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Mazur RD, Cron DC, Goldberg DS, Yeh H, Dageforde LA. Racial-ethnic differences in liver transplant waitlist outcomes in patients with hepatocellular carcinoma before and after recent changes to allocation policy. Clin Transplant 2024; 38:e15365. [PMID: 38804605 DOI: 10.1111/ctr.15365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 02/07/2024] [Accepted: 05/14/2024] [Indexed: 05/29/2024]
Abstract
BACKGROUND In May 2019, liver transplant (LT) allocation policy changed to limit MELD exception points for hepatocellular carcinoma (HCC) to median MELD at transplant minus three (MMaT-3). We evaluated this policy's impact on waitlist outcomes for HCC candidates, by race and ethnicity, hypothesizing that the introduction of the MMaT-3 reduced inequities in waitlist outcomes. METHODS Retrospective cohort study of the Scientific Registry for Transplant Recipients, including all adult LT candidates (N = 10 751) who received HCC exception points from May 17, 2017 to May 18, 2019 (pre-policy; N = 6627) to May 19, 2019 to March 1, 2021 (post-policy; N = 4124). We compared incidence of LT and waitlist removal for death or becoming too sick pre- and post-policy for non-Hispanic White, non-Hispanic Black, Hispanic/Latinx, and Asian patients using competing risk regression adjusted for candidate characteristics. RESULTS One-year cumulative incidence of LT decreased significantly pre-/post-policy among White (77.4% vs. 64.5%; p < .01) and Black (76.2% vs. 63.1%; p < .01) candidates only, while a 1-year incidence of death/non-LT waitlist removal decreased significantly only among Hispanics (13.4% vs. 7.5%; p < .01). After covariate adjustment, the effect of the policy change was a significantly decreased incidence of LT for White (SHR: .63 compared to pre-policy; p < .001), Black (SHR: .62; p < .001), and Asian (SHR: .68; p = .002), but no change for Hispanic patients. Only Hispanic patients had a significant decrease in death/waitlist removal after the policy change (SHR: .69; p = .04). Compared to White patients in the pre-policy era, Hispanic (SHR: .88, p < .007) and Asian candidates (SHR: .72; p < .001) had lower unadjusted incidence of LT. This disparity was mitigated in the post-policy era where Hispanic patients had higher likelihood of LT than Whites (SHR: 1.22; p = .002). For the outcome of death/non-LT waitlist removal, the only significant difference was a 42% lower incidence of waitlist removal for Asian compared to White patients in the post-policy era (SHR: .58; p = .03). CONCLUSION Among LT recipients with HCC, racial/ethnic subpopulations were differentially affected by the MMAT-3 policy, resulting in a post-policy reduction of some of the previous disparities.
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Affiliation(s)
| | - David C Cron
- Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - David S Goldberg
- Division of Digestive Health and Liver Diseases, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Heidi Yeh
- Harvard Medical School, Boston, Massachusetts, USA
- Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Leigh Anne Dageforde
- Harvard Medical School, Boston, Massachusetts, USA
- Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
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Fernandes da Silva C, Keeshan A, Cooper C. Hepatitis B virus genotypes influence clinical outcomes: A review. CANADIAN LIVER JOURNAL 2023; 6:347-352. [PMID: 38020195 PMCID: PMC10652982 DOI: 10.3138/canlivj-2023-0003] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 03/28/2023] [Indexed: 12/01/2023]
Abstract
Hepatitis B virus (HBV) is a hepatotropic virus that affects approximately 296 million people worldwide. A crucial step to HBV replication is the transcription of its infectious DNA from its viral RNA intermediate. The production of the RNA intermediate hinges on reverse transcription, and therefore the lack of proofreading in that process commonly yields mutants and has led to nine well-described genotypes (A-I) and over 30 known sub-genotypes of the virus. The influence of genotype on HBV infection outcomes, which include fibrosis progression, cirrhosis, and hepatocellular carcinoma (HCC), remain uncertain. This review aims to analyze the influence of HBV genotype on the risk of development of these outcomes. The response to current and future HBV therapies is considered. Further study of larger and more diverse samples will hopefully resolve outstanding uncertainties.
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Affiliation(s)
| | - Alexa Keeshan
- Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
| | - Curtis Cooper
- Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
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Badshah Y, Shabbir M, Zafar S, Mussarat U, Ikram A, Javed S, Akhtar H. Impact of IL-12B Genetic Variants on Antiviral Treatment Response among Hepatitis B Patients in Pakistan. LIVERS 2023; 3:494-506. [DOI: 10.3390/livers3030034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2025] Open
Abstract
HBV is a continuous major global health concern. Genetic factors of hosts are known to play a role in HBV infection outcomes. This study aimed to reveal the association of IL-12b 3′ UTR variant rs3212227 in HBV patients. Genotyping was performed using ARMS-PCR to detect IL-12b rs3212227 polymorphism. The patients were categorized into groups based on their response to the antiviral therapy. Group I: non-sustained virological response (NSR); Group II: sustained virological responders (SVR); and Group III: HBV-positive fresh cases. ALT levels were measured to evaluate liver function, and viral load was determined to evaluate viral infectivity among the study groups. The variant genotype CC was found to be significantly associated with the non-sustained virological response to the antiviral therapy (with a p-value of 0.0117; OR = 2.914; RR = 1.556). It was also determined that the genotype CC was the most prevalent genotype among both genders in the NSR group. Viral load was found to be 6-fold higher in Group III compared to Group I and Group II. The results suggest that genotype CC is the most prevalent genotype in the NSR groups, and it is associated with a poor response to antiviral therapy in Pakistani patients with HBV infection.
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Affiliation(s)
- Yasmin Badshah
- Atta ur Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad 44000, Pakistan
| | - Maria Shabbir
- Atta ur Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad 44000, Pakistan
| | - Sameen Zafar
- Atta ur Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad 44000, Pakistan
| | - Uzma Mussarat
- Department of Pathology (Microbiology), Islamic International Medical College, Rawalpindi 46000, Pakistan
| | - Aamer Ikram
- Global Health Security Agenda (GHSA), Center for Disease Control (CDC), National Institute of Health (NIH), Islamabad 44000, Pakistan
| | - Sumbal Javed
- Global Health Security Agenda (GHSA), Center for Disease Control (CDC), National Institute of Health (NIH), Islamabad 44000, Pakistan
| | - Hashaam Akhtar
- Global Health Security Agenda (GHSA), Center for Disease Control (CDC), National Institute of Health (NIH), Islamabad 44000, Pakistan
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4
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Raihan R, Akbar SMF. A Narrative Review on the Specific Pattern of HBV Genotype in Bangladesh: Clinical Implications for Management. Euroasian J Hepatogastroenterol 2023; 13:152-158. [PMID: 38222956 PMCID: PMC10785131 DOI: 10.5005/jp-journals-10018-1412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Accepted: 11/21/2023] [Indexed: 01/16/2024] Open
Abstract
Background and aims Bangladesh's unique epidemiological landscape presents an intriguing puzzle. This South Asian nation, with its complex sociodemographic and environmental factors, is home to a diverse array of hepatitis-B virus (HBV) genotypes, identified as Genotype C, with Genotypes D and A also making a significant contribution to the viral landscape. Reviewing such insights is necessary not only to underscore the country's regional diversity in HBV strains but also to bring into focus the clinical implications these genetic variations may have on disease progression and management. Methods A thorough database search covered various sources using relevant keywords like "Hepatitis B virus genotypes", "HBV genotypes in Bangladesh", and "HBV clinical implications". The review synthesized findings and analyzed HBV genotype prevalence and clinical implications in Bangladesh. Results Genotypes C and D collectively represent 82% of chronic hepatitis-B infection (CHB) cases in Bangladesh, underscoring their regional prevalence. The geographic context is pivotal in understanding HBV infection dynamics and disease progression in this area. Notably, genotype C and the presence of A1762T/G1764A mutations appear to have a distinct impact on disease development, potentially affecting the immune response in CHB patients. This highlights the need for tailored management approaches in this specific region. Further research is vital to confirm and elaborate on these findings, particularly in relation to how these mutations influence the host's immune response. Conclusion and clinical significance In summary, studies on HBV genotypes in Bangladesh stress the need for genotype-specific clinical considerations and more research to improve diagnostics and therapies. How to cite this article Raihan R, Akbar SMF. A Narrative Review on the Specific Pattern of HBV Genotype in Bangladesh: Clinical Implications for Management. Euroasian J Hepato-Gastroenterol 2023;13(2):152-158.
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Affiliation(s)
- Ruksana Raihan
- Department of Microbiology, US Bangla Medical College and Hospital, University of Malaya, Dhaka, Bangladesh
| | - Sheikh Mohammad Fazle Akbar
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine; Research Center for Global and Local Infectious Diseases, Faculty of Medicine, Oita University, Oita; Miyakawa Memorial Research Foundation, Tokyo, Japan
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5
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Li J, Li J, Chen S, Xu W, Zhang J, Tong S. Clinical isolates of hepatitis B virus genotype C have higher in vitro transmission efficiency than genotype B isolates. J Med Virol 2023; 95:e28879. [PMID: 37314050 PMCID: PMC10404337 DOI: 10.1002/jmv.28879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 05/18/2023] [Accepted: 06/02/2023] [Indexed: 06/15/2023]
Abstract
Serum samples were collected from 54 hepatitis B e antigen (HBeAg)-positive Chinese patients infected with hepatitis B virus (HBV) subgenotype B2 or C2. They were compared for transmission efficiency using same volume of samples or infectivity using same genome copy number. Adding polyethylene glycol (PEG) during inoculation did not increase infectivity of fresh samples but markedly increased infectivity following prolonged sample storage. Differentiated HepaRG cells infected without PEG produced more hepatitis B surface antigen (HBsAg) and higher HBsAg/HBeAg ratio than sodium taurocholate cotransporting polypeptide (NTCP)-reconstituted HepG2 cells infected with PEG. They better supported replication of core promoter mutant in contrast to wild-type (WT) virus by HepG2/NTCP cells. Overall, subgenotype C2 samples had higher viral load than B2 samples, and in general produced more HBeAg, HBsAg, and replicative DNA following same-volume inoculation. Precore mutant was more prevalent in subgenotype B2 and had reduced transmission efficiency. When same genome copy number of viral particles was inoculated, viral signals were not necessarily higher for three WT C2 isolates than four WT B2 isolates. Using viral particles generated from cloned HBV genome, three WT C2 isolates showed slightly reduced infectivity than three B2 isolates. In conclusion, subgenotype C2 serum samples had higher transmission efficiency than B2 isolates in association with higher viral load and lower prevalence of precore mutant, but not necessarily higher infectivity. PEG-independent infection by HBV viremic serum samples is probably attributed to a labile host factor.
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Affiliation(s)
- Jing Li
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China
- Liver Research Center, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, Rhode Island 02903, USA
- Department of Infectious Diseases, First Affiliated Hospital of Medical College, Xi’an Jiaotong University, Xi’an, Shaanxi Province 710061, China
| | - Jisu Li
- Liver Research Center, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, Rhode Island 02903, USA
| | - Shiqi Chen
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Weicheng Xu
- Department of Infectious Diseases, First Affiliated Hospital of Medical College, Xi’an Jiaotong University, Xi’an, Shaanxi Province 710061, China
| | - Jiming Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Shuping Tong
- Liver Research Center, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, Rhode Island 02903, USA
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6
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Sant'Anna TB, Araujo NM. Hepatitis B Virus Genotype D: An Overview of Molecular Epidemiology, Evolutionary History, and Clinical Characteristics. Microorganisms 2023; 11:1101. [PMID: 37317074 PMCID: PMC10221421 DOI: 10.3390/microorganisms11051101] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 04/19/2023] [Accepted: 04/20/2023] [Indexed: 06/16/2023] Open
Abstract
The hepatitis B virus (HBV) genotype D (HBV/D) is the most extensively distributed genotype worldwide with distinct molecular and epidemiological features. This report provides an up-to-date review on the history of HBV/D subgenotyping and misclassifications, along with large-scale analysis of over 1000 HBV/D complete genome sequences, with the aim of gaining a thorough understanding of the global prevalence and geographic distribution of HBV/D subgenotypes. We have additionally explored recent paleogenomic findings, which facilitated the detection of HBV/D genomes dating back to the late Iron Age and provided new perspectives on the origins of modern HBV/D strains. Finally, reports on distinct disease outcomes and responses to antiviral therapy among HBV/D subgenotypes are discussed, further highlighting the complexity of this genotype and the importance of HBV subgenotyping in the management and treatment of hepatitis B.
