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1
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Marlet J, Lier C, Roch E, Moreau A, Combe B, Handala L, Lefeuvre S, Maugey M, Elkrief L, d'Alteroche L, Potier P, Brand D, Gaudy-Graffin C. Evolution and phenotypic characterization of whole HBV genome in compliant patients experiencing unexplained entecavir treatment failure. Antiviral Res 2021; 192:105106. [PMID: 34214504 DOI: 10.1016/j.antiviral.2021.105106] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 04/29/2021] [Accepted: 05/31/2021] [Indexed: 12/20/2022]
Abstract
Entecavir treatment failure can be observed in compliant patients despite an absence of detectable resistance mutations by Pol/RT Sanger sequencing. We hypothesized that these unexplained treatment failures could rely on other mechanisms of viral resistance, especially on mutations selected outside of the Pol/RT domain. Partial virological response to entecavir was observed in three patients treated with immunosuppressive drugs, without selection of Pol/RT resistance mutations. Mutations selected in the whole HBV genome during entecavir treatment and potentially associated with resistance were searched for using deep sequencing and characterized using a phenotypic resistance assay. Mutations Q206K (pre-core/core), Q120K (pre-S1/pre-S2, T-cell epitope) and A300E (spacer domain) were selected during entecavir treatment in patient #1 but were not associated with an increased level of resistance to entecavir or an increase in HBV replication capacity. Core promoter mutations T1753G, A1762T and G1764A were present as major mutations before and after treatment in patient #1. HBs Ag immune escape mutations were present as major mutations before and after treatment in patients #2 (sK122R, sT126I, sP127S and sG145R) and #3 (sM133I). We demonstrated that PVR to entecavir does not require selection of any resistance mutation in the whole HBV genome. Our results demonstrate that major mutations can be selected outside of the Pol/RT domain before or during entecavir treatment. These mutations could contribute to entecavir treatment failure by other mechanisms than an increased level of resistance.
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Affiliation(s)
- Julien Marlet
- INSERM U1259, Université de Tours et CHRU de Tours, France; Service de Bactériologie-Virologie-Hygiène, CHRU de Tours, France.
| | - Clément Lier
- INSERM U1259, Université de Tours et CHRU de Tours, France; Service de Bactériologie-Virologie-Hygiène, CHRU de Tours, France
| | | | - Alain Moreau
- INSERM U1259, Université de Tours et CHRU de Tours, France
| | - Benjamin Combe
- INSERM U1259, Université de Tours et CHRU de Tours, France
| | - Lynda Handala
- INSERM U1259, Université de Tours et CHRU de Tours, France
| | | | - Morgan Maugey
- INSERM U1259, Université de Tours et CHRU de Tours, France
| | - Laure Elkrief
- Service D'Hépato-gastroentérologie, CHRU de Tours, France
| | | | - Pascal Potier
- Service D'Hépato-gastroentérologie, CHR D'Orléans, France
| | - Denys Brand
- INSERM U1259, Université de Tours et CHRU de Tours, France; Service de Bactériologie-Virologie-Hygiène, CHRU de Tours, France
| | - Catherine Gaudy-Graffin
- INSERM U1259, Université de Tours et CHRU de Tours, France; Service de Bactériologie-Virologie-Hygiène, CHRU de Tours, France
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2
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El-Mokhtar MA, Hetta HF, Mekky MA, Abd El-Kareem DM, Ramadan M, Salah M, Mohamed NA, El-Masry EA, Adel S, Sayed IM. Characterization of Antigen Escape Mutations in Chronic HBV-Infected Patients in Upper Egypt. Infect Drug Resist 2021; 14:2419-2427. [PMID: 34234472 PMCID: PMC8254413 DOI: 10.2147/idr.s315299] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Accepted: 05/24/2021] [Indexed: 12/27/2022] Open
Abstract
Background Mutations within the “a” determinant region (position 124–147) that is present in the major hydrophilic region (MHR, position 99–160) of the hepatitis B surface antigen (HBsAg) are associated with vaccine-escape, lack of diagnosis, and failure to hepatitis B immunoglobulin (HBIG) therapy. Data regarding the amino acid changes of “a” determinant region of HBsAg are limited in Egypt. The prevalence and mutations in this region among chronic HBV (CHB)-infected patients in Upper Egypt are not known. Material and Methods Blood samples were collected from HBsAg-positive CHB-infected patients (n=123) admitted to Assiut University Hospitals. Serum samples were screened for HBsAg, HBeAg, anti-HBs and anti-HBe antibodies using commercially available ELISA kits. Viral load was determined by qPCR. In addition, mutational analysis was carried out targeting the HBV surface gene to determine the HBV genotype and vaccine escape mutations. Results Sequencing analysis of HBV DNA revealed that genotype D is the major circulating type (81.3%), followed by genotype E (18.7%). Analysis of the HBV genome revealed that 103/123 (83.7%) patients showed wild-type sequences and 20/123 (16.3%) showed mutations in the HBsAg gene. Mutation in seventeen patients (17/20, 85%) showed only one mutation, and three patients showed two mutations (3/20, 15%) in the “a” determinant region. The observed mutations were T115S (3/20, 15%), P120T/S (3/20, 15%), T126S (1/20, 5%), Q129R (2/20, 10%), M133T (2/20, 10%), S143L (5/20, 25%), D144E/A (3/20, 15%), and G145R/A (4/20, 20%). Mutations in the “a” determinant region were detected in genotype D isolates only. Conclusion We described for the first time the prevalence and characterization of vaccine escape mutants in CHB patients in Upper Egypt. Mutational analysis of the “a” determinant region revealed the presence of a wide spectrum of mutants in the circulating HBV isolates that could be a potential threat to HBV diagnosis, therapy success, and HBV vaccination program in Upper Egypt.
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Affiliation(s)
- Mohamed A El-Mokhtar
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, 71515, Egypt
| | - Helal F Hetta
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, 71515, Egypt
| | - Mohamed A Mekky
- Department of Tropical Medicine and Gastroenterology, Assiut University Hospital, Assiut, Egypt
| | - Doaa M Abd El-Kareem
- Department of Clinical Pathology, Faculty of Medicine Assiut University, Assiut, Egypt
| | - Mohammed Ramadan
- Microbiology and Immunology Department, Faculty of Pharmacy Al-Azhar University-Assiut branch, Assiut, 71526, Egypt
| | - Mohammed Salah
- Microbiology and Immunology Department, Faculty of Pharmacy Port Said University, Port Said, 42526, Egypt
| | - Nahed A Mohamed
- Department of Medical Biochemistry, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Eman A El-Masry
- Microbiology and Immunology Unit, Department of Pathology, College of Medicine, Jouf University, Al-Jouf, Saudi Arabia.,Department of Medical Microbiology and Immunology, College of Medicine, Menoufia University, Menoufia, Egypt
| | - Sara Adel
- Department of Clinical Pathology, Faculty of Medicine, Al-Azhar University, Assiut, 71515, Egypt
| | - Ibrahim M Sayed
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, 71515, Egypt.,Department of Pathology, School of Medicine, University of California, San Diego, CA, 92093, USA
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3
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Svicher V, Salpini R, Malagnino V, Piermatteo L, Alkhatib M, Cerva C, Sarmati L. New Markers in Monitoring the Reactivation of Hepatitis B Virus Infection in Immunocompromised Hosts. Viruses 2019; 11:v11090783. [PMID: 31450680 PMCID: PMC6784136 DOI: 10.3390/v11090783] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2019] [Revised: 08/21/2019] [Accepted: 08/23/2019] [Indexed: 02/07/2023] Open
Abstract
Hepatitis B virus (HBV) persistence is at the basis of HBV reactivation as a consequence of chemotherapy and immunosuppressive treatments. The identification of early viral replication indicators and markers of effective HBV immunological control would be useful in monitoring patients who are at risk of potential viral reactivation during the course of immunosuppressive treatment. Currently, international guidelines have shared some criteria to identify patients with a low, medium or high risk of HBV reactivation; however, permanently placing a patient in a definitive category is not always easy. More often, patients move from one category to another during the course of their immunosuppressive treatment; therefore, in many cases, there are no precise indicators or tools for monitoring possible reactivation and establishing the duration and suspension of antiviral prophylaxis. Historically, the sequence of HBV antigens and antibodies and HBV DNA levels has been used to evaluate the different stages of the acute and chronic phases of an HBV infection. In the last few years, new biomarkers, such as anti-HBs and anti-HBc titres, HBV core-related antigen (HBcrAg), ultra-sensitive HBsAg evaluation and HBV RNA, have been used in patients with an HBV infection to evaluate their diagnostic and prognostic potential. The aim of this review is to evaluate the published results on the use of new infection markers in the diagnosis and monitoring of HBV reactivation over the course of immunosuppressive treatments. Moreover, the importance of viral genotypic studies was emphasized, given the diagnostic and therapeutic implications of the mutational profiles of HBsAg during the HBV reactivation phase.
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Affiliation(s)
- Valentina Svicher
- Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Romina Salpini
- Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Vincenzo Malagnino
- Clinic of Infectious Diseases, Department of System Medicine, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Lorenzo Piermatteo
- Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Mohammad Alkhatib
- Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Carlotta Cerva
- Clinic of Infectious Diseases, Department of System Medicine, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Loredana Sarmati
- Clinic of Infectious Diseases, Department of System Medicine, University of Rome Tor Vergata, 00133 Rome, Italy.
