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1
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Uchida T, Imamura M, Hayes CN, Suehiro Y, Teraoka Y, Ohya K, Aikata H, Abe-Chayama H, Ishida Y, Tateno C, Hara Y, Hino K, Okamoto T, Matsuura Y, Aizaki H, Wake K, Kohara M, Liang TJ, Oka S, Chayama K. HBV with precore and basal core promoter mutations exhibits a high replication phenotype and causes ER stress-mediated cell death in humanized liver chimeric mice. Hepatology 2023; 78:929-942. [PMID: 36896966 PMCID: PMC11519831 DOI: 10.1097/hep.0000000000000335] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 01/25/2023] [Indexed: 03/11/2023]
Abstract
BACKGROUND AND AIMS Mutations within the precore (PC) and basal core promoter (BCP) regions of the HBV genome are associated with fulminant hepatitis and HBV reactivation. These mutations may enhance viral replication, but little is known about whether they directly induce damage to the liver. We investigated mechanisms of direct cytopathic effects induced by the infection with PC/BCP mutants in the absence of immune response in vitro and in vivo . APPROACH AND RESULTS Mice with humanized livers and hepatocytes derived from humanized mice were infected with either wild-type or mutant-type PC/BCP HBV, and the HBV replication and human hepatocyte damage were evaluated. HBV proliferated vigorously in mice with PC/BCP-mutant infection, and the severe loss of human hepatocytes with a slight human ALT elevation subsequently occurred only in PC/BCP mutant mice. In PC/BCP mutant infection, the accumulation of HBsAg in humanized livers colocalized with the endoplasmic reticulum, leading to apoptosis through unfolded protein response in HBV-infected hepatocytes. RNA-sequencing revealed the molecular characteristics of the phenotype of PC/BCP mutant infection in a humanized mouse model. Reduced ALT elevation and higher HBV DNA levels in this model are consistent with characteristics of HBV reactivation, indicating that the hepatocyte damage in this model might mimic HBV reactivation followed by hepatocyte damage under immunosuppressive conditions. CONCLUSION PC and BCP mutations were associated with enhanced viral replication and cell death induced by ER stress using HBV infection models. These mutations might be associated with liver damage in patients with fulminant hepatitis or HBV reactivation.
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Affiliation(s)
- Takuro Uchida
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Michio Imamura
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - C. Nelson Hayes
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yosuke Suehiro
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yuji Teraoka
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kazuki Ohya
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hiromi Abe-Chayama
- Research Center for Hepatology and Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Center for Medical Specialist Graduate Education and Research, Hiroshima, Japan
| | - Yuji Ishida
- Research Center for Hepatology and Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- PhoenixBio Co., Ltd., Higashihiroshima, Japan
| | - Chise Tateno
- Research Center for Hepatology and Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- PhoenixBio Co., Ltd., Higashihiroshima, Japan
| | - Yuichi Hara
- Department of Hepatology and Pancreatology, Kawasaki Medical School, Kurashiki, Japan
| | - Keisuke Hino
- Department of Hepatology and Pancreatology, Kawasaki Medical School, Kurashiki, Japan
| | - Toru Okamoto
- Institute for Advanced Co-creation Studies, Research Institute for Microbial Diseases Osaka University, Osaka, Japan
- Center for Infectious Disease Education and Research, Osaka University, Osaka, Japan
| | - Yoshiharu Matsuura
- Center for Infectious Disease Education and Research, Osaka University, Osaka, Japan
- Department of Virus Control, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Hideki Aizaki
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Kenjiro Wake
- Liver Research Unit, Minophagen Pharmaceutical Co., Ltd., Tokyo, Japan
| | - Michinori Kohara
- Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - T. Jake Liang
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Shiro Oka
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kazuaki Chayama
- Research Center for Hepatology and Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Collaborative Research Laboratory of Medical Innovation, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
- Hiroshima Institute of Life Sciences, Hiroshima, Japan
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Gherlan GS. Occult hepatitis B - the result of the host immune response interaction with different genomic expressions of the virus. World J Clin Cases 2022; 10:5518-5530. [PMID: 35979101 PMCID: PMC9258381 DOI: 10.12998/wjcc.v10.i17.5518] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 01/30/2022] [Accepted: 04/04/2022] [Indexed: 02/06/2023] Open
Abstract
With over 40 years of history, occult hepatitis B infection (OBI) continues to remain an important and challenging public health problem. Defined as the presence of replication-competent hepatitis B virus (HBV) DNA (i.e., episomal HBV covalently closed circular DNA) in the liver and/or HBV DNA in the blood of people who test negative for hepatitis B surface antigen (HBsAg) in currently available assays, OBI is currently diagnosed using polymerase chain reaction (PCR) and real-time PCR assays. However, all efforts should be made to exclude a false negative HBsAg in order to completely follow the definition of OBI. In recent years, significant advances have been made in understanding the HBV lifecycle and the molecular mechanisms that lead to the persistence of the virus in the occult form. These factors are mainly related to the host immune system and, to a smaller proportion, to the virus. Both innate and adaptive immune responses are important in HBV infection management, and epigenetic changes driven by host mechanisms (acetylation, methylation, and microRNA implication) are added to such actions. Although greater genetic variability in the S gene of HBV isolated from OBIs was found compared with overt infection, the mechanisms of OBI are not mainly viral mutations.
