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Li G, Yang D, Liu X, Zhang T, Liu H, Zou J, Xu Z, Chen X, Dai L, Chen H, Lu F. Precore mutation enhances viral replication to facilitate persistent infection especially in HBeAg-negative patients. Virol Sin 2024; 39:319-330. [PMID: 38492851 PMCID: PMC11074699 DOI: 10.1016/j.virs.2024.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Accepted: 03/11/2024] [Indexed: 03/18/2024] Open
Abstract
Naturally occurred precore (PC, G1896A) and/or basal core promoter (BCP, A1762T/G1764A) mutations are prevalent in chronic HBV-infected patients, especially those under HBeAg-negative status. However, the replicative capacity of HBV with PC/BCP mutations remains ambiguous. Herein, meta-analysis showed that, only under HBeAg-negative status, the serum HBV DNA load in patients with PC mutation was 7.41-fold higher than those without the mutation. Both PC mutation alone and BCP + PC mutations promoted HBV replication in cell and hydrodynamic injection mouse models. In human hepatocyte chimeric mouse model, BCP + PC mutations led to elevated replicative capacity and intrahepatic core protein accumulation. Mechanistically, preC RNA harboring PC mutation could serve as mRNA to express core and P proteins, and such pgRNA-like function favored the maintenance of cccDNA pool under HBeAg-negative status. Additionally, BCP + PC mutations induced more extensive and severe human hepatocyte damage as well as activated endoplasmic reticulum stress and TNF signaling pathway in livers of chimeric mice. This study indicates that HBeAg-negative patients should be monitored on HBV mutations regularly and are expected to receive early antiviral treatment to prevent disease progression.
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Affiliation(s)
- Guixin Li
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, 100044, China
| | - Danli Yang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University, Beijing, 100191, China
| | - Xin Liu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University, Beijing, 100191, China
| | - Ting Zhang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University, Beijing, 100191, China
| | - Hui Liu
- Baruch S. Blumberg Institute, Doylestown, PA, 18901, USA
| | - Jun Zou
- Shenzhen Sanyuansheng Biotechnology Co., Ltd, Shenzhen, 518000, China
| | - Zimeng Xu
- Precision Medicine Center of Zhengzhou University, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Xiangmei Chen
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University, Beijing, 100191, China
| | - Lizhong Dai
- Peking University-Sansure Biotech Joint Laboratory of Molecular Medicine, Sansure Biotech Co., Ltd, Changsha, 410205, China.
| | - Hongsong Chen
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, 100044, China.
| | - Fengmin Lu
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, 100044, China; Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University, Beijing, 100191, China.
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Yang HC, Su TH. Viral and Host Factors Affecting Disease Progression of Hepatitis B Virus Infection. HEPATITIS B VIRUS AND LIVER DISEASE 2021:205-230. [DOI: 10.1007/978-981-16-3615-8_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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3
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Manne V, Gochanour E, Kowdley KV. Current perspectives into the evaluation and management of hepatitis B: a review. Hepatobiliary Surg Nutr 2019; 8:361-369. [PMID: 31489305 DOI: 10.21037/hbsn.2019.02.09] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Hepatitis B is a widespread disease which affects millions of people worldwide. Chronic hepatitis B (CHB) can lead to significant morbidity and mortality due to complications such as cirrhosis and hepatocellular carcinoma. The pathophysiology of hepatitis is critical to diagnosing CHB. Deciding which patients with CHB should be treated is an important decision as treatment can often lead to better outcomes in the appropriate patient population. The nucleos(t)ide analog inhibitors entecavir and tenofovir are currently the mainstay of treatment as they are able to successfully suppress the virus and lead to fewer complications. Novel therapies are currently being developed which may offer a potential cure for this disease in the future.
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Affiliation(s)
- Vignan Manne
- Liver Care Network, Swedish Medical Center, Seattle, WA, USA
| | - Eric Gochanour
- Liver Care Network, Swedish Medical Center, Seattle, WA, USA
| | - Kris V Kowdley
- Liver Care Network, Swedish Medical Center, Seattle, WA, USA
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4
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Kramvis A, Kostaki EG, Hatzakis A, Paraskevis D. Immunomodulatory Function of HBeAg Related to Short-Sighted Evolution, Transmissibility, and Clinical Manifestation of Hepatitis B Virus. Front Microbiol 2018; 9:2521. [PMID: 30405578 PMCID: PMC6207641 DOI: 10.3389/fmicb.2018.02521] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Accepted: 10/03/2018] [Indexed: 12/18/2022] Open
Abstract
Hepatitis B virus (HBV) infection, a global public health problem can be asymptomatic, acute or chronic and can lead to serious consequences of infection, including cirrhosis, and hepatocellular carcinoma. HBV, a partially double stranded DNA virus, belongs to the family Hepadnaviridae, and replicates via reverse transcription of an RNA intermediate. This reverse transcription is catalyzed by a virus-encoded polymerase that lacks proof reading ability, which leads to sequence heterogeneity. HBV is classified into nine genotypes and at least 35 subgenotypes, which may be characterized by distinct geographical distributions. This HBV diversification and distinct geographical distribution has been proposed to be the result of the co-expansion of HBV with modern humans, after their out-of-Africa migration. HBeAg is a non-particulate protein of HBV that has immunomodulatory properties as a tolerogen that allows the virus to establish HBV infection in vivo. During the natural course of infection, there is seroconversion from a HBeAg-positive phase to a HBeAg-negative, anti-HBe-positive phase. During this seroconversion, there is loss of tolerance to infection and immune escape-HBeAg-negative mutants can be selected in response to the host immune response. The different genotypes and, in some cases, subgenotypes develop different mutations that can affect HBeAg expression at the transcriptional, translational and post-translational levels. The ability to develop mutations, affecting HBeAg expression, can influence the length of the HBeAg-positive phase, which is important in determining both the mode of transmission and the clinical course of HBV infection. Thus, the different genotypes/subgenotypes have evolved in such a way that they exhibit different modes of transmission and clinical manifestation of infection. Loss of HBeAg may be a sign of short-sighted evolution because there is loss of tolerogenic ability of HBeAg and HBeAg-negative virions are less transmissible. Depending on their ability to lead to HBeAg seroconversion, the genotype/subgenotypes exhibit varying degrees of short-sighted evolution. The “arms race” between HBV and the immune response to HBeAg is multifaceted and its elucidation intricate, with transmissibility and persistence being important for the survival of the virus. We attempt to shed some light on this complex interplay between host and virus.
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Affiliation(s)
- Anna Kramvis
- Hepatitis Virus Diversity Research Unit, Department of Internal Medicine, Faculty of Health Science, University of the Witwatersrand, Johannesburg, South Africa
| | - Evangelia-Georgia Kostaki
- Department of Hygiene, Epidemiology and Medical Statistics, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Angelos Hatzakis
- Department of Hygiene, Epidemiology and Medical Statistics, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Dimitrios Paraskevis
- Department of Hygiene, Epidemiology and Medical Statistics, Medical School, National and Kapodistrian University of Athens, Athens, Greece
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5
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Colombatto P, Barbera C, Bortolotti F, Maina AM, Moriconi F, Cavallone D, Calvo P, Oliveri F, Bonino F, Brunetto MR. HBV pre-core mutant in genotype-D infected children is selected during HBeAg/anti-HBe seroconversion and leads to HBeAg negative chronic hepatitis B in adulthood. J Med Virol 2018; 90:1232-1239. [PMID: 29488227 DOI: 10.1002/jmv.25068] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2017] [Accepted: 02/23/2018] [Indexed: 12/26/2022]
Abstract
Selection of HBeAg defective HBV mutants (mt) during childhood might influence infection outcome in adults. Aim of this study was to correlate the dynamics of pre-core HBV mutant (pre-C mt) selection with virological/clinical outcomes in children followed-up until adulthood. Eighty subjects (50-M/30-F), 70 HBeAg-positive (87.5%), and 10 (12.5%) HBeAg-negative/anti-HBe-positive at the admission, mostly genotype D infected (91.2%), with median age of 6.5 (range: 0.2-17) years, were followed-up for 14.3 years (range: 1.1-24.5); 46 (57.5%) received IFN treatment. HBV-DNA and q-HBsAg were tested by commercial assays, Pre-Core 1896 mt by direct-sequence, oligo-hybridization-assay, and allele-specific-PCR (sensitivity: 30%, 10%, and 0.1% of total viremia). HBeAg/anti-HBe seroconversion (SC) occurred in 55/70 (78.6%) children. After SC, 8 (14.6%) developed HBeAg-negative chronic hepatitis (CHB), 41 (74.5%) remain with HBeAg-negative chronic infection, and 6 (10.9%) lost HBsAg. Baseline HBV-DNA and HBsAg were lower in SC than in no-SC children (median: 7.35 vs 8.95 Log IU/mL, P = 0.005, and 4.72 vs 5.04 Log IU/mL, P = 0.015). The prevalence of pre-C mt increased rapidly (10-40%) around SC. Eventually, pre-C mt was detected in 100% of CHB, in 33% of chronic infections without disease, and in 16% of subjects who cleared HBsAg (P < 0.001). HBV-DNA levels remained slightly higher in carriers of HBeAg negative infection with dominant/mixed pre-C mt populations, than in those with dominant pre-C wt (mean Log IU/mL: 3.83 and 3.42 vs 2.67, P = 0.007). In conclusion, pre-C-mt is selected during HBeAg/anti-HBe SC in children with poor control of HBV replication, leading to HBeAg-negative chronic-active-hepatitis during adulthood.
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Affiliation(s)
- Piero Colombatto
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Centre of the Tuscany Region for Chronic Liver Disease and Cancer, University Hospital of Pisa, Pisa, Italy
| | - Cristiana Barbera
- Paediatric Gastroenterology Unit, Regina Margherita Children Hospital, Torino, Italy
| | | | - Anna M Maina
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Centre of the Tuscany Region for Chronic Liver Disease and Cancer, University Hospital of Pisa, Pisa, Italy
| | - Francesco Moriconi
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Centre of the Tuscany Region for Chronic Liver Disease and Cancer, University Hospital of Pisa, Pisa, Italy
| | - Daniela Cavallone
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Centre of the Tuscany Region for Chronic Liver Disease and Cancer, University Hospital of Pisa, Pisa, Italy
| | - Pierluigi Calvo
- Paediatric Gastroenterology Unit, Regina Margherita Children Hospital, Torino, Italy
| | - Filippo Oliveri
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Centre of the Tuscany Region for Chronic Liver Disease and Cancer, University Hospital of Pisa, Pisa, Italy
| | - Ferruccio Bonino
- University of Pittsburgh Medical Center Institute for Health, Chianciano Terme, Siena, Italy.,Fondazione Italiana Fegato, AREA Science Park, Campus Basovizza, Trieste, Italy
| | - Maurizia R Brunetto
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Centre of the Tuscany Region for Chronic Liver Disease and Cancer, University Hospital of Pisa, Pisa, Italy.,Internal Medicine, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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6
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Yang HC. Viral Factors Affecting Disease Progression. HEPATITIS B VIRUS AND LIVER DISEASE 2018:119-133. [DOI: 10.1007/978-981-10-4843-2_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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7
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Yang HC, Shih YF, Liu CJ. Viral Factors Affecting the Clinical Outcomes of Chronic Hepatitis B. J Infect Dis 2017; 216:S757-S764. [PMID: 29156050 DOI: 10.1093/infdis/jix461] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Chronic hepatitis B (CHB) exhibits a variety of clinical outcomes, ranging from spontaneous resolution of hepatitis B to severe adverse consequences, including the development of cirrhosis, hepatic failure, and hepatocellular carcinoma. The heterogeneous clinical courses of chronic hepatitis B virus (HBV) infection reflect the complex host-virus interactions, and point to the difficulty and necessity of identifying the patients at risk. With the advance of HBV virology, several viral factors have been found to be associated with the long-term clinical outcomes of CHB patients. Different viral factors probe different aspects of CHB. Integration of these viral factors may help to determine the disease state of patients more accurately, and identify the patients who require timely antiviral therapy to prevent the development of detrimental clinical outcomes. In this article, we will introduce the conventional and emerging viral factors that are associated with clinical outcomes and discuss their utility in a clinical setting.