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4
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Tillmann HL, Samuel G. Current state-of-the-art pharmacotherapy for the management of hepatitis B infection. Expert Opin Pharmacother 2019; 20:873-885. [PMID: 30857443 DOI: 10.1080/14656566.2019.1583744] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Hepatitis B virus (HBV) infection remains a global challenge with several hundred million infected individuals. Disease activity can be controlled, and adverse outcomes prevented when treatment can be provided. Frequently life-long therapy is required instead of defined treatment periods such as with the case of Hepatitis C Virus (HCV) infection. AREAS COVERED In this review, the authors provide an overview of current start of the art therapy for HBV and indicate where variation from the current guidelines could be considered. Certain patients may be eligible for treatment with suboptimal therapies when their baseline viral load is low. Identifying ideal candidates for interferon therapy will result in good sustained responses for some patients. EXPERT OPINION The biggest challenge remains linking patients to care and therapy. Patients can nowadays be sufficiently treated before the disease advances to a more progressed phase. However, future therapies must be extremely safe and ideally limit the required treatment period. Given Hepatitis D Virus's dependence on HBV and being a disease with an unmet clinical need, HDV may be the best target group for the development of a functional cure for hepatitis B.
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Affiliation(s)
- Hans L Tillmann
- a Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Brody School of Medicine , East Carolina University , Greenville , NC , USA.,b Specialty Clinic , Greenville VA Health Care Center , Greenville , NC , USA
| | - Gbeminiyi Samuel
- a Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Brody School of Medicine , East Carolina University , Greenville , NC , USA
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5
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Ababneh NA, Sallam M, Kaddomi D, Attili AM, Bsisu I, Khamees N, Khatib A, Mahafzah A. Patterns of hepatitis B virus S gene escape mutants and reverse transcriptase mutations among genotype D isolates in Jordan. PeerJ 2019; 7:e6583. [PMID: 30867996 PMCID: PMC6410685 DOI: 10.7717/peerj.6583] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Accepted: 02/08/2019] [Indexed: 12/18/2022] Open
Abstract
Background Hepatitis B virus (HBV) is an important infectious cause of morbidity and mortality in Jordan. HBV genotype D is the most prevalent in the country. Virus escape mutants in the HBV S region is an important public health problem halting preventive efforts. The aim of the current study was to investigate patterns of HBV escape and resistance mutations and to assess domestic transmission of the virus. Methods Patients infected with HBV were recruited at Jordan University Hospital (n = 56) and were diagnosed during (1984-2012). A total of 37 partial HBV S sequences were generated using Sanger's method. Mutation analysis was done using the HIV grade HBV drug resistance interpretation online tool and Geno2pheno (HBV) online tools. Domestic transmission of HBV was assessed using maximum likelihood phylogenetic inference with similar GenBank sequences. Results Genotyping revealed an exclusive presence of sub-genotype D1. Typical HBV escape mutants were identified in seven patients. These mutations included: L109R, Q129R, M133L, S143L and D144E with overall prevalence of 18.9% (95% CI [9.5-34.2]). Reverse transcriptase (RT) sequence analysis showed mutations in three patients with overall prevalence of 8.1% (95% CI [2.8-21.3]). RT mutations included: V173L, S202I, L180M, M204V and T184A. Transmission cluster analysis revealed a relatively high proportion of infections taking place as a result of domestic spread (29.7%). Conclusions Based on our findings, RT mutation analysis appears to be of high value before the initiation of therapy in patients with chronic HBV infection in Jordan. Phylogenetic analyses revealed a considerable proportion of local spread in the country which should be considered in the preventive infection control efforts.
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Affiliation(s)
- Nidaa A Ababneh
- Cell Therapy Center (CTC), University of Jordan, Amman, Jordan
| | - Malik Sallam
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, University of Jordan, Amman, Jordan.,Department of Clinical Laboratories and Forensic Medicine, Jordan University Hospital, Amman, Jordan.,Department of Translational Medicine, Faculty of Medicine, Lund University, Malmö, Sweden
| | - Doaa Kaddomi
- Gastroenterology and Liver Division, Department of Internal Medicine, Jordan University Hospital, Amman, Jordan
| | | | - Isam Bsisu
- School of Medicine, University of Jordan, Amman, Jordan
| | - Nadia Khamees
- Gastroenterology and Liver Division, Department of Internal Medicine, Jordan University Hospital, Amman, Jordan
| | - Amer Khatib
- Gastroenterology and Liver Division, Department of Internal Medicine, Jordan University Hospital, Amman, Jordan
| | - Azmi Mahafzah
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, University of Jordan, Amman, Jordan.,Department of Clinical Laboratories and Forensic Medicine, Jordan University Hospital, Amman, Jordan
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6
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Zhang Q, Chen J, Pan M, Liu J, Liu T, Zhou YH. Comparison of replication competence of wild-type and lamivudine-resistant hepatitis B virus isolates from a chronic hepatitis B patient. Virus Res 2018; 255:165-170. [DOI: 10.1016/j.virusres.2018.07.021] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Revised: 07/30/2018] [Accepted: 07/30/2018] [Indexed: 12/16/2022]
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7
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Colagrossi L, Hermans LE, Salpini R, Di Carlo D, Pas SD, Alvarez M, Ben-Ari Z, Boland G, Bruzzone B, Coppola N, Seguin-Devaux C, Dyda T, Garcia F, Kaiser R, Köse S, Krarup H, Lazarevic I, Lunar MM, Maylin S, Micheli V, Mor O, Paraschiv S, Paraskevis D, Poljak M, Puchhammer-Stöckl E, Simon F, Stanojevic M, Stene-Johansen K, Tihic N, Trimoulet P, Verheyen J, Vince A, Lepej SZ, Weis N, Yalcinkaya T, Boucher CAB, Wensing AMJ, Perno CF, Svicher V. Immune-escape mutations and stop-codons in HBsAg develop in a large proportion of patients with chronic HBV infection exposed to anti-HBV drugs in Europe. BMC Infect Dis 2018; 18:251. [PMID: 29859062 PMCID: PMC5984771 DOI: 10.1186/s12879-018-3161-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2017] [Accepted: 05/23/2018] [Indexed: 12/27/2022] Open
Abstract
Background HBsAg immune-escape mutations can favor HBV-transmission also in vaccinated individuals, promote immunosuppression-driven HBV-reactivation, and increase fitness of drug-resistant strains. Stop-codons can enhance HBV oncogenic-properties. Furthermore, as a consequence of the overlapping structure of HBV genome, some immune-escape mutations or stop-codons in HBsAg can derive from drug-resistance mutations in RT. This study is aimed at gaining insight in prevalence and characteristics of immune-associated escape mutations, and stop-codons in HBsAg in chronically HBV-infected patients experiencing nucleos(t)ide analogues (NA) in Europe. Methods This study analyzed 828 chronically HBV-infected European patients exposed to ≥ 1 NA, with detectable HBV-DNA and with an available HBsAg-sequence. The immune-associated escape mutations and the NA-induced immune-escape mutations sI195M, sI196S, and sE164D (resulting from drug-resistance mutation rtM204 V, rtM204I, and rtV173L) were retrieved from literature and examined. Mutations were defined as an aminoacid substitution with respect to a genotype A or D reference sequence. Results At least one immune-associated escape mutation was detected in 22.1% of patients with rising temporal-trend. By multivariable-analysis, genotype-D correlated with higher selection of ≥ 1 immune-associated escape mutation (OR[95%CI]:2.20[1.32–3.67], P = 0.002). In genotype-D, the presence of ≥ 1 immune-associated escape mutations was significantly higher in drug-exposed patients with drug-resistant strains than with wild-type virus (29.5% vs 20.3% P = 0.012). Result confirmed by analysing drug-naïve patients (29.5% vs 21.2%, P = 0.032). Strong correlation was observed between sP120T and rtM204I/V (P < 0.001), and their co-presence determined an increased HBV-DNA. At least one NA-induced immune-escape mutation occurred in 28.6% of patients, and their selection correlated with genotype-A (OR[95%CI]:2.03[1.32–3.10],P = 0.001). Finally, stop-codons are present in 8.4% of patients also at HBsAg-positions 172 and 182, described to enhance viral oncogenic-properties. Conclusions Immune-escape mutations and stop-codons develop in a large fraction of NA-exposed patients from Europe. This may represent a potential threat for horizontal and vertical HBV transmission also to vaccinated persons, and fuel drug-resistance emergence. Electronic supplementary material The online version of this article (10.1186/s12879-018-3161-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Luna Colagrossi
- Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Via Montpellier, 1, 00133, Rome, Italy
| | - Lucas E Hermans
- Virology, Department of Medical Microbiology, University Medical Centre Utrecht, Utrecht, The Netherlands.,Department of Viroscience, Erasmus Medical Centre, Rotterdam, The Netherlands
| | - Romina Salpini
- Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Via Montpellier, 1, 00133, Rome, Italy
| | - Domenico Di Carlo
- Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Via Montpellier, 1, 00133, Rome, Italy
| | - Suzan D Pas
- Department of Viroscience, Erasmus Medical Centre, Rotterdam, The Netherlands
| | - Marta Alvarez
- Servicio de Microbiología, Hospital San Cecilio, Instituto de Investigación Biosanitaria ibs.GRANADA, Hospitales Universitarios de Granada, Granada, Spain
| | - Ziv Ben-Ari
- Liver Disease Centre, Sheba Medical Centre, Ramat Gan, Israel
| | - Greet Boland
- Virology, Department of Medical Microbiology, University Medical Centre Utrecht, Utrecht, The Netherlands
| | | | - Nicola Coppola
- Malattie Infettive, Seconda Università degli studi di Napoli, Naples, Italy
| | | | - Tomasz Dyda
- Molecular Diagnostics Laboratory, Hospital of Infectious Diseases, Warsaw, Poland
| | - Federico Garcia
- Servicio de Microbiología, Hospital San Cecilio, Instituto de Investigación Biosanitaria ibs.GRANADA, Hospitales Universitarios de Granada, Granada, Spain
| | - Rolf Kaiser
- Institute of Virology, University of Cologne, Cologne, Germany
| | - Sukran Köse
- Izmir Tepecik Education and Research Hospital, Clinic of Infectious Diseases and Clinical Microbiology, Izmir, Turkey
| | - Henrik Krarup
- Section of Molecular Diagnostics, Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
| | - Ivana Lazarevic
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Maja M Lunar
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Sarah Maylin
- Service de Microbiologie, University Paris Diderot, Hôpital Saint Louis, Paris, France
| | | | - Orna Mor
- National HIV Reference Laboratory, Central Virology Laboratory, Ministry of Health, Tel Hashomer, Ramat Gan, Israel
| | - Simona Paraschiv
- Molecular Diagnostics Laboratory, National Institute for Infectious Diseases "Matei Bals", Bucharest, Romania
| | - Dimitros Paraskevis
- National Retrovirus Reference Centre, Department of Hygiene, Epidemiology and Medical Statistics, Faculty of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Mario Poljak
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | | | - François Simon
- Service de Microbiologie, University Paris Diderot, Hôpital Saint Louis, Paris, France
| | - Maja Stanojevic
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | | | - Nijaz Tihic
- Institute of Microbiology, Polyclinic for Laboratory Diagnostics, University Clinical Centre Tuzla, Tuzla, Bosnia and Herzegovina
| | - Pascale Trimoulet
- Virology Laboratory, Centre Hospitalier Régional et Université "Victor Segalen", Bordeaux, France
| | - Jens Verheyen
- Institute of Virology, University-Hospital, University Duisburg-Essen, Essen, Germany
| | - Adriana Vince
- University of Zagreb School of Medicine and University Hospital for Infectious Diseases, Zagreb, Croatia
| | - Snjezana Zidovec Lepej
- University of Zagreb School of Medicine and University Hospital for Infectious Diseases, Zagreb, Croatia
| | - Nina Weis
- Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Copenhagen, Denmark
| | | | - Charles A B Boucher
- Department of Viroscience, Erasmus Medical Centre, Rotterdam, The Netherlands
| | - Annemarie M J Wensing
- Virology, Department of Medical Microbiology, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - Carlo F Perno
- Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Via Montpellier, 1, 00133, Rome, Italy.