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Affiliation(s)
- George Sebastian Gherlan
- Department of Infectious Diseases, “Carol Davila” University of Medicine and Pharmacy, Bucharest 030303, Romania
- Department of Infectious Diseases, “Dr. Victor Babes” Hospital of Infectious and Tropical Diseases, Bucharest 030303, Romania
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3
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de Almeida Pondé RA. Dynamic profile of the HBeAg-anti-HBe system in acute and chronic hepatitis B virus infection: A clinical-laboratory approach. Mol Biol Rep 2020; 48:843-854. [PMID: 33296069 DOI: 10.1007/s11033-020-06056-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 12/01/2020] [Indexed: 02/08/2023]
Abstract
Wild-type HBV infection is followed by the blood expression of its widely known serological markers of infection, and designated as, hepatitis B virus surface antigen (HBsAg) and its antibody (anti-HBs), anti-HBc antibodies (IgM/IgG), and hepatitis B virus 'e' antigen (HBeAg) and its antibody (anti-HBe). These markers are detected as the infection develops and its kinetic behavior serves as a basis for monitoring the disorder and for diagnosing the clinical form or infection phase. Among these, the HBeAg-anti-HBe system markers demonstrate a dynamic profile whose interpretation, both in the acute or chronic HBV infection context, can offer greater difficulty to the health professionals, due to its particularities. This review offers a revisit to the markers dynamics of this system in the acute and chronic HBV infection and to the clinical and laboratory significance of its expression in these two clinical contexts.
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Affiliation(s)
- Robério Amorim de Almeida Pondé
- Laboratory of Human Virology, Institute of Tropical Pathology and Public Health, Federal University of Goiás, Goiânia, Goiás, Brazil. .,Secretaria de Estado da Saúde -SES/Superintendência de Vigilância em Saúde-SUVISA/GO, Gerência de Vigilância Epidemiológica-GVE/Coordenação de Análises e Pesquisas-CAP, Goiânia, Goiás, Brazil.
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4
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Takeda H, Yamashita T, Ueda Y, Sekine A. Exploring the hepatitis C virus genome using single molecule real-time sequencing. World J Gastroenterol 2019; 25:4661-4672. [PMID: 31528092 PMCID: PMC6718035 DOI: 10.3748/wjg.v25.i32.4661] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Revised: 07/04/2019] [Accepted: 07/19/2019] [Indexed: 02/06/2023] Open
Abstract
Single molecular real-time (SMRT) sequencing, also called third-generation sequencing, is a novel sequencing technique capable of generating extremely long contiguous sequence reads. While conventional short-read sequencing cannot evaluate the linkage of nucleotide substitutions distant from one another, SMRT sequencing can directly demonstrate linkage of nucleotide changes over a span of more than 20 kbp, and thus can be applied to directly examine the haplotypes of viruses or bacteria whose genome structures are changing in real time. In addition, an error correction method (circular consensus sequencing) has been established and repeated sequencing of a single-molecule DNA template can result in extremely high accuracy. The advantages of long read sequencing enable accurate determination of the haplotypes of individual viral clones. SMRT sequencing has been applied in various studies of viral genomes including determination of the full-length contiguous genome sequence of hepatitis C virus (HCV), targeted deep sequencing of the HCV NS5A gene, and assessment of heterogeneity among viral populations. Recently, the emergence of multi-drug resistant HCV viruses has become a significant clinical issue and has been also demonstrated using SMRT sequencing. In this review, we introduce the novel third-generation PacBio RSII/Sequel systems, compare them with conventional next-generation sequencers, and summarize previous studies in which SMRT sequencing technology has been applied for HCV genome analysis. We also refer to another long-read sequencing platform, nanopore sequencing technology, and discuss the advantages, limitations and future perspectives in using these third-generation sequencers for HCV genome analysis.
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Affiliation(s)
- Haruhiko Takeda
- Department of Omics-based Medicine, Center for Preventive Medical Science, Chiba University, Chiba 260-0856, Japan
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
| | - Taiki Yamashita
- Department of Omics-based Medicine, Center for Preventive Medical Science, Chiba University, Chiba 260-0856, Japan
| | - Yoshihide Ueda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
| | - Akihiro Sekine
- Department of Omics-based Medicine, Center for Preventive Medical Science, Chiba University, Chiba 260-0856, Japan
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5
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Wu SS, Shan QY, Xie WX, Chen B, Huang Y, Guo Y, Xie XY, Lu MD, Peng BG, Kuang M, Shen SL, Wang W. Outcomes after hepatectomy of patients with positive HBcAb Non-B Non-C hepatocellular carcinoma compared to overt hepatitis B virus hepatocellular carcinoma. Clin Transl Oncol 2019; 22:401-410. [PMID: 31172445 DOI: 10.1007/s12094-019-02141-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Accepted: 05/21/2019] [Indexed: 12/11/2022]
Abstract
PURPOSE Hepatitis B core antibody (HBcAb) positivity is regarded as a sensitive marker for occult and prior hepatitis B virus (HBV) infection. However, the prognosis of patients with HBcAb-positive in non-B, non-C hepatocellular carcinoma (NBNC-HCC) remains unclear. The study aimed to compare the clinicopathological characteristics of patients with HBcAb-positive NBNC-HCC to those with overt HBV (hepatitis B surface antigen positive) HCC. METHODS 306 HCC patients underwent hepatectomy were divided into two groups: an overt HBV-HCC group and HBcAb-positive NBNC-HCC group. Then patients were analyzed using propensity score matching (PSM) to reduce selection bias. Clinicopathological characteristics and survival outcomes were compared between the two groups. Univariate and multivariate analysis for risk factors were also evaluated. RESULTS HBcAb-positive NBNC-HCC group showed comparable survival outcomes to the overt HBV-HCC group (3-year overall survival rates 66% vs 62%, 69% vs 53%; 3-year recurrence-free survival rates 49% vs 40%, 47% vs 37%; P > 0.05) before and after PSM. Patients with HBcAb-positive NBNC-HCC were older, had more complications, higher proportions of vascular invasion, and larger tumor sizes but lower proportions of cirrhosis, elevated alanine aminotransferase and prothrombin time. CONCLUSIONS HBcAb-positive NBNC-HCC group had more advanced tumors, but their prognosis was relatively comparable to that of the other group. Therefore, we believe that screening is also necessary in HBcAb-positive patients for early detection of HCC, especially in the elderly.