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Affiliation(s)
- Thaís B Sant'Anna
- Laboratory of Molecular Virology and Parasitology, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro 21041-250, RJ, Brazil
| | - Natalia M Araujo
- Laboratory of Molecular Virology and Parasitology, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro 21041-250, RJ, Brazil
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Kikuchi K, Fukuda K, Hayashi S, Maeda T, Takashima Y, Fujita M, Ikuta K, Anjiki K, Tachibana S, Onoi Y, Matsumoto T, Kuroda R, Matsubara T. Polyarthritis presented in a patient with untreated chronic hepatitis B infection. Mod Rheumatol Case Rep 2023; 7:320-323. [PMID: 36214605 DOI: 10.1093/mrcr/rxac075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 07/10/2022] [Accepted: 09/23/2022] [Indexed: 01/04/2023]
Abstract
Hepatitis B virus (HBV) infection can cause arthritis, but it is rarely reported. In the current report, we present a case of chronic polyarthritis in a patient with untreated HBV infection. A 63-year-old woman suffering from polyarthritis in her fingers visited our institution. She had experienced exacerbations and remissions of polyarthritis for more than 20 years. She had been diagnosed with rheumatoid arthritis and had been treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and nonsteroidal anti-inflammatory drugs by her primary care doctor, but the csDMARDs were discontinued at the request of the patient 10 years before the first visit to our hospital. The blood test showed negative for rheumatoid factor and anticyclic citrullinated peptides antibody but positive for hepatitis B surface antigen. Hepatitis B surface antigen and HBV-Deoxyribo Nucleic Acid (DNA) were increased to 312.6 (IU/ml) and 4.6 (log copies/ml), respectively. Based on the results of abdominal computed tomography and echography, she was diagnosed with liver cirrhosis. Treatment for HBV infection was begun with oral tenofovir at 25 mg/day. The polyarthritis in her fingers gradually disappeared and has not relapsed for 6 months after the initiation of treatment for HBV infection. When polyarthritis is diagnosed, the possibility that chronic HBV infection can be one of the causes of polyarthritis should be considered.
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Affiliation(s)
- Kenichi Kikuchi
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Koji Fukuda
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.,Department of Orthopaedics, Matsubara Mayflower Hospital, Kato, Japan
| | - Shinya Hayashi
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Toshihisa Maeda
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yoshinori Takashima
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Masahiro Fujita
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Kenmei Ikuta
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Kensuke Anjiki
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Shotaro Tachibana
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yuma Onoi
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Tomoyuki Matsumoto
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Ryosuke Kuroda
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Tsukasa Matsubara
- Department of Orthopaedics, Matsubara Mayflower Hospital, Kato, Japan
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Kato T, Akari H. [Neutralization of hepatitis B virus with vaccine-escape mutations by novel hepatitis B vaccine with large-HBs antigen]. Uirusu 2023; 72:149-158. [PMID: 38220203 DOI: 10.2222/jsv.72.149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2024]
Abstract
Although the current hepatitis B (HB) vaccine comprising yeast-derived small hepatitis B surface antigen (HBsAg) is potent and safe and used worldwide, specific concerns should not be ignored, such as the attenuated prophylaxis against hepatitis B virus (HBV) infection with specific amino acid polymorphisms, called vaccine-escape mutations (VEMs). We investigated a novel HB vaccine consisting of large-HBsAg that covers the shortcomings of the current HB vaccine in a nonhuman primate model. The yeast-derived large-HBsAg was mixed with the adjuvant and used to immunize rhesus macaques, and the induction of antibodies to HBsAg was compared with that of the current HB vaccine. The current HB vaccine predominantly induced antibodies to small-HBsAg, whereas immunization with the large-HBsAg vaccine mainly induced antibodies to the preS1 region. Although the antibodies induced by the current HB vaccine could not prevent infection of HBV with VEMs, the large-HBsAg vaccine-induced antibodies neutralized infection of HBV with VEMs at levels similar to those of the wild type. The HBV genotypes that exhibited attenuated neutralization by induced antibodies differed between these vaccines. In conclusion, the novel HB vaccine consisting of large-HBsAg was revealed to be useful to compensate for shortcomings of the current HB vaccine. The combined use of these HB vaccines may be able to induce antibodies that can neutralize HBV strains with VEMs or multiple HBV genotypes.
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Affiliation(s)
- Takanobu Kato
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Hirofumi Akari
- Center for the Evolutionary Origins of Human Behavior, Kyoto University, Aichi, Japan
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Kumar R. Review on hepatitis B virus precore/core promoter mutations and their correlation with genotypes and liver disease severity. World J Hepatol 2022; 14:708-718. [PMID: 35646275 PMCID: PMC9099108 DOI: 10.4254/wjh.v14.i4.708] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 09/04/2021] [Accepted: 03/27/2022] [Indexed: 02/06/2023] Open
Abstract
Of 350 million people worldwide are chronically infected with hepatitis B virus (HBV) and are at risk of developing cirrhosis and hepatocellular carcinoma (HCC) later in life. HBV is the most diverse DNA virus, and its genome is composed of four open reading frames: Presurface antigen/surface antigen gene (preS/S), precore/core gene (preC/C), polymerase gene (P), and the X gene (X). HBV produces quasispecies naturally or in response to antiviral agents because of the absence of proofreading activity amid reverse transcription and a high replication rate. The virus has 10 genotypes (A to J) with different geographical distributions. There are various HBV mutations in the HBV genome, including preC/C mutations, preS/S mutations, P gene mutations, and X gene mutations. The core promoter region plays a vital part in the replication, morphogenesis and pathogenesis of the virus. The precore region also plays a crucial role in viral replication. Both core promoter and precore mutations rescue the virus from host immune surveillance and result in the formation of mutated strains that may have altered pathogenicity. preC/C mutations are associated with liver disease progression. Precore mutations stop hepatitis B e antigen (HBeAg) production and basal core promoter mutations downregulate HBeAg production. Mutations in the basal core promoter are also associated with increased HBV replication and an increased incidence of advanced liver diseases such as cirrhosis and HCC. The emergence of antiviral-resistant mutations is the main reason for treatment failure. This review focuses mainly on preC/C promoter mutations and their correlation with genotypes and liver disease severity. Thorough perception and knowledge of HBV genetic variety and mutants could be vital to discover techniques for the prognosis and control of HBV infection.
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Affiliation(s)
- Rajesh Kumar
- Department of School Education, Haryana Government, Panchkula 134109, Haryana, India
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Elizalde MM, Tadey L, Mammana L, Quarleri JF, Campos RH, Flichman DM. Biological Characterization of Hepatitis B virus Genotypes: Their Role in Viral Replication and Antigen Expression. Front Microbiol 2021; 12:758613. [PMID: 34803982 PMCID: PMC8600256 DOI: 10.3389/fmicb.2021.758613] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Accepted: 10/13/2021] [Indexed: 01/12/2023] Open
Abstract
Hepatitis B virus (HBV) inter-host evolution has resulted in genomic diversification reflected in the existence of nine genotypes (A-I) and numerous subgenotypes. There is growing evidence that genotypes influence HBV natural history, clinical outcomes, and treatment response. However, the biological characteristics underlying these differences have not yet been established. By transfecting HuH-7 cells with unit-length constructs of genotypes A2, B2, C1, D1, and F1b, we identified major differences in HBV replicative capacity and antigen expression across genotypes. Genotypes B2 and F1b showed a 2-fold increase in cccDNA levels compared to the other genotypes (p<0.005). Genotype A2 expressed the lowest pgRNA levels, with a 70-fold decrease in relation to the other genotypes (p<0.0001), while genotype B2 showed the lowest Precore RNA levels, with a 100-fold reduction compared to genotype A2 (p<0.0001). The highest intracellular HBV DNA levels were observed for genotype B2 and the lowest for genotypes A2 and C1 (p<0.0001). Regarding antigen expression, genotype F1b secreted the highest HBsAg levels and genotype D1 the lowest (p<0.0001), while genotypes A2 and B2 showed the highest intracellular HBsAg levels (p<0.0001). Interestingly, genotype C1 secreted the highest HBeAg levels, while genotype A2 showed the highest intracellular levels (p<0.0001). Finally, the analysis of the intra/extracellular antigen ratios revealed that most genotypes retained intracellularly 5-20% of the antigens, except the genotype A2 that retained 50% of the total expressed antigens. In conclusion, this study provides new insights into the biological characteristics of HBV genotypes, being the first study to comparatively analyze European (A and D) and Asian (B and C) genotypes with the Latin American (F) genotype. The differences in HBV replication and antigen expression might contribute to understand the differential role of genotypes in pathogenesis.
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Affiliation(s)
- María Mercedes Elizalde
- Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), CONICET, Universidad de Buenos Aires, Buenos Aires, Argentina.,Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Luciana Tadey
- Unidad de Virología, Hospital de Infecciosas "Francisco J. Muñiz", Buenos Aires, Argentina
| | - Lilia Mammana
- Unidad de Virología, Hospital de Infecciosas "Francisco J. Muñiz", Buenos Aires, Argentina
| | - Jorge Fabián Quarleri
- Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), CONICET, Universidad de Buenos Aires, Buenos Aires, Argentina.,Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Rodolfo Héctor Campos
- Departamento de Microbiología, Inmunología, Biotecnología y Genética, Cátedra de Virología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.,Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Diego Martín Flichman
- Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), CONICET, Universidad de Buenos Aires, Buenos Aires, Argentina.,Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
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11
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Datfar T, Doulberis M, Papaefthymiou A, Hines IN, Manzini G. Viral Hepatitis and Hepatocellular Carcinoma: State of the Art. Pathogens 2021; 10:pathogens10111366. [PMID: 34832522 PMCID: PMC8619105 DOI: 10.3390/pathogens10111366] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Revised: 09/26/2021] [Accepted: 10/18/2021] [Indexed: 02/06/2023] Open
Abstract
Viral hepatitis is one of the main causes leading to hepatocellular carcinoma (HCC). The continued rise in incidence of HCC suggests additional factors following infection may be involved. This review examines recent studies investigating the molecular mechanisms of chronic hepatitis and its association with hepatocarcinogenesis. Hepatitis B virus patients with genotype C display an aggressive disease course leading to HCC more than other genotypes. Furthermore, hepatitis B excretory antigen (HBeAg) seems to be a more sensitive predictive tumor marker exhibiting a six-fold higher relative risk in patients with positive HBsAg and HBeAg than those with HBsAg only. Single or combined mutations of viral genome can predict HCC development in up to 80% of patients. Several mutations in HBx-gene are related with higher HCC incidence. Overexpression of the core protein in HCV leads to hepatocellular lipid accumulation associated with oncogenesis. Reduced number and decreased functionality of natural killer cells in chronic HCV individuals dysregulate their surveillance function in tumor and viral cells resulting in HCC. Furthermore, high T-cell immunoglobulin and mucin 3 levels supress CD8+ T-cells, which lead to immunological dysregulation. Hepatitis D promotes HCC development indirectly via modifications to innate immunity, epigenetic alterations and production of reactive oxygen species with the LHDAg being the most highly associated with HCC development. Summarizing the results, HBV and HCV infection represent the most associated forms of viral hepatitis causing HCC. Further studies are warranted to further improve the prediction of high-risk patients and development of targeted therapeutics preventing the transition from hepatic inflammation–fibrosis to cancer.
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Affiliation(s)
- Toofan Datfar
- Department of General and Visceral Surgery, Hospital of Aarau, 5001 Aarau, Switzerland;
- Correspondence: ; Tel.: +41-76-4930834
| | - Michael Doulberis
- Department of Gastroenterology and Hepatology, Hospital of Aarau, 5001 Aarau, Switzerland;
| | | | - Ian N. Hines
- Department of Nutrition Science, East Carolina University, Greenville, NC 27858, USA;
| | - Giulia Manzini
- Department of General and Visceral Surgery, Hospital of Aarau, 5001 Aarau, Switzerland;
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12
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Hayashi S, Nagaoka K, Tanaka Y. Blood-Based Biomarkers in Hepatitis B Virus-Related Hepatocellular Carcinoma, Including the Viral Genome and Glycosylated Proteins. Int J Mol Sci 2021; 22:ijms222011051. [PMID: 34681709 PMCID: PMC8540379 DOI: 10.3390/ijms222011051] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/08/2021] [Accepted: 10/11/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC) development and is a global public health issue. High performance biomarkers can aid the early detection of HCC development in HBV-infected individuals. In addition, advances in the understanding of the pathogenesis of HBV infection and in clinical laboratory techniques have enabled the establishment of disease-specific tests, prediction of the progression of liver diseases, including HCC, and auxiliary diagnosis of HCC, using blood-based methods instead of biopsies of liver or HCC tissues. Viral factors such as the HBV genotype, HBV genetic mutations, HBV DNA, and HBV-related antigens, as well as host factors, such as tumor-associated proteins and post-translational modifications, especially glycosylated proteins, can be blood-based, disease-specific biomarkers for HCC development in HBV-infected patients. In this review, we describe the clinical applications of viral biomarkers, including the HBV genome and glycosylated proteins, for patients at a risk of HBV-related HCC, based on their molecular mechanisms. In addition, we introduce promising biomarker candidates for practical use, including colony stimulating factor 1 receptor (CSF1R), extracellular vesicles, and cell-free, circulating tumor DNA. The clinical use of such surrogate markers may lead to a better understanding of the risk of disease progression and early detection of HCC in HBV-infected patients, thereby improving their prognosis.