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Affiliation(s)
- Hung-Chih Yang
- Department of Microbiology.,Graduate Institute of Clinical Medicine.,Department of Internal Medicine.,Hepatitis Research Center, National Taiwan University College of Medicine and National Taiwan University Hospital
| | - Yi-Fen Shih
- Department of Physical Therapy and Assistive Technology, National Yang-Ming University, Taipei, Taiwan
| | - Chun-Jen Liu
- Graduate Institute of Clinical Medicine.,Department of Internal Medicine.,Hepatitis Research Center, National Taiwan University College of Medicine and National Taiwan University Hospital
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Jansen L, Welkers MRA, van Dort KA, Takkenberg RB, Lopatin U, Zaaijer HL, de Jong MD, Reesink HW, Kootstra NA. Viral minority variants in the core promoter and precore region identified by deep sequencing are associated with response to peginterferon and adefovir in HBeAg negative chronic hepatitis B patients. Antiviral Res 2017; 145:87-95. [PMID: 28754258 DOI: 10.1016/j.antiviral.2017.07.013] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2017] [Revised: 06/10/2017] [Accepted: 07/24/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Precore (PC) and basal core promoter (BCP) mutations are associated with responses to interferon-based treatment in HBeAg-positive chronic hepatitis B (CHB) patients. Here, we identify viral minority variants in these regions and assess association with response to peginterferon-alfa (Peg-IFN) and adefovir combination therapy. PATIENTS AND METHODS Ultra-deep pyrosequencing analysis of the BCP and PC region was performed for 89 CHB patients (42 HBeAg-positive; 47 HBeAg-negative), at baseline and during treatment. Specifically, associations of individual positions with the HBeAg-negative phenotype were studied, as well as the association of the most prevalent mutations with combined response in HBeAg-positive and -negative patients at week 72 (HBeAg negativity, HBV-DNA <2000 IU/mL and ALT normalization at 24 weeks of treatment-free follow-up). RESULTS The mutations most strongly correlated with the HBeAg-negative phenotype were at positions 1762/1764 and 1896/1899 in the BCP and PC region, respectively. No major changes in nucleotide composition of these positions were observed during treatment. In HBeAg-negative patients, a combined presence of 1764A and 1896A was correlated with lower ALT levels (p = 0.004), whereas the presence of 1899A was correlated with higher age (p = 0.030), lower HBV-DNA level (p = 0.036), and previous IFN therapy (p = 0.032). The presence of 1764A/1896A or the absence of 1899A at baseline, was associated with lower response rates, after adjustment for HBV genotype (p = 0.031 and p = 0.017) and HBsAg level (p = 0.035 and p = 0.022). CONCLUSION We identified novel correlations between common BCP and PC variants with response to Peg-IFN and adefovir in HBeAg-negative patients. Ultimately, this may guide the selection of those patients most likely to benefit from Peg-IFN-based treatment.
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Affiliation(s)
- Louis Jansen
- Gastroenterology and Hepatology, Academic Medical Center (AMC), University of Amsterdam (UvA), Amsterdam, The Netherlands; Experimental Immunology, AMC, UvA, The Netherlands
| | | | | | - R Bart Takkenberg
- Gastroenterology and Hepatology, Academic Medical Center (AMC), University of Amsterdam (UvA), Amsterdam, The Netherlands
| | - Uri Lopatin
- Assembly Pharmaceuticals, Bloomington, IN, USA
| | | | | | - Hendrik W Reesink
- Gastroenterology and Hepatology, Academic Medical Center (AMC), University of Amsterdam (UvA), Amsterdam, The Netherlands; Experimental Immunology, AMC, UvA, The Netherlands
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9
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Chung KH, Kim W, Kim BG, Lee HY, Jin E, Cho Y, Seo JY, Kim HY, Jung YJ, Kim JW, Jeong JB, Lee KL. Hepatitis B Surface Antigen Quantification across Different Phases of Chronic Hepatitis B Virus Infection Using an Immunoradiometric Assay. Gut Liver 2016; 9:657-64. [PMID: 25717049 PMCID: PMC4562784 DOI: 10.5009/gnl14188] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND/AIMS Quantification of hepatitis B surface antigen (HBsAg) is an emerging serologic test and may be useful for identifying treatment strategies for chronic hepatitis B (CHB). This study aimed to evaluate HBsAg titers during the natural course of CHB and identify correlations between HBsAg titers and hepatitis B virus (HBV) DNA concentrations across different CHB phases measured using an immunoradiometric assay (IRMA). METHODS CHB phases were defined on the basis of HBV DNA concentrations, the presence of hepatitis B e antigen/antibody (HBeAg/Ab) and serum alanine aminotransferase levels. Serum HBsAg titers and paired HBV DNA concentrations in the different phases of CHB were compared using 627 serum samples. RESULTS Mean HBsAg titers were significantly higher in the immunotolerant (IT) phase and immunoreactive (IR) HBeAg-positive phase than in the low-replicative (LR) and HBeAg-negative CHB (ENH) states. The correlation between HBsAg titers and HBV DNA concentrations was modest in the IT (n=36, r=0.804, p<0.001) and IR (n=48, r=0.773, p<0.001) phases, and it was poor in the LR state (n=116, r=0.289, p=0.002); however, no significant correlation was observed in the ENH state (n=67, r=0.146, p=0.237) or in the oral nucleos(t)ide analogue-treated group (n=267). CONCLUSIONS HBsAg quantification using IRMA might be useful for discriminating different CHB phases and different stages of chronic liver disease.
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Affiliation(s)
- Kwang Hyun Chung
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Won Kim
- Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea
| | - Byeong Gwan Kim
- Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea
| | - Ho-Young Lee
- Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Eunhyo Jin
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Yuri Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Ji Yeon Seo
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hwi Young Kim
- Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea
| | - Yong Jin Jung
- Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea
| | - Ji Won Kim
- Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea
| | - Ji Bong Jeong
- Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea
| | - Kook Lae Lee
- Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea
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11
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Kramvis A. The clinical implications of hepatitis B virus genotypes and HBeAg in pediatrics. Rev Med Virol 2016; 26:285-303. [PMID: 27139263 PMCID: PMC5084815 DOI: 10.1002/rmv.1885] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2016] [Revised: 04/02/2016] [Accepted: 04/04/2016] [Indexed: 12/12/2022]
Abstract
Although a successful vaccine against HBV has been implemented in 184 countries, eradication of hepatitis B virus (HBV) is still not on the horizon. There are over 240 million chronic carriers of HBV globally. The risk of developing chronic hepatitis ranges from >90% in newborns of hepatitis Be antigen (HBeAg)‐positive mothers, 25%–35% in children under 5 years of age and <5% in adults. HBeAg, a non‐particulate viral protein, is a marker of HBV replication. This is the only HBV antigen to cross the placenta, leading to specific unresponsiveness of helper T cells to the capsid protein and HBeAg in newborns. HBeAg is tolerated in utero and acts as a tolerogen after birth. Perinatal transmission is frequent when mothers are HBeAg‐positive, whereas it occurs less frequently when mothers are HBeAg‐negative. Sequence heterogeneity is a feature of HBV. Based on an intergroup divergence >7.5% across the complete genome, HBV is classified phylogenetically into at least nine genotypes. With between ~4% and 8% intergroup nucleotide divergence, genotypes A–D, F, H and I are classified further into subgenotypes. HBV genotypes/subgenotypes may have distinct geographical distribution and can develop different mutations in the regions of the HBV genome that code for HBeAg. These differences can be related to the role of HBV genotypes to the natural history of infection and mode of transmission. Thus genotypes/subgenotypes of HBV can be responsible for the different natural history of infection and modes of transmission in children, found in various regions of the world, where different genotypes/subgenotypes prevail. Copyright © 2016 John Wiley & Sons, Ltd.