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Affiliation(s)
- Shan-Shan Wu
- Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Quan-Yuan Shan
- Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Wen-Xuan Xie
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Bin Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yang Huang
- Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yu Guo
- Department of General Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xiao-Yan Xie
- Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Ming-De Lu
- Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.,Department of Hepatobiliary Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Bao-Gang Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Ming Kuang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Shun-Li Shen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
| | - Wei Wang
- Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
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6
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Inuzuka T, Ueda Y, Arasawa S, Takeda H, Matsumoto T, Osaki Y, Uemoto S, Seno H, Marusawa H. Expansion of viral variants associated with immune escape and impaired virion secretion in patients with HBV reactivation after resolved infection. Sci Rep 2018; 8:18070. [PMID: 30584239 PMCID: PMC6305382 DOI: 10.1038/s41598-018-36093-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Accepted: 11/05/2018] [Indexed: 02/07/2023] Open
Abstract
HBV reactivation could be induced under immunosuppressive conditions in patients with resolved infection. This study aimed to clarify the viral factors associated with the pathogenesis of HBV reactivation in association with the immunosuppressive status. Whole HBV genome sequences were determined from the sera of 24 patients with HBV reactivation, including 8 cases under strong immunosuppression mediated by hematopoietic stem cell transplantation (HSCT) and 16 cases without HSCT. Ultra-deep sequencing revealed that the prevalence of genotype B and the ratio of non-synonymous to synonymous evolutionary changes in the surface (S) gene were significantly higher in non-HSCT cases than in patients with HSCT. Those non-synonymous variants included immune escape (6/16 cases) and MHC class II-restricted T-cell epitope variants (6/16 cases). Furthermore, reactivated HBV in 11 of 16 (69%) non-HSCT cases possessed substitutions associated with impaired virion secretion, including E2G, L77R, L98V, T118K, and Q129H in the S region, and M1I/V in the PreS2 region. In conclusion, virologic features of reactivated HBV clones differed depending on the intensity of the immunosuppressive condition. HBV reactivation triggered by immunosuppressive conditions, especially those without HSCT, was characterized by the expansion of variants associated with immune escape, MHC class II-restricted T-cell epitope alterations, and/or impaired virion secretion.
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Affiliation(s)
- Tadashi Inuzuka
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.,Research Center for Hepatitis and Immunology National Center for Global Health and Medicine, Chiba, Japan.,Research Fellow of Japan Society for the Promotion of Science, Tokyo, Japan
| | - Yoshihide Ueda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Soichi Arasawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Haruhiko Takeda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.,Research Fellow of Japan Society for the Promotion of Science, Tokyo, Japan
| | - Tomonori Matsumoto
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.,Research Fellow of Japan Society for the Promotion of Science, Tokyo, Japan
| | - Yukio Osaki
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
| | - Shinji Uemoto
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroshi Seno
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroyuki Marusawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. .,Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan.
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7
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Blackard JT, Sherman KE. Hepatitis B virus (HBV) reactivation-The potential role of direct-acting agents for hepatitis C virus (HCV). Rev Med Virol 2018; 28:e1984. [PMID: 29761585 PMCID: PMC6233878 DOI: 10.1002/rmv.1984] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Revised: 04/04/2018] [Accepted: 04/05/2018] [Indexed: 12/16/2022]
Abstract
Hepatitis C virus (HCV) is known to inhibit hepatitis B virus (HBV) replication in patients with HBV/HCV coinfection. Reactivation of HBV in patients treated for HCV with direct-acting agents (DAAs) has emerged recently as an important clinical consideration. A growing number of case reports and case series support the association between new HCV treatments and HBV reactivation. Yet, very little is known about the specific viral characteristics that facilitate reactivation as functional characterization of the reactivated HBV has been conducted only rarely. This review provides the most recent data on HBV reactivation in the context of DAA initiation and highlights the existing viral genomic data from reactivating viruses. Current functional studies of HBV reactivation are largely limited by the retrospective identification of cases, no standardization of genomic regions that are studied with respect to HBV reactivation, and the lack of inclusion of nonreactivating controls to establish specific viral mutations that are associated with HBV reactivation. Importantly, none of these sequencing studies included cases of HBV reactivation after initiation of DAAs. While new HCV treatments have revolutionized care for HCV infected patients, HBV reactivation will likely increase in frequency, as DAAs are more commonly prescribed. Pretreatment determination of HBV status and thoughtful management of HBV coinfections will be necessary and lead to improved patient safety and yield optimal treatment results.