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13
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Liu Q, Tian Y, Li Y, Zhang W, Cai W, Liu Y, Ren Y, Liang Z, Zhou P, Zhang Y, Bao Y, Li Y. In vivo therapeutic effects of affinity-improved-TCR engineered T-cells on HBV-related hepatocellular carcinoma. J Immunother Cancer 2021; 8:jitc-2020-001748. [PMID: 33323464 PMCID: PMC7745518 DOI: 10.1136/jitc-2020-001748] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/15/2020] [Indexed: 12/24/2022] Open
Abstract
Background In patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), virus-specific cytotoxic T lymphocytes (CTLs) fail to eliminate HCC cells expressing HBV antigens. As the expression of viral antigen in HBV-associated HCC may decrease to allow tumor to escape immune attacks, we hypothesized that an HBV surface antigen (HBsAg)-specific affinity-improved-T-cell receptor (TCR) will enable T cells to target HCC more effectively than corresponding wild-type-TCR. We also postulated that TCR promiscuity can be exploited to efficiently capture HBV variants that can hinder CTL-based therapeutics. Methods We applied flexi-panning to isolate affinity-improved TCRs binding to a variant antigen, the human leukocyte antigen (HLA)-A*02:01-restricted nonapeptide HBs371-379-ILSPFLPLL, from libraries constructed with a TCR cloned using the decapeptide HBs370-379-SIVSPFIPLL. The potency and safety of the affinity-improved-TCR engineered T-cells (Ai-TCR-T) were verified with potentially cross-reactive human and HBV-variant peptides, tumor and normal cells, and xenograft mouse models. Results Ai-TCR-T cells retained cognate HBV antigen specificity and recognized a wide range of HBV genotypic variants with improved sensitivity and cytotoxicity. Cell infusions produced complete elimination of HCC without recurrence in the xenograft mouse models. Elevated accumulation of CD8+ Ai-TCR-T cells in tumors correlated with tumor shrinkage. Conclusion The in vitro and in vivo studies demonstrated that HBsAg-specific Ai-TCR-T cells had safety profiles similar to those of their wild-type counterparts and significantly enhanced potency. This study presents an approach to develop new therapeutic strategies for HBV-related HCC.
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Affiliation(s)
- Qi Liu
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China.,University of the Chinese Academy of Sciences, Beijing, China
| | - Ye Tian
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China
| | - Yanyan Li
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China
| | - Wei Zhang
- Hefei Institute of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Hefei, Anhui, China
| | - Wenxuan Cai
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China
| | - Yaju Liu
- Hefei Institute of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Hefei, Anhui, China
| | - Yuefei Ren
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China.,School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
| | - Zhaoduan Liang
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China
| | - Peipei Zhou
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China.,Institute of Physical Science and Information Technology, Anhui University, Hefei, Anhui, China
| | - Yajing Zhang
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China.,University of the Chinese Academy of Sciences, Beijing, China
| | - Yifeng Bao
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China
| | - Yi Li
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China .,University of the Chinese Academy of Sciences, Beijing, China
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14
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Samant H, Amiri HS, Zibari GB. Addressing the worldwide hepatocellular carcinoma: epidemiology, prevention and management. J Gastrointest Oncol 2021; 12:S361-S373. [PMID: 34422400 PMCID: PMC8343080 DOI: 10.21037/jgo.2020.02.08] [Citation(s) in RCA: 84] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Accepted: 01/22/2020] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common cancer in the world with rising incidence. Globally, there has been substantial variation in prevalence of risk factors for HCC over years, like control of viral hepatitis in developing countries but growing epidemic of fatty liver disease in developed world. Changing epidemiology of HCC is related to trends in these risk factors. HCC remains asymptomatic until it is very advanced which makes early detection by surveillance important in reducing HCC related mortality. Management of HCC. depends on stage of the tumor and severity of underlying liver disease. At present, resection and transplant are still the best curative options for small HCC, but recent advances in locoregional therapy and molecular targeted systemic therapy has changed the management for HCC at intermediate and advanced stages. This review is overview of global epidemiology, prevention, surveillance and emerging therapies for hepatocellular carcinoma.
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Affiliation(s)
- Hrishikesh Samant
- Division of Gastroenterology and Hepatology, LSU Health Science Center, Shreveport, LA, USA
| | - Hosein Shokouh Amiri
- John C McDonald Transplant Center, Willis Knighton Health System, Shreveport, LA, USA
| | - Gazi B. Zibari
- John C McDonald Transplant Center, Willis Knighton Health System, Shreveport, LA, USA
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15
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Cooper SL, King WC, Mogul DB, Ghany MG, Schwarz KB. Clinical significance of quantitative e antigen in a cohort of hepatitis B virus-infected children and adults in North America. J Viral Hepat 2021; 28:1042-1056. [PMID: 33893706 DOI: 10.1111/jvh.13520] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 04/12/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND In chronic hepatitis B (CHB) viral infection, e antigen positivity (HBeAg+) is associated with high levels of viral replication and infectivity. Furthermore, HBeAg-positive CHB is associated with a liver disease spectrum ranging from none to severe. AIM To assess whether the level of circulating HBeAg is associated with different clinical presentations of HBeAg-positive CHB. METHODS A cross-sectional analysis was conducted among HBV mono-infected participants enrolled in Hepatitis B Research Network (HBRN) cohorts to explore clinical and virological associations with quantitative HBeAg (qHBeAg). RESULTS Among 763 HBeAg+ participants (56% female; 85% Asian; median age 26 years), multivariable median regression modelling significantly associated qHBeAg with liver injury (inverse qHBeAg association with ALT p<.001 and APRI p<.001), and with both race and age (p=0.01). Among Asians, qHBeAg was inversely related to age; a relationship less clear among Blacks and Whites. Among Asians also, median qHBeAg levels were higher among those infected with HBV genotype C versus B (p<0.001), suggesting causal virologic differences. Across all races, median qHBeAg was higher in women (p=.01). Independent of sex, age, race and HBV genotype, qHBeAg was higher in participants with predominant wild-type versus basal core promoter and/or precore 'stop' viral variants (p<0.001). CONCLUSION Lower qHBeAg was observed among HBRN participants with the greatest degree of liver injury independent of demographics and HBV genotype. These data support longitudinal studies to examine the role of qHBeAg in modulating the host immune response and predicting the outcomes of chronic HBV infection.
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Affiliation(s)
| | - Wendy C King
- Graduate School of Public, Health University of Pittsburgh, Pittsburgh, PA, USA
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16
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Abstract
Chronic hepatitis B (CHB) remains a global healthcare burden. Although the recent developments in the field have led to a reduction in incidence, the morbidity and mortality including liver cirrhosis and hepatocellular carcinoma (HCC) remain a formidable challenge. Advances in understanding the immunopathogenesis of CHB have led to a recent change in clinical categorization. EASL introduced the term hepatitis B 'e' antigen (HBeAg)-negative chronic infection, to replace the historical term 'inactive carrier' disease phase, the commonest CHB phase. Although this disease phase is associated with a favorable prognosis, it is not a truly 'inactive' disease phase with no ostensible liver disease, as inferred by the previous anachronistic terminology, and the risk of spontaneous reactivation and the potential risk of disease progression and HCC development are not negligible. Likewise, the APASL also uses the term "Incidentally Detected Asymptomatic Hepatitis B surface antigen (HBsAg)-positive Subject (IDAHS)", comprising all HBsAg-positive subjects who are incidentally detected during routine tests, without any previous or present symptoms of liver disease. This entity includes HBV infection with varied stages of liver disease. Antiviral treatment is generally reserved for patients with active inflammation and/or at risk of disease progression and HCC development. HBsAg loss is considered an optimal treatment endpoint, and may also be achievable in HBeAg-negative chronic infection and IDAHS. In light of this, and the emerging novel HBV therapies, lowering the treatment threshold and a 'Treat All' approach should now be considered. In this review, we summarize the literature and guidance on HBeAg-negative chronic infection, and we make a concerted effort to present the reasons why the one-dimensional term 'inactive carrier' should be abandoned.
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17
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Ganesan M, Eikenberry A, Poluektova LY, Kharbanda KK, Osna NA. Role of alcohol in pathogenesis of hepatitis B virus infection. World J Gastroenterol 2020; 26:883-903. [PMID: 32206001 PMCID: PMC7081008 DOI: 10.3748/wjg.v26.i9.883] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 02/09/2020] [Accepted: 02/14/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) and alcohol abuse often contribute to the development of end-stage liver disease. Alcohol abuse not only causes rapid progression of liver disease in HBV infected patients but also allows HBV to persist chronically. Importantly, the mechanism by which alcohol promotes the progression of HBV-associated liver disease are not completely understood. Potential mechanisms include a suppressed immune response, oxidative stress, endoplasmic reticulum and Golgi apparatus stresses, and increased HBV replication. Certainly, more research is necessary to gain a better understanding of these mechanisms such that treatment(s) to prevent rapid liver disease progression in alcohol-abusing HBV patients could be developed. In this review, we discuss the aforementioned factors for the higher risk of liver diseases in alcohol-induced HBV pathogenies and suggest the areas for future studies in this field.
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Affiliation(s)
- Murali Ganesan
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, NE 68105, United States
| | - Allison Eikenberry
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, NE 68105, United States
| | - Larisa Y Poluektova
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Kusum K Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, NE 68105, United States
| | - Natalia A Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, NE 68105, United States
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18
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Ogawa M, Kamimura S, Kanda T, Takahashi H, Mizutani T, Matsumoto N, Yamamoto T, Nirei K, Matsuoka S, Takei M, Moriyama M. Long-term follow-up of a Japanese patient with hepatitis B virus genotype H and human immunodeficiency virus coinfection. Future Virol 2019. [DOI: 10.2217/fvl-2019-0089] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Hepatitis B virus (HBV) genotypes affect the pathogenesis of disease progression during the course of HBV infection. In Japan, HBV genotype H is one of the rare HBV genotypes. We recovered HBV genotype H from a blood sample from a Japanese HIV-infected patient with acute exacerbation of chronic HBV infection. Due to the development of drugs for treating HBV and HIV, HBV genotype H and HIV coinfection has been well controlled by nucleos(t)ide analogs and highly active antiretroviral therapy, respectively, from 2002 to 2019. Further study is needed with regard to HBV genotype H and its pathogenesis.
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Affiliation(s)
- Masahiro Ogawa
- Division of Gastroenterology & Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo 173-8610, Japan
| | - Shinya Kamimura
- Division of Gastroenterology & Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo 173-8610, Japan
| | - Tatsuo Kanda
- Division of Gastroenterology & Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo 173-8610, Japan
| | - Hiroshi Takahashi
- Division of Gastroenterology & Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo 173-8610, Japan
| | - Taku Mizutani
- Division of Gastroenterology & Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo 173-8610, Japan
| | - Naoki Matsumoto
- Division of Gastroenterology & Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo 173-8610, Japan
| | - Toshiki Yamamoto
- Division of Gastroenterology & Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo 173-8610, Japan
| | - Kazushige Nirei
- Division of Gastroenterology & Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo 173-8610, Japan
| | - Shunichi Matsuoka
- Division of Gastroenterology & Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo 173-8610, Japan
| | - Masami Takei
- Division of Hematology & Rheumatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo 173-8610, Japan
| | - Mitsuhiko Moriyama
- Division of Gastroenterology & Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo 173-8610, Japan
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19
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Haga H, Saito T, Okumoto K, Tomita K, Katsumi T, Mizuno K, Nishina T, Watanabe H, Ueno Y. Incidence of development of hepatocellular carcinoma in Japanese patients infected with hepatitis B virus is equivalent between genotype B and C in long term. J Viral Hepat 2019; 26:866-872. [PMID: 30924226 DOI: 10.1111/jvh.13099] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Revised: 02/01/2019] [Accepted: 02/21/2019] [Indexed: 12/19/2022]
Abstract
Hepatitis B virus (HBV) genotypes B (HBV/B) and C (HBV/C) are the most prevalent genotypes among Japanese patients with hepatitis. Reportedly, HBV/C infection has been associated with more severe disease progression, manifesting as developing cirrhosis and hepatocellular carcinoma (HCC), than HBV/B infection. However, no long-term studies have examined the development of HCC in HBV/B-infected patients in Japan. The aims of our study were to compare the incidence of HCC in HBV/B- or HBV/C-infected patients. A total of 241 patients were followed up among 295 hepatitis B surface antigen (HBsAg)-positive carriers. Genotypes of HBV were A in 1% (4/295), B in 61% (179/295), C in 37% (110/295) and D in 1% (2/295) patients, and 96% of HBV/B were infected with subgenotype Bj. The mean age at HCC diagnosis was significantly higher in HBV/B than in HBV/C (67.0 ± 10.0 vs 57.7 ± 8.0 years, P < 0.001). The value of FIB-4 index was significantly higher in HBV/B than in HBV/C (P < 0.01). The rate of HCC was higher in HBV/C than in HBV/B, and a significant difference was observed until the 20-year observation period (P = 0.048). However, thereafter, HCC associated with HBV/B increased, and no significant difference was observed between HBV/B and HBV/C. HCC development was consistently observed even in HBV/B infection, especially among elderly patients with advanced fibrosis compared with HBV/C. HBV/B-infected patients developed HCC later in life, and in the long term, we found no differences in incidence of HCC development rates between these two genotypes.
