M. Di Bisceglie
- Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, MO
| | | | - Munira Hussain
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI
| | - Timothy R. Morgan
- Division of Gastroenterology, University of California Irvine, Irvine, CA, Gastroenterology Service, VA Long Beach Healthcare System, Long Beach, CA
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Tan YW. Antiviral treatment of hepatitis B virus and hepatitis C virus co-infection. Shijie Huaren Xiaohua Zazhi 2011; 19:1614-1619. [DOI: 10.11569/wcjd.v19.i15.1614] [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] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are among the most common causes of advanced chronic liver disease worldwide. HBV/HCV co-infection is not uncommon with an estimated 7-20 million individuals affected worldwide. Patients with HBV/HCV co-infection have an increased risk of cirrhosis, hepatocellular carcinoma (HCC), and even death. The pathophysiology of HBV/HCV co-infection is complex, as different patterns of virological dominance may occur, which can even fluctuate over time. Recently, combination of pegylated interferon (PEG-IFN) plus ribavirin has been explored in HBV/HCV-coinfected patients who are positive for HCV-RNA. In this paper, we summarize the epidemiology, viral interaction and clinical features of HBV/HCV co-infection and the available treatment options. Detailed serological and virological evaluations are required for HBV/HCV-co-infected patients before initiation of antiviral therapy. At present, PEG-IFN-a plus ribavirin should be the treatment of choice in patients with dominant HCV replication. However, HBV rebound may occur after elimination of HCV, and thus close monitoring for both viruses is recommended even for patients with initially suppressed HBV DNA.
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Selim HS, Abou-Donia HA, Taha HA, El Azab GI, Bakry AF. Role of occult hepatitis B virus in chronic hepatitis C patients with flare of liver enzymes. Eur J Intern Med 2011; 22:187-90. [PMID: 21402251 DOI: 10.1016/j.ejim.2010.12.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2010] [Revised: 10/28/2010] [Accepted: 12/01/2010] [Indexed: 12/12/2022]
Abstract
BACKGROUND Occult HBV infection is defined by detection of HBV DNA in the serum or liver tissue of patients who test negative for HBsAg. The prevalence of occult HBV is higher in hepatitis C virus (HCV) positive patients than HCV negative patients and may have an impact on their clinical outcome. In this study, we evaluated the role of occult hepatitis B virus infection in chronic hepatitis C patients with ALT flare. METHODS Sixty HBsAg negative patients with chronic hepatitis C virus infection were included. Patients were divided into 2 groups according to their ALT level: 30 patients with normal or slightly high ALT and 30 patients with ALT flare (≥ 5 times normal values). Patients in both groups were examined for the detection of anti-HBs, anti-HBc IgM, and anti-HBc IgG. HBV DNA was detected using semi-nested PCR technique. RESULTS In patients with normal or slightly high ALT, HBV DNA was detected in 4 (13.3%) patients, while in those with ALT flare, HBV DNA was detected in 19 (63.3%) patients (p<0.001). No association was found between the presence of HBV DNA and various serology markers of HBV infection. CONCLUSION Presence of occult hepatitis B, with its added deleterious effect, must always be considered in chronic hepatitis C patients especially those with flare in liver enzymes; HBsAg should not be used alone for the diagnosis of HBV infection.
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Affiliation(s)
- Heba S Selim
- Microbiology Department, High Institute of Public Health, Alexandria University, Egypt
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Fernandez-Rodriguez CM, Gutierrez ML, Lledó JL, Casas ML. Influence of occult hepatitis B virus infection in chronic hepatitis C outcomes. World J Gastroenterol 2011; 17:1558-1562. [PMID: 21472121 PMCID: PMC3070126 DOI: 10.3748/wjg.v17.i12.1558] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2010] [Revised: 10/26/2010] [Accepted: 11/02/2010] [Indexed: 02/06/2023] Open
Abstract
Persistence of hepatitis B virus-DNA in the sera, peripheral blood mononuclear cells or in the liver of hepatitis B surface antigen (HBsAg)-negative patients with or without serological markers of previous exposure (antibodies to HBsAg and/or to HB-core antigen) defines the entity called occult hepatitis B infection (OBI). Co-infection with hepatitis B and hepatitis C viruses is frequent in highly endemic areas. While this co-infection increases the risk of liver disease progression, development of cirrhosis and hepatocellular carcinoma and also increases the rate of therapeutic failure to interferon-based treatments than either virus alone, a potentially negative effect of OBI on clinical outcomes and of therapeutic response to current antiviral regimes of patients with chronic hepatitis C remains inconclusive.