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Affiliation(s)
- Jason T Blackard
- Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Kenneth E Sherman
- Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
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8
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Goyal A, Chauhan R. The dynamics of integration, viral suppression and cell-cell transmission in the development of occult Hepatitis B virus infection. J Theor Biol 2018; 455:269-280. [PMID: 29969598 DOI: 10.1016/j.jtbi.2018.06.020] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2018] [Revised: 06/20/2018] [Accepted: 06/25/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND Out of several phases of HBV infection, the least understood phase is occult hepatitis B virus infection. The paucity of data due to non-availability of biological tissues and the prerequisite of ultra-sensitive assays for the detection of occult hepatitis B virus infection prompted us to utilize mathematical modeling in determining mechanisms that lead to occult hepatitis B virus infection and characteristics of HBV infection during occult hepatitis B virus infection. METHODS We proposed two mathematical models (M1 and M2), considering two different phenomenon for episomal maintenance and accumulation of covalently closed circular DNA (cccDNA) in infected hepatocytes: (i) M1 - recirculation of the relaxed circular DNA/double-stranded linear DNA from cytoplasm to the nucleus, and (ii) M2 - reinfection of infected hepatocytes with virions. We further incorporated the dynamics of integrated Hepatitis B virus DNA (iHBV) to investigate its role in the development of occult hepatitis B virus infection. RESULTS The analysis showed that the main mechanism for the spread of infection during occult hepatitis B virus infection is cell-to-cell transmission and not cell-free virus transmission. A significant viral suppression (of at least 99% from its peak production values) was essential but not sufficient in the development of occult hepatitis B virus infection under M1; however under M2, the viral suppression was neither sufficient nor essential as the inhibition of the production of HBsAg without viral suppression can also explain the development of occult hepatitis B virus infection. Our analysis also revealed that occult hepatitis B virus infection seropositive cases are more likely to progress into liver cirrhosis compared to occult hepatitis B virus infection seronegative cases. The iHBV was found to be mostly silent (by either being absent or non-productive for HBsAg) during occult hepatitis B virus infection. CONCLUSION The viral suppression is neither essential nor sufficient to explain the development of occult hepatitis B virus infection on its own. Not only the viral suppression but the inhibition -of the production and the export of HBsAg from cccDNA and iHBV also plays an important role in the development of occult hepatitis B virus infection. This is the first study, which incorporates the dynamics of iHBV and shows that HBV primarily spreads via cell-cell transmission during occult hepatitis B virus infection.
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Affiliation(s)
- Ashish Goyal
- Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico 87545, USA.
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9
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Long-Term Follow-Up of Acute Hepatitis B: New Insights in Its Natural History and Implications for Antiviral Treatment. Genes (Basel) 2018; 9:genes9060293. [PMID: 29895748 PMCID: PMC6027296 DOI: 10.3390/genes9060293] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Revised: 06/04/2018] [Accepted: 06/07/2018] [Indexed: 12/15/2022] Open
Abstract
Acute hepatitis B infection (AHB) is still a common viral acute hepatitis worldwide. As vaccination, antiviral treatment, and immigration are bound to affect the epidemiological landscape of HBV infections, and some of its aspects need to be investigated: (1) the circulation of vaccine escape mutants and of primary drug resistant strains; (2) the change in HBV genotype prevalence; and (3) the clinical implications of AHB and the probability of chronification. The serological, virological, and clinical parameters of 75 patients, acutely infected by HBV, were gathered for a retrospective study. Long-term follow up, either to complete seroconversion or for up to five years, was possible for 44 patients. Sequence analysis of the reverse transcriptase/HBsAg and precore regions was performed to investigate the molecular epidemiology and pathogenesis of recent infections by HBV. Genotype distribution in AHB in Italian patients was radically different from that of chronic infections, with a dramatic increase of extra-European genotypes (A1, F), suggesting that a proportion of AHBs are currently related to imported strains. None of the documented infections occurred in vaccinated individuals, while HBsAg variants (potentially vaccine escape variants) were rare and less prevalent than in chronic infections. No drug resistant strains were observed. Spontaneous viral clearance occurred in all but three cases. Time to viral clearance was inversely proportional to liver damage, but HBsAg titer on day 28 and, better still, HBsAg decay from day 0 to day 28 after admission, were the best predictors of chronification. They are, thus, potentially useful to guide antiviral treatment to prevent chronic evolution.