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Affiliation(s)
- Hiroaki Haga
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Takafumi Saito
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan.,School of Nursing, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Kazuo Okumoto
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Kyoko Tomita
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Tomohiro Katsumi
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Kei Mizuno
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Taketo Nishina
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Hisayoshi Watanabe
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Yoshiyuki Ueno
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
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20
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Raihan R, Akbar SMF, Al Mahtab M, Takahashi K, Masumoto J, Tabassum S, Tee KK, Binti Mohamed R. Genomic analysis of Hepatitis B virus and its association with disease manifestations in Bangladesh. PLoS One 2019; 14:e0218744. [PMID: 31251754 PMCID: PMC6599139 DOI: 10.1371/journal.pone.0218744] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Accepted: 06/07/2019] [Indexed: 12/23/2022] Open
Abstract
The direct cytopathic effects of the hepatitis B virus (HBV) on subsequent liver damage are not fully understood in HBV-infected patients. However, associations between the prevalence of various HBV genotypes and the extent of liver damage have been reported from different parts of the world. The purpose of this study was to determine the distribution of HBV genotypes in patients with chronic HBV infection in Bangladesh, a country of 160 million people, of which approximately 3–6 million are chronically infected HBV patients. In addition, whole and partial genome sequencing of HBV was performed to evaluate the relationship between HBV mutations and genotypes. We found that 42% of the patients with low HBV DNA and normal levels of alanine aminotransferase (ALT) had HBV genotype D. In contrast, the HBV genotype C was dominant among patients with high HBV DNA levels (>2000 IU/ml) and elevated ALT and in patients with liver cirrhosis (LC) and hepatocellular carcinomas (HCC). Whole and partial genome sequences of HBV revealed that most patients with LC and HCC had HBV genotype C with mutations at the T1762/A1764 positions. It seems that Bangladesh represents a borderline country, situated within East Asia, which mainly consists of individuals with HBV genotypes B and C, whereas in the western parts of Asia, HBV genotypes A and D are prevalent. Bangladesh is, therefore, an excellent model for the comparison of the pathophysiology of three major HBV genotypes in a single population. The findings of this study suggest a possible association between HBV viral factors and the extent of liver damage in chronic HBV-infected patients.
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Affiliation(s)
- Ruksana Raihan
- Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
- * E-mail: ,
| | - Sheikh Mohammad Fazle Akbar
- Department of Pathology, Ehime University Proteo-Science Center, Ehime University Graduate School of Medicine, Toon City, Ehime, Japan
| | - Mamun Al Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Kazuaki Takahashi
- Department of Medical Sciences, Tokyo-Shinagawa Hospital, Shinagawa, Tokyo, Japan
| | - Junya Masumoto
- Department of Pathology, Ehime University Proteo-Science Center, Ehime University Graduate School of Medicine, Toon City, Ehime, Japan
| | - Shahina Tabassum
- Department of Virology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Kok Keng Tee
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
- School of Healthcare and Medical Sciences, Sunway University, Bandar Sunway, Selangor Darul Ehsan, Malaysia
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21
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KASL clinical practice guidelines for management of chronic hepatitis B. Clin Mol Hepatol 2019; 25:93-159. [PMID: 31185710 PMCID: PMC6589848 DOI: 10.3350/cmh.2019.1002] [Citation(s) in RCA: 161] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Accepted: 03/25/2019] [Indexed: 02/06/2023] Open
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22
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Ren CC, Chen QY, Wang XY, Harrison TJ, Yang QL, Hu LP, Liu HB, He X, Jia HH, Fang ZL. Novel subgenotype D11 of hepatitis B virus in NaPo County, Guangxi, bordering Vietnam. J Gen Virol 2019; 100:828-837. [PMID: 30990399 DOI: 10.1099/jgv.0.001257] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Hepatitis B virus has been classified into 10 genotypes and 48 subgenotypes worldwide. We found previously, through polymerase chain reaction (PCR) amplification of a sample collected in 2011, that an HBsAg carrier was infected with two genotypes (B and D) of HBV. We carried out cloning, sequencing and phylogenetic analysis of the complete genomes and, for confirmation, analysed a sample collected from the same individual in 2018. Fifteen complete sequences were obtained from each sample. The carrier was infected in 2011 by genotypes B and D and by various recombinants, but only genotype D was present in 2018. The major and minor parents of the recombinants are genotypes B and D, respectively, although the recombination breakpoints vary among them. All 23 genotype D isolates form a cluster, branching out from other subgenotype D sequences and supported by a 100 % bootstrap value. Based on complete genome sequences, almost all of the estimated intragroup nucleotide divergence values between our isolates and HBV subgenotypes D1-D10 exceed 4 %. Compared to the other subgenotypes (D1-D10), 35 unique amino acids were present in our isolates. Our data provide evidence for a novel subgenotype, provisionally designated HBV subgenotype D11.
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Affiliation(s)
- Chuang-Chuang Ren
- 1Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning, Guangxi 530028, PR China.,2School of Preclinical Medicine, Guangxi Medical University, UCL Medical School, 22 ShuangYong Road Nanning, Guangxi 530021, PR China
| | - Qin-Yan Chen
- 1Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning, Guangxi 530028, PR China
| | - Xue-Yan Wang
- 1Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning, Guangxi 530028, PR China
| | | | - Qing-Li Yang
- 1Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning, Guangxi 530028, PR China
| | - Li-Ping Hu
- 1Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning, Guangxi 530028, PR China
| | - Hua-Bing Liu
- 1Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning, Guangxi 530028, PR China.,2School of Preclinical Medicine, Guangxi Medical University, UCL Medical School, 22 ShuangYong Road Nanning, Guangxi 530021, PR China
| | - Xiang He
- 4Guangdong Provincial Institute of Public Health, Guangdong Provincial Center for Disease Control and Prevention, Guangzhou 511430, PR China
| | - Hui-Hua Jia
- 1Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning, Guangxi 530028, PR China.,2School of Preclinical Medicine, Guangxi Medical University, UCL Medical School, 22 ShuangYong Road Nanning, Guangxi 530021, PR China
| | - Zhong-Liao Fang
- 1Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning, Guangxi 530028, PR China
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23
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Molecular Mechanisms Driving Progression of Liver Cirrhosis towards Hepatocellular Carcinoma in Chronic Hepatitis B and C Infections: A Review. Int J Mol Sci 2019. [PMID: 30889843 DOI: 10.3390/ijms] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Almost all patients with hepatocellular carcinoma (HCC), a major type of primary liver cancer, also have liver cirrhosis, the severity of which hampers effective treatment for HCC despite recent progress in the efficacy of anticancer drugs for advanced stages of HCC. Here, we review recent knowledge concerning the molecular mechanisms of liver cirrhosis and its progression to HCC from genetic and epigenomic points of view. Because ~70% of patients with HCC have hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection, we focused on HBV- and HCV-associated HCC. The literature suggests that genetic and epigenetic factors, such as microRNAs, play a role in liver cirrhosis and its progression to HCC, and that HBV- and HCV-encoded proteins appear to be involved in hepatocarcinogenesis. Further studies are needed to elucidate the mechanisms, including immune checkpoints and molecular targets of kinase inhibitors, associated with liver cirrhosis and its progression to HCC.
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Molecular Mechanisms Driving Progression of Liver Cirrhosis towards Hepatocellular Carcinoma in Chronic Hepatitis B and C Infections: A Review. Int J Mol Sci 2019; 20:ijms20061358. [PMID: 30889843 PMCID: PMC6470669 DOI: 10.3390/ijms20061358] [Citation(s) in RCA: 183] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2019] [Revised: 02/23/2019] [Accepted: 03/14/2019] [Indexed: 02/07/2023] Open
Abstract
Almost all patients with hepatocellular carcinoma (HCC), a major type of primary liver cancer, also have liver cirrhosis, the severity of which hampers effective treatment for HCC despite recent progress in the efficacy of anticancer drugs for advanced stages of HCC. Here, we review recent knowledge concerning the molecular mechanisms of liver cirrhosis and its progression to HCC from genetic and epigenomic points of view. Because ~70% of patients with HCC have hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection, we focused on HBV- and HCV-associated HCC. The literature suggests that genetic and epigenetic factors, such as microRNAs, play a role in liver cirrhosis and its progression to HCC, and that HBV- and HCV-encoded proteins appear to be involved in hepatocarcinogenesis. Further studies are needed to elucidate the mechanisms, including immune checkpoints and molecular targets of kinase inhibitors, associated with liver cirrhosis and its progression to HCC.
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Wang X, Huang K, Zeng X, Liu Z, Liao X, Yang C, Yu T, Han C, Zhu G, Qin W, Peng T. Diagnostic and prognostic value of mRNA expression of phospholipase C β family genes in hepatitis B virus‑associated hepatocellular carcinoma. Oncol Rep 2019; 41:2855-2875. [PMID: 30896816 PMCID: PMC6448089 DOI: 10.3892/or.2019.7066] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Accepted: 03/05/2019] [Indexed: 02/07/2023] Open
Abstract
Four phospholipase C β (PLCB) isoforms, PLCB1, PLCB2, PLCB3 and PLCB4, have been previously investigated regarding their roles in the metabolism of inositol lipids and cancer. The present study aimed to explore the association between PLCB1-4 and hepatocellular carcinoma (HCC). Data from 212 patients with hepatitis B virus-associated HCC were used to analyze the diagnostic and prognostic significance of PLCB genes in. A nomogram predicted the survival probability. Gene set enrichment analysis explored gene ontology terms and the metabolic pathways associated with PLCB genes. Validation of the prognostic values of PLCB genes was performed using the Gene Expression Profiling Interactive Analysis website. PLCB1 and PLCB2 were revealed to have diagnostic value for HCC (0.869 and 0.836 area under the curve, respectively; both P≤0.05). The combination analysis of these genes had an advantage over each alone (0.905 PLCB1 and PLCB2, and 0.877 PLCB1 and PLCB3 area under the curve; P≤0.05). PLCB1 was associated with overall survival (OS) and recurrence-free survival (RFS; adjusted P=0.002 and P=0.001, respectively). A nomogram predicted survival probability of patients with HCC at 1, 3- and 5-years. Gene set enrichment analysis indicated that PLCB1 and PLCB2 are involved in the cell cycle, cell division and the PPAR signaling pathway, among other functions. Validation using GEPIA revealed that PLCB1 and PLCB2 were associated with OS and PLCB1 and PLCB4 were associated with RFS. PLCB1 and PLCB2 exhibited diagnostic value for HCC and their combination had an advantage over each individually. PLCB1 has OS and RFS prognostic value for patients with HCC.
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Affiliation(s)
- Xiangkun Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Ketuan Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Xianmin Zeng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Zhengqian Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Xiwen Liao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Chengkun Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Tingdong Yu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Chuangye Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Guangzhi Zhu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Wei Qin
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
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Molecular Characterization of Coexistence of HBsAg and Anti-HBs in a Patients Infected with HBV Genotype I. HEPATITIS MONTHLY 2019. [DOI: 10.5812/hepatmon.81740] [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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Torres MC, Civetta E, D'amico C, Barbini L. Hepatitis B virus in Mar del Plata, Argentina: Genomic characterization and evolutionary analysis of subgenotype F1b. J Med Virol 2019; 91:791-802. [PMID: 30570771 DOI: 10.1002/jmv.25383] [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: 07/13/2018] [Accepted: 12/14/2018] [Indexed: 11/07/2022]
Abstract
The aim is to describe the molecular epidemiology and perform a genomic characterization of hepatitis B virus (HBV) circulating in Mar del Plata and to identify the origin and diversification patterns of the most prevalent genotype. The S gene and the region encompassing the X gene, basal core promoter (BCP), and precore (preC) was analyzed in 56 samples. They were genotyped as: 80% F1b, 9% A2, 7% D3, and 2% D1. A recombinant F4/D2 genome was detected. The double substitution G1764A/A1762T at the BCP (reduced HBeAg expression) was found in 20% F1b, 2% A2, 2% D1, and 2% D3 samples. A unique D3 presented the G1896A substitution at the preC (HBeAg negative phenotype). A 13% of the samples showed mutations at the HBsAg "a" immunodeterminant (escape from neutralizing antibodies). Mutations at the polymerase (antiviral resistance) were found in 52% of the samples. Coalescent analysis of subgenotype F1b, the most prevalent in the city, showed that viral diversification in Mar del Plata started by year 2000. F1b was the most prevalent genotype detected, being a characteristic of actual HBV infections in Mar del Plata. Local HBV exhibit clinically relevant mutations, but a minority of them was shown to be associated to potential vaccination escape or antiviral resistance. Nevertheless, further studies are needed to determine whether any of these mutants could pose a threat to prevention, diagnosis, or treatment.