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Affiliation(s)
- Anna Kramvis
- Hepatitis Virus Diversity Research Unit (HVDRU), Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
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12
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Gededzha MP, Muzeze M, Burnett RJ, Amponsah-Dacosta E, Mphahlele MJ, Selabe SG. Complete genome analysis of hepatitis B virus in human immunodeficiency virus infected and uninfected South Africans. J Med Virol 2016; 88:1560-6. [PMID: 26890489 DOI: 10.1002/jmv.24502] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/14/2016] [Indexed: 12/21/2022]
Abstract
Hepatitis B virus (HBV) and human immunodeficiency virus (HIV) infections are highly endemic in South Africa. Data on the complete genome sequences of HBV in HIV-positive patients in South Africa are scanty. This study characterized the complete HBV genome isolated from both HIV-positive and negative patients at the Dr George Mukhari Academic Hospital (DGMAH), Pretoria. Serum samples from nine (five HIV-positive and four HIV-negative) patients attending the DGMAH from 2007 to 2011 were serologically tested, amplified, and sequenced for complete genome. Phylogenetic tree was constructed using MEGA6.0. Mutations were analyzed by comparing the sequences with genotype-matched GenBank references. Eight patients were HBsAg positive, with only one from the HIV positive group being negative. Phylogenetic analysis of the complete genome sequences classified them into five genotypes; A1 (n = 4), A2 (n = 1), C1 (n = 2), D1 (n = 1), and D3 (n = 1). Deletions up to 35 nucleotides in length were identified in this study. No drug resistance mutations were identified in the P ORF, while the L217R mutation was identified in one subgenotype A2 sequence. The double (A1762T/G1764A) and triple (T1753C/A1762T/G1764A) mutations in the Basal core promoter were identified in four and two sequences, respectively. In the core region, mutation G1888A was identified in four of the subgenotype A1 sequences. In conclusion, this study has added to the limited South African data on HBV genotypes and mutations in HBV/HIV co-infected and HBV mono-infected patients, based on complete HBV genome analysis. Subgenotype A1 was predominant, and no drug-resistant mutants were detected in the study. J. Med. Virol. 88:1560-1566, 2016. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Maemu P Gededzha
- Department of Virology, HIV and Hepatitis Research Unit, Sefako Makgatho Health Sciences University and National Health Laboratory Service, Pretoria, South Africa
| | - Muxe Muzeze
- Department of Virology, HIV and Hepatitis Research Unit, Sefako Makgatho Health Sciences University and National Health Laboratory Service, Pretoria, South Africa
| | - Rosemary J Burnett
- Department of Virology, HIV and Hepatitis Research Unit, Sefako Makgatho Health Sciences University and National Health Laboratory Service, Pretoria, South Africa
| | - Edina Amponsah-Dacosta
- Department of Virology, HIV and Hepatitis Research Unit, Sefako Makgatho Health Sciences University and National Health Laboratory Service, Pretoria, South Africa
| | | | - Selokela G Selabe
- Department of Virology, HIV and Hepatitis Research Unit, Sefako Makgatho Health Sciences University and National Health Laboratory Service, Pretoria, South Africa
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13
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Loustaud-Ratti V, Jacques J, Debette-Gratien M, Carrier P. Hepatitis B and elders: An underestimated issue. Hepatol Res 2016; 46:22-8. [PMID: 25651806 DOI: 10.1111/hepr.12499] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2014] [Revised: 01/17/2015] [Accepted: 02/02/2015] [Indexed: 12/16/2022]
Abstract
As the world's population becomes older, the burden of hepatitis B virus in elderly has to be considered. The liver changes with aging and its function is eventually altered. The prevalence of hepatitis B virus is paradoxically more important in elderly in areas having vaccination programs, because of a loosening of the prevention in older patients. Some differences in hepatitis B presentation must be enhanced in elderly: lower spontaneous hepatitis B surface antigen clearance after a recent contamination, major risk of cirrhosis and hepatocarcinoma. Acute hepatitis B seems to be more often symptomatic, with a great risk of chronicity. Hepatocarcinoma linked to hepatitis B virus has a higher prevalence and a different presentation in elderly. Its treatment is the same as in younger people but is less often possible. Liver transplantation is contraindicated after 70 years old. Hepatitis B treatment panel is the same as in younger people (pegylated interferon, nucleoside or nucleotide agents). It gives identical results with no particular adverse events if the precautions for use are followed. Vaccination is less efficient, as in immunocompromised patients, and needs specific protocols.
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Affiliation(s)
- Véronique Loustaud-Ratti
- Federation of Hepatology, Gastroenterology and Hepatology Unit, CHU Limoges.,INSERM UMR 850, School of Medicine, Limoges, France
| | - Jérémie Jacques
- Federation of Hepatology, Gastroenterology and Hepatology Unit, CHU Limoges
| | | | - Paul Carrier
- Federation of Hepatology, Gastroenterology and Hepatology Unit, CHU Limoges
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14
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Samal J, Kandpal M, Vivekanandan P. Hepatitis B “e” antigen-mediated inhibition of HBV replication fitness and transcription efficiency in vitro. Virology 2015; 484:234-240. [DOI: 10.1016/j.virol.2015.06.011] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2014] [Revised: 02/25/2015] [Accepted: 06/02/2015] [Indexed: 01/04/2023]
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15
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Chang ML, Jeng WJ, Liaw YF. Clinical events after cessation of lamivudine therapy in patients recovered from hepatitis B flare with hepatic decompensation. Clin Gastroenterol Hepatol 2015; 13:979-86. [PMID: 25445774 DOI: 10.1016/j.cgh.2014.10.023] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2014] [Revised: 10/14/2014] [Accepted: 10/15/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Before guidelines were issued, many patients with hepatitis B flare and hepatic decompensation had discontinued lamivudine therapy instead of indefinite therapy. We investigated their outcomes. METHODS We performed a retrospective cohort study of 263 consecutive patients with chronic hepatitis B (94 with cirrhosis) who recovered from a flare of hepatitis with hepatic decompensation and were followed after cessation of lamivudine therapy. Clinical events that occurred during the follow-up period were assessed by chart review and analysis of results from retrospective assays. RESULTS The mean duration of lamivudine therapy was 12.1 ± 8.6 months; data were collected from patients for 89.1 ± 38.7 months after therapy ended. In the first year off therapy, 29.9% of patients had clinical relapse, 16.2% had hepatitis flares, and 8.2% had hepatic decompensation. There was no significant difference in the incidence of hepatic decompensation between patients with and without cirrhosis. Hepatocellular carcinoma developed in 14 patients 20-109 months after cessation of therapy, with 5-year cumulative incidence of 5.2% in patients with cirrhosis. Three patients with cirrhosis died of hepatic decompensation 38-76 months after cessation of therapy (5-year cumulative mortality, 2.9%). Multivariate analyses showed that men were more likely than women to have recurrence of hepatic decompensation (hazard ratio [HR], 4.339; P = .014). Liver cirrhosis (HR, 2.766; P = .041) and age (HR, 1.054; P = .023) increased risk for hepatocellular carcinoma. CONCLUSIONS Cessation of lamivudine therapy after recovery from hepatitis B flare with decompensation was safe for most patients. However, 8.2% develop decompensation within 1 year and can be rescued by timely retreatment. With close monitoring, the stopping strategy could be a feasible alternative to indefinite therapy, especially in low resource settings.
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Affiliation(s)
- Ming-Ling Chang
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
| | - Wen-Juei Jeng
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
| | - Yun-Fan Liaw
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan.
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16
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Natural history of chronic hepatitis B virus infection. Med Microbiol Immunol 2014; 204:5-10. [PMID: 25540037 DOI: 10.1007/s00430-014-0369-7] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2014] [Accepted: 10/02/2014] [Indexed: 02/06/2023]
Abstract
Hepatitis B virus infection represents a major global health problem. Currently, there are more than 240 million chronically infected people worldwide. The development of chronic hepatitis B virus-mediated liver disease may lead to liver fibrosis, cirrhosis and eventually hepatocellular carcinoma. Recently, the discovery of the viral entry receptor sodium taurocholate cotransporting polypeptide has facilitated new approaches for a better understanding of viral physiopathology. Hopefully, these novel insights may give rise to the development of more effective antiviral therapy concepts during the next years. In this review, we will discuss the natural history of hepatitis B virus infection including the viral biology, the clinical course of infection and the role of the immune response.
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Della Corte C, Nobili V, Comparcola D, Cainelli F, Vento S. Management of chronic hepatitis B in children: an unresolved issue. J Gastroenterol Hepatol 2014; 29:912-9. [PMID: 24863185 DOI: 10.1111/jgh.12550] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/04/2013] [Indexed: 12/11/2022]
Abstract
Although a rather benign course of chronic hepatitis B virus (HBV) infection during childhood has been described, 3-5% and 0.01-0.03% of chronic carriers develop cirrhosis or hepatocellular carcinoma before adulthood. Considering the whole lifetime, the risk of hepatocellular carcinoma rises to 9-24% and the incidence of cirrhosis to 2-3% per year. The aim of this article is to review the current knowledge regarding the natural history and treatment of chronic hepatitis B in children and to focus on critical aspects and unresolved questions in the management of childhood HBV infection. A literature search was carried out on MEDLINE, EMBASE, and Web of Science for articles published in English in peer-reviewed journals from January 1980 to February 2013. The search terms used included "Hepatitis B virus infection," "children," "HBV," "interferon," "lamivudine," "adefovir," "entecavir," and "tenofovir." Articles resulting from these searches and relevant references cited in the articles retrieved were reviewed. The current goals of therapy are to suppress viral replication, reduce liver inflammation, and reverse liver fibrosis. Therapeutic options for children are currently limited, and the risk for viral resistance to current and future therapies is a particular concern. Based on the data available at this time, it is the consensus of the panel that it is not appropriate to treat children in the immune-tolerant phase or in the inactive carrier state. For children in the immune-active or reactivation phases, liver histology can help guide treatment decisions. Outside of clinical trials, interferon is the agent of choice in most cases; currently, available nucleoside analogs are secondary therapies.
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Affiliation(s)
- Claudia Della Corte
- HepatoMetabolic Diseases Unit, Children's Hospital Bambino Gesù, Rome, Italy
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18
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Pourkarim MR, Vergote V, Amini-Bavil-Olyaee S, Sharifi Z, Sijmons S, Lemey P, Maes P, Alavian SM, Van Ranst M. Molecular characterization of hepatitis B virus (HBV) strains circulating in the northern coast of the Persian Gulf and its comparison with worldwide distribution of HBV subgenotype D1. J Med Virol 2014; 86:745-57. [PMID: 24532489 DOI: 10.1002/jmv.23864] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/24/2013] [Indexed: 12/17/2022]
Abstract
Iran is a large country that covers the northern coast of the Persian Gulf. Iranian residents of this coastal region interact closely with people from neighboring countries because of historical and cultural relationships, as well as economic activities. In addition, the inhabitants of this border region have experienced several wars, which have affected public health infrastructures. This study characterized for the first time, the evolution of the full-length genome of HBV strains in asymptomatic carrier patients living in this particular region. In addition, this study was compared and complemented by a comprehensive evolutionary analysis of the worldwide geographical distribution of HBV subgenotype D1. Evolutionary analysis demonstrates that patients living in the northern coast of the Persian Gulf are mainly infected with HBV subgenotype D1, subtype ayw2. Specific mutations related to advanced liver disease were found more frequently in these strains compared to other strains isolated from asymptomatic carriers from other regions of Iran. This global comprehensive analysis showed that HBV subgenotype D1 strains have a worldwide distribution and that human mobility and immigration had a large impact on dispersal of HBV subgenotype D1, subtype ayw2 in Middle Eastern countries such as Iran, Syria, and Turkey. In addition to association of subtype ayw2 with subgenotype D1, it was demonstrated that other HBV subtypes like adw2, ayw1, and ayw3 are associated with HBV subgenotype D1 in different regions of the world. This study also revealed a remarkable distribution of subgenotype D1, subtype ayw4 although this particular subtype is associated with subgenotype D4 of HBV in European countries.