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10
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Kimura M, Nishikawa K, Sakamaki H, Mizokami M, Kimura K. Reduced therapeutic effect of antiviral drugs in patients with hepatitis B virus reactivation after hematopoietic stem cell transplantation. Hepatol Res 2018; 48:469-478. [PMID: 29235226 DOI: 10.1111/hepr.13044] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Revised: 12/02/2017] [Accepted: 12/07/2017] [Indexed: 12/16/2022]
Abstract
AIM Patients with resolved hepatitis B virus (HBV) infection following hematopoietic stem cell transplantation (HSCT) are potentially at high risk of HBV reactivation. Although antiviral drug therapy is recommended when HBV DNA reappears in the serum, drug efficacy after HBV reactivation remains unclear. METHODS Host immune response against HBV was investigated by immunological analyses at 12 months after entecavir (ETV) treatment in six HSCT-treated and five non-HSCT-treated patients with HBV reactivation, and 18 patients with chronic hepatitis B (CHB). Peripheral HBV-specific CD8+ T cells were analyzed for total numbers by flow cytometry and tetramer staining, as was intracellular γ-interferon (IFN-γ) production and CD107a expression in response to HBV peptides. Interleukin-10 (IL-10)-expressing CD19+ B-cell count and serum inflammatory cytokine levels were also analyzed. RESULTS Serum HBV DNA was detectable in HSCT-treated patients with HBV reactivation at 12 months compared with other groups, indicating insufficient ETV efficacy against HBV. The HBV-specific CD8+ T-cell counts in HSCT-treated patients with HBV reactivation were significantly lower compared with those in non-HSCT patients. Additionally, IFN-γ production and CD107a expression by CD8+ T cells after incubation with HBV peptides was significantly reduced in HSCT-treated compared with CHB patients at 12 months after ETV treatment. Conversely, HSCT-treated patient serum IL-10 levels were significantly elevated compared with those in non-HSCT patients. Finally, IL-10-producing CD19+ B-cell counts were increased in HSCT-treated compared with CHB patients. CONCLUSION After HBV reactivation, ETV efficacy was impaired in HSCT-treated patients as evidenced by low HBV-specific CD8+ T-cell counts and high B-cell IL-10 production.
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Affiliation(s)
| | | | - Hisashi Sakamaki
- Division of Hematology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
| | - Masashi Mizokami
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
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11
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Yang L, Li T, Li W, Tang X, Li J, Long R, Fu Y, Allain JP, Li C. Occult Hepatitis B Virus Infection in Hyperlipidemia Patients. TOHOKU J EXP MED 2018; 241:255-261. [PMID: 28381700 DOI: 10.1620/tjem.241.255] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Chronic hepatitis B virus (HBV) infection is associated with lower prevalence of hyperlipidemia (HLP). However, occult HBV infection (OBI) in HLP patients has not yet been explored. OBI is defined as the presence of detectable HBV DNA in serum or liver tissue but undetectable HBV surface antigen in serum. In this study, 1,036 HLP patients and 1,134 replacement blood donor controls were recruited. Among them, 252 HLP patients and 255 blood donors with antibody to HBV core positive were selected and analyzed. HBV DNA was confirmed by nucleic acid testing assays, and nucleotide mutations were analyzed. OBI was detected in 9.5% (24/252) of HLP patients and 2.4% (6/255) of blood donors, respectively (P < 0.001). In HLP population, 41.7% of OBI and 13.6% of non-OBI carriers were associated with daily alcohol consuming > 30 g/day (P < 0.01), while in control population those rates were not statistically different between OBI and non-OBI carriers (P > 0.05). Viral load of OBI in HLP patients was higher than that of OBI in blood donors (P < 0.05), which was a positive correlation between total cholesterol and HBV viral load levels (r = 0.474 P = 0.019). HBV vaccination rate was found significantly lower in OBI HLP patients than that in non-OBI HLP patients (P < 0.01). Importantly, mutations were found in basic core promoter region of HBV among OBI HLP patients. In conclusion, the frequency of OBI is significantly higher in HLP patients, especially those patients with heavy daily alcohol consumption.
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Affiliation(s)
- Liu Yang
- Department of Transfusion Medicine, School of Laboratory Medicine and Biotechnology, Southern Medical University
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12
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Wang X, Xu L, Chen Y, Liu A, Wang L, Xu P, Liu Y, Li L, Meng F. Integrating nested PCR with high-throughput sequencing to characterize mutations of HBV genome in low viral load samples. Medicine (Baltimore) 2017; 96:e7588. [PMID: 28746207 PMCID: PMC5627833 DOI: 10.1097/md.0000000000007588] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Due to the low viral load of hepatitis B virus (HBV) in plasma samples, conventional techniques have limitations to the detection of antiviral resistance mutations. To solve the problem, we developed a fast, highly sensitive, and accurate method to sequence the HBV whole-genome sequencing in plasma samples which had various viral loads from very low to high.Twenty-one plasma samples were collected from patients who were carriers of HBV from the Hangzhou First People's Hospital. Two pairs of conserved, overlapping, nested primers were used to amplify and sequence the whole HBV genome in 8 plasma samples with different viral loads. High-throughput sequencing was performed on Illumina MiSeq platform. Concomitantly, 3 samples were directly sequenced without PCR amplification. We compared amplicon-sequencing with direct sequencing to develop a method for amplifying and characterizing the whole genome of HBV.HBV genome was amplified from all samples and verified by Sanger sequencing, regardless of the viral loads. Sequencing results revealed that only a few reads were mapped to the HBV genome following direct sequencing, while the amplicon-sequencing reads had a good coverage and depth. We identified 50 intrahost single nucleotide variations (iSNVs), 14 of which were low frequency mutations. Interestingly, iSNVs were more common in low viral load samples than in high viral load samples, and mutations in the reverse transcriptase (RT) region were most prevalent.We conclude that amplicon-sequencing is not only a practical method to detect HBV infection with a high sensitivity and accuracy but also enables to detect mutations in the HBV genome in low viral load samples from HBV-infected patients. Thus, our findings provide a new diagnosis method of HBV infection, which is capable of detection of low frequent mutations in low viral load samples.