| | - Valentina Svicher
- Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Via Montpellier, 1, 00133, Rome, Italy.
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8
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Mok S, Mohan S, Hunter KM, Wang YR, Judge TA. Entecavir for patients with lamivudine‐resistant chronic hepatitis B virus infection. Cochrane Database Syst Rev 2017; 2017:CD012495. [PMCID: PMC6464809 DOI: 10.1002/14651858.cd012495] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/31/2023]
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To evaluate the benefits and harms of entecavir versus no intervention, placebo, and non‐entecavir interventions in adults with lamivudine‐resistant, chronic hepatitis B virus infection.
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Affiliation(s)
- Shaffer Mok
- Cooper University Hospital at Rowan University School of MedicineDepartment of Internal Medicine, Division of Gastroenterology and Liver Diseases501 Fellowship RoadSuite 101Mt. LaurelUSA08054
| | - Sachin Mohan
- Cooper University HospitalDepartment of Internal Medicine3rd floor, 401 Haddon AvenueCamdenUSA08103
| | - Krystal M Hunter
- Cooper University HospitalBiostatistics/Research Institute1 Cooper PlazaCamdenUSA08103
| | - Yize R Wang
- Cooper University Hospital at Rowan University School of MedicineDepartment of Internal Medicine, Division of Gastroenterology and Liver Diseases501 Fellowship RoadSuite 101Mt. LaurelUSA08054
| | - Thomas A Judge
- Cooper University Hospital at Rowan University School of MedicineDepartment of Internal Medicine, Division of Gastroenterology and Liver Diseases501 Fellowship RoadSuite 101Mt. LaurelUSA08054
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9
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Mok S, Mohan S, Hunter KM, Wang YR, Judge TA. Emtricitabine for adults with lamivudine-resistant chronic hepatitis B virus infection. Hippokratia 2017. [DOI: 10.1002/14651858.cd012496] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Affiliation(s)
- Shaffer Mok
- Cooper University Hospital at Rowan University School of Medicine; Department of Internal Medicine, Division of Gastroenterology and Liver Diseases; 501 Fellowship Road Suite 101 Mt. Laurel NJ USA 08054
| | - Sachin Mohan
- Cooper University Hospital; Department of Internal Medicine; 3rd floor, 401 Haddon Avenue Camden NJ USA 08103
| | - Krystal M Hunter
- Cooper University Hospital; Biostatistics/Research Institute; 1 Cooper Plaza Camden NJ USA 08103
| | - Yize R Wang
- Cooper University Hospital at Rowan University School of Medicine; Department of Internal Medicine, Division of Gastroenterology and Liver Diseases; 501 Fellowship Road Suite 101 Mt. Laurel NJ USA 08054
| | - Thomas A Judge
- Cooper University Hospital at Rowan University School of Medicine; Department of Internal Medicine, Division of Gastroenterology and Liver Diseases; 501 Fellowship Road Suite 101 Mt. Laurel NJ USA 08054
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10
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Persistent risk of HBV reactivation despite extensive lamivudine prophylaxis in haematopoietic stem cell transplant recipients who are anti-HBc-positive or HBV-negative recipients with an anti-HBc-positive donor. Clin Microbiol Infect 2016; 22:946.e1-946.e8. [PMID: 27475741 DOI: 10.1016/j.cmi.2016.07.021] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Revised: 07/08/2016] [Accepted: 07/16/2016] [Indexed: 02/08/2023]
Abstract
The overall rate of hepatitis B virus (HBV) reactivation was evaluated in a population of 373 haematological stem cell transplant (HSCT) patients treated with lamivudine (LMV) if they were anti-HBc-positive/HBV-DNA-negative recipients or if they were HBV-negative recipients with an anti-HBc-positive donor. The incidence of HBV reactivation was calculated in two groups of autologous (auto) or allogeneic (allo) HSCT patients who were stratified according to their HBV serostatus. The former group included 57 cases: 10 auto-HSCT and 27 allo-HSCT anti-HBc-positive recipients, two auto-HSCT and three allo-HSCT inactive carriers, and 15 allo-HSCT recipients with an anti-HBc-positive donor. Forty-seven (82.4%) patients in this group received LMV prophylaxis (the median (interquartile range, IQR) of LMV treatment was 30 (20-38) months). The second group consisted of 320 anti-HBc-negative auto-HSCT and allo-HSCT recipients with anti-HBc-negative donors. None of these patients received any prophylaxis. Two patients in the first group and two in the second group experienced reactivation of HBV infection, with an incidence of 3.5% (95% CI 0.4-12.1%) and 0.6% (95% CI 0.1-2.2%), respectively. Only one out of four reactivated patients was LMV-treated. The cumulative probability of HBV reactivation at 6 years from HSCT was 15.8% (95% CI 15.2-16.4%). Three of four viral isolates obtained from the HBV-reactivated patients harboured mutations in the immune-active HBsAg-region. In a HSCT population carefully evaluated for HBV prophylaxis, a risk of HBV reactivation persisted in the group of patients who were not LMV-treated. Only one LMV-treated patient experienced reactivation of HBV with a resistant HBV isolate.
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Rezaee R, Poorebrahim M, Najafi S, Sadeghi S, Pourdast A, Alavian SM, Alavian SE, Poortahmasebi V. Impacts of the G145R Mutation on the Structure and Immunogenic Activity of the Hepatitis B Surface Antigen: A Computational Analysis. HEPATITIS MONTHLY 2016; 16:e39097. [PMID: 27642350 PMCID: PMC5018363 DOI: 10.5812/hepatmon.39097] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Revised: 05/17/2016] [Accepted: 06/11/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND Vaccine-escaped hepatitis B virus (HBV) mutations occur within the "a" determinant area, which is located in the major hydrophilic region (MHR) of the hepatitis B surface antigen (HBsAg) protein. It is now well established that the common G145R mutation is highly capable of escaping from HBsAg immune recognition. However, the impacts of this mutation on the structure and immunogenic activity of HBsAg have been poorly investigated. OBJECTIVES The present study analyzed the effects of the G145R mutation on the structure and immunogenic activity of the HBsAg. MATERIALS AND METHODS Three-dimensional (3D) structure of HBsAg for both the wild-type and G145R mutant were predicted and refined using several web tools. After quantitative evaluations, the effects of the G145R mutation on the secondary and 3D structures of the HBsAg were investigated. In parallel, the immunogenic activity of the wild-type and mutant HBsAg was also analyzed using a ClusPro docking server as well as the IEDB web tool. Further analyses were performed via molecular dynamics (MD) simulations using the GROMACS v5.0.2 simulation package. RESULTS The G145R mutation causes a considerable reduction in the immunogenic activity of the HBsAg through a conformational change in the HBsAg antigenic loops. This mutation inserts a new β-strand in the "a" determinant region of the HBsAg, leading to a reduced binding affinity to its monoclonal antibody, MAb12. The G145R mutation also increased the compactness and stability of the HBsAg by enhancing the rigidity of the "a" determinant. CONCLUSIONS These data will be beneficial for designing more advanced antibodies for the recognition of the HBsAg in diagnostics. In addition, the results of this study may assist in the design or development of more effective hepatitis B vaccines.