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Affiliation(s)
| | - Elida Civetta
- Unidad de Hepatología y Alcoholismo, HIGA Dr. O. Alende, Mar del Plata, Argentina
| | - Claudia D'amico
- Centro de Especialidades Médicas Ambulatorias, Unidad de Hepatología, Mar del Plata, Argentina
| | - Luciana Barbini
- Departamento de Química, FCEyN, UNMdP, Buenos Aires, Argentina
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Ho CH, Chen SH, Tsai HW, Wu IC, Chang TT. Fully galactosyl-fucosyl-bisected IgG 1 reduces anti-HBV efficacy and liver histological improvement. Antiviral Res 2019; 163:1-10. [PMID: 30611775 DOI: 10.1016/j.antiviral.2018.12.021] [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: 07/18/2018] [Accepted: 12/28/2018] [Indexed: 12/13/2022]
Abstract
N-glycosylation on the crystallizable fragment (Fc) governs antibody-mediated immune responses. This study addressed the relevance of N-acetylglucosamine (GlcNAc)-bisected IgG1 on the disease progression and treatment efficacy in the immune active phase of chronic hepatitis B virus (HBV) infection. Serum IgG1N-glycan patterns from 166 HBV e antigen (HBeAg)-positive patients were analyzed using liquid chromatography-tandem mass spectrometry. The proportion of GlcNAc-bisected IgG1 on the disease severity and efficacy of nucleos(t)ide analogue treatment were investigated. Cytokine-dependent regulations of IgG1 GlcNAc bisection were also addressed using mouse IgG1-producing hybridoma cells. We found that IgG1 bearing a fully galactosyl-fucosyl-N-acetylglucosamine-bisected (G2FN) glycoform in HBeAg-positive patients was associated with high levels of HBV DNA or HBV surface antigen, alanine aminotransferase <2 upper limits of normal, and a mild liver injury. Moreover, baseline IgG1-G2FN ≧ 1.5% was linked to lower probabilities of virological response (HBV DNA undetectable in serum), HBeAg seroconversion, HBV core antigen loss, and liver histological improvement after treatment. Cox and logistic regression analyses revealed that IgG1-G2FN was an unfavorable factor for the virological response (hazard ratio = 0.620, 95% confidence interval = 0.466-0.825, P = 0.001) or liver histological improvement (odds ratio = 0.513, 95% confidence interval = 0.279-0.943, P = 0.032), respectively. Results from in vitro studies showed that transforming growth factor (TGF)-β1 treatment downregulated mannosyl β-1,4-N-acetylglucosaminyltransferase 3 and β-1,4-galactosyltransferase 1 activities and thereby IgG1-G2FN production, and this phenomenon reflected an inverse correlation between IgG1-G2FN and TGF-β1 in sera of patients (r = -0.431, P < 0.001). In conclusion, IgG1-G2FN was related to an attenuated liver inflammation and unfavorable treatment responses in patients with HBeAg-positive chronic hepatitis B.
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Affiliation(s)
- Cheng-Hsun Ho
- Department of Medical Laboratory Science, College of Medicine, I-Shou University, Kaohsiung, Taiwan.
| | - Shu-Hui Chen
- Department of Chemistry, National Cheng Kung University, Tainan, Taiwan.
| | - Hung-Wen Tsai
- Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
| | - I-Chin Wu
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
| | - Ting-Tsung Chang
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
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Genotype Matters in Patients with Acute-on-chronic Liver Failure Due to Reactivation of Chronic Hepatitis B. Clin Transl Gastroenterol 2018; 9:202. [PMID: 30416197 PMCID: PMC6230554 DOI: 10.1038/s41424-018-0071-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Revised: 08/20/2018] [Accepted: 10/09/2018] [Indexed: 12/30/2022] Open
Abstract
Background Acute-on-chronic liver failure (ACLF) can be caused by reactivation of chronic hepatitis B virus (HBV) infection (HBV-ACLF). It’s unclear whether HBV genotypes affect the clinical and therapeutical outcomes of patients with HBV-ACLF. This study was to investigate the short-term antiviral response and overall survival in HBV-ACLF patients treated by tenofovir or entecavir. Methods Seventy-three consecutive patients with HBV-ACLF were stratified into genotype B group (n = 33) and C group (n = 40). They were prospectively followed-up. Results At 2 weeks, the genotype B group had significantly lower HBV-DNA load (P = 0.005), greater HBV-DNA decline (P = 0.026), higher proportion of patients with HBV-DNA < 500 IU/ml (P = 0.007), improved Child-Turcotte-Pugh (CTP; P = 0.032) and model for end-stage liver disease (MELD; P = 0.039) scores compared to the genotype C group. At three months, survivors in both groups had undetectable HBV-DNA loads, comparable CTP (P = 0.850) and MELD (P = 0.861) scores; the genotype C group had markedly lower overall survival rate than the B group (P = 0.013). The genotype (hazard ratio [HR]: 2.138; 95% confidence interval [CI]: 1.034–4.143; P = 0.041), MELD score (HR:1.664, 95%CI: 1.077–2.571; P = 0.022) and HBV-DNA decline (HR: 0.225, 95% CI: 0.067–0.758; P = 0.016) at 2 weeks were significantly associated with mortality at 3 months. No severe adverse event was noted. Conclusions Genotype B was associated with better short-term antiviral response and clinical outcome compared to genotype C in patients with HBV-ACLF.
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Wu IC, Liu WC, Chang TT. Applications of next-generation sequencing analysis for the detection of hepatocellular carcinoma-associated hepatitis B virus mutations. J Biomed Sci 2018; 25:51. [PMID: 29859540 PMCID: PMC5984823 DOI: 10.1186/s12929-018-0442-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Accepted: 04/30/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Next-generation sequencing (NGS) is a powerful and high-throughput method for the detection of viral mutations. This article provides a brief overview about optimization of NGS analysis for hepatocellular carcinoma (HCC)-associated hepatitis B virus (HBV) mutations, and hepatocarcinogenesis of relevant mutations. MAIN BODY For the application of NGS analysis in the genome of HBV, four noteworthy steps were discovered in testing. First, a sample-specific reference sequence was the most effective mapping reference for NGS. Second, elongating the end of reference sequence improved mapping performance at the end of the genome. Third, resetting the origin of mapping reference sequence could probed deletion mutations and variants at a certain location with common mutations. Fourth, using a platform-specific cut-off value to distinguish authentic minority variants from technical artifacts was found to be highly effective. One hundred and sixty-seven HBV single nucleotide variants (SNVs) were found to be studied previously through a systematic literature review, and 12 SNVs were determined to be associated with HCC by meta-analysis. From comprehensive research using a HBV genome-wide NGS analysis, 60 NGS-defined HCC-associated SNVs with their pathogenic frequencies were identified, with 19 reported previously. All the 12 HCC-associated SNVs proved by meta-analysis were confirmed by NGS analysis, except for C1766T and T1768A which were mainly expressed in genotypes A and D, but including the subgroup analysis of A1762T. In the 41 novel NGS-defined HCC-associated SNVs, 31.7% (13/41) had cut-off values of SNV frequency lower than 20%. This showed that NGS could be used to detect HCC-associated SNVs with low SNV frequency. Most SNV II (the minor strains in the majority of non-HCC patients) had either low (< 20%) or high (> 80%) SNV frequencies in HCC patients, a characteristic U-shaped distribution pattern. The cut-off values of SNV frequency for HCC-associated SNVs represent their pathogenic frequencies. The pathogenic frequencies of HCC-associated SNV II also showed a U-shaped distribution. Hepatocarcinogenesis induced by HBV mutated proteins through cellular pathways was reviewed. CONCLUSION NGS analysis is useful to discover novel HCC-associated HBV SNVs, especially those with low SNV frequency. The hepatocarcinogenetic mechanisms of novel HCC-associated HBV SNVs defined by NGS analysis deserve further investigation.
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Affiliation(s)
- I-Chin Wu
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan, 70403, Taiwan, Republic of China.,Infectious Disease and Signaling Research Center, National Cheng Kung University, Tainan, Taiwan, Republic of China
| | - Wen-Chun Liu
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan, 70403, Taiwan, Republic of China.,Infectious Disease and Signaling Research Center, National Cheng Kung University, Tainan, Taiwan, Republic of China
| | - Ting-Tsung Chang
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan, 70403, Taiwan, Republic of China.
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31
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Khatun M, Mondal RK, Pal S, Baidya A, Bishnu D, Banerjee P, Santra AK, Dhali GK, Banerjee S, Chowdhury A, Datta S. Distinctiveness in virological features and pathogenic potentials of subgenotypes D1, D2, D3 and D5 of Hepatitis B virus. Sci Rep 2018; 8:8055. [PMID: 29795338 PMCID: PMC5966457 DOI: 10.1038/s41598-018-26414-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Accepted: 05/11/2018] [Indexed: 12/13/2022] Open
Abstract
Distinct clinical features of HBV infection have been associated with different viral genotype/subgenotype. HBV Genotype-D comprised of 10 subgenotypes, D1–D10, whose clinical implications still remain elusive. We investigated for the first-time, the virologic characteristics and cytopathic effects of four non-recombinant D-subgenotypes, D1/D2/D3/D5. Expressions of viral/host genes were evaluated in Huh7 cells transfected with full-length, linear-monomers of HBV/D-subgenotypes or pGL3-Basic vector carrying subgenotype-specific HBx. Intracellular HBV-DNA and pregenomic-RNA levels were high in D1/D2 than D3/D5. Expressions of PreC-mRNA and HBx were highest for D2 and D1 respectively, whereas PreS2/S-transcript was significantly reduced in D5. Increased apoptotic cell death and marked upregulation in caspase-3/Bax/TNF-R1/FasR/TRAIL-R1/ROS/MCP-1/IP-10/MIP-1β expression were noticed specifically in D2- and also in D3-transfected cells, while D5 resulted in over-expression of ER-stress-markers. D-subgenotype-transfected Huh7 cells were co-cultured with PBMC of healthy-donors or LX-2 cells and significant increase in pro-inflammatory cytokines in PBMC and fibrogenic-markers in LX-2 were noticed in presence of D2/D3. Further, Huh7 cells transfected with D1, in particular and also D5, displayed remarkable induction of EMT-markers and high proliferative/migratory abilities. Collectively, our results demonstrated that D2/D3 were more associated with hepatic apoptosis/inflammation/fibrosis and D1/D5 with increased risk of hepatocarcinogenesis and emphasize the need for determining HBV-subgenotype in clinical practice.
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Affiliation(s)
- Mousumi Khatun
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research (I.P.G.M.E. & R.), Kolkata, India
| | - Rajiv Kumar Mondal
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research (I.P.G.M.E. & R.), Kolkata, India
| | - Sourina Pal
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research (I.P.G.M.E. & R.), Kolkata, India
| | - Ayana Baidya
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research (I.P.G.M.E. & R.), Kolkata, India
| | - Debasree Bishnu
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research (I.P.G.M.E. & R.), Kolkata, India
| | - Priyanka Banerjee
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research (I.P.G.M.E. & R.), Kolkata, India
| | - Amal Kumar Santra
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research (I.P.G.M.E. & R.), Kolkata, India
| | - Gopal Krishna Dhali
- Department of Gastroenterology, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research (I.P.G.M.E. & R.), Kolkata, India
| | - Soma Banerjee
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research (I.P.G.M.E. & R.), Kolkata, India
| | - Abhijit Chowdhury
- Department of Hepatology, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research (I.P.G.M.E. & R.), Kolkata, India
| | - Simanti Datta
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research (I.P.G.M.E. & R.), Kolkata, India.
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Heath RD, Tahan V. Natural History of Hepatitis B Virus. VIRAL HEPATITIS: CHRONIC HEPATITIS B 2018:1-10. [DOI: 10.1007/978-3-319-93449-5_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Nwe Win N, Nakamoto S, Myint Sein M, Moriyama M, Kanda T, Shirasawa H. Hepatitis B Virus Genotype C is Predominant in Myanmar. Diseases 2017; 6:diseases6010003. [PMID: 29278399 PMCID: PMC5871949 DOI: 10.3390/diseases6010003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Revised: 12/23/2017] [Accepted: 12/25/2017] [Indexed: 12/12/2022] Open
Abstract
Myanmar is adjacent to India, Bangladesh, Thailand, Laos and China. In Myanmar, the prevalence of hepatitis B virus (HBV) infections is 6.5% and accounts for 60% of hepatocellular carcinoma. HBV has nine genotypes that have been identified by molecular genetic analysis. HBV genotypes are associated with several clinical features. We reviewed the prevalence of HBV genotypes in Myanmar and neighboring countries. We also reviewed HBV genotypes in refugees from Myanmar. HBV subgenotype C1 is predominant in Myanmar. As HBV genotype C is associated with hepatocellular carcinoma (HCC), it is important to screen for cirrhosis and HCC and to prevent their development in HBV-infected individuals of Myanmar.