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Affiliation(s)
- Xianjun Wang
- Clinical Laboratory, Hangzhou First People's Hospital
| | - Lihui Xu
- Clinical Laboratory, Hangzhou First People's Hospital
| | - Yueming Chen
- Clinical Laboratory, Hangzhou First People's Hospital
| | - Anbing Liu
- Clinical Laboratory, Hangzhou First People's Hospital
| | | | - Peisong Xu
- Department of Research Service, Zhiyuan Inspection Medical Institute, Hangzhou, Zhejiang, People's Republic of China
| | - Yunhui Liu
- Department of Research Service, Zhiyuan Inspection Medical Institute, Hangzhou, Zhejiang, People's Republic of China
| | - Lei Li
- Department of Research Service, Zhiyuan Inspection Medical Institute, Hangzhou, Zhejiang, People's Republic of China
| | - Fei Meng
- Department of Research Service, Zhiyuan Inspection Medical Institute, Hangzhou, Zhejiang, People's Republic of China
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Evolution of multi-drug resistant HCV clones from pre-existing resistant-associated variants during direct-acting antiviral therapy determined by third-generation sequencing. Sci Rep 2017; 7:45605. [PMID: 28361915 PMCID: PMC5374541 DOI: 10.1038/srep45605] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Accepted: 02/28/2017] [Indexed: 02/07/2023] Open
Abstract
Resistance-associated variant (RAV) is one of the most significant clinical challenges in treating HCV-infected patients with direct-acting antivirals (DAAs). We investigated the viral dynamics in patients receiving DAAs using third-generation sequencing technology. Among 283 patients with genotype-1b HCV receiving daclatasvir + asunaprevir (DCV/ASV), 32 (11.3%) failed to achieve sustained virological response (SVR). Conventional ultra-deep sequencing of HCV genome was performed in 104 patients (32 non-SVR, 72 SVR), and detected representative RAVs in all non-SVR patients at baseline, including Y93H in 28 (87.5%). Long contiguous sequences spanning NS3 to NS5A regions of each viral clone in 12 sera from 6 representative non-SVR patients were determined by third-generation sequencing, and showed the concurrent presence of several synonymous mutations linked to resistance-associated substitutions in a subpopulation of pre-existing RAVs and dominant isolates at treatment failure. Phylogenetic analyses revealed close genetic distances between pre-existing RAVs and dominant RAVs at treatment failure. In addition, multiple drug-resistant mutations developed on pre-existing RAVs after DCV/ASV in all non-SVR cases. In conclusion, multi-drug resistant viral clones at treatment failure certainly originated from a subpopulation of pre-existing RAVs in HCV-infected patients. Those RAVs were selected for and became dominant with the acquisition of multiple resistance-associated substitutions under DAA treatment pressure.
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14
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Genetic basis of hepatitis virus-associated hepatocellular carcinoma: linkage between infection, inflammation, and tumorigenesis. J Gastroenterol 2017; 52:26-38. [PMID: 27714455 DOI: 10.1007/s00535-016-1273-2] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Accepted: 09/23/2016] [Indexed: 02/04/2023]
Abstract
Hepatitis virus infection is a leading cause of chronic liver disease, including cirrhosis and hepatocellular carcinoma (HCC). Although anti-viral therapies against hepatitis B virus (HBV) and hepatitis C virus (HCV) have dramatically progressed during the past decade, the estimated number of people chronically infected with HBV and/or HCV is ~370 million, and hepatitis virus-associated hepatocarcinogenesis is a serious health concern worldwide. Understanding the mechanism of virus-associated carcinogenesis is crucial toward both treatment and prevention, and the recently developed whole genome/exome sequencing analysis using next-generation sequencing technologies has contributed to unveiling the landscape of genetic and epigenetic aberrations in not only tumor tissues but also the background liver tissues underlying chronic liver damage caused by hepatitis virus infection. Several major mechanisms underlie the genetic and epigenetic aberrations in the hepatitis virus-infected liver, such as the generation of reactive oxidative stress, ectopic expression of DNA mutator enzymes, and dysfunction of the DNA repair system. In addition, direct oncogenic effects of hepatitis virus, represented by the integration of HBV-DNA, are observed in infected hepatocytes. Elucidating the whole picture of genetic and epigenetic alterations, as well as the mechanisms of tumorigenesis, will facilitate the development of efficient treatment and prevention strategies for hepatitis virus-associated HCC.
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Leung P, Eltahla AA, Lloyd AR, Bull RA, Luciani F. Understanding the complex evolution of rapidly mutating viruses with deep sequencing: Beyond the analysis of viral diversity. Virus Res 2016; 239:43-54. [PMID: 27888126 DOI: 10.1016/j.virusres.2016.10.014] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Revised: 10/24/2016] [Accepted: 10/25/2016] [Indexed: 12/24/2022]
Abstract
With the advent of affordable deep sequencing technologies, detection of low frequency variants within genetically diverse viral populations can now be achieved with unprecedented depth and efficiency. The high-resolution data provided by next generation sequencing technologies is currently recognised as the gold standard in estimation of viral diversity. In the analysis of rapidly mutating viruses, longitudinal deep sequencing datasets from viral genomes during individual infection episodes, as well as at the epidemiological level during outbreaks, now allow for more sophisticated analyses such as statistical estimates of the impact of complex mutation patterns on the evolution of the viral populations both within and between hosts. These analyses are revealing more accurate descriptions of the evolutionary dynamics that underpin the rapid adaptation of these viruses to the host response, and to drug therapies. This review assesses recent developments in methods and provide informative research examples using deep sequencing data generated from rapidly mutating viruses infecting humans, particularly hepatitis C virus (HCV), human immunodeficiency virus (HIV), Ebola virus and influenza virus, to understand the evolution of viral genomes and to explore the relationship between viral mutations and the host adaptive immune response. Finally, we discuss limitations in current technologies, and future directions that take advantage of publically available large deep sequencing datasets.