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Affiliation(s)
- Reza Rezaee
- Ministry of Health and Medical Education, Deputy of Curative Affairs, Budget Administration, Tehran, IR Iran
| | - Mansour Poorebrahim
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, IR Iran
| | - Saeideh Najafi
- Department of Microbiology, Tonekabon branch, Islamic Azad University, Tonekabon, Mazandaran, IR Iran
| | - Solmaz Sadeghi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, IR Iran
| | - Alieh Pourdast
- Department of Infectious Diseases, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, IR Iran
| | - Seyed Moayed Alavian
- Middle East Liver Diseases (MELD) Center, Tehran, IR Iran
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
| | - Seyed Ehsan Alavian
- Middle East Liver Diseases (MELD) Center, Tehran, IR Iran
- Hepatitis B Molecular Laboratory, Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, IR Iran
| | - Vahdat Poortahmasebi
- Hepatitis B Molecular Laboratory, Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, IR Iran
- Corresponding Author: Vahdat Poortahmasebi, Hepatitis B Molecular Laboratory, Department of Virology, School of Public Health, Tehran University of Medical Sciences, P. O. Box: 151556446, Tehran, IR Iran. Tel: +98-2188992660, E-mail:
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Rational Basis for Optimizing Short and Long-term Hepatitis B Virus Prophylaxis Post Liver Transplantation: Role of Hepatitis B Immune Globulin. Transplantation 2016; 99:1321-34. [PMID: 26038873 PMCID: PMC4539198 DOI: 10.1097/tp.0000000000000777] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Antiviral therapy using newer nucleos(t)ide analogues with lower resistance rates, such as entecavir or tenofovir, suppress hepatitis B virus (HBV) replication, improve liver function in patients with compensated or decompensated cirrhosis, and delay or obviate the need for liver transplantation in some patients. After liver transplantation, the combination of long-term antiviral and low-dose hepatitis B Immune globulin (HBIG) can effectively prevent HBV recurrence in greater than 90% of transplant recipients. Some forms of HBV prophylaxis need to be continued indefinitely after transplantation but, in patients with a low-risk of HBV recurrence (i.e., HBV DNA levels undetectable before transplantation), it is possible to discontinue HBIG and maintain only long-term nucleos(t)ide analogue(s) therapy. A more cautious approach is necessary for those patients with high pretransplant HBV DNA levels, those with limited antiviral options if HBV recurrence occurs (i.e., HIV or hepatitis D virus coinfection, preexisting drug resistance), those with a high risk of hepatocellular carcinoma recurrence, and those at risk of noncompliance with antiviral therapy. In this group, HBIG-free prophylaxis cannot be recommended. The combination of long-term antiviral and low-dose Hepatitis B Immune globulin (HBIG) can effectively prevent HBV recurrence in > 90% of liver transplant recipients. In patients with low HBV DNA levels, nucleos(t)ide analogue(s) treatment without HBIG is possible.
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Mok S, Mohan S, Hunter KM, Wang YR, Judge TA. Continued lamivudine for adults with lamivudine-resistant chronic hepatitis B virus infection. Hippokratia 2016. [DOI: 10.1002/14651858.cd012168] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Shaffer Mok
- Cooper University Hospital at Rowan University School of Medicine; Department of Internal Medicine, Division of Gastroenterology and Liver Diseases; 501 Fellowship Road Suite 101 Mt. Laurel NJ USA 08054
| | - Sachin Mohan
- Cooper University Hospital; Department of Internal Medicine; 3rd floor, 401 Haddon Avenue Camden USA 08103
| | - Krystal M Hunter
- Cooper University Hospital; Biostatistics/Research Institute; 1 Cooper Plaza Camden NJ USA 08103
| | - Yize R Wang
- Cooper University Hospital at Rowan University School of Medicine; Department of Internal Medicine, Division of Gastroenterology and Liver Diseases; 501 Fellowship Road Suite 101 Mt. Laurel NJ USA 08054
| | - Thomas A Judge
- Cooper University Hospital at Rowan University School of Medicine; Department of Internal Medicine, Division of Gastroenterology and Liver Diseases; 501 Fellowship Road Suite 101 Mt. Laurel NJ USA 08054
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Mok S, Mohan S, Hunter KM, Wang YR, Judge TA. Interferon for people with lamivudine-resistant chronic hepatitis B virus infection. Hippokratia 2016. [DOI: 10.1002/14651858.cd012138] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Affiliation(s)
- Shaffer Mok
- Cooper University Hospital at Rowan University School of Medicine; Department of Internal Medicine, Division of Gastroenterology and Liver Diseases; 501 Fellowship Road Suite 101 Mt. Laurel NJ USA 08054
| | - Sachin Mohan
- Cooper University Hospital; Department of Internal Medicine; 3rd floor, 401 Haddon Avenue Camden USA 08103
| | - Krystal M Hunter
- Cooper University Hospital; Biostatistics/Research Institute; 1 Cooper Plaza Camden NJ USA 08103
| | - Yize R Wang
- Cooper University Hospital at Rowan University School of Medicine; Department of Internal Medicine, Division of Gastroenterology and Liver Diseases; 501 Fellowship Road Suite 101 Mt. Laurel NJ USA 08054
| | - Thomas A Judge
- Cooper University Hospital at Rowan University School of Medicine; Department of Internal Medicine, Division of Gastroenterology and Liver Diseases; 501 Fellowship Road Suite 101 Mt. Laurel NJ USA 08054
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15
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Mok S, Mohan S, Hunter KM, Wang YR, Judge TA. Adefovir dipivoxil for adults with lamivudine-resistant chronic hepatitis B virus infection. Hippokratia 2015. [DOI: 10.1002/14651858.cd011981] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Affiliation(s)
- Shaffer Mok
- Cooper University Hospital at Rowan University School of Medicine; Department of Internal Medicine, Division of Gastroenterology and Liver Diseases; 501 Fellowship Road Suite 101 Mt. Laurel NJ USA 08054
| | - Sachin Mohan
- Cooper University Hospital; Department of Internal Medicine; 3rd floor, 401 Haddon Avenue Camden USA 08103
| | - Krystal M Hunter
- Cooper University Hospital; Biostatistics/Research Institute; 1 Cooper Plaza Camden NJ USA 08103
| | - Yize R Wang
- Cooper University Hospital; Department of Internal Medicine, Division of Gastroenterology and Liver Diseases; 501 Fellowship Road Suite 101 Mt. Laurel NJ USA 08054
| | - Thomas A Judge
- Cooper University Hospital; Department of Internal Medicine, Division of Gastroenterology and Liver Diseases; 501 Fellowship Road Suite 101 Mt. Laurel NJ USA 08054
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16
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Chronic Hepatitis B with Spontaneous Severe Acute Exacerbation. Int J Mol Sci 2015; 16:28126-45. [PMID: 26703566 PMCID: PMC4691034 DOI: 10.3390/ijms161226087] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Revised: 11/03/2015] [Accepted: 11/09/2015] [Indexed: 02/08/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection is a major global health problem with an estimated 400 million HBV carriers worldwide. In the natural history of chronic hepatitis B (CHB), spontaneous acute exacerbation (AE) is not uncommon, with a cumulative incidence of 10%–30% every year. While exacerbations can be mild, some patients may develop hepatic decompensation and even die. The underlying pathogenesis is possibly related to the activation of cytotoxic T lymphocyte-mediated immune response against HBV. An upsurge of serum HBV DNA usually precedes the rise of alanine aminotransferase (ALT) and bilirubin. Whether antiviral treatment can benefit CHB with severe AE remains controversial, but early nucleos(t)ide analogues treatment seemed to be associated with an improved outcome. There has been no randomized study that compared the effects of different nucleos(t)ide analogues (NA) in the setting of CHB with severe AE. However, potent NAs with good resistance profiles are recommended. In this review, we summarized current knowledge regarding the natural history, pathogenetic mechanisms, and therapeutic options of CHB with severe AE.
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Zhang Q, Han T, Nie CY, Ha FS, Liu L, Liu H. Tenofovir rescue regimen following prior suboptimal response to entecavir and adefovir combination therapy in chronic hepatitis B patients exposed to multiple treatment failures. J Med Virol 2015; 87:1013-21. [PMID: 25716029 DOI: 10.1002/jmv.24153] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/07/2015] [Indexed: 12/16/2022]
Abstract
In clinical practice, establishing a subsequent optimum treatment for chronic hepatitis B patients with a history of multiple NAs treatment failures, including a suboptimal response to a final therapy with combined ETV and ADV, is a complicated but crucial challenge. This study investigated the efficacy and safety of a tenofovir rescue regimen in these patients. A total of six eligible patients were enrolled and were switched to a tenofovir rescue regimen. At baseline, the genotypes and genotypic mutations of the reverse transcriptase and surface gene were determined by ultra-deep pyrosequencing, and further clonal analyses of the reverse transcriptase domain were performed to identify multidrug-resistant HBV strains. In addition, HBV DNA levels, serology, and biochemistry parameters were monitored at baseline and every 3 months, and abdominal ultrasonography was performed at baseline and every 6 months. All patients were confirmed to harbor LAM-related resistant HBV strains. After switching to the tenofovir rescue treatment, all patients had an undetectable level of HBV DNA within 6 months and achieved normalization of the ALT level within 9 months. These virological and biochemical responses persisted until the end of the observation period. None of the patients developed clinical deterioration or any adverse events related to the tenofovir therapy during the median 16.5-month follow-up. In conclusion, the tenofovir rescue regimen can be employed confidently as a highly effective and safe treatment choice following a suboptimal response to ETV plus ADV therapy for a subset of chronic hepatitis B patients with a history of multiple unsuccessful antiviral treatments.