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Affiliation(s)
- Nan Nwe Win
- Department of Molecular Virology, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba 260-8677, Japan.
| | - Shingo Nakamoto
- Department of Molecular Virology, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba 260-8677, Japan.
| | - Myint Myint Sein
- Department of Molecular Virology, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba 260-8677, Japan.
| | - Mitsuhiko Moriyama
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo 173-8610, Japan.
| | - Tatsuo Kanda
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo 173-8610, Japan.
| | - Hiroshi Shirasawa
- Department of Molecular Virology, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba 260-8677, Japan.
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Rajoriya N, Combet C, Zoulim F, Janssen HLA. How viral genetic variants and genotypes influence disease and treatment outcome of chronic hepatitis B. Time for an individualised approach? J Hepatol 2017; 67:1281-1297. [PMID: 28736138 DOI: 10.1016/j.jhep.2017.07.011] [Citation(s) in RCA: 106] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2017] [Revised: 06/27/2017] [Accepted: 07/12/2017] [Indexed: 12/12/2022]
Abstract
Chronic hepatitis B virus (HBV) infection remains a global problem. Several HBV genotypes exist with different biology and geographical prevalence. Whilst the future aim of HBV treatment remains viral eradication, current treatment strategies aim to suppress the virus and prevent the progression of liver disease. Current strategies also involve identification of patients for treatment, namely those at risk of progressive liver disease. Identification of HBV genotype, HBV mutants and other predictive factors allow for tailoured treatments, and risk-surveillance pathways, such as hepatocellular cancer screening. In the future, these factors may enable stratification not only of treatment decisions, but also of patients at risk of higher relapse rates when current therapies are discontinued. Newer technologies, such as next-generation sequencing, to assess drug-resistant or immune escape variants and quasi-species heterogeneity in patients, may allow for more information-based treatment decisions between the clinician and the patient. This article serves to discuss how HBV genotypes and genetic variants impact not only upon the disease course and outcomes, but also current treatment strategies. Adopting a personalised genotypic approach may play a role in future strategies to combat the disease. Herein, we discuss new technologies that may allow more informed decision-making for response guided therapy in the battle against HBV.
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Affiliation(s)
- Neil Rajoriya
- Toronto Centre for Liver Diseases, Toronto General Hospital, 200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada
| | - Christophe Combet
- Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de recherche en cancérologie de Lyon, Lyon 69XXX, France
| | - Fabien Zoulim
- Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de recherche en cancérologie de Lyon, Lyon 69XXX, France; Department of Hepatology, Groupement Hospitalier Nord, Hospices Civils de Lyon, Lyon, France
| | - Harry L A Janssen
- Toronto Centre for Liver Diseases, Toronto General Hospital, 200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada.
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35
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Gao S, Joshi SS, Osiowy C, Chen Y, Coffin CS, Duan ZP. Chronic hepatitis B carriers with acute on chronic liver failure show increased HBV surface gene mutations, including immune escape variants. Virol J 2017; 14:203. [PMID: 29065883 PMCID: PMC5655973 DOI: 10.1186/s12985-017-0870-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Accepted: 10/13/2017] [Indexed: 02/07/2023] Open
Abstract
Background The pathogenesis of acute-on-chronic liver failure (ACLF) in chronic hepatitis B (CHB) is not well understood. The aim of this study was to investigate whether there is an association between HBV polymerase (P)/overlapping surface (S) gene and basal core promoter (BCP)/precore (PC) variants and development of ACLF in CHB. Methods Two CHB patient cohorts were compared: (i) ACLF (N = 12) (11/12 M, median age 52 yrs., 5/9 genotype C, 6/12 HBeAg+), (ii) 27 treatment native CHB carriers (15/27 M, median age 44 yrs., 9 genotype B, 10 genotype C, 1 genotype A, 5 genotype D, 2 genotype E). Clonal sequencing of PCR-amplified HBV P/S and BCP/PC gene fragments was done and HBV diversity, frequency of immune escape (IE) and drug resistance (DR) mutations and mutations in BCP/PC gene (G1896A and A1762T/G1764A), were compared between each group. Results Our data showed the incidence of IE and clusters of mutations in the HBV S region was significantly greater in ACLF patients vs. treatment naïve CHB patients (p < 0.05). Additionally, a significantly higher frequency of G1896A and A1762T/G1764A mutations were found in HBeAg negative than in ACLF patients (p < 0.0001). Conclusion In our study, ACLF was not associated with a specific genomic mutation. However, higher frequency of IE mutations along with various mutations clustering in the HBV S region could contribute to or be an outcome of ACLF in CHB infection. (words 226). Electronic supplementary material The online version of this article (10.1186/s12985-017-0870-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Shan Gao
- Artificial Liver Center, Beijing Youan Hospital, Capital Medical University, 8 Xitoutiao, Youwai Street, Beijing, 100069, China.,Calgary Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary 6D21, Teaching, Research and Wellness Building, 3280 Hospital Drive N.W, Calgary, AB, T2N 4Z6, Canada.,Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Shivali S Joshi
- Calgary Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary 6D21, Teaching, Research and Wellness Building, 3280 Hospital Drive N.W, Calgary, AB, T2N 4Z6, Canada.,Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Carla Osiowy
- Bloodborne Pathogens and Hepatitis Laboratory of the National Microbiology Laboratory, Winnipeg, MB, Canada
| | - Y Chen
- Artificial Liver Center, Beijing Youan Hospital, Capital Medical University, 8 Xitoutiao, Youwai Street, Beijing, 100069, China
| | - Carla S Coffin
- Calgary Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary 6D21, Teaching, Research and Wellness Building, 3280 Hospital Drive N.W, Calgary, AB, T2N 4Z6, Canada. .,Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
| | - Z-P Duan
- Artificial Liver Center, Beijing Youan Hospital, Capital Medical University, 8 Xitoutiao, Youwai Street, Beijing, 100069, China.
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Liu T, Wang F, Zhang S, Wang F, Meng Q, Zhang G, Cui F, Dunzhu D, Yin W, Bi S, Shen L. Whole-gene analysis of two groups of hepatitis B virus C/D inter-genotype recombinant strains isolated in Tibet, China. PLoS One 2017; 12:e0179846. [PMID: 28654691 PMCID: PMC5487078 DOI: 10.1371/journal.pone.0179846] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2016] [Accepted: 06/05/2017] [Indexed: 12/21/2022] Open
Abstract
Tibet is a highly hepatitis B virus (HBV) endemic area. Two types of C/D recombinant HBV are commonly isolated in Tibet and have been previously described. In an effort to better understand the molecular characteristic of these C/D recombinant strains from Tibet, we undertook a multistage random sampling project to collect HBsAg positive samples. Molecular epidemiological and bio-informational technologies were used to analyze the characteristics of the sequences found in this study. There were 60 samples enrolled in the survey, and we obtained 19 whole-genome sequences. 19 samples were all C/D recombinant, and could be divided into two sub-types named C/D1 and C/D2 according to the differences in the location of the recombinant breakpoint. The recombination breakpoint of the 10 strains belonging to the C/D1 sub-type was located at nt750, while the 9 stains belonging to C/D2 had their recombination break point at nt1530. According to whole-genome sequence analysis, the 19 identified strains belong to genotype C, but the nucleotide distance was more than 5% between the 19 strains and sub-genotypes C1 to C15. The distance between C/D1with C2 was 5.8±2.1%, while the distance between C/D2 with C2 was 6.4±2.1%. The parental strain was most likely sub-genotype C2. C/D1 strains were all collected in the middle and northern areas of Tibet including Lhasa, Linzhi and Ali, while C/D2 was predominant in Shannan in southern Tibet. This indicates that the two recombinant genotypes are regionally distributed in Tibet. These results provide important information for the study of special HBV recombination events, gene features, virus evolution, and the control and prevention policy of HBV in Tibet.
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Affiliation(s)
- Tiezhu Liu
- National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Fuzhen Wang
- National Immunization Program, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Shuang Zhang
- National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Feng Wang
- National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Qingling Meng
- National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Guomin Zhang
- National Immunization Program, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Fuqiang Cui
- National Immunization Program, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Dorji Dunzhu
- Tibetan Center for Disease Control and Prevention, Lhasa, Tibet, China
| | - Wenjiao Yin
- National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Shengli Bi
- National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Liping Shen
- National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
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Xu W, Yu J, Wong VWS. Mechanism and prediction of HCC development in HBV infection. Best Pract Res Clin Gastroenterol 2017; 31:291-298. [PMID: 28774411 DOI: 10.1016/j.bpg.2017.04.011] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Accepted: 04/28/2017] [Indexed: 02/07/2023]
Abstract
Chronic hepatitis B virus (HBV) infection remains one of the leading causes of hepatocellular carcinoma (HCC) globally. Over the past few decades, the risk factors of HCC in patients with chronic hepatitis B have been well characterized, and can be divided into host and viral factors. A few groups have also derived and validated HCC prediction scores based on these risk factors. In general, the scores have high negative predictive value in identifying a low risk group who may not need HCC surveillance in the next 3-5 years. The scores have been tested originally in Asian patients, and results on their performance in the Caucasian population are conflicting. Furthermore, new research has identified genetic factors and new virological markers (e.g. hepatitis B surface antigen and core-related antigen levels) for HCC, but they are yet to be applied in routine clinical practice.
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Affiliation(s)
- Weiqi Xu
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
| | - Jun Yu
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong; Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong
| | - Vincent Wai-Sun Wong
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong; Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong.
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38
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Kim EJ, Yeon JE, Kwon OS, Lee HN, Shin SK, Kang SH, Byun KS, Kim JH, Kwon SY, Suh SJ, Yim HJ, Kim YS, Kim JH. Rapid Alanine Aminotransferase Normalization with Entecavir and Hepatocellular Carcinoma in Hepatitis B Virus-Associated Cirrhosis. Dig Dis Sci 2017; 62:808-816. [PMID: 28035553 DOI: 10.1007/s10620-016-4431-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Accepted: 12/20/2016] [Indexed: 12/23/2022]
Abstract
BACKGROUND Sustained abnormal serum alanine aminotransferase (ALT) levels can increase the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B. AIM This study is aimed to confirm the impact of rapid ALT normalization (≤30 IU/L) on HCC risk in patients with hepatitis B virus (HBV)-associated cirrhosis after entecavir (ETV) commencement. METHODS A total of 578 treatment-naïve patients with HBV-associated cirrhosis (mean age 51 ± 9 years, male sex 63.3%) were treated with ETV for more than 1 year. Serum ALT and HBV DNA levels were measured at three time points (baseline, 6, and 12 months after ETV commencement) and subjected to risk factor analysis. RESULTS Median follow-up after ETV commencement was 43 (12-98) months. Cumulative incidences of HCC at 1, 3, 5, and 7 years were 0.3, 8.5, 19.5, and 30.6%, respectively. Univariate Cox regression analysis showed that older age, abnormal ALT at 6 months or 12 months, and lower platelet count were significant risk factors for HCC. However, gender, HBeAg positivity, abnormal ALT levels or HBV DNA levels at baseline, and detectable HBV DNA at 6 or 12 months were not risk factors. Multivariate analysis showed that older age (P < 0.001), abnormal ALT at 12 months (P = 0.006), and lower platelet count (P = 0.034) were the risk factors for HCC. CONCLUSIONS Abnormal serum ALT levels after ETV commencement are significant risk factor for HCC. Therefore, ALT should be rapidly normalized to minimize the risk of HCC development in patients with HBV-associated cirrhosis.