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Affiliation(s)
- Preston Leung
- School of Medical Sciences, Faculty of Medicine, UNSW Australia, Sydney, NSW 2052, Australia; The Kirby Institute, UNSW Australia, Sydney, NSW 2052, Australia
| | - Auda A Eltahla
- School of Medical Sciences, Faculty of Medicine, UNSW Australia, Sydney, NSW 2052, Australia; The Kirby Institute, UNSW Australia, Sydney, NSW 2052, Australia
| | - Andrew R Lloyd
- The Kirby Institute, UNSW Australia, Sydney, NSW 2052, Australia
| | - Rowena A Bull
- School of Medical Sciences, Faculty of Medicine, UNSW Australia, Sydney, NSW 2052, Australia; The Kirby Institute, UNSW Australia, Sydney, NSW 2052, Australia
| | - Fabio Luciani
- School of Medical Sciences, Faculty of Medicine, UNSW Australia, Sydney, NSW 2052, Australia; The Kirby Institute, UNSW Australia, Sydney, NSW 2052, Australia.
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16
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Pattullo V. Prevention of Hepatitis B reactivation in the setting of immunosuppression. Clin Mol Hepatol 2016; 22:219-37. [PMID: 27291888 PMCID: PMC4946398 DOI: 10.3350/cmh.2016.0024] [Citation(s) in RCA: 85] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Accepted: 04/27/2016] [Indexed: 12/13/2022] Open
Abstract
Advances in the treatment of malignant and inflammatory diseases have developed over time, with increasing use of chemotherapeutic and immunosuppressive agents of a range of drug classes with varying mechanism and potency in their effects on the immune system. These advances have been met with the challenge of increased risk of hepatitis B virus (HBV) reactivation in susceptible individuals. The magnitude of risk of HBV reactivation is associated with the individual’s HBV serological status and the potency and duration of immunosuppression. Individuals with chronic hepatitis B (CHB) and previously infected but serologically cleared HBV infection are both susceptible to HBV reactivation. HBV reactivation in the setting of immunosuppression is a potentially life threatening condition leading to liver failure and death in extreme cases. It is important to recognize that HBV reactivation in the setting of immunosuppression is potentially preventable. Therefore, identification of patients at risk of HBV reactivation and institution of prophylactic antiviral therapy prior to initiation of immunosuppression is essential.
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Affiliation(s)
- Venessa Pattullo
- Department of Gastroenterology, Royal North Shore Hospital, Sydney, Australia
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Apidechkul T, Pongwiriyakul S. Factors associated with HIV and HBV co-infection in Northern Thailand. ASIAN PACIFIC JOURNAL OF TROPICAL DISEASE 2016. [DOI: 10.1016/s2222-1808(15)61008-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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18
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Bivigou-Mboumba B, François-Souquière S, Deleplancque L, Sica J, Mouinga-Ondémé A, Amougou-Atsama M, Chaix ML, Njouom R, Rouet F. Broad Range of Hepatitis B Virus (HBV) Patterns, Dual Circulation of Quasi-Subgenotype A3 and HBV/E and Heterogeneous HBV Mutations in HIV-Positive Patients in Gabon. PLoS One 2016; 11:e0143869. [PMID: 26764909 PMCID: PMC4713159 DOI: 10.1371/journal.pone.0143869] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Accepted: 11/09/2015] [Indexed: 12/20/2022] Open
Abstract
Integrated data on hepatitis B virus (HBV) patterns, HBV genotypes and mutations are lacking in human immunodeficiency virus type 1 (HIV-1) co-infected patients from Africa. This survey was conducted in 2010-2013 among 762 HIV-1-positive adults from Gabon who were predominantly treated with 3TC-based antiretroviral treatment. HBV patterns were identified using immunoassays detecting total antibody to hepatitis B core antigen (HBcAb), hepatitis B surface antigen (HBsAg), IgM HBcAb, hepatitis B e antigen (HBeAg), antibody to HBsAg (HBsAb) and an in-house real-time PCR test for HBV DNA quantification. Occult hepatitis B (OBI) was defined by the presence of isolated anti-HBc with detectable serum HBV DNA. HBV genotypes and HBV mutations were analyzed by PCR-direct sequencing method. Seventy-one (9.3%) patients tested positive for HBsAg, including one with acute hepatitis B (0.1%; 95% CI, 0.0%-0.2%), nine with HBeAg-positive chronic hepatitis B (CHB) (1.2%; 95% CI, 0.6%-2.2%), 16 with HBeAg-negative CHB (2.1%; 95% CI, 1.2%-3.3%) and 45 inactive HBV carriers (5.9%; 95% CI, 4.4%-7.8%). Sixty-one (8.0%; 95% CI, 6.2%-10.1%) patients showed OBI. Treated patients showed similar HBV DNA levels to those obtained in untreated patients, regardless of HBV patterns. Around 15.0% of OBI patients showed high (>1,000 UI/mL) viremia. The mutation M204V/I conferring resistance to 3TC was more common in HBV/A (47.4%) than in HBV/E isolates (0%) (P = .04). Our findings encouraged clinicians to promote HBV vaccination in patients with no exposure to HBV and to switch 3TC to universal TDF in those with CHB.