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Affiliation(s)
- Qian Zhang
- The Third Central Clinical College of Tianjin Medical University, Tianjin, China; Department of Hepatology, Tianjin Third Central Hospital, Tianjin, China
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18
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Thio CL, Hawkins C. Hepatitis B Virus and Hepatitis Delta Virus. MANDELL, DOUGLAS, AND BENNETT'S PRINCIPLES AND PRACTICE OF INFECTIOUS DISEASES 2015:1815-1839.e7. [DOI: 10.1016/b978-1-4557-4801-3.00148-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Fan J, Wang Y, Xiong H, Guo X, Cheng YC. Impact of the rtI187V polymerase substitution of hepatitis B virus on viral replication and antiviral drug susceptibility. J Gen Virol 2014; 95:2523-2530. [PMID: 25028473 DOI: 10.1099/vir.0.066886-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
A high prevalence of the rtI187V polymerase substitution of hepatitis B virus (HBV) was detected in nucleoside/nucleotide-analogue-naive and -treated chronic hepatitis B (CHB) patients. We aimed at assessing the replicative capacity and susceptibility to lamivudine (LAM) and adefovir (ADV) in vitro of HBV harbouring rtI187V alone or in conjunction with LAM- or ADV-resistant mutations. The reverse transcriptase region of HBV isolates was directly sequenced from a cohort of 300 CHB patients from China. Replication-competent HBV constructs containing rtI187V and combined with LAM-resistant (rtM204I, rtL180M/rtM204V) mutations were generated, and compared with WT, LAM-resistant single (rtM204I) or double (rtL180M/rtM204V) and ADV-resistant (rtN236T) clones. In a Chinese cohort of 300 CHB patients, 8.7 % (26/300) showed substitution of rtI187 with V. Of note, the rtI187V prevalence in HBV genotype B was significantly higher than that in HBV genotype C (95.2 vs 4.8 %). In vitro phenotypic assays showed that the viruses bearing the rtI187V substitution had impaired replication efficacy when compared with the WT and the virus carrying rtI187V combined with LAM-resistant single or double mutations showed even more significantly impaired replicative capacities. Furthermore, rtI187V HBV remained susceptible towards treatment with LAM or ADV in vitro whereas the combination of the rtI187V substitution with LAM-resistant mutations rendered HBV resistant to LAM but still sensitive to ADV. Our study revealed that the rtI187V substitution in the HBV polymerase frequently occurred in CHB patients, particularly those with HBV genotype B. However, the emergence of the rtI187V substitution significantly impaired viral replication but without affecting drug sensitivity in vitro.
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Affiliation(s)
- Jiyun Fan
- Department of Microbiology and Immunology, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Ying Wang
- Department of Microbiology and Immunology, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Hui Xiong
- Chinese National Human Genome Center, Shanghai, PR China
| | - Xiaokui Guo
- Department of Microbiology and Immunology, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Yung-Chi Cheng
- Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA
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20
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Matthews PC, Geretti AM, Goulder PJR, Klenerman P. Epidemiology and impact of HIV coinfection with hepatitis B and hepatitis C viruses in Sub-Saharan Africa. J Clin Virol 2014; 61:20-33. [PMID: 24973812 DOI: 10.1016/j.jcv.2014.05.018] [Citation(s) in RCA: 101] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2014] [Revised: 05/22/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023]
Abstract
Human immunodeficiency virus (HIV), Hepatitis B (HBV) and Hepatitis C (HCV) are blood-borne viruses with potentially shared routes of transmission. In high-income settings, the impact of antiretroviral therapy (ART) on survival has unmasked chronic liver disease from viral hepatitis B or hepatitis C as a leading cause of morbidity and mortality in individuals with HIV infection. It is now feared that progressive liver disease may threaten the success of ART programmes in developing countries, where HCV or HBV testing and monitoring are not yet systematic among HIV-infected patients and ART use is generally blind to these co-infections. We set out to review recent data from Sub-Saharan Africa, in order to build a detailed and up-to-date picture of the epidemiology and emerging impact of HBV and HCV coinfection in countries at the heart of the HIV pandemic. There is a preponderance of HIV/HBV coinfection compared to HIV/HCV in this region, and significant caveats exist regarding the accuracy of published HCV seroprevalence surveys. Morbidity and mortality of coinfection is significant, and may be further enhanced in African populations due to the influence of host, viral and environmental factors. Careful scrutiny of the coinfection problem is vital to inform an approach to directing resources, planning public health initiatives, providing clinical care, and guiding future research.
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Affiliation(s)
- Philippa C Matthews
- Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, South Parks Road, Oxford OX1 3SY, UK; Department of Infectious Diseases and Microbiology, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK.
| | - Anna Maria Geretti
- Institute of Infection and Global Health, University of Liverpool, 8 West Derby Street, Liverpool L69 7BE, UK
| | - Philip J R Goulder
- Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, South Parks Road, Oxford OX1 3SY, UK; Department of Paediatrics, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK
| | - Paul Klenerman
- Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, South Parks Road, Oxford OX1 3SY, UK; Department of Infectious Diseases and Microbiology, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK; NIHR Biomedical Research Centre, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK
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Park GC, Hwang S, Ahn CS, Kim KH, Moon DB, Ha TY, Song GW, Jung DH, Shin YW, Kim SH, Chang KH, Namgoong JM, Park CS, Park HW, Park YH, Kang SH, Jung BH, Lee SG. Analysis of S gene mutation of the hepatitis B virus in adult liver transplant recipients showing resistance to hepatitis B immunoglobulin therapy. Transplant Proc 2014; 45:3047-51. [PMID: 24157033 DOI: 10.1016/j.transproceed.2013.08.055] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND A considerable proportion of recipients of liver transplantations who are presented hepatitis B immunoglobulin (HBIG) monotherapy for hepatitis B virus (HBV) prophylaxis develop HBIG resistance. In this study, we investigated the mutation patterns in the major hydrophilic region (MHR) of amino acid sequences 100 to 160. METHODS Using the gene sequence analyzer for amino acid sequences 0 to 226 in the S/pre-S region we analyzed blood samples of 15 patients showing HBIG resistance after high-dose HBIG prophylaxis. RESULTS Various mutations in the MHR were observed in 14/15 samples: Gly145Arg mutation in 8/13 Adr subtype and 1/2 Ayw subtype samples (60%). The next most common mutation was Gly165Trp in 8/13 Adr subtype but neither of 2 Ayw subtype samples (53.3%). Concurrent antiviral resistance was noted in 5 patients: lamivudine (n = 5), or entecavir (n = 3), but not adefovir, suggesting the occurrence of simultaneous, antiviral cross-resistances. Two patients underwent retransplantation due to the progression of HBV infection despite vigorous antiviral therapy. At diagnosis of HBV recurrence, the mean HBV DNA load was 6.5 × 10(6) copies/mL; 4 patients showed paradoxical coexistence of anti-HBs and HBsAg. Currently, 2 subjects show low-level HBV DNA replication in peripheral blood, although the other 12 had no DNA replication after prolonged antiviral therapy. CONCLUSIONS This study suggested that various mutations in the "a" determinant were associated with HBIG resistance. Since treatment failure to rescue antiviral therapy was often associated with delayed detection of HBV recurrence rather than concurrent antiviral resistance, frequent HBV surveillance using more sensitive screening tests, such as HBeAg and HBV DNA polymerase chain reaction assay, seems to be mandatory.
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Affiliation(s)
- G-C Park
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Al Baqlani SA, Sy BT, Ratsch BA, Al Naamani K, Al Awaidy S, Busaidy SA, Pauli G, Bock CT. Molecular epidemiology and genotyping of hepatitis B virus of HBsAg-positive patients in Oman. PLoS One 2014; 9:e97759. [PMID: 24835494 PMCID: PMC4023993 DOI: 10.1371/journal.pone.0097759] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Accepted: 04/22/2014] [Indexed: 02/06/2023] Open
Abstract
Background Hepatitis B virus (HBV) infection is a major global health burden with distinct geographic public health significance. Oman is a country with intermediate HBV carrier prevalence; however, little is known about the incidence of HBV variants in circulation. We investigated the HBV genotype distribution, the occurrence of antiviral resistance, and HBV surface antigen (HBsAg) escape mutations in HBsAg-positive patients in Oman. Methods Serum samples were collected from 179 chronically HBV-infected patients enrolled in various gastroenterology clinics in Oman. HBV genotypes were determined by sequencing and phylogenetic analysis. Mutations in the HBV polymerase and the HBsAg gene were characterized by mutational analysis. Results HBV genotypes D (130/170; 76.47%) and A (32/170; 18.28%) are predominant in Oman. The HBV genotypes C and E were less frequent (each 1.18%), while the HBV genotypes B, G, F, and H were not detected. Four patients revealed HBV genotype mixtures (HBV-A/D and D/C). The analyses of vaccine escape mutations yield that 148/170 (87.06%) HBV sequences were wild type. 22/170 (12.94%) HBV sequences showed mutations in the “a” determinant of the HBsAg domain. Two patients showed the described HBV vaccine escape mutation sP120T. 8/146 (5.48%) HBV isolates harbored mutations in the HBV polymerase known to confer resistance against antiviral therapy. Especially the lamivudine resistance mutations rtL180M/rtM204V and rtM204I were detected. Conclusion This study shows the distribution of HBV genotypes, therapy resistance, and vaccine escape mutations in HBV-infected patients in Oman. Our findings will have a major impact on therapy management and diagnostics of chronic HBV infections in Oman to control HBV infection in this intermediate HBV-endemic country.