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Affiliation(s)
- Mahmoud Reza Pourkarim
- Department of Microbiology and Immunology, Laboratory of Clinical and Epidemiological Virology, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium; Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
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19
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Sede M, Lopez-Ledesma M, Frider B, Pozzati M, Campos RH, Flichman D, Quarleri J. Hepatitis B virus depicts a high degree of conservation during the immune-tolerant phase in familiarly transmitted chronic hepatitis B infection: deep-sequencing and phylogenetic analysis. J Viral Hepat 2013; 21:650-61. [PMID: 25244642 DOI: 10.1111/jvh.12196] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2013] [Accepted: 09/08/2013] [Indexed: 12/13/2022]
Abstract
When intrafamilial transmission of hepatitis B virus (HBV) occurs, a virus with the same characteristics interacts with diverse hosts' immune systems and may thus result in different mutations to escape immune pressure. In this study, the HBV genomic characterization was assessed longitudinally after intrafamilial transmission using nucleotide sequence data of phylogenetic and mutational analyses, including those obtained by deep-sequencing for the first time. Furthermore, HBeAg-anti-HBe profile and variability of HBV core-derived epitopes were also evaluated. Strong evidence was obtained from intrafamilial transmission of HBV genotype D1 by phylogenetic inferences. HBV isolates exhibited high degree (~99%) of genomic conservation for almost 20 years, when patients were persistently HBeAg positive with normal amino transferase levels. This identity remained high among immune-tolerant siblings. In contrast, it diminished significantly (P = 0.02) when the mother cleared HBeAg (immune clearance phase). By deep-sequencing, the quantitative analysis of the dynamics of basal core promoter (BCP) (A1762T, G1764A; A1766C; T1773C; 8-bp deletion; and other) and precore (G1896A) variants among HBV isolates from family members exhibited differences during the follow-up. However, only those from the mother showed amino acid variations at core protein that would impair their MHC-II binding. Hence, when intrafamilial transmission occurs, HBV was highly conserved under the immune-tolerant phase, but it exhibited mutations more frequently during the immune clearance phase. The analysis of the HBV BCP and precore mutants after intrafamilial HBV transmission contributes to a better understanding of how they evolve over time.
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Affiliation(s)
- M Sede
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina; Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Universidad de Buenos Aires, Buenos Aires, Argentina
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20
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The Possible Role of TLR2 in Chronic Hepatitis B Patients with Precore Mutation. Adv Virol 2013; 2013:780319. [PMID: 24187552 PMCID: PMC3800624 DOI: 10.1155/2013/780319] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2013] [Accepted: 08/26/2013] [Indexed: 12/17/2022] Open
Abstract
Recognition mechanisms of innate immune response help to improve immunotherapeutic strategies in HBeAg-negative chronic hepatitis B (CHB). Toll-like receptor 2 (TLR2) is an important component of innate immunity. In this study, the frequency of precore mutations of the hepatitis B virus (HBV) and serum TLR2 were evaluated in CHB patients. Fifty-one patients with chronic hepatitis B, negative for HBeAg and detectable HBV DNA, were examined for the presence of mutations in pre-core region of HBV genome by direct sequencing. Serum TLR2 was measured by enzyme-linked immunosorbent assay. Interactions of truncated HBeAg and TLR2 proteins were evaluated with molecular docking software. The G1896A pre-core mutation were detected in 29 (57%) which was significantly associated with higher concentration of serum TLR2 in comparison with patients without this mutation (4.8 ± 2.9 versus 3.4 ± 2.2 ng/mL, P = 0.03). There was also a significant correlation between serum ALT and TLR-2 (r = 0.46; P = 0.01). Docking results illustrated residues within the N-terminus of truncated HBeAg and TLR2, which might facilitate the interaction of these proteins. These findings showed the dominance of G1896A pre-core mutation of HBV variants in this community which was correlated with serum TLR2. Moreover TLR2 is critical for induction of inflammatory cytokines and therefore ALT elevation.
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21
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22
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Zoutendijk R, Sonneveld MJ, Reijnders JGP, van Vuuren AJ, Biesta P, Hansen BE, Boonstra A, Janssen HLA. Precore and core promoter mutants are associated with higher HBeAg seroconversion but low disease remission rates in HBV patients treated with nucleos(t)ide analogues. J Viral Hepat 2013; 20:322-7. [PMID: 23565614 DOI: 10.1111/jvh.12033] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2012] [Accepted: 09/27/2012] [Indexed: 12/18/2022]
Abstract
HBeAg seroconversion in HBV patients is considered an important event. We determined precore (PC) and base core promoter (BCP) mutations in 137 HBeAg-positive nucleos(t)ide analogues (NA) treated patients by INNO-LiPA HBV PreCore assay (Innogenetics). The majority of patients with nongenotype A had PC/BCP mutants present at baseline (P = 0.02). During 29 months of therapy, 45 patients achieved HBeAg seroconversion. Probability of HBeAg seroconversion was higher in patients with PC and/or BCP mutants (P = 0.01). After HBeAg seroconversion, patients with BCP mutants had more HBeAg relapse (P = 0.07), and PC mutants less often achieved HBV DNA < 2000 IU/mL (P = 0.07).
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Affiliation(s)
- R Zoutendijk
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
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23
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Yang HC, Chen CL, Shen YC, Peng CY, Liu CJ, Tseng TC, Su TH, Chuang WL, Yu ML, Dai CY, Liu CH, Chen PJ, Chen DS, Kao JH. Distinct evolution and predictive value of hepatitis B virus precore and basal core promoter mutations in interferon-induced hepatitis B e antigen seroconversion. Hepatology 2013; 57:934-43. [PMID: 23112104 DOI: 10.1002/hep.26121] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2012] [Accepted: 10/14/2012] [Indexed: 12/11/2022]
Abstract
UNLABELLED Precore (PC) (G1896A) and basal core promoter (BCP) (A1762T/G1764A) mutations of the hepatitis B virus (HBV) genome often emerge in chronic hepatitis B (CHB) patients. Their roles in hepatitis B e antigen (HBeAg) seroconversion induced by interferon (IFN) therapy remain controversial, partly because quantitative analysis for these mutants is lacking. This study aimed to develop a new assay to accurately quantify the PC and BCP mutant percentages and correlate their dynamic changes with IFN-induced HBeAg seroconversion in HBeAg-positive CHB patients. The PC and BCP mutant percentages were analyzed by polymerase chain reaction (PCR)-pyrosequencing. Our results showed that this quantitative assay for PC and BCP mutants achieved high accuracy (R(2) > 0.99) within a range between 10% and 90% mutants. We examined dynamic changes of the PC and BCP mutant percentages following IFN treatment in 203 HBeAg-positive CHB patients. By multiple logistic regression analysis, we found that the chance of HBeAg seroconversion increased by 2.2% (odds ratio [OR] = 1.022, 95% confidence interval [CI]: 1.009-1.034, P = 0.001) and 2.3% (OR = 1.023, 95% CI: 1.010-1.037, P = 0.001) per 1% increase of the pretreatment PC and BCP mutant percentages, respectively, after adjustment for other predictors. However, only the pretreatment PC mutation percentage was significantly associated with HBeAg seroconversion with HBV DNA < 2,000 IU/mL (OR = 1.030, 95% CI: 1.014-1.047, P < 0.001). Furthermore, the mutant percentage of PC, but not BCP, in patients achieving HBeAg seroclearance with HBV DNA < 20,000 IU/mL increased significantly during IFN treatment (P = 0.039). Interestingly, patients with HBeAg seroconversion who had a high PC mutant percentage at the end of IFN treatment tended to exhibit high viremia after seroconversion. CONCLUSION Quantitative analysis of PC and BCP mutants can predict IFN-induced HBeAg seroconversion and demonstrate their distinct evolution patterns during HBeAg seroconversion. (HEPATOLOGY 2013).
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Affiliation(s)
- Hung-Chih Yang
- Department of Microbiology, Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, and Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
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24
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Paganelli M, Stephenne X, Sokal EM. Chronic hepatitis B in children and adolescents. J Hepatol 2012; 57:885-96. [PMID: 22634122 DOI: 10.1016/j.jhep.2012.03.036] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2011] [Revised: 03/16/2012] [Accepted: 03/20/2012] [Indexed: 02/07/2023]
Affiliation(s)
- Massimiliano Paganelli
- Pediatric Gastroenterology and Liver Unit, Cliniques St Luc, Université Catholique de Louvain, Brussels, Belgium
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25
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Ha WY, Lau CC, Yue PYK, Hung KKM, Chan K, Chui SH, Chui AKK, Yam WC, Wong RNS. Simultaneous Detection of Precore/Basal Core Promoter Mutations in Hepatitis B Virus Using Arrayed Primer Extension. Mol Diagn Ther 2012; 10:125-34. [PMID: 16669611 DOI: 10.1007/bf03256452] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
BACKGROUND Hepatitis B is a major disease that causes serious public health problems worldwide. The loss of HBeAg expression due to point mutations or single nucleotide polymorphisms (SNPs) in the precore/basal core promoter region of the hepatitis B virus (HBV) is associated with hepatocellular cirrhosis and carcinoma. Simultaneous screening for these mutations is strongly advocated for monitoring disease development in HBV-infected patients. The aim of this study is to apply arrayed primer extension (APEX) for the detection of HBV SNPs at the precore/basal core promoter. METHODS AND RESULTS We optimized APEX for simultaneous detection of eight potential sites of SNPs in the precore/basal core promoter region of HBV. The precore/basal core promoter regions of HBV from 36 HBV-infected patients were amplified by PCR. After purification and DNA fragmentation, the short, single-stranded HBV DNA fragments were allowed to hybridize with the oligonucleotides corresponding to the sites of SNPs immobilized on glass slides, followed by incorporation of different fluorescently labeled dideoxynucleotides. This allows fast and unequivocal discrimination between wild-type and mutant genotypes with high dideoxy-nucleotide incorporation efficiency, sensitivity, and specificity. The coexistence of both genotypes was also detected; this was undetected by DNA sequencing. CONCLUSION The simultaneous detection of SNPs in HBV precore/basal core promoter by APEX enables large-scale diagnostic analysis, which can be extended to the whole HBV genome.
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Affiliation(s)
- Wai-Yan Ha
- Research and Development Division, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong
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26
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Barbini L, Tadey L, Fernandez S, Bouzas B, Campos R. Molecular characterization of hepatitis B virus X gene in chronic hepatitis B patients. Virol J 2012; 9:131. [PMID: 22769058 PMCID: PMC3432627 DOI: 10.1186/1743-422x-9-131] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2011] [Accepted: 07/08/2012] [Indexed: 12/13/2022] Open
Abstract
Background HBV-X protein is associated with the pathogenesis of HBV related diseases, specially in hepatocellular carcinomas of chronic patients. Genetic variability of the X gene includes genotypic specific variations and mutations emerging during chronic infection. Its coding sequence overlaps important regions for virus replication, including the basal core promoter. Differences in the X gene may have implications in biological functions of the protein and thus, affect the evolution of the disease. There are controversial results about the consequences of mutations in this region and their relationship with pathogenesis. The purpose of this work was to describe the diversity of HBV-X gene in chronic hepatitis patients infected with different genotypes, according to liver disease. Methods HBV-X gene was sequenced from chronic hepatitis B patient samples, analyzed by phylogeny and genotyped. Nucleotide and aminoacid diversity was determined calculating intragenetic distances. Mutations at 127, 130 and 131 aminoacids were considered in relation to liver disease. Results The most prevalent genotype detected in this cohort was F (F1 and F4), followed by D and A. Most of the samples corresponding to genotypes A and F1 were HBeAg(+) and for genotypes D and F4, HBeAg(−) samples were represented in a higher percentage. Intragenetic distance values were higher in HBeAg(−) than in positive samples for all genotypes, and lower in overlapped regions, compared to single codification ones. Nucleotide and aminoacid diversities were higher in HBeAg(−), than in HBeAg(+) samples. Conclusions Independently of the infecting genotypes, mutations at any of 127, 130 and/or 131 aminoacid positions and HBeAg(−) status were associated with mild liver disease in this cohort.