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Affiliation(s)
- Eui Joo Kim
- Division of Gastroenterology, Department of Internal Medicine, Gachon University Gil Medical Center, 21, Namdong-daero 774 beon-gil, Namdong-gu, Incheon, 21565, South Korea
| | - Jong Eun Yeon
- Department of Internal Medicine, Korea University Medical College, Korea University Guro Hospital, 97 Gurodong-gil, Guro-gu, Seoul, 08308, South Korea
| | - Oh Sang Kwon
- Division of Gastroenterology, Department of Internal Medicine, Gachon University Gil Medical Center, 21, Namdong-daero 774 beon-gil, Namdong-gu, Incheon, 21565, South Korea.
| | - Heon Nam Lee
- Division of Gastroenterology, Department of Internal Medicine, Gachon University Gil Medical Center, 21, Namdong-daero 774 beon-gil, Namdong-gu, Incheon, 21565, South Korea
| | - Seung Kak Shin
- Division of Gastroenterology, Department of Internal Medicine, Gachon University Gil Medical Center, 21, Namdong-daero 774 beon-gil, Namdong-gu, Incheon, 21565, South Korea
| | - Seong Hee Kang
- Department of Internal Medicine, Korea University Medical College, Korea University Guro Hospital, 97 Gurodong-gil, Guro-gu, Seoul, 08308, South Korea
| | - Kwan Soo Byun
- Department of Internal Medicine, Korea University Medical College, Korea University Guro Hospital, 97 Gurodong-gil, Guro-gu, Seoul, 08308, South Korea
| | - Jeong Han Kim
- Department of Internal Medicine, Konkuk University School of Medicine, Konkuk University Medical Center, 120-1 Neungdong-ro, Hwayang-dong, Gwangjin-gu, Seoul, 05030, South Korea
| | - So Young Kwon
- Department of Internal Medicine, Konkuk University School of Medicine, Konkuk University Medical Center, 120-1 Neungdong-ro, Hwayang-dong, Gwangjin-gu, Seoul, 05030, South Korea
| | - Sang Jun Suh
- Department of Internal Medicine, Korea University Medical College, Korea University Ansan Hospital, 123 Jeokgeum-ro, Danwon-Gu, Ansan-Si, Gyeonggi-Do, 15355, South Korea
| | - Hyung Joon Yim
- Department of Internal Medicine, Korea University Medical College, Korea University Ansan Hospital, 123 Jeokgeum-ro, Danwon-Gu, Ansan-Si, Gyeonggi-Do, 15355, South Korea
| | - Yun Soo Kim
- Division of Gastroenterology, Department of Internal Medicine, Gachon University Gil Medical Center, 21, Namdong-daero 774 beon-gil, Namdong-gu, Incheon, 21565, South Korea
| | - Ju Hyun Kim
- Division of Gastroenterology, Department of Internal Medicine, Gachon University Gil Medical Center, 21, Namdong-daero 774 beon-gil, Namdong-gu, Incheon, 21565, South Korea
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Golsaz-Shirazi F, Shokri F. Hepatitis B immunopathogenesis and immunotherapy. Immunotherapy 2016; 8:461-77. [PMID: 26973127 DOI: 10.2217/imt.16.3] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Worldwide there are over 248 million chronic carriers of HBV of whom about a third eventually develop severe HBV-related complications. Due to the major limitations of current therapeutic approaches, the development of more effective strategies to improve therapeutic outcomes in chronic hepatitis B (CHB) patients seems crucial. Immune activation plays a critical role in spontaneous viral control; therefore, new modalities based on stimulation of the innate and adaptive immune responses could result in the resolution of infection and are promising approaches. Here, we summarize the HBV immunopathogenesis, and discuss the encouraging results obtained from the promising immune-based innovations, such as therapeutic vaccination, cytokine therapy, cell-based therapies and blocking inhibitory receptors, as current and future immunotherapeutic interventions.
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Affiliation(s)
- Forough Golsaz-Shirazi
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Fazel Shokri
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.,Monoclonal Antibody Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
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40
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Tajiri H, Takano T, Tanaka H, Ushijima K, Inui A, Miyoshi Y, Ozono K, Abukawa D, Endo T, Brooks S, Tanaka Y. Hepatocellular carcinoma in children and young patients with chronic HBV infection and the usefulness of alpha-fetoprotein assessment. Cancer Med 2016; 5:3102-3110. [PMID: 27748053 PMCID: PMC5119965 DOI: 10.1002/cam4.917] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Revised: 08/13/2016] [Accepted: 08/18/2016] [Indexed: 12/18/2022] Open
Abstract
The aims of the study were to elucidate the clinical characteristics of patients who developed hepatocellular carcinoma (HCC) related to persistent HBV infection since childhood and to investigate usefulness of assessing alpha‐fetoprotein (AFP) in this population. A nationwide multicenter survey of children with chronic HBV infection was performed. Among 548 patients, 15 patients developed HCC at the median age of 15 years (range 9–36), including 13 males and 2 females. A case–control comparison showed that HBeAg seroconversion and liver cirrhosis were associated with the occurrence of HCC. Of the 15 HCC patients, 5 were treated with interferon and none of them responded to interferon therapy as compared with 12 of the 17 responders in the control group. Of the 15 patients, 10 died and 9 of the 10 who died never visited any medical facilities until diagnosis of HCC, while the remaining 5 surviving patients never stopped their clinic visits. The usefulness of AFP assessment was shown by the findings that AFP levels were elevated in all HCC cases, that elevations in AFP levels were detected prior to the diagnosis in the surviving patients, and that sensitivity of AFP as a diagnostic test for HCC was very high among 40 patients including our 14 and an additional 26 collected from the literature. HBeAg seroconversion and liver cirrhosis are associated with the occurrence of HCC. Regular measurement of AFP might be helpful to watch for the occurrence of HCC when following children and young patients with chronic HBV infection since childhood
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Affiliation(s)
- Hitoshi Tajiri
- Department of Pediatrics, Osaka General Medical Center, Osaka, Japan
| | - Tomoko Takano
- Department of Pediatrics, Osaka General Medical Center, Osaka, Japan
| | - Hideo Tanaka
- Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan
| | - Kosuke Ushijima
- Department of Pediatrics, Kurume University Medical Center, Kurume, Japan
| | - Ayano Inui
- Department of Pediatric Hepatology and Gastroenterology, Saiseikai Yokohama City Tobu Hospital, Yokohama, Japan
| | - Yoko Miyoshi
- Department of Pediatrics, Osaka University Hospital, Suita, Japan
| | - Keiichi Ozono
- Department of Pediatrics, Osaka University Hospital, Suita, Japan
| | - Daiki Abukawa
- Department of Pediatrics, Miyagi Children's Hospital, Sendai, Japan
| | - Takeshi Endo
- Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Stephen Brooks
- Department of Microbiology/Immunology, State University of New York at Buffalo, New York
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
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Mahmood M, Anwar MA, Khanum A, Zaman N, Raza A. Distribution and clinical significance of hepatitis B virus genotypes in Pakistan. BMC Gastroenterol 2016; 16:104. [PMID: 27565427 PMCID: PMC5002161 DOI: 10.1186/s12876-016-0513-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Accepted: 08/03/2016] [Indexed: 02/07/2023] Open
Abstract
Background Hepatitis B virus (HBV) genotype and its role in disease progression and patients’ response to antiviral treatment, is not well studied in Pakistan. This comprehensive study was aimed to determine the distribution of HBV genotypes in Pakistan and their possible association with phases of HBV infection. Methods A total of 840 HBsAg positive samples was collected and tested for HBV DNA quantity. Samples below 100 IU/ml were excluded from the study. A total of 715 samples representing all the six parts of the country were genotyped by type specific primer PCR method. Clinical data of only 384 patients was compared as the remaining 332 were either receiving antiviral treatment or their infection phase was not confirmed. Results Genotype D was found in 509 samples (71.2 %), genotype A in 55 samples (7.7 %) and mixed infection with genotypes A and D in 124 samples (17.3 %). Genotypes B, C and E were identified in less than 1 % of the total samples. Genotype A, D and their mixture (A + D) were compared for severity of HBV infection. Significant differences were not found in distribution of HBV genotypes among different disease stages. Conclusion HBV genotype D was the predominant infection in all study areas of Pakistan followed by mixed genotypes infection (A + D) whereas genotype A has 10 times lower prevalence than genotype D. Genotypes B, C, E and F altogether make only 1.5 % of the prevalence. Genotype do not appears to show the severity of liver disease.
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Affiliation(s)
- Majid Mahmood
- Department of Zoology, The University of Poonch, Rawalakot, Azad Jammu and Kashmir, 12350, Pakistan. .,Department of Zoology, Pir Mehr Ali Shah Arid Agriculture University, Rawalpindi, 46300, Pakistan.
| | - Muhammad Asim Anwar
- Department of General Medicine, Pakistan Atomic Energy Commission (PAEC) General Hospital, Islamabad, 44000, Pakistan
| | - Azra Khanum
- Barani Institute of Management Sciences (BIMS), Rawalpindi, 46300, Pakistan
| | - Nasib Zaman
- Center for Biotechnology & Microbiology, University of Swat, Swat, 19130, Pakistan
| | - Abida Raza
- Diagnostic Department, Nuclear Medicine, Oncology and Radiotherapy Institute (NORI), Islamabad, 44000, Pakistan
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Qin Y, Zhou X, Jia H, Chen C, Zhao W, Zhang J, Tong S. Stronger enhancer II/core promoter activities of hepatitis B virus isolates of B2 subgenotype than those of C2 subgenotype. Sci Rep 2016; 6:30374. [PMID: 27461034 PMCID: PMC4961966 DOI: 10.1038/srep30374] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Accepted: 07/04/2016] [Indexed: 12/14/2022] Open
Abstract
Hepatitis B virus (HBV) genotype C causes prolonged chronic infection and increased risk for liver cancer than genotype B. Our previous work revealed lower replication capacity of wild-type genotype C2 than B2 isolates. HBV DNA replication is driven by pregenomic RNA, which is controlled by core promoter (CP) and further augmented by enhancer I (ENI) and enhancer II (ENII). DNA fragments covering these regulatory elements were amplified from B2 and C2 isolates to generate luciferase reporter constructs. As ENII is fully embedded in CP, we inserted HBV DNA fragments in the sense orientation to determine their combined activities, and in the antisense orientation to measure enhancer activities alone. Genotype B2 isolates displayed higher ENI+ENII+CP, ENII+CP, and ENII activities, but not ENI or ENI+ENII activity, than C2 isolates. The higher ENII+CP activity was partly attributable to 4 positions displaying genotype-specific variability. Exchanging CP region was sufficient to revert the replication phenotypes of several B2 and C2 clones tested. These results suggest that a weaker ENII and/or CP at least partly accounts for the lower replication capacities of wild-type C2 isolates, which could drive the subsequent acquisition of CP mutations. Such mutations increase genome replication and are implicated in liver cancer development.
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Affiliation(s)
- Yanli Qin
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Xueshi Zhou
- Department of Infectious Diseases, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Haodi Jia
- Key Lab of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Chaoyang Chen
- Key Lab of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Weifeng Zhao
- Department of Infectious Diseases, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Jiming Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Shuping Tong
- Key Lab of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University, Shanghai, China.,The Liver Research Center, Rhode Island Hospital, Warren Alpert School of Medicine, Brown University, Providence, RI, USA
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Ingle PV, Samsudin SZ, Chan PQ, Ng MK, Heng LX, Yap SC, Chai ASH, Wong ASY. Development and novel therapeutics in hepatocellular carcinoma: a review. Ther Clin Risk Manag 2016; 12:445-55. [PMID: 27042086 PMCID: PMC4801152 DOI: 10.2147/tcrm.s92377] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
This review summarizes the epidemiological trend, risk factors, prevention strategies such as vaccination, staging, current novel therapeutics, including the drugs under clinical trials, and future therapeutic trends for hepatocellular carcinoma (HCC). As HCC is the third most common cause of cancer-related death worldwide, its overall incidence remains alarmingly high in the developing world and is steadily rising across most of the developed and developing world. Over the past 15 years, the incidence of HCC has more than doubled and it increases with advancing age. Chronic infection with hepatitis B virus is the leading cause of HCC, closely followed by infection with hepatitis C virus. Other factors contributing to the development of HCC include alcohol abuse, tobacco smoking, and metabolic syndrome (including obesity, diabetes, and fatty liver disease). Treatment options have improved in the past few years, particularly with the approval of several molecular-targeted therapies. The researchers are actively pursuing novel therapeutic targets as well as predictive biomarker for treatment of HCC. Advances are being made in understanding the mechanisms underlying HCC, which in turn could lead to novel therapeutics. Nevertheless, there are many emerging agents still under clinical trials and yet to show promising results. Hence, future therapeutic options may include different combination of novel therapeutic interventions.
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Affiliation(s)
| | - Sarah Zakiah Samsudin
- Department of Pharmacy Practice, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia
| | - Pei Qi Chan
- Department of Pharmacy Practice, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia
| | - Mei Kei Ng
- Department of Pharmacy Practice, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia
| | - Li Xuan Heng
- Department of Pharmacy Practice, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia
| | - Siu Ching Yap
- Department of Pharmacy Practice, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia
| | - Amy Siaw Hui Chai
- Department of Pharmacy Practice, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia
| | - Audrey San Ying Wong
- Department of Pharmacy Practice, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia
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El Hadad S, Alakilli S, Rabah S, Sabir J. Sequence analysis of sub-genotype D hepatitis B surface antigens isolated from Jeddah, Saudi Arabia. Saudi J Biol Sci 2016; 25:838-847. [PMID: 29740253 PMCID: PMC5936882 DOI: 10.1016/j.sjbs.2016.03.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2015] [Revised: 02/16/2016] [Accepted: 03/05/2016] [Indexed: 12/20/2022] Open
Abstract
Little is known about the prevalence of HBV genotypes/sub-genotypes in Jeddah province, although the hepatitis B virus (HBV) was identified as the most predominant type of hepatitis in Saudi Arabia. To characterize HBV genotypes/sub-genotypes, serum samples from 15 patients with chronic HBV were collected and subjected to HBsAg gene amplification and sequence analysis. Phylogenetic analysis of the HBsAg gene sequences revealed that 11 (48%) isolates belonged to HBV/D while 4 (18%) were associated with HBV/C. Notably, a HBV/D sub-genotype phylogenetic tree identified that eight current isolates (72%) belonged to HBV/D1, whereas three isolates (28%) appeared to be more closely related to HBV/D5, although they formed a novel cluster supported by a branch with 99% bootstrap value. Isolates belonging to D1 were grouped in one branch and seemed to be more closely related to various strains isolated from different countries. For further determination of whether the three current isolates belonged to HBV/D5 or represented a novel sub-genotype, HBV/DA, whole HBV genome sequences would be required. In the present study, we verified that HBV/D1 is the most prevalent HBV sub-genotype in Jeddah, and identified novel variant mutations suggesting that an additional sub-genotype designated HBV/DA should be proposed. Overall, the results of the present HBsAg sequence analyses provide us with insights regarding the nucleotide differences between the present HBsAg/D isolates identified in the populace of Jeddah, Saudi Arabia and those previously isolated worldwide. Additional studies with large numbers of subjects in other areas might lead to the discovery of the specific HBV strain genotypes or even additional new sub-genotypes that are circulating in Saudi Arabia.