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Affiliation(s)
| | - Bui Tien Sy
- Department of Infectious Diseases, Robert Koch Institute, Berlin, Germany
- Vietnam Military Medical University, Ha Dong, Ha Noi, Viet Nam
- Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany
| | - Boris A. Ratsch
- Department of Infectious Diseases, Robert Koch Institute, Berlin, Germany
| | | | - Salah Al Awaidy
- Office of the Undersecretary for Health Affairs – Ministry of Health, Muscat, Oman
| | | | - Georg Pauli
- Department of Infectious Diseases, Robert Koch Institute, Berlin, Germany
| | - C.-Thomas Bock
- Department of Infectious Diseases, Robert Koch Institute, Berlin, Germany
- * E-mail:
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Hong MZ, Huang WQ, Min F, Xu JC, Lin Z, Fang KN, Pan JS. Enhanced HBsAg synthesis correlates with increased severity of fibrosis in chronic hepatitis B patients. PLoS One 2014; 9:e87344. [PMID: 24498079 PMCID: PMC3909099 DOI: 10.1371/journal.pone.0087344] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2013] [Accepted: 12/20/2013] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND AND AIMS Little is known about whether low serum HBsAg levels result from impaired HBsAg synthesis or a reduced number of hepatocytes caused by advanced liver fibrosis. Therefore, we investigated the capacity for HBsAg synthesis in a cross-sectional cohort of treatment-naïve chronic hepatitis B patients. METHODS Chronic hepatitis B patients (n = 362) were enrolled; liver biopsies were performed and liver histology was scored, and serum HBsAg and HBV DNA levels were investigated. In the enrolled patients, 183 out of 362 have quantitative serum HBsAg levels. Tissue HBsAg was determined by immunohistochemistry. RESULTS A positive correlation between serum HBsAg and HBV DNA levels was revealed in HBeAg(+) patients (r = 0.2613, p = 0.0050). In HBeAg(+) patients, serum HBsAg and severity of fibrosis were inversely correlated (p = 0.0094), whereas tissue HBsAg levels correlated positively with the stage of fibrosis (p = 0.0280). After applying the mean aminopyrine breath test as a correction factor, adjusted serum HBsAg showed a strong positive correlation with fibrosis severity in HBeAg(+) patients (r = 0.5655, p<0.0001). The adjusted serum HBsAg values predicted 'moderate to severe' fibrosis with nearly perfect performance in both HBeAg(+) patients (area under the curve: 0.994, 95% CI: 0.983-1.000) and HBeAg(-) patients (area under the curve: 1.000, 95% CI: 1.000-1.000). CONCLUSIONS Although serum HBsAg levels were negatively correlated with fibrosis severity in HBeAg(+) patients, aminopyrine breath test-adjusted serum HBsAg and tissue HBsAg, two indices that are unaffected by the number of residual hepatocytes, were positively correlated with fibrosis severity. Furthermore, adjusted serum HBsAg has an accurate prediction capability.
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Affiliation(s)
- Mei-Zhu Hong
- Department of Infectious Diseases, Chenggong Hospital affiliated to Xiamen University (The 174th Hospital of PLA), Xiamen, China
| | - Wen-Qi Huang
- Department of Infectious Diseases, Chenggong Hospital affiliated to Xiamen University (The 174th Hospital of PLA), Xiamen, China
| | - Feng Min
- Department of Infectious Diseases, Chenggong Hospital affiliated to Xiamen University (The 174th Hospital of PLA), Xiamen, China
| | - Jin-Chao Xu
- Department of Infectious Diseases, Chenggong Hospital affiliated to Xiamen University (The 174th Hospital of PLA), Xiamen, China
| | - Zhen Lin
- Department of Pathology, Chenggong Hospital affiliated with Xiamen University (The 174th Hospital of PLA), Xiamen, China
| | - Kuang-Nan Fang
- Department of Statistics, School of Economics, Xiamen University, Xiamen, China
- * E-mail: (KNF); (JSP)
| | - Jin-Shui Pan
- Department of Gastroenterology, Zhongshan Hospital affiliated with Xiamen University, Xiamen, China
- * E-mail: (KNF); (JSP)
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24
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Roche B, Samuel D. Treatment of patients with HBV-related decompensated cirrhosis and liver transplanted patients. Clin Liver Dis 2013; 17:451-73. [PMID: 23905816 DOI: 10.1016/j.cld.2013.05.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Antiviral therapy using newer nucleos(t)ide analogs with lower resistance rates could suppress hepatitis B virus (HBV) replication, improve liver function in patients with compensated or decompensated cirrhosis, delay or obviate liver transplantation in some patients, and reduce the risk of HBV recurrence. Some form of HBV prophylaxis needs to be continued indefinitely posttransplant. However, in patients with a low-risk of HBV recurrence it is possible to discontinue hepatitis B immunoglobulins and maintain long-term nucleos(t)ide analog therapy. Currently, treatment of posttransplantation hepatitis B is a less important clinical problem than it was historically because effective antiviral therapies exist to rescue patients who failed initial prophylaxis.
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Affiliation(s)
- Bruno Roche
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Villejuif F-94800, France
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25
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Sayan M, Cavdar C, Dogan C. Naturally occurring polymerase and surface gene variants of hepatitis B virus in Turkish hemodialysis patients with chronic hepatitis B. Jpn J Infect Dis 2013. [PMID: 23183201 DOI: 10.7883/yoken.65.495] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The aim of this study was to assess the frequencies and patterns of naturally occurring genotypic resistance to nucleos(t)ide analogues (NUCs) and typical hepatitis B surface antigen (HBsAg) amino acid substitutions in naive hemodialysis (HD) patients with chronic hepatitis B. In order to achieve this, the genotypic resistance to NUCs and HBsAg amino acid substitutions were classified into primary/compensatory resistance mutation and antiviral drug-associated potential vaccine-escape mutation (ADAPVEM)/typical HBsAg amino acid substitution, respectively. Direct sequencing of polymerase (pol) gene of hepatitis B virus (HBV) was performed on DNA samples obtained from 248 HBsAg-positive Turkish patients. Overall, 38% (n = 94) of HBsAg-positive HD patients had detectable HBV DNA in their serum. Naturally occurring primary and compensatory resistance mutations to NUCs were detected in 30% (n = 28) and 52% (n = 49) of HD patients, respectively. However, 6 types of ADAPVEMs and 48 types of typical HBsAg amino acid substitutions were found in 10.6% (n = 10) and 46% (n = 43) of the HD patients, respectively. Our study suggests that every HD patient diagnosed with chronic hepatitis B, who is a potential candidate for NUCs treatment, should also be monitored for the baseline pol gene sequence changes before the initial treatment, for a more effective management of future treatment options. Further, a relatively higher frequency of ADAPVEMs variants needs to be addressed as a public health problem.
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Affiliation(s)
- Murat Sayan
- PCR Unit, Clinical Laboratory, Faculty of Medicine, University of Kocaeli, Kocaeli, Turkey. sayanmurat＠hotmail.com
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26
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Tillmann HL. Hepatitis C infection and presence of advanced fibrosis: wait or treat? Why wait? There is no time to lose, is there? J Hepatol 2013; 58:412-4. [PMID: 23247067 DOI: 10.1016/j.jhep.2012.12.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2012] [Accepted: 12/04/2012] [Indexed: 12/04/2022]
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Martin CM, Welge JA, Rouster SD, Shata MT, Sherman KE, Blackard JT. Mutations associated with occult hepatitis B virus infection result in decreased surface antigen expression in vitro. J Viral Hepat 2012; 19:716-23. [PMID: 22967103 PMCID: PMC3442934 DOI: 10.1111/j.1365-2893.2012.01595.x] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Occult hepatitis B virus (HBV) infection is characterized by the absence of detectable hepatitis B surface antigen (HBsAg) in the serum, despite detectable HBV DNA. Investigations of the mechanisms underlying the development of occult HBV infection are lacking in the current literature, although viral mutations in the surface region, resulting in decreased HBsAg expression or secretion, represent one potential mechanism. Wild-type HBsAg expression vectors were constructed from genotype-matched chronic HBV sequences. Site-directed mutagenesis was then utilized to introduce three genotype A mutations - M103I, K122R and G145A - associated with occult HBV infection in vivo, alone and in combination, into the wild-type HBsAg vectors. Transfection of Huh7 and HepG2 cell lines was performed, and cell culture supernatants and cell lysates were collected over 7 days to assess the effects of these mutations on extracellular and intracellular HBsAg levels. The G145A mutation resulted in significantly decreased extracellular and intracellular HBsAg expression in vitro. The most pronounced reduction in HBsAg expression was observed when all three mutations were present. The mutations evaluated in vitro in the current study resulted in decreased HBsAg expression and potentially increased hepatic retention and/or decreased hepatic secretion of synthesized HBsAg, which could explain the lack of HBsAg detection that is characteristic of occult HBV infection in vivo.