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Affiliation(s)
- Luciana Barbini
- Catedra de Virologia, Facultad de Farmacia y Bioquimica, Universidad de Buenos Aires, Buenos Aires, Argentina.
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27
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Sonneveld MJ, Rijckborst V, Zeuzem S, Heathcote EJ, Simon K, Senturk H, Pas SD, Hansen BE, Janssen HLA. Presence of precore and core promoter mutants limits the probability of response to peginterferon in hepatitis B e antigen-positive chronic hepatitis B. Hepatology 2012; 56:67-75. [PMID: 22307831 DOI: 10.1002/hep.25636] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2011] [Accepted: 01/24/2012] [Indexed: 12/12/2022]
Abstract
UNLABELLED Peginterferon (PEG-IFN) treatment of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) results in HBeAg loss in 30% of patients, but clearance of hepatitis B virus (HBV) DNA and hepatitis B surface antigen (HBsAg) from serum is less often achieved. We investigated whether the presence of precore (PC) and basal core promoter (BCP) mutants before PEG-IFN treatment affects serological and virological response. A total of 214 HBeAg-positive CHB patients treated with PEG-IFN ± lamivudine for 52 weeks in a global randomized trial were classified at baseline as wildtype (WT) or non-WT (detectable mutants at PC/BCP) by line-probe assay. Response was assessed at 6 months posttreatment and through long-term follow-up (LTFU). Mutants were detected in 64% of patients, in varying frequencies across HBV genotypes A through D. Patients with WT had higher baseline HBV DNA, HBeAg, and HBsAg levels than patients with non-WT. Patients with WT were more likely to achieve HBeAg loss with HBV DNA <10,000 copies/mL (response, 34 versus 11%, P < 0.001) and HBsAg clearance (18 versus 2%, P < 0.001) at week 78 than non-WT patients. Among WT patients who achieved HBeAg clearance at week 78, 78% had undetectable HBV DNA and 61% achieved HBsAg clearance at LTFU (versus 26% and 15% in non-WT patients, P < 0.001 for both). The presence of WT virus at baseline was an independent predictor of response (odds ratio [OR] 2.90, 95% confidence interval [CI]: 1.15-7.31, P = 0.023) and HBsAg clearance (OR 5.58, 95% CI: 1.26-24.63, P = 0.013) and patients with non-A genotypes with detectable mutants had a low probability of response. CONCLUSION The presence of only WT virus at baseline is a strong predictor of response (HBeAg loss with HBV DNA <10,000 copies/mL) to PEG-IFN for HBeAg-positive CHB. Patients with detectable PC and/or BCP mutants have a lower probability of response and are less optimal candidates for PEG-IFN therapy.
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Affiliation(s)
- Milan J Sonneveld
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
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28
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Yang HI, Hung HL, Lee MH, Liu J, Jen CL, Su J, Wang LY, Lu SN, You SL, Iloeje UH, Chen CJ. Incidence and determinants of spontaneous seroclearance of hepatitis B e antigen and DNA in patients with chronic hepatitis B. Clin Gastroenterol Hepatol 2012; 10:527-34.e1-2. [PMID: 22178461 DOI: 10.1016/j.cgh.2011.12.019] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2011] [Revised: 11/05/2011] [Accepted: 12/01/2011] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS The spontaneous seroclearance of hepatitis B e antigen (HBeAg) and hepatitis B virus (HBV) DNA are important markers of progression of chronic HBV infection. We performed a long-term cohort study to elucidate the incidence and determinants of HBeAg and HBV DNA seroclearance in patients with chronic hepatitis B. METHODS A total of 1289 participants with a serum HBV DNA level of 10,000 copies/mL or more and without cirrhosis when the study began (1991-1992) were followed up until June 2004. A subset of patients that tested positive for HBeAg at baseline (n = 439) was included in the analysis of HBeAg seroclearance. Cox proportional hazards models were used to estimate seroclearance rate ratios for various determinants associated with the outcomes. RESULTS After 3161.2 person-years of follow-up evaluation, HBeAg seroclearance occurred in 187 participants (incidence rate, 5.9 per 100 person-years). The cumulative lifetime incidence of HBeAg seroclearance among patients who were 30 to 40, or 50, 60, 70, or 74 years old was 38.8%, 69.4%, 81.9%, 89.1%, and 95.5%, respectively. Major predictors of HBeAg seroclearance included female sex, genotype B, the precore 1896 mutant, increased serum levels of alanine aminotransferase, and low baseline serum levels of HBV DNA. The median (interquartile range) serum level of HBV DNA at the time of HBeAg seroclearance was 177,801 copies/mL (4941-3,247,560 copies/mL). HBV DNA seroclearance occurred in 199 participants (15.4%) during the mean follow-up period of 7.8 years (incidence rate, 1.97 per 100 person-years). The cumulative lifetime incidence of HBV DNA seroclearance at 40, 50, 60, 70, and 77 years old was 10.0%, 25.0%, 38.8%, 54.2%, and 82.8%, respectively. Lower levels of HBV DNA at study entry and among those with the precore 1896 wild-type variant were associated with an increased rate of HBV DNA seroclearance. Among individuals who were HBeAg-seropositive at study entry and cleared serum HBV DNA during the follow-up period, 89% had cleared HBeAg by the time they had an undetectable serum level of HBV DNA. CONCLUSIONS Serum level of HBV DNA is the most important predictor of seroclearance of HBeAg and HBV DNA. This finding supports current clinical guidelines for antiviral treatments of chronic hepatitis B.
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Affiliation(s)
- Hwai-I Yang
- Molecular and Genomic Epidemiology Center, China Medical University Hospital, Taichung, Taiwan.
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Abstract
As life expectancy continues to rise, elderly adults represent a rapidly growing proportion of the population. The likelihood of complications of acute and chronic liver disease and overall mortality are higher in elderly populations. Several physiological changes associated with aging, greater prevalence of co-morbid conditions, and cumulative exposure to hepatotropic viruses and environmental hepatotoxins may contribute to worse outcomes of viral hepatitis in the elderly. Although pharmacotherapy for hepatitis B and C continues to evolve, the efficacy, tolerability, and side effects of these agents have not been studied extensively in elderly adults. Immunization against hepatitis A and B in naïve elderly adults is an important public health intervention that needs to be revised and broadened.
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Sonneveld MJ, Wong VWS, Woltman AM, Wong GLH, Cakaloglu Y, Zeuzem S, Buster EHCJ, Uitterlinden AG, Hansen BE, Chan HLY, Janssen HLA. Polymorphisms near IL28B and serologic response to peginterferon in HBeAg-positive patients with chronic hepatitis B. Gastroenterology 2012; 142:513-520.e1. [PMID: 22108195 DOI: 10.1053/j.gastro.2011.11.025] [Citation(s) in RCA: 127] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2011] [Revised: 11/02/2011] [Accepted: 11/04/2011] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS A limited number of patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B respond to treatment with peginterferon alfa (PEG-IFN). We investigated whether IL28B genotypes are associated with response. METHODS We studied 205 HBeAg-positive patients who were treated with PEG-IFN (some were also treated with lamivudine) at 11 European and Asian hospitals; genotype analysis was performed for IL28B rs12980275 and rs12979860. Response was defined as HBeAg loss with the appearance of antibodies to hepatitis B e antigen (anti-HBe) at the end of PEG-IFN therapy (HBeAg seroconversion), along with HBeAg seroconversion and hepatitis B surface antigen clearance during long-term follow-up. RESULTS The patients were infected with hepatitis B virus (HBV) genotypes A (13%), B (20%), C (47%), and D (13%). The proportions of IL28B genotypes were 77%, 19%, and 5% for AA/AG/GG at rs12980275 and also for CC/CT/TT at rs12979860, respectively. IL28B genotype was significantly associated with HBeAg seroconversion at the end of treatment (P < .001); the adjusted odds ratio for seroconversion was 3.16 (95% confidence interval [CI], 1.26-8.52; P = .013) for AA versus AG/GG at rs12980275 after adjustment for HBV genotype, age, levels of HBV DNA and alanine aminotransferase, and combination therapy. IL28B genotype was independently associated with an increased probability of HBeAg seroconversion during long-term follow-up (adjusted hazard ratio [HR], 2.14; 95% CI, 1.14-4.31; P = .018 for AA vs AG/GG by Cox regression analysis). Similar results were obtained for rs12979860. IL28B genotype was also associated with hepatitis B surface antigen clearance (HR, 3.47 for AA vs AG/GG; 95% CI, 1.04-13.48; P = .042). CONCLUSIONS Polymorphisms near IL28B are independently associated with serologic response to PEG-IFN in patients with HBeAg-positive chronic hepatitis B.
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Affiliation(s)
- Milan J Sonneveld
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
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Viral load, genotypes, and mutants in hepatitis B virus-related hepatocellular carcinoma: special emphasis on patients with early hepatocellular carcinoma. Dig Dis Sci 2012; 57:232-8. [PMID: 21837473 DOI: 10.1007/s10620-011-1844-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2011] [Accepted: 07/19/2011] [Indexed: 02/06/2023]
Abstract
BACKGROUND/AIMS The role of viral factors in the pathogenesis of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is still inconclusive. Whether virological features such as viral load or mutants might change with the progression of HCC remains unknown. A case-control study including patients with early HCC and HBsAg carriers who are presumed to be at the minimal potential of HCC as controls might better identify factors significantly associated with HCC development. METHODS Virological features were compared between 59 patients with early HCC (a solitary tumor of size ≤ 3 cm) and 101 patients with non-early HCC. A case-control study was performed by comparing 59 patients with early HCC and 1:2 age-matched inactive carriers with persistent normal alanine aminotransferase (ALT) levels. RESULTS HBV DNA levels, HBV genotypes, and the frequency of precore A1896 and basal core promoter T1762/A1764 mutations showed no significant difference between patients with early HCC and those with non-early HCC. In the case-control study, patients with early HCC had significantly higher HBV DNA levels, and higher frequencies of genotype C HBV and basal core promoter T1762/A1764 mutation, but a similar frequency of precore A1896 mutation. Multiple logistic regression analysis identified HBV DNA levels ≥ 2,000 IU/mL and basal core promoter T1762/A1764 mutation as being independent factors for HCC development. Additionally, there was a synergistic effect between high viral load and basal core promoter T1762/A1764 mutation on HCC development. CONCLUSIONS Virological features did not change significantly with the progression of HCC. HBV DNA levels ≥ 2,000 IU/mL and basal core promoter T1762/A1764 mutation were two independent viral factors for HCC.