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Affiliation(s)
- Berthold Bivigou-Mboumba
- Laboratoire de Rétrovirologie, Centre International de Recherches Médicales de Franceville (CIRMF), Franceville, Gabon
- Unité Mixte de Recherche VIH et Maladies Infectieuses Associées (UMR-VIH-MIA), CIRMF, Libreville, Gabon
- * E-mail: ;
| | | | - Luc Deleplancque
- Laboratoire de Rétrovirologie, Centre International de Recherches Médicales de Franceville (CIRMF), Franceville, Gabon
| | - Jeanne Sica
- Centre de Traitement Ambulatoire (CTA), Franceville, Gabon
| | - Augustin Mouinga-Ondémé
- Laboratoire de Rétrovirologie, Centre International de Recherches Médicales de Franceville (CIRMF), Franceville, Gabon
| | | | - Marie-Laure Chaix
- Laboratoire de Virologie, AP-HP, Hôpital Saint Louis; INSERM U941, Université Paris Diderot; Laboratoire associé au Centre national de Référence du VIH, Paris, France
| | - Richard Njouom
- Service de Virologie, Centre Pasteur du Cameroun, Yaoundé, Cameroun
| | - François Rouet
- Laboratoire de Rétrovirologie, Centre International de Recherches Médicales de Franceville (CIRMF), Franceville, Gabon
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20
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Kamitsukasa H, Iri M, Tanaka A, Nagashima S, Takahashi M, Nishizawa T, Okamoto H. Spontaneous reactivation of hepatitis B virus (HBV) infection in patients with resolved or occult HBV infection. J Med Virol 2015; 87:589-600. [PMID: 25612181 DOI: 10.1002/jmv.24115] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/17/2014] [Indexed: 12/22/2022]
Abstract
Reactivation of a former hepatitis B virus (HBV) infection can be triggered by immunosuppressive therapy, diseases associated with an immunocompromised state, organ transplantation or the withdrawal of antiviral drugs. Despite the absence of such risk factors, a spontaneous reactivation of HBV replication occurred in two elderly patients with resolved or occult HBV infection. A 73-year-old male underwent coronary artery bypass grafting in October 2008, and was negative for HBsAg but positive for anti-HBs. In July 2009, his serum became positive for HBsAg, HBeAg and HBV DNA (6.4 log copies/ml; genotype C), but negative for anti-HBc IgM, with abrupt elevation of the liver enzymes. The entire genomic sequence of HBV recovered from this patient revealed no mutations in the core promoter and precore regions that interfere with HBeAg production. A 76-year-old male with a history of endoscopic mucosal resection for esophageal cancer in 2002 and an initial diagnosis of diabetes mellitus in 2009, at which time he was negative for HBsAg. He was found to be positive for HBsAg in September 2012 during a laboratory examination performed prior to the resection of recurrent esophageal cancer, despite a low HBV load (2.1 log copies/ml). Three months later, without the administration of any anticancer drugs, the HBV DNA (genotype B) level increased to 5.1 log copies/ml. A precore G1896A variant with high quasispecies diversity was recovered from the patient. Aging, surgical stress and complication of disease(s) associated with compromised immunity, such as cancer, arteriosclerosis and diabetes mellitus may trigger spontaneous HBV reactivation.
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Affiliation(s)
- Hiroshi Kamitsukasa
- Department of Gastroenterology, National Hospital Organization, Tokyo National Hospital, Kiyose, Tokyo, Japan
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The intracellular HBV DNAs as novel and sensitive biomarkers for the clinical diagnosis of occult HBV infection in HBeAg negative hepatocellular carcinoma in China. PLoS One 2014; 9:e107162. [PMID: 25229710 PMCID: PMC4167849 DOI: 10.1371/journal.pone.0107162] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Accepted: 08/05/2014] [Indexed: 01/01/2023] Open
Abstract
This study aimed to investigate the virological status in liver (both tumor and adjacent non-tumor tissue), the clinical features and the contribution of occult HBV infection (OBI) to postoperative prognosis in HBeAg-negative(−) hepatocellular carcinoma (HCC) patients in China. Using quantitative TaqMan fluorescent real-time PCR assays, HBV covalently closed circular DNA (cccDNA) and total DNA (tDNA) were both quantified in 11 (HBsAg(−)) and 57 (HBsAg-positive(+)) pairs of tumor tissue (TT) and adjacent non-tumor tissue (ANTT) obtained from HBeAg(−) HCC patients who received no antiviral treatment and were negative for anti-HCV before surgical treatment. Of 11 HBsAg(−) patients, 36% were with HBsAb(+) HBeAb(+) HBcAb(+). However, only 9% of the HBsAg(−) patients were HBsAb(−) HBeAb(+) HBcAb(+), which accounted for the majority (93%) in the HBsAg(+) group. TT and ANTT HBV tDNAs in 11 HCC patients with HBsAg (−) and HBeAg (−) were all detectable. HBV cccDNA and tDNA were all lower in the HBsAg(−) group than those in the HBsAg(+) group. By Kaplan-Meier analysis, patients with OBI were associated with a lower risk of cirrhosis and better overall survival (OS). The intracellular HBV DNAs, such as HBV cccDNA and tDNA are valuable biological markers for the diagnosis of occult HBV infection in HCC patients. This would assist the clinical implementation of a more personalized therapy for viral re-activation control and improve the survival rate of OBI patients.
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