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Affiliation(s)
- Christina M. Martin
- Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, OH 45267
| | - Jeffrey A. Welge
- Departments of Psychiatry and Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH 45267
| | - Susan D. Rouster
- Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, OH 45267
| | - Mohamed Tarek Shata
- Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, OH 45267
| | - Kenneth E. Sherman
- Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, OH 45267
| | - Jason T. Blackard
- Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, OH 45267, Address requests for reprints to: Jason Blackard, PhD Division of Digestive Diseases University of Cincinnati College of Medicine ML 0595, 231 Albert Sabin Way Cincinnati, OH 45267 Phone: (513) 558-4389 Fax: (513) 558-1744
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28
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Makondo E, Bell TG, Kramvis A. Genotyping and molecular characterization of hepatitis B virus from human immunodeficiency virus-infected individuals in southern Africa. PLoS One 2012; 7:e46345. [PMID: 23029487 PMCID: PMC3460816 DOI: 10.1371/journal.pone.0046345] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2012] [Accepted: 08/30/2012] [Indexed: 12/12/2022] Open
Abstract
Hepatitis B virus (HBV) and human immunodeficiency virus (HIV) are hyperendemic in sub-Saharan Africa. The HBV genotypes prevailing in HIV-infected Africans are unknown. Our aim was to determine the HBV genotypes in HIV-infected participants and to identify clinically significant HBV mutations. From 71 HBV DNA+ve HIV-infected participants, 49 basic core promoter/precore (BCP/PC) and 29 complete S regions were successfully sequenced. Following phylogenetic analysis of 29 specimens in the complete S region, 28 belonged to subgenotype A1 and one to D3. Mutations affecting HBeAg expression at the transcriptional (1762T1764A), translational (Kozak 1809–1812, initiation 1814–1816, G1896A with C1858T), or post translational levels (G1862T), were responsible for the high HBeAg-negativity observed. The G1862T mutation occurred only in subgenotype A1 isolates, which were found in one third (7/21) of HBsAg−ve participants, but in none of the 18 HBsAg+ve participants (p<0.05). Pre-S deletion mutants were detected in four HBsAg+ve and one HBsAg−ve participant/s. The following mutations occurred significantly more frequently in HBV isolated in this study than in strains of the same cluster of the phylogenetic tree: ps1F25L, ps1V88L/A; ps2Q10R, ps2 R48K/T, ps2A53V and sQ129R/H, sQ164A/V/G/D, sV168A and sS174N (p<0.05). ps1I48V/T occurred more frequently in females than males (p<0.05). Isolates with sV168A occurred more frequently in participants with viral loads >200 IU per ml (p<0.05) and only sS174N occurred more frequently in HBsAg−ve than in HBsAg+ve individuals (p<0.05). Prior to initiation of ART, ten percent, 3 of 29 isolates sequenced, had drug resistance mutations rtV173L, rtL180M+rtM204V and rtV214A, respectively. This study has provided important information on the molecular characteristics of HBV in HIV-infected southern Africans prior to ART initiation, which has important clinical relevance in the management of HBV/HIV co-infection in our unique setting.
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Affiliation(s)
| | | | - Anna Kramvis
- Hepatitis Virus Diversity Research Programme, Department of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa
- * E-mail:
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29
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Stravitz RT, Shiffman ML, Kimmel M, Puri P, Luketic VA, Sterling RK, Sanyal AJ, Cotterell AH, Posner MP, Fisher RA. Substitution of tenofovir/emtricitabine for Hepatitis B immune globulin prevents recurrence of Hepatitis B after liver transplantation. Liver Int 2012; 32:1138-45. [PMID: 22348467 DOI: 10.1111/j.1478-3231.2012.02770.x] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2011] [Accepted: 01/24/2012] [Indexed: 12/30/2022]
Abstract
BACKGROUND Hepatitis B immune globulin (HBIg) with or without nucleos(t)ide analogue (NA) inhibitors has been shown to prevent recurrence of hepatitis B virus (HBV) following orthotopic liver transplantation (OLT). However, the use of HBIg has many disadvantages. AIMS The present study was performed to determine if converting patients from HBIg ± NA to combination NA therapy could prevent recurrence of HBV. METHODS Twenty-one recipients without evidence of HBV recurrence on HBIg ± NA for ≥ 6 months were enrolled. Patients received their last injection of HBIg at the time they initiated tenofovir disoproxil fumarate/emtricitabine (TDF/FTC; Truvada(®) ) and were followed up for 31.1 ± 9.0 [range 15-47] months. RESULTS After 1 year, 3 patients (14%) had detectable HBsAg, one of whom was non-compliant. Two of 3 with recurrence cleared HBsAg by last follow-up on TDF/FTC; the non-compliant patient became HBV DNA-undetectable with re-institution of TDF/FTC. TDF/FTC saved $12,469/year over our standard-of-care, monthly intramuscular HBIg/lamivudine. There was no evidence of a general adverse effect of TDF/FTC on renal function. However, 3 patients developed reversible acute renal failure; on renal biopsy, 1 had possible TDF/FTC-induced acute tubular necrosis. CONCLUSIONS Substitution of TDF/FTC for HBIg prevented recurrence of HBV DNA in 100% (20/20) of patients who were compliant with the medication and led to substantial cost savings over HBIg-containing regimens.
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Affiliation(s)
- R Todd Stravitz
- Section of Hepatology, Division of Gastroenterology, Hume-Lee Transplant Center, Virginia Commonwealth University, Richmond, VA 23298-0341, USA.
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30
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Abstract
Evolution of RNA viruses occurs through disequilibria of collections of closely related mutant spectra or mutant clouds termed viral quasispecies. Here we review the origin of the quasispecies concept and some biological implications of quasispecies dynamics. Two main aspects are addressed: (i) mutant clouds as reservoirs of phenotypic variants for virus adaptability and (ii) the internal interactions that are established within mutant spectra that render a virus ensemble the unit of selection. The understanding of viruses as quasispecies has led to new antiviral designs, such as lethal mutagenesis, whose aim is to drive viruses toward low fitness values with limited chances of fitness recovery. The impact of quasispecies for three salient human pathogens, human immunodeficiency virus and the hepatitis B and C viruses, is reviewed, with emphasis on antiviral treatment strategies. Finally, extensions of quasispecies to nonviral systems are briefly mentioned to emphasize the broad applicability of quasispecies theory.
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Affiliation(s)
- Esteban Domingo
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), C/ Nicolás Cabrera, Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain.
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31
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Gish R, Jia JD, Locarnini S, Zoulim F. Selection of chronic hepatitis B therapy with high barrier to resistance. THE LANCET. INFECTIOUS DISEASES 2012; 12:341-53. [PMID: 22326017 DOI: 10.1016/s1473-3099(11)70314-0] [Citation(s) in RCA: 106] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Antiviral drug resistance is a crucial factor that frequently determines the success of long-term therapy for chronic hepatitis B. The development of resistance to nucleos(t)ide analogues has been associated with exacerbations in liver disease and increased risk of emergence of multidrug resistance. The selection of a potent nucleos(t)ide analogue with a high barrier to resistance as a first-line therapy, such as entecavir or tenofovir, provides the best chance of achieving long-term treatment goals and should be used wherever possible. The barrier to resistance of a given nucleos(t)ide analogue is influenced by genetic barrier, drug potency, patient adherence, pharmacological barrier, viral fitness, mechanism of action, and cross-resistance. In countries with limited health-care resources, the selection of a therapy with a high barrier to resistance is not always possible and alternative strategies for preventing resistance might be needed, although limited data are available to support these strategies.
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Affiliation(s)
- Robert Gish
- Center for Hepatobiliary Disease and Abdominal Transplantation, UC San Diego Health System, San Diego, CA, USA
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32
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Abstract
Hepatitis B virus (HBV) can be classified into nine immunological subtypes or eight genotypes. The most prevalent genotypes in Asia are genotypes B and C. HBV is transmitted parenteraly and can produce either asymptomatic or symptomatic disease. Although the consequences of acute hepatitis B can be severe, serious sequelae are associated with chronic infections. HBV seroprevalence ranges from intermediate (2%-7%) to high (≥8%) levels in Asia. Several strategies for the control and prevention of HBV infection have been found to be efficacious. They include vaccination and the administration of HBIG, interferon-a and nucleoside/nucleotide analogues. However, these procedures also apply selective pressures on HBV in infected individuals leading to the generation and accumulation of mutations in the S gene. Most of these mutations occur in the major hydrophilic region (MHR) of the S gene. These mutations create public health concerns as they can be responsible for reactivation of hepatitis B and occult hepatitis B infection. The inability to detect occult infections means that these individuals may become blood donors. This suggests that new strategies for donor evaluation and selection may need to be developed to protect the blood supply.