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Hung CH, Chen CH, Lu SN, Wang JH, Hu TH, Huang CM, Tsai MC, Lee CM. Precore/core promoter mutations and hepatitis B virus genotype in hepatitis B and C dually infected patients treated with interferon-based therapy. Antiviral Res 2011; 93:55-63. [PMID: 22061616 DOI: 10.1016/j.antiviral.2011.10.018] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2011] [Revised: 09/15/2011] [Accepted: 10/19/2011] [Indexed: 12/16/2022]
Abstract
We studied the prevalence and distribution of precore/basal core promoter (BCP) mutations and hepatitis B virus (HBV) genotypes in HBV/hepatitis C virus (HCV) dually-infected patients, and evaluated their impact on long-term HBV response of interferon (IFN)-based therapy. The HBV genotypes and sequences of the precore/BCP regions were determined in 180 HBV/HCV dually-infected patients and were compared with 90 age, sex and hepatitis B e antigen-matched chronic hepatitis B controls. Serum HBV DNA and hepatitis B surface antigen (HBsAg) were assessed every 3-6 months after therapy with IFN or pegylated-IFN plus ribavirin in 135 dually-infected patients with active hepatitis C. Dually-infected patients had a higher prevalence of genotype C HBV (P=0.022) and a lower frequency of G1896A mutation (P=0.004) as compared with controls. Among dually-infected patients, genotype C was associated with a higher frequency of A1762T/G1764A mutation (P<0.001), but with lower HBV DNA (P<0.001) and a lower frequency of A1752T/G (P=0.008), C1799G (P<0.001) and G1896A mutation (P<0.001) than genotype B. Based on Cox proportional hazards model, young age (hazard ratio (HR)=0.952, P=0.001), sustained virological response to HCV (HR=4.638, P=0.044), C1766T mutation (HR=5.216, P=0.003) and A1846T mutation (HR=2.332, P=0.031) correlated with HBV DNA reactivation (⩾2000IU/ml) after therapy. Age (HR=1.068, P=0.020), G1896A mutation (HR=0.140, P=0.01) and A1846T mutation (HR=0.086, P=0.018) were associated with HBsAg seroclearance independently. In conclusion, specific mutations in the precore/BCP regions could be useful in predicting long-term HBV response in HBV/HCV dually-infected patients treated with IFN-based therapy.
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Affiliation(s)
- Chao-Hung Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
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Cortes-Mancera F, Loureiro CL, Hoyos S, Restrepo JC, Correa G, Jaramillo S, Norder H, Pujol FH, Navas MC. Etiology and Viral Genotype in Patients with End-Stage Liver Diseases admitted to a Hepatology Unit in Colombia. HEPATITIS RESEARCH AND TREATMENT 2011; 2011:363205. [PMID: 21941645 PMCID: PMC3177233 DOI: 10.1155/2011/363205] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/21/2011] [Accepted: 07/21/2011] [Indexed: 12/11/2022]
Abstract
Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are the principal risk factor associated to end-stage liver diseases in the world. A study was carried out on end-stage liver disease cases admitted to an important hepatology unit in Medellin, the second largest city in Colombia. From 131 patients recruited in this prospective study, 71% of cases were diagnosed as cirrhosis, 12.2% as HCC, and 16.8% as cirrhosis and HCC. Regarding the risk factors of these patients, alcohol consumption was the most frequent (37.4%), followed by viral etiology (17.6%). Blood and/or hepatic tissue samples from patients with serological markers for HCV or HBV infection were characterized; on the basis of the phylogenetic analysis of HCV 5' UTR and HBV S gene, isolates belonged to HCV/1 and HBV/F3, respectively. These results confirm the presence of strains associated with poor clinical outcome, in patients with liver disease in Colombia; additionally, HBV basal core promoter double mutant was identified in HCC cases. Here we show the first study of cirrhosis and/or HCC in Colombian and HBV and HCV molecular characterization of these patients. Viral aetiology was not the main risk factor in this cohort but alcohol consumption.
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Affiliation(s)
- Fabian Cortes-Mancera
- Grupo de Gastrohepatología, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia
- Instituto Tecnológico Metropolitano (ITM), Institución Universitaria Adscrita a la Alcaldía de Medellín, Medellín 549 59, Colombia
| | - Carmen Luisa Loureiro
- Laboratorio de Virología Molecular, CMBC, Instituto Venezolano de Investigaciones Científicas, Apdo. 20632, Caracas 1020A, Venezuela, Caracas, Venezuela
| | - Sergio Hoyos
- Grupo de Gastrohepatología, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia
- Unidad de Hepatología y Trasplante Hepático, Hospital Pablo Tobón Uribe (HPTU), Calle 78B 69-240, Medellín, Colombia
| | - Juan-Carlos Restrepo
- Grupo de Gastrohepatología, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia
- Unidad de Hepatología y Trasplante Hepático, Hospital Pablo Tobón Uribe (HPTU), Calle 78B 69-240, Medellín, Colombia
| | - Gonzalo Correa
- Grupo de Gastrohepatología, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia
- Unidad de Hepatología y Trasplante Hepático, Hospital Pablo Tobón Uribe (HPTU), Calle 78B 69-240, Medellín, Colombia
| | - Sergio Jaramillo
- Grupo de Gastrohepatología, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia
- Unidad de Hepatología y Trasplante Hepático, Hospital Pablo Tobón Uribe (HPTU), Calle 78B 69-240, Medellín, Colombia
| | - Helene Norder
- Department of Virology, Swedish Institute for Infectious Disease Control, 171 82 Solna, Sweden
| | - Flor Helene Pujol
- Laboratorio de Virología Molecular, CMBC, Instituto Venezolano de Investigaciones Científicas, Apdo. 20632, Caracas 1020A, Venezuela, Caracas, Venezuela
| | - Maria-Cristina Navas
- Grupo de Gastrohepatología, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia
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Characterization of the basal core promoter and precore regions in anti-HBe-positive inactive carriers of hepatitis B virus. Int J Infect Dis 2011; 15:e314-20. [PMID: 21367634 DOI: 10.1016/j.ijid.2010.12.009] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2010] [Revised: 12/15/2010] [Accepted: 12/21/2010] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The study of hepatitis B virus (HBV) genomic heterogeneity has become a major issue in investigations aimed at understanding the relationship between HBV mutants and the wide spectrum of clinical and pathological conditions associated with HBV infection. Although most chronically infected HBV patients are inactive carriers, several virological aspects of this state remain unclear. METHODS In order to determine the prevalence and clinical significance of mutations in the basal core promoter (BCP) and precore (pC) regions among inactive carriers, the nucleotide sequences from 41 inactive carriers were analyzed and compared with those from 29 individuals with chronic active hepatitis. RESULTS Genotypes A (24.3%), D (37.1%), F1b (12.9%), and F4 (18.6%) were the most prevalent. Mutations in the BCP/pC regions were observed in most of the inactive carriers (92.7%) and in most of the patients with chronic active hepatitis (93.1%). The prevalence of mutation 1764(A) was significantly higher in patients with chronic active hepatitis (65.5%) than in inactive carriers (36.6%) (p=0.038), whereas the prevalences of mutations at the other positions analyzed were not significantly different. Older patients (>50 years) showed BCP/pC patterns with a higher number of substitutions. Mutations were found to be biased by genotype: the 1896(A) mutation was highly prevalent in genotypes D and F4, while alternative substitutions in the pC region were more prevalent in genotypes A and F1b. CONCLUSIONS Mutations in the BCP/pC regions are the hallmark of chronic anti-HBe-positive individuals; nevertheless, the even distribution of mutations in active and inactive carriers suggests that BCP/pC mutations may occur during HBV infection not strictly related to the HBV infection activity.
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Liaw YF, Brunetto MR, Hadziyannis S. The natural history of chronic HBV infection and geographical differences. Antivir Ther 2011; 15 Suppl 3:25-33. [PMID: 21041901 DOI: 10.3851/imp1621] [Citation(s) in RCA: 102] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Although chronic HBV infection is a global health issue, there are geographical differences in the mode of transmission, prevalence and HBV genotype distribution. Chronic HBV infection is a dynamic state of interactions between HBV, hepatocytes and immune cells of the host. Accordingly, the natural history of chronic HBV infection typically starts with an immune tolerant phase, followed by an immune clearance phase and finally an inactive phase. The duration of the immune tolerant phase is usually long in chronic HBV infection acquired perinatally or in early childhood, otherwise the duration is very short. During the inactive phase, spontaneous hepatitis B surface antigen (HBsAg) seroclearance might occur at an annual rate of 1-2%; however, HBV reactivation with hepatitis activity could occur over time in one-quarter to one-third of HBsAg-seropositive patients. This occurs more frequently in males and in patients infected with genotypes D, C and B. The effort of active HBV replication-triggered immune clearance is the driving force of liver injury and subsequent disease progression in patients with hepatitis B e antigen (HBeAg)-positive or HBeAg-negative hepatitis. Clinical studies have shown that chronic HBV infection in western countries is associated with a higher incidence of cirrhosis, but lower incidence of hepatocellular carcinoma, than in Asian countries. The geographical differences in age at the time of infection and predominant HBV genotype could account for the variance in the natural history of chronic HBV infection; however, some of these differences might actually result from comparisons between cohorts with different age, gender distribution or fibrosis stage.
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Affiliation(s)
- Yun-Fan Liaw
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan.
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Wu S, Imazeki F, Kurbanov F, Fukai K, Arai M, Kanda T, Yonemitsu Y, Tanaka Y, Mizokami M, Yokosuka O. Evolution of hepatitis B genotype C viral quasi-species during hepatitis B e antigen seroconversion. J Hepatol 2011; 54:19-25. [PMID: 20932594 DOI: 10.1016/j.jhep.2010.06.018] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2009] [Revised: 06/04/2010] [Accepted: 06/07/2010] [Indexed: 01/21/2023]
Abstract
BACKGROUND & AIMS Although the evolution of viral quasi-species may be related to the pathological status of disease, little is known about this phenomenon in hepatitis B, particularly with respect to hepatitis B e antigen (HBeAg) seroconversion. METHODS Nucleotide sequences of the hepatitis B virus (HBV) X/precore/core region was analyzed at five time-points in four groups of chronic hepatitis B patients, interferon-induced seroconverters (IS, N = 9), interferon non-responders (IN, N = 9), spontaneous seroconverters (SS, N = 9), and non-seroconverters (SN, N = 9) followed during 60 months on an average. Only patients with genotype C were studied. RESULTS Analysis of 1800 nucleotide sequences showed that there was no statistical difference between the nucleotide genetic distances of seroconverters (IS and SS; 6.9 × 10⁻³ substitutions (st)/site and 6.7 × 10⁻³ st/site, respectively) and those of non-seroconverters (IN and SN; 5.3 × 10⁻³ st/site and 3.8 × 10⁻³ st/site, respectively) before seroconversion. Compared to non-seroconverters (IN and SN; 5.1 × 10⁻³ st/site and 5.9 × 10⁻³ st/site, respectively), the sequence diversity of seroconverters (IS and SS; 10.9 × 10⁻³ st/site and 9.9 × 10⁻³ st/site, respectively) was significantly higher after seroconversion (p < 0.05), and was higher in seroconverters after seroconversion than before seroconversion (p < 0.05), while this changed very little in non-seroconverters during the observation period. Phylogenetic trees showed greater complexity in secoconverters than non-seroconverters. Parsimony-based estimation of the direction of sequence change between descendants and ancestors before HBeAg seroconversion, revealed higher frequencies of transversional A to T substitution in seroconverters (0.06 vs. 0.02, p = 0.0036) that coincided with the dynamics of quasi-species possessing A1762T mutation. CONCLUSIONS The distinctly greater viral diversity in HBeAg seroconverters after seroconversion could be related to escape mutants resulting from stronger selection pressure.