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Key Words
- C/pre C, HBV core/pre Core gene
- DDBJ, DNA Data Bank of Japan
- EMBL, European Molecular Biology Laboratory
- HAV, hepatitis A virus
- HBV sub-genotypes
- HBV, hepatitis B virus
- HBV/D
- HBsAg
- HBsAg, HBV surface antigen
- HCC, hepatocellular carcinoma
- HCV, hepatitis C virus
- Hepatitis B virus
- IFN, interferon
- P, HBV polymerase gene
- PCR, polymerase chain reaction
- Population studies
- Pre S1/Pre S2/S, HBsAg genes
- Viral isolates
- X, HBV X gene
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Affiliation(s)
- Sahar El Hadad
- Department of Biological Science, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Saleha Alakilli
- Department of Biological Science, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Samar Rabah
- Department of Biological Science, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Jamal Sabir
- Department of Biological Science, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
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Sukowati CHC, El-Khobar KE, Ie SI, Anfuso B, Muljono DH, Tiribelli C. Significance of hepatitis virus infection in the oncogenic initiation of hepatocellular carcinoma. World J Gastroenterol 2016; 22:1497-1512. [PMID: 26819517 PMCID: PMC4721983 DOI: 10.3748/wjg.v22.i4.1497] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Revised: 08/06/2015] [Accepted: 10/13/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide. Chronic infection of hepatitis B virus (HBV) and/or hepatitis C virus (HCV) is a major risk factor in the development of the HCC, independently from excessive alcohol abuse and metabolic disease. Since the biology of HBV and HCV is different, their oncogenic effect may go through different mechanisms, direct and/or indirect. Viral hepatitis infection is associated with cellular inflammation, oxidative stress, and DNA damage, that may lead to subsequent hepatic injuries such as chronic hepatitis, fibrosis, cirrhosis, and finally HCC. Direct oncogenic properties of these viruses are related with their genotypic characteristics and the ability of viral proteins to interact with host proteins, thus altering the molecular pathways balance of the cells. In addition, the integration of HBV DNA, especially the gene S and X, in a particular site of the host genome can disrupt chromosomal stability and may activate various oncogenic mechanisms, including those in hematopoietic cells. Recently, several studies also had demonstrated that viral hepatitis could trigger the population of hepatic cancer stem cells. This review summarize available pre-clinical and clinical data in literature regarding oncogenic properties of HBV and HCV in the early initiation of HCC.
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MESH Headings
- Animals
- Carcinoma, Hepatocellular/epidemiology
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Cell Transformation, Viral
- Gene Expression Regulation, Neoplastic
- Gene Expression Regulation, Viral
- Genotype
- Hepacivirus/genetics
- Hepacivirus/pathogenicity
- Hepatitis B virus/genetics
- Hepatitis B virus/pathogenicity
- Hepatitis B, Chronic/complications
- Hepatitis B, Chronic/virology
- Hepatitis C, Chronic/complications
- Hepatitis C, Chronic/virology
- Host-Pathogen Interactions
- Humans
- Liver Neoplasms/epidemiology
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Liver Neoplasms/virology
- Neoplastic Stem Cells/metabolism
- Neoplastic Stem Cells/pathology
- Neoplastic Stem Cells/virology
- Oncogenes
- Risk Factors
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48
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Zhang ZH, Wu CC, Chen XW, Li X, Li J, Lu MJ. Genetic variation of hepatitis B virus and its significance for pathogenesis. World J Gastroenterol 2016; 22:126-144. [PMID: 26755865 PMCID: PMC4698480 DOI: 10.3748/wjg.v22.i1.126] [Citation(s) in RCA: 76] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2015] [Accepted: 11/13/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) has a worldwide distribution and is endemic in many populations. Due to its unique life cycle which requires an error-prone reverse transcriptase for replication, it constantly evolves, resulting in tremendous genetic variation in the form of genotypes, sub-genotypes, and mutations. In recent years, there has been considerable research on the relationship between HBV genetic variation and HBV-related pathogenesis, which has profound implications in the natural history of HBV infection, viral detection, immune prevention, drug treatment and prognosis. In this review, we attempted to provide a brief account of the influence of HBV genotype on the pathogenesis of HBV infection and summarize our current knowledge on the effects of HBV mutations in different regions on HBV-associated pathogenesis, with an emphasis on mutations in the preS/S proteins in immune evasion, occult HBV infection and hepatocellular carcinoma (HCC), mutations in polymerase in relation to drug resistance, mutations in HBV core and e antigen in immune evasion, chronicalization of infection and hepatitis B-related acute-on-chronic liver failure, and finally mutations in HBV x proteins in HCC.
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49
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Sarin SK, Kumar M, Lau GK, Abbas Z, Chan HLY, Chen CJ, Chen DS, Chen HL, Chen PJ, Chien RN, Dokmeci AK, Gane E, Hou JL, Jafri W, Jia J, Kim JH, Lai CL, Lee HC, Lim SG, Liu CJ, Locarnini S, Al Mahtab M, Mohamed R, Omata M, Park J, Piratvisuth T, Sharma BC, Sollano J, Wang FS, Wei L, Yuen MF, Zheng SS, Kao JH. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int 2016; 10:1-98. [PMID: 26563120 PMCID: PMC4722087 DOI: 10.1007/s12072-015-9675-4] [Citation(s) in RCA: 1883] [Impact Index Per Article: 209.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Accepted: 09/14/2015] [Indexed: 02/06/2023]
Abstract
Worldwide, some 240 million people have chronic hepatitis B virus (HBV), with the highest rates of infection in Africa and Asia. Our understanding of the natural history of HBV infection and the potential for therapy of the resultant disease is continuously improving. New data have become available since the previous APASL guidelines for management of HBV infection were published in 2012. The objective of this manuscript is to update the recommendations for the optimal management of chronic HBV infection. The 2015 guidelines were developed by a panel of Asian experts chosen by the APASL. The clinical practice guidelines are based on evidence from existing publications or, if evidence was unavailable, on the experts' personal experience and opinion after deliberations. Manuscripts and abstracts of important meetings published through January 2015 have been evaluated. This guideline covers the full spectrum of care of patients infected with hepatitis B, including new terminology, natural history, screening, vaccination, counseling, diagnosis, assessment of the stage of liver disease, the indications, timing, choice and duration of single or combination of antiviral drugs, screening for HCC, management in special situations like childhood, pregnancy, coinfections, renal impairment and pre- and post-liver transplant, and policy guidelines. However, areas of uncertainty still exist, and clinicians, patients, and public health authorities must therefore continue to make choices on the basis of the evolving evidence. The final clinical practice guidelines and recommendations are presented here, along with the relevant background information.
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Affiliation(s)
- S K Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India.
| | - M Kumar
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - G K Lau
- Division of Gastroenterology and Hepatology, Humanity and Health Medical Centre, Hong Kong SAR, China
- The Institute of Translational Hepatology, Beijing, China
| | - Z Abbas
- Department of Hepatogastroenterlogy, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
| | - H L Y Chan
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
| | - C J Chen
- Genomics Research Center, Academia Sinica, National Taiwan University, Taipei, Taiwan
| | - D S Chen
- Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - H L Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - P J Chen
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - R N Chien
- Liver Research Unit, Chang Gung Memorial Hospital and University, Chilung, Taiwan
| | - A K Dokmeci
- Department of Gastroenterology, Ankara University School of Medicine, Ankara, Turkey
| | - Ed Gane
- New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand
| | - J L Hou
- Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Guangzhou, China
| | - W Jafri
- Department of Medicine, Aga Khan University, Karachi, Pakistan
| | - J Jia
- Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | | | - C L Lai
- Department of Medicine, University of Hong Kong, Hong Kong, China
| | - H C Lee
- Internal Medicine Asan Medical Center, Seoul, Korea
| | - S G Lim
- Division of Gastroenterology and Hepatology, National University Health System, Singapore, Singapore
| | - C J Liu
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - S Locarnini
- Research and Molecular Development, Victorian Infectious Diseases Reference Laboratory, Melbourne, Australia
| | - M Al Mahtab
- Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - R Mohamed
- Department of Medicine, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia
| | - M Omata
- Yamanashi Hospitals (Central and Kita) Organization, 1-1-1 Fujimi, Kofu-shi, Yamanashi, 400-8506, Japan
| | - J Park
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - T Piratvisuth
- NKC Institute of Gastroenterology and Hepatology, Prince of Songkla University, Songkhla, Thailand
| | - B C Sharma
- Department of Gastroenterology, G.B. Pant Hospital, New Delhi, India
| | - J Sollano
- Department of Medicine, University of Santo Tomas, Manila, Philippines
| | - F S Wang
- Treatment and Research Center for Infectious Diseases, Beijing 302 Hospital, Beijing, China
| | - L Wei
- Peking University Hepatology Institute, Beijing, China
| | - M F Yuen
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Hong Kong, Pofulam, Hong Kong
| | - S S Zheng
- Department of Hepatobiliary and Pancreatic Surgery, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang Province, China
| | - J H Kao
- Graduate Institute of Clinical Medicine and Hepatitis Research Center, National Taiwan University College of Medicine, National Taiwan University Hospital, Taipei, Taiwan
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50
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Wu Q, Xu C, Li J, Li L, Yan G, Yue L, Zeng Y, Huang H, Deng G, Wang Y. Evolution and mutations of hepatitis B virus quasispecies in genotype B and C during vertical transmission. J Med Virol 2015; 88:1018-26. [PMID: 26531675 DOI: 10.1002/jmv.24424] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/02/2015] [Indexed: 12/15/2022]
Abstract
Evolution patterns of HBV QS between genotype B and C during vertical transmission are not well understood. In this study, we enrolled 10 HBV infected mother-infant pairs (four pairs with genotype B, four pairs with genotype C, and two with co-infection) without anti-viral therapy. Serum HBV DNA of mothers and infants were sequenced, HBV QS complexity and diversity were analyzed, polymorphisms and mutation sites were recorded, and phylogenetic trees were performed. Our result showed that the QS complexities in P (amino acid), C/PreC (amino acid), and PreS1 (nucleotide) gene were significantly higher in mothers than in infants in pairs with genotype C (P < 0.05), however, full-length and other genes showed non-significant differences (P > 0.05). Unlike genotype C, QS complexity of P gene (nucleotide) was significantly higher in infants than in mothers (P < 0.05) in pairs with genotype B, similarly, QS complexities of full-length and other genes (except Pre S2) were also higher in infants than in mothers but without significant differences (P > 0.05). QS diversities of full-length and most genes in genotype B were comparable between mothers and their infants (P > 0.05), in pairs with genotype C, dS of P, X, RT genes, genetic distance of Pre S1 gene (amino acid) and dN of Pre S1 gene were significant higher in mothers than in infants (P < 0.05). Several HBV mutations correlated with immune escape, e antigen loss and drug resistance were observed in infants. The results indicated that differences of HBV QS evolution patterns between genotype B and C during vertical transmission might contribute to distinct prognosis.
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Affiliation(s)
- Quanxin Wu
- Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China.,The Chongqing Key Laboratory for Research of Infectious Diseases, Chongqing, China.,Cadre Ward Two, Wuhan General Hospital of Guangzhou Military Command, Wuhan, China
| | - Cheng Xu
- Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China.,The Chongqing Key Laboratory for Research of Infectious Diseases, Chongqing, China
| | - Junnan Li
- Department of Gynecology and Obstetrics, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Li Li
- Department of Gynecology and Obstetrics, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Guohua Yan
- Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China.,The Chongqing Key Laboratory for Research of Infectious Diseases, Chongqing, China
| | - Liangliang Yue
- National Plateau Wetland Research Center, Southwest Forest University, Kunming, China
| | - Yi Zeng
- Department of Gynecology and Obstetrics, The First People's Hospital, Zigong, Sichuan, China
| | - Hongfei Huang
- Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China.,The Chongqing Key Laboratory for Research of Infectious Diseases, Chongqing, China
| | - Guohong Deng
- Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China.,The Chongqing Key Laboratory for Research of Infectious Diseases, Chongqing, China
| | - Yuming Wang
- Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China.,The Chongqing Key Laboratory for Research of Infectious Diseases, Chongqing, China
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