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Said M, El-Raziky MS, Abdel-Hamid M, Saad Y, Hashem M, Zakaria S, Mohamed MK, Esmat G. Impact of past HBV exposure on virological response to combined interferon ribavirin therapy in patients with chronic HCV genotype 4. ACTA ACUST UNITED AC 2011. [DOI: 10.4236/ojim.2011.12010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
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Qin H, Liu B, Shi T, Liu Y, Sun Y, Ma Y. Tumour necrosis factor-alpha polymorphisms and hepatocellular carcinoma: a meta-analysis. J Int Med Res 2010; 38:760-8. [PMID: 20819413 DOI: 10.1177/147323001003800304] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The genetic basis of susceptibility to hepatocellular carcinoma (HCC) is poorly understood. To summarize the quantitative association between polymorphisms of the tumour necrosis factor-alpha (TNFA) gene and HCC, a meta-analysis of relevant studies was performed. Ten case-control studies involving 1421 HCC cases were identified from the Medline, Embase and Current Contents databases. Combined results based on all studies showed that patients with HCC had a significantly lower frequency of the TNFA gene polymorphism -308GG than healthy controls. When stratifying for race, results were similar among Asians and Caucasians. When comparing with hepatitis B virus infection cases, no statistical association was found. This meta-analysis suggests that TNFA -308GG gene polymorphism is associated with a modest decrease in the risk of HCC.
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Affiliation(s)
- H Qin
- Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
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Roman S, Tanaka Y, Khan A, Kurbanov F, Kato H, Mizokami M, Panduro A. Occult hepatitis B in the genotype H-infected Nahuas and Huichol native Mexican population. J Med Virol 2010; 82:1527-1536. [PMID: 20648606 DOI: 10.1002/jmv.21846] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Mexico is considered to be a low endemic country for HBV infection. However, a high anti-HBc against a low hepatitis B surface antigen (HBsAg) seroprevalence is the reported characteristic of native Mexicans. HBV diagnosis and genotype distribution was examined in native populations (Nahuas and Huichol, n = 306), and compared to a non-native population (Mestizos, n = 17). Overall, 6% of the natives were positive for HBsAg and 33% had detectable anti-HBc. HBsAg prevalence was lower in Nahuas compared to Huichols (1.4% vs. 9.4%, P < 0.002). Occult hepatitis B was detected in 14.2% (41/289) of natives, who either tested positive (5.88%, 17/289 HBsAg-negative) or negative for anti-HBc marker (8%, 24/289 HBsAg-negative). Age-adjusted anti-HBc seroprevalence and HBsAg quantitation revealed a sub-optimal sensitivity of conventional immunoassays. Nahuas had HBV/H and Huichol had HBV/A as the predominant genotypes followed by genotypes D, C, B, A, and D, G and H, respectively. A less variable HBV/H was characteristic in Mestizos, compared to a much variable HBV/H identified among the Nahuas. In conclusion, these findings indicate a high HBV endemicity among native Mexican groups where occult B infection is common. The different distribution of HBV genotypes among natives suggests multiple reservoirs of HBV from which these genotypes spread into the local communities. High anti-HBc seroprevalence against a low HBsAg prevalence rate may be due to the limited sensitivity of the immunoassays for the detection of HBsAg that are available in Mexico and/or unknown immunogenetic characteristics of native Mexicans.