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Affiliation(s)
- Shuang Wu
- Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
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Dupinay T, Restorp K, Leutscher P, Rousset D, Chemin I, Migliani R, Magnius L, Norder H. High prevalence of hepatitis B virus genotype E in Northern Madagascar indicates a West-African lineage. J Med Virol 2010; 82:1515-26. [PMID: 20648605 DOI: 10.1002/jmv.21865] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The prevalence of hepatitis B virus (HBV) markers was investigated in 563 inhabitants aged 15-55 years from a sugar cane region, Sirama, and from a village, Mataipako, in Northern Madagascar. Serological markers of past or present infection were significantly higher in Sirama, 74% versus 45%. There was no difference in the prevalence of chronic HBsAg carriers, 8.7% versus 8.5% between the two regions. Sequencing the S gene in 45 strains revealed a predominance of genotype E, in 53%, followed by subgenotype A1 in 22%, and genotype D in 18%. Phylogenetic analyses of the genotype E strains showed homology with West African strains. All A1 isolates were similar to Malawi strains. Most genotype D strains were subgenotype D7 and related to strains from Somalia and Tunisia. One genotype D strain formed a branch between Pacific D4 and African D7 strains at neighbor-joining analysis. The pre-core stop mutant was found in 33% of the genotype D strains, 17% of E but not in any A1 strain. The high prevalence and low variability of genotype E strains in only two villages, indicates a rather recent introduction of this genotype into Madagascar from West Africa, possibly through migration or slave trade. The wider spread and genetic relationship of genotype D with East African and Austronesian strains indicate an earlier introduction of this genotype. Molecular epidemiology of HBV may thus be used to complement linguistic and genetic studies on past human migrations in Africa.
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Asim M, Malik A, Sarma MP, Polipalli SK, Begum N, Ahmad I, Khan LA, Husain SA, Akhtar N, Husain S, Thayumanavan L, Singla R, Kar P. Hepatitis B virus BCP, Precore/core, X gene mutations/genotypes and the risk of hepatocellular carcinoma in India. J Med Virol 2010; 82:1115-25. [PMID: 20513073 DOI: 10.1002/jmv.21774] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The study aims to characterize mutations of the HBV genome involving BCP, Precore/core and X regions and also defines HBV genotypes in patients of hepatocellular carcinoma (HCC). The study involved 150 HBV-related HCC cases and 136 HBV-related chronic liver disease patients without HCC as controls. HBV DNA was subjected to mutational analysis using SSCP technique, genotyping by RFLP, and direct nucleotide sequencing. HBV DNA was found in 58.7% (88/150) of the HCC cases and 74.3% (101/136) of controls. HBV mutants were observed in 44.3% of HCC cases and 43.2% of controls. HBV/D was prevalent amongst the patients and controls, followed by HBV/A. The prevalence of the TT1504 mutation in the X gene, the V1753 and T1762/A1764 mutations in the BCP region, and G1914 mutation in the core gene were significantly higher in the HCC group than in the non-HCC group. Multivariate analyses showed that the TT1504, V1753, A1762T/G1764A, and the G1914 mutations and the patient's age, sex, and HBeAg status increased the risk of HCC development significantly. Also, patients with HCC had lower levels of serum albumin, viral load, and platelet counts but higher values of alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, and Alpha feto-protein than those of controls (P < 0.001 for all comparisons). HBV/D was the predominant genotype associated with HCC cases seen in India. The presence of different types of HBV mutations, age, sex, HBeAg status, and viral load was found to increase significantly the risk of HCC development in India.
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Affiliation(s)
- Mohammad Asim
- Department of Medicine, Maulana Azad Medical College, University of Delhi, New Delhi, India
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Ducancelle A, Servant-Delmas A, Beuvelet T, Balan V, Pivert A, Maniez M, Laperche S, Lunel-Fabiani F. [Results of a novel real-time PCR, sequence analysis, Inno-LiPA line probe assays in the detection of hepatitis B virus G1896A precore mutation in French blood donors]. ACTA ACUST UNITED AC 2010; 59:e21-7. [PMID: 20843617 DOI: 10.1016/j.patbio.2010.07.014] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2010] [Accepted: 07/29/2010] [Indexed: 12/31/2022]
Abstract
AIM To screen hepatitis B virus (HBV) genotypes and associated basal core promoter (BCP; T1762A/A1764) and precore (PC; A1896) mutations among the 100 HBV surface antigen (HBsAg) positive voluntary blood donors in France. METHODS HBV genotypes were determined by using direct sequence analysis. Three methods were used to detect G1896A mutation: non-commercial real-time PCR (PCRTR°, line probe assay (InnoLiPA HBV PreCore, INNOGENETICS(®)) and direct sequencing of precore gene. HBV viral load was quantified with two commercial real-time PCR (COBAS(®) AmpliPrep/COBAS(®) TaqMan(®) HBV Test/Roche and Real Time HBV/M2000/Abbott). RESULTS The mean age of donors was 30 (18-64). Patients were from Africa (42%), Europa (50%), and Asia (8%). HBV/D was the most predominant (37%) genotype followed by HBV/A (31%) and HBV/E (22%). PC and BCP mutants were found in 57% with Inno-LIPA HBV test and 59% with both PCRTR and sequencing methods. A significant difference in the viral load of blood donors with wild and PC mutants was observed with the Taqman Cobas real time PCR (3,19 Log(10) UI/ml versus 4,93 Log(10) UI/ml, p < 0.05). Precore phenotype determination was in agreement with the three PC mutation detection methods in 56% of cases. CONCLUSIONS Non-Caucasian genotype E was present in the French blood donors. PC mutation was more common than BCP mutations in this study. As HBV infected blood donors were more often asymptomatic carriers, we could speculate that the G1896A mutation may favour the asymptomatic state, supporting previous observations.
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Affiliation(s)
- A Ducancelle
- Laboratoire de virologie, CHU d'Angers, 4, rue Larrey, 49000 Angers, France.
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Chu CM, Chen YC, Tai DI, Liaw YF. Level of hepatitis B virus DNA in inactive carriers with persistently normal levels of alanine aminotransferase. Clin Gastroenterol Hepatol 2010; 8:535-40. [PMID: 20304099 DOI: 10.1016/j.cgh.2010.03.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2010] [Revised: 02/24/2010] [Accepted: 03/06/2010] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Little is known about the level of hepatitis B virus (HBV) DNA in individuals with chronic, inactive HBV infections. Patients who test positive for the antibody to hepatitis B e antigen (anti-HBe) and have normal levels of alanine aminotransferase for more than 10 years have a low risk of HBV reactivation and are considered to be inactive carriers. We investigated HBV DNA levels in inactive carriers and identified factors that correlated with this state among anti-HBe-positive carriers with HBV DNA levels of 10(4) copies/mL or greater (5.26 copies/mL = 1 IU/mL). METHODS HBV DNA levels were assayed in 250 inactive carriers with persistently normal alanine aminotransferase levels for more than 10 years. Clinical and virologic features were compared between inactive carriers (with HBV DNA levels > or =10(4) copies/mL) and age-matched patients with HBe antigen-negative chronic hepatitis (controls, n = 90). RESULTS The median level of HBV DNA among inactive carriers was 3.70 log(10) copies/mL (range, undetectable to 5.98 log(10) copies/mL). Ninety (36%) had levels of 10(4) copies/mL or greater. Compared with control patients, significant differences of inactive carriers included sex (more female patients), lower HBV DNA levels, and lower prevalence of genotype C virus and the basal core promoter mutation T1762/A1764. The prevalence of the precore mutation A1896 was similar between groups. Multiple logistic regression analyses identified male sex, HBV DNA levels greater than 10(5) copies/mL, and the basal core promoter mutation as independent factors that correlated with active disease. CONCLUSIONS Nearly 40% of inactive carriers had HBV DNA levels of 10(4) copies/mL or greater. Female sex, HBV DNA levels of 10(4) to 10(5) copies/mL, and wild-type basal core promoter correlated with inactive carrier state.
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Affiliation(s)
- Chia-Ming Chu
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan.
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Hepatitis B virus DNA level predicts hepatic decompensation in patients with acute exacerbation of chronic hepatitis B. Clin Gastroenterol Hepatol 2010; 8:541-5. [PMID: 20298811 DOI: 10.1016/j.cgh.2010.02.023] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2010] [Accepted: 02/27/2010] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Acute exacerbations of chronic hepatitis B virus (HBV) infection can lead to hepatic decompensation. It is important to identify factors that predict the development of hepatic decompensation during exacerbation so that antiviral therapy can be initiated immediately. METHODS Acute exacerbation, defined by an abrupt increase in alanine aminotransferase (ALT) levels to >5-fold the upper limit of normal, occurred in 110 hepatitis B e antigen (HBeAg)-seropositive non-cirrhotic patients (138 episodes). The patients were monitored every 1 to 2 weeks for serum levels of ALT, bilirubin, albumin, and prothrombin. Sex, age, HBV genotype, ALT level, HBV viral load, and the causes (spontaneous or relapse from antiviral treatment) of exacerbation were included in multivariate logistic regression analyses. The receiver operating characteristic curve was used to identify the optimal cut-off value of serum HBV DNA level to identify patients at risk for decompensation. RESULTS Seven of the 138 episodes of acute exacerbation (5.1%) resulted in hepatic decompensation; serum HBV DNA level was the only significant risk factor (P = .003). The area under the receiver operating characteristic curve was 88.6% (P < .001). A serum HBV DNA cut-off value of 1.55 x 10(9) copies/mL predicted decompensation with a sensitivity of 85.7%, a specificity of 85.5%, a negative prediction value of 99.1%, and positive prediction value of 24.0%. CONCLUSIONS During acute exacerbation of HBeAg-positive chronic hepatitis B, a serum HBV DNA cut-off value of 1.55 x 10(9) copies/mL can be used to identify patients in need of immediate antiviral therapy.