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Affiliation(s)
- Sonia Roman
- Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara, Fray Antonio Alcalde, Health Sciences Centre, University of Guadalajara, Guadalajara, Jalisco, Mexico
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Abstract
IMPORTANCE OF THE FIELD Hepatitis B (HBV) and hepatitis C (HCV) virus infections are among the most common causes of advanced chronic liver disease worldwide. HBV/HCV coinfection is not uncommon with an estimated 7 - 20 million individuals affected worldwide. Patients with HBV/HCV coinfection have an increased risk for cirrhosis, hepatocellular carcinoma (HCC) and even death. AREAS COVERED IN THIS REVIEW The pathophysiology of HBV/HCV coinfection is complex, as different patterns of virological dominance may occur, which can even fluctuate over time. Recently, combination of pegylated interferon (PEG-IFN) plus ribavirin has been explored in HBV/HCV coinfected patients who are positive for HCV-RNA. HBV polymerase inhibitors may be indicated if HBV-DNA concentrations are above 2000 IU/ml. In this review, we summarize the epidemiology, viral interaction, its clinical features and the available treatment options. WHAT THE READER WILL GAIN Insights into viral interaction of HBV/HCV coinfection and treatment individualization strategies are provided in the review. TAKE HOME MESSAGE Detailed serological and virological evaluations are required for HBV/HCV coinfected patients before initiation of antiviral therapy. At present, PEG-IFN-alpha plus ribavirin should be the treatment of choice in patients with dominant HCV replication. However, HBV rebound may occur after elimination of HCV, and thus close monitoring for both viruses is recommended even for patients with initially suppressed HBV-DNA.
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Affiliation(s)
- Andrej Potthoff
- Hannover Medical School, Medizinische Hochschule Hannover, Department of Gastroenterology, Hepatology and Endocrinology, Carl Neuberg Str. 1, D-30625 Hannover, Germany
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Chemin I, Zoulim F. Hepatitis B virus induced hepatocellular carcinoma. Cancer Lett 2009; 286:52-59. [PMID: 19147276 DOI: 10.1016/j.canlet.2008.12.003] [Citation(s) in RCA: 142] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2008] [Revised: 11/21/2008] [Accepted: 12/02/2008] [Indexed: 12/11/2022]
Abstract
A number of risk factors appear to play a role in Hepatocellularcinoma (HCC), HBV infection being one of the most important. Chronic inflammation and cytokines are key determinants in the development of fibrosis and liver cell proliferation. HBV DNA integration and/or expression of HBV proteins may have a direct effect on cellular functions. Occult hepatitis B virus infection is characterized by persistence of HBV DNA in hepatitis B surface antigen-negative individuals. There are evidences that occult HBV is a risk factor for the development of HCC and that the potential mechanisms whereby overt HBV might induce tumour formation are mostly maintained.
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Affiliation(s)
- I Chemin
- INSERM, U871, 69003 Lyon, France.
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Habibollahi P, Safari S, Daryani NE, Alavian SM. Occult hepatitis B infection and its possible impact on chronic hepatitis C virus infection. Saudi J Gastroenterol 2009; 15:220-4. [PMID: 19794265 PMCID: PMC2981836 DOI: 10.4103/1319-3767.56089] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
As a well-recognized clinical phenomenon, persistent detectable viral genome in liver or sera in the absence of other serological markers for active hepatitis B virus (HBV) replication is called occult HBV infection. The main mechanism through which occult infection occurs is not completely understood and several possible explanations, such as integration into human genome and maintenance in peripheral mononuclear cells, exist. Occult HBV infection has been reported in different populations, especially among patients with Hepatitis C (HCV) related liver disease. The probable impact of occult HBV in patients with chronic HCV infection has been previously investigated and the evidence suggests a possible correlation with lower response to anti-viral treatment, higher grades of liver histological changes, and also developing hepatocellular carcinoma. However, in the absence of conclusive results, further studies should be conducted to absolutely assess the impact of occult HBV contamination on the HCV related liver disease.
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Affiliation(s)
- Peiman Habibollahi
- Gastroenterology Division, Tehran University of Medical Sciences, Tehran, Iran
| | - Saeid Safari
- Gastroenterology Division, Tehran University of Medical Sciences, Tehran, Iran
| | - Nasser E. Daryani
- Department of Internal Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed M. Alavian
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran, Iran,Address for correspondence: Dr. Seyed Moayyed Alavian, Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences and Tehran Hepatitis Center, Tehran, Iran. E-mail:
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Tanaka K. Does occult hepatitis B virus infection cause hepatocellular carcinoma in patients with chronic liver disease related to hepatitis C virus? Hepatol Res 2008; 38:543-5. [PMID: 18452481 DOI: 10.1111/j.1872-034x.2008.00350.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Katsuaki Tanaka
- Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan
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