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Zampino R, Marrone A, Merola A, Trani B, Cirillo G, Karayiannis P, Coppola N, Zappalà R, Utili R, Ruggiero G, Adinolfi LE. Long-term outcome of hepatitis B and hepatitis C virus co-infection and single HBV infection acquired in youth. J Med Virol 2009; 81:2012-20. [DOI: 10.1002/jmv.21560] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Abstract
HBV replicates through reverse transcription of an RNA intermediate; the inherent lack of proofreading causes a high mutation frequency. Mutations in the precore and core promoter regions that abolish or reduce the production of hepatitis B e antigen occur most commonly. Patients with these HBV variants remain viremic and can develop progressive liver disease. Mutations in the core promoter region are associated with an increased risk of hepatocellular carcinoma. Exogenous selection pressure might favor certain mutations. Mutations in the HBV polymerase that confer resistance to nucleoside and nucleotide analog treatments are a major barrier to the success of therapy for hepatitis B. The development of antiviral drug resistance negates the initial treatment response and can lead to hepatitis flares and hepatic decompensation. Prompt addition of another drug to which the virus is not cross-resistant is required. Mutations in the HBV surface protein that facilitate escape from host immunity are responsible for the failure of immune prophylaxis in infants who received HBV vaccine and in liver transplant recipients who received hepatitis B immune globulin.
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Abstract
Since the introduction of the hepatitis B vaccine and other preventive measures, the worldwide prevalence of hepatitis B infection has fallen. However, chronic infection remains a challenging global health problem, with more than 350 million people chronically infected and at risk of hepatic decompensation, cirrhosis, and hepatocellular carcinoma. An improved understanding of hepatitis B virology, immunology, and the natural course of chronic infection, has identified hepatitis B virus replication as the key driver of immune-mediated liver injury and disease progression. The approval of potent oral antiviral agents has revolutionised hepatitis B treatment since 1998. Conventional and pegylated interferon alfa and nucleoside and nucleotide analogues are widely authorised treatments, and monotherapy with these drugs greatly suppresses virus replication, reduces hepatitis activity, and halts disease progression. However, hepatitis B virus is rarely eliminated, and drug resistance is a major drawback during long term therapy. The development of new drugs and strategies is needed to improve treatment outcomes.
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Affiliation(s)
- Yun-Fan Liaw
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
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A mechanism to explain the selection of the hepatitis e antigen-negative mutant during chronic hepatitis B virus infection. J Virol 2008; 83:1379-92. [PMID: 19004949 DOI: 10.1128/jvi.01902-08] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Hepatitis B virus (HBV) expresses two structural forms of the nucleoprotein, the intracellular nucleocapsid (hepatitis core antigen [HBcAg]) and the secreted nonparticulate form (hepatitis e antigen [HBeAg]). The aim of this study was to evaluate the ability of HBcAg- and HBeAg-specific genetic immunogens to induce HBc/HBeAg-specific CD4(+)/CD8(+) T-cell immune responses and the potential to induce liver injury in HBV-transgenic (Tg) mice. Both the HBcAg- and HBeAg-specific plasmids primed comparable immune responses. Both CD4(+) and CD8(+) T cells were important for priming/effector functions of HBc/HBeAg-specific cytotoxic T-lymphocyte (CTL) responses. However, a unique two-step immunization protocol was necessary to elicit maximal CTL priming. Genetic vaccination did not prime CTLs in HBe- or HBc/HBeAg-dbl-Tg mice but elicited a weak CTL response in HBcAg-Tg mice. When HBc/HBeAg-specific CTLs were adoptively transferred into HBc-, HBe-, and HBc/HBeAg-dbl-Tg mice, the durations of the liver injury and inflammation were significantly greater in HBeAg-Tg recipient mice than in HBcAg-Tg mice. Importantly, liver injury in HBc/HBeAg-dbl-Tg mice was similar to the injury observed in HBeAg-Tg mice. Loss of HBeAg synthesis commonly occurs during chronic HBV infection; however, the mechanism of selection of HBeAg-negative variants is unknown. The finding that hepatocytes expressing wild-type HBV (containing both HBcAg and HBeAg) are more susceptible to CTL-mediated clearance than hepatocytes expressing only HBcAg suggest that the HBeAg-negative variant may have a selective advantage over wild-type HBV within the livers of patients with chronic infection during an immune response and may represent a CTL escape mutant.
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Poustchi H, Mohamadkhani A, Bowden S, Montazeri G, Ayres A, Revill P, Farrell GC, Locarnini S, George J, Malekzadeh R. Clinical significance of precore and core promoter mutations in genotype D hepatitis B-related chronic liver disease. J Viral Hepat 2008; 15:753-60. [PMID: 18507754 DOI: 10.1111/j.1365-2893.2008.00998.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The impact of mutations in the precore and basal core promoter (BCP) regions of the hepatitis B virus on the course of chronic liver disease is not well established. We sought to examine the relationship of these characteristics to the clinical expression of liver disease in patients infected with genotype D chronic hepatitis B (CHB). BCP and precore mutations in 110 patients with genotype D1 CHB were determined and correlated with clinical phenotype. Of 110 patients, 95 (86.5%) were HBeAg-negative. Compared with HBeAg-positive subjects, HBeAg-negative patients were over a decade older and had lower viral loads (3.70 +/- 0.98 vs 5.77 +/- 0.69 log copies/ml, P < 0.001). The double mutation A1762T-G1764A was more prevalent in patients with advanced liver disease (AdLD) and was associated with higher alanine aminotransferase and viral load. After adjusting for age, there was a more than fourfold increase in the risk of AdLD with this mutation (OR = 4.4; 95% CI: 1.13-16.92, P < 0.03). Conversely, the G1757A substitution was associated with protection, being 90% less frequent among patients with AdLD (P = 0.001). The results indicate that in genotype D CHB, the presence of the A1762T-G1764A mutation was associated with more aggressive liver disease while the G1757A substitution was associated with protection from advanced disease.
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Affiliation(s)
- H Poustchi
- Medical Science , University Tehran, Iran
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Ito K, Tanaka Y, Kato M, Fujiwara K, Sugauchi F, Sakamoto T, Shinkai N, Orito E, Mizokami M. Comparison of complete sequences of hepatitis B virus genotype C between inactive carriers and hepatocellular carcinoma patients before and after seroconversion. J Gastroenterol 2007; 42:837-44. [PMID: 17940837 DOI: 10.1007/s00535-007-2100-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2007] [Accepted: 07/31/2007] [Indexed: 02/04/2023]
Abstract
BACKGROUND Most patients who acquire chronic hepatitis B virus (HBV) infection by perinatal transmission become inactive carriers (IC) after hepatitis B e (HBe) antigen seroconversion, whereas some patients have persistent abnormal serum transaminase levels and develop hepatocellular carcinoma (HCC) in the anti-HBe-positive phase. The aim of this study was to investigate the HCC-related mutations of HBV. METHODS Complete sequences of HBV were examined among eight IC and eight HCC patients infected with HBV genotype C before and after seroconversion. RESULTS The frequency of the T1653 mutation tended to be higher among HCC patients after seroconversion (16.7% vs. 62.5%; P = 0.086). The prevalence of a basal core promoter double mutation (T1762/A1764) was high among both IC and HCC patients after seroconversion (83.3% vs. 87.5%; P = 0.825). Among the HCC patients, a pre-S deletion mutant was detected in 62.5% patients before seroconversion, and in 37.5% patients after seroconversion. The core deletion mutant was also detected in 50% of HCC patients only before seroconversion. Deletion mutants of the pre-S or core region before seroconversion were significantly associated with HCC patients (0% vs. 62.5%; P = 0.007, 0% vs. 50%; P = 0.021, respectively). CONCLUSIONS Our data showed a significant association of pre-S and core deletion mutants before seroconversion with HCC development. The T1653 mutation after seroconversion was frequently found in HCC patients infected with HBV genotype C. These results suggest that mutations may be predictive factor for development of HCC.
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Affiliation(s)
- Kiyoaki Ito
- Department of Clinical Molecular Informative Medicine, Nagoya City University Graduate School of Medical Sciences, 1-Kawasumi, Mizuho, Nagoya 467-8601, Japan
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Lin CL, Kao JH. Viremia profiles in hepatitis B virus carrier children with spontaneous e antigen seroconversion: a case of déjà vu? Gastroenterology 2007; 133:1052-3; author reply 1053-4. [PMID: 17854613 DOI: 10.1053/j.gastro.2007.07.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
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49
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Shinkai N, Tanaka Y, Ito K, Mukaide M, Hasegawa I, Asahina Y, Izumi N, Yatsuhashi H, Orito E, Joh T, Mizokami M. Influence of hepatitis B virus X and core promoter mutations on hepatocellular carcinoma among patients infected with subgenotype C2. J Clin Microbiol 2007; 45:3191-7. [PMID: 17652471 PMCID: PMC2045330 DOI: 10.1128/jcm.00411-07] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Hepatitis B virus (HBV) genotypes/subgenotypes and their related mutations in the HBV genome have been reported to be associated with hepatocellular carcinoma (HCC). To determine the HCC-associated mutations of the HBV genome in the entire X, core promoter, and precore/core regions, a cross-sectional control study was conducted comparing 80 Japanese patients infected with HBV C2 and suffering from HCC with 80 age-, sex-, and hepatitis B e antigen (HBeAg) status-matched patients without HCC (non-HCC group). Each HBeAg-positive group (31 with HCC; 29 without HCC) and HBeAg-negative group (49 with HCC; 51 without HCC) was also matched with respect to age and sex. The C1479, T1485, H1499, A1613, T1653, V1753, T1762/A1764, and A1896 mutations were frequent in this population. The prevalences of the T1653 mutation in the box alpha region and the V1753 and T1762/A1764 mutations in the basal core promoter region were significantly higher in the HCC group than in the non-HCC group (56% versus 30%, 50% versus 24%, and 91% versus 73% [P = 0.0013, P = 0.0010, and P = 0.0035, respectively]). The platelet count was significantly lower for the HCC group than for the non-HCC group (10.7 x 10(4) +/- 5.1 x 10(4) versus 17.3 x 10(4) +/- 5.1 x 10(4) platelets/mm(3) [P < 0.0001]). Regardless of HBeAg status, the prevalence of the T1653 mutation was higher in the HCC group (52% versus 24% [P = 0.036] for HBeAg-positive patients and 59% versus 33% [P = 0.029] for HBeAg-negative patients). In the multivariate analysis, the presence of T1653, the presence of V1753, and a platelet count of < or =10 x 10(4)/mm(3) were independent predictive factors for HCC (odds ratios [95% confidence intervals], 4.37 [1.53 to 12.48], 7.98 [2.54 to 25.10], and 24.39 [8.11 to 73.33], respectively). Regardless of HBeAg status, the T1653 mutation increases the risk of HCC in Japanese patients with HBV/C2.
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Affiliation(s)
- Noboru Shinkai
- Department of Clinical Molecular Informative Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
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50
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Lau CC, Yue PYK, Chui SH, Chui AKK, Yam WC, Wong RNS. Detection of single nucleotide polymorphisms in hepatitis B virus precore/basal core promoter region by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Anal Biochem 2007; 366:93-5. [PMID: 17498640 DOI: 10.1016/j.ab.2007.03.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2006] [Revised: 03/06/2007] [Accepted: 03/07/2007] [Indexed: 11/25/2022]
Affiliation(s)
- C C Lau
- Department of Biology, Science Faculty, Hong Kong Baptist University, Hong Kong
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