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Affiliation(s)
- Michael A Purdy
- Division of Viral Hepatitis, MS-A33, Centers for Disease Control and Prevention, 1600 Clifton Rd NE, Atlanta, GA 30329, USA
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33
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Costantini A, Marinelli K, Biagioni G, Monachetti A, Ferreri ML, Butini L, Montroni M, Manzin A, Bagnarelli P. Molecular analysis of hepatitis B virus (HBV) in an HIV co-infected patient with reactivation of occult HBV infection following discontinuation of lamivudine-including antiretroviral therapy. BMC Infect Dis 2011; 11:310. [PMID: 22054111 PMCID: PMC3239326 DOI: 10.1186/1471-2334-11-310] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2011] [Accepted: 11/04/2011] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Occult hepatitis B virus (HBV) infection (OBI) is characterized by HBV DNA persistence even though the pattern of serological markers indicates an otherwise resolved HBV infection. Although OBI is usually clinically silent, immunocompromised patients may experience reactivation of the liver disease. CASE PRESENTATION We report the case of an individual with human immunodeficiency virus (HIV) infection and anti-HBV core antibody positivity, who experienced severe HBV reactivation after discontinuation of lamivudine-including antiretroviral therapy (ART). HBV sequencing analysis showed a hepatitis B surface antigen escape mutant whose presence in an earlier sample excluded reinfection. Molecular sequencing showed some differences between two isolates collected at a 9-year interval, indicating HBV evolution. Resumption of ART containing an emtricitabine/tenofovir combination allowed control of plasma HBV DNA, which fell to undetectable levels. CONCLUSION This case stresses the ability of HBV to evolve continuously, even during occult infection, and the effectiveness of ART in controlling OBI reactivation in HIV-infected individuals.
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Affiliation(s)
- Andrea Costantini
- Clinical Immunology Unit, Department of Clinical and Molecular Sciences, Università Politecnica Marche, Via Tronto 10/a, 60020 Ancona, Italy
| | - Katia Marinelli
- Virology Unit, Department of Biomedical Sciences and Public Health, Università Politecnica Marche, Via Tronto 10/a, 60020 Ancona, Italy
| | - Giulia Biagioni
- Virology Unit, Department of Biomedical Sciences and Public Health, Università Politecnica Marche, Via Tronto 10/a, 60020 Ancona, Italy
| | - Alessia Monachetti
- Virology Unit, Department of Biomedical Sciences and Public Health, Università Politecnica Marche, Via Tronto 10/a, 60020 Ancona, Italy
| | - Monica L Ferreri
- Virology Unit, Department of Biomedical Sciences and Public Health, Università Politecnica Marche, Via Tronto 10/a, 60020 Ancona, Italy
| | - Luca Butini
- Clinical Immunology Unit, Department of Clinical and Molecular Sciences, Università Politecnica Marche, Via Tronto 10/a, 60020 Ancona, Italy
| | - Maria Montroni
- Clinical Immunology Unit, Department of Clinical and Molecular Sciences, Università Politecnica Marche, Via Tronto 10/a, 60020 Ancona, Italy
| | - Aldo Manzin
- Section of Medical Microbiology, Department of Biomedical Science and Technology, Università di Cagliari, S.S.554, Bivio per Sestu, 09124 Monserrato (CA), Italy
| | - Patrizia Bagnarelli
- Virology Unit, Department of Biomedical Sciences and Public Health, Università Politecnica Marche, Via Tronto 10/a, 60020 Ancona, Italy
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34
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Zhu Y, Curtis M, Borroto-Esoda K. HBV DNA replication mediated by cloned patient HBV reverse transcriptase genes from HBV genotypes A–H and its use in antiviral phenotyping assays. J Virol Methods 2011; 173:340-6. [DOI: 10.1016/j.jviromet.2011.03.006] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2010] [Revised: 03/03/2011] [Accepted: 03/03/2011] [Indexed: 01/07/2023]
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35
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Hwang S, Ahn CS, Song GW, Kim KH, Moon DB, Oh HB, Lim YS, Lee HC, Ha TY, Jung DH, Chung YH, Lee SG. Posttransplantation prophylaxis with primary high-dose hepatitis B immunoglobulin monotherapy and complementary preemptive antiviral add-on. Liver Transpl 2011; 17:456-65. [PMID: 21445929 DOI: 10.1002/lt.22226] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
A considerable proportion of liver transplantation recipients who receive hepatitis B immunoglobulin (HBIG) monotherapy for hepatitis B virus (HBV) prophylaxis develop resistance to HBIG. We retrospectively assessed the efficacy of HBV prophylaxis in 1524 patients who received primary high-dose HBIG monotherapy (n = 1463) or with a preemptive antiviral add-on as secondary combination therapy (n = 61). At a median follow-up time of 57 months, 106 (7.3%) patients receiving HBIG monotherapy experienced HBV recurrence, with a 10-year HBV recurrence rate of 9.8%, compared to none of the patients receiving preemptive combination therapy (P = 0.047). Thirteen patients (12.3%) with HBV recurrence failed antiviral therapy, leading to death or retransplantation. Response rates to rescue therapy before and after use of adefovir/entecavir were 44.4% and 91.8%, respectively. Acute exacerbation was not associated with treatment failure, but required prolonged treatment. Of 84 surviving patients with HBV recurrence, 44 (52.4%) showed no evidence of blood HBV DNA. The Gly145Arg mutation was found in 11 of 15 (73.3%) patients, whereas 25 of 71 (35.2%), 2 of 29 (6.9%), and 4 of 8 (50%) patients were resistant to lamivudine, adefovir, and entecavir, respectively. In conclusion, our finding of a 10-year HBV recurrence rate of 9.8% in patients receiving high-dose HBIG monotherapy indicates that this treatment is effective but requires complementary measures. Strict surveillance following HBIG monotherapy is necessary to enhance responses to rescue antiviral therapy. Preemptive conversion to combination therapy has a complementary role in prophylaxis with primary high-dose HBIG monotherapy, especially for patients at high risk of HBV recurrence.
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Affiliation(s)
- Shin Hwang
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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36
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Abstract
HBV has evolved a unique life cycle that results in the production of enormous viral loads during active replication without actually killing the infected cells directly. Two of the key events in the viral life cycle of HBV involve firstly the generation of a covalently closed circular (ccc)DNA transcriptional template, either from input genomic DNA or newly replicated capsid-associated DNA, and secondly, reverse transcription of the viral pregenomic (pg)RNA to form progeny HBV DNA genomes. New data are emerging regarding the epigenetic control of cccDNA, which might represent another key factor involved in the pathogenesis and natural history of the disease. Because HBV uses reverse transcription to copy its genome, mutant viral genomes emerge frequently. Particular selection pressures, both endogenous (host immune clearance) and exogenous (vaccines and antiviral drugs), readily select out these escape mutants. The particular viral mutations or combination of mutations that directly affect the clinical outcome of infection are not known; however, four major 'pathways' of antiviral drug resistance-associated substitutions have now been identified. Further studies are clearly needed to identify the pathogenetic basis and clinical sequelae arising from the selection of these particular mutants. In the clinical context of antiviral drug resistance, treating physicians need to adopt therapeutic strategies that effectively control viral replication. Finally, the role of host genetics in influencing the outcome of HBV disease in the context of natural history and therapy is beginning to aid understanding in pathogenesis and, when this knowledge is linked to pathogen-specific databases, this should translate into more individualized patient care.
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Affiliation(s)
- Stephen Locarnini
- Victorian Infectious Diseases Reference Laboratory, North Melbourne, Victoria, Australia.
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37
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Strasfeld L, Chou S. Antiviral drug resistance: mechanisms and clinical implications. Infect Dis Clin North Am 2010; 24:809-33. [PMID: 20674805 DOI: 10.1016/j.idc.2010.07.001] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Antiviral drug resistance is an increasing concern in immunocompromised patient populations, where ongoing viral replication and prolonged drug exposure lead to the selection of resistant strains. Rapid diagnosis of resistance can be made by associating characteristic viral mutations with resistance to various drugs as determined by phenotypic assays. Management of drug resistance includes optimization of host factors and drug delivery, selection of alternative therapies based on knowledge of mechanisms of resistance, and the development of new antivirals. This article discusses drug resistance in herpesviruses and hepatitis B.
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Affiliation(s)
- Lynne Strasfeld
- Division of Infectious Diseases, Oregon Health & Science University, Portland, OR 97239, USA.
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38
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Wei C, Chong YT, Wen JZ, Li YW, Li G. Characterization of hepatitis virus B isolated from a multi-drug refractory patient. Virus Res 2010; 155:254-8. [PMID: 20970466 DOI: 10.1016/j.virusres.2010.10.018] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2010] [Revised: 10/14/2010] [Accepted: 10/14/2010] [Indexed: 01/03/2023]
Abstract
Prolonged treatment of chronic hepatitis B (CHB) with nucleoside analogues (NAs) almost invariably engenders viral resistance, and sequential NAs monotherapy can promote multi-drug resistance. This study aimed to investigate the molecular characteristics and the mutation profile of multi-drug resistant hepatitis B virus (HBV). The complete genome of HBV isolated from a multi-drug refractory patient was amplified and cloned, and 22 clones were selected for sequencing. The homology of the full-length genome between clones ranged from 98.7% to 99.9%. A precore stop codon mutation of G1896A and basic core promoter (BCP) mutations A1762T/G1764A were detected in a majority of clones. A phylogenetic analysis showed that all clones were classified as subgenotype B2. Three mutations in the surface (S) antigen region, sC76Y, sP120T and sI195M, were detected in 100%, 100% and 77.3% of the clones, respectively. In the core (C) antigen region, a mutation at codon 135 (cP135Q) was detected in 100% of clones. Lamivudine (LAM)-resistant mutations, rtL180M and rtM204V/I were detected in 86.4% of clones. Adefovir (ADV) or entecavir (ETV)-resistant mutations were not detected. Several novel mutations, such as rtT128N, rtA222T, rtS256G, rtL271M, rtS332R, and rtN/T337D, were present in a majority of clones. Furthermore, six pairs of mutations in the overlapping reverse transcriptase (RT) gene and S gene were detected. In conclusion, the complex HBV mutation profile detected in the multi-drug refractory patient highlights the problems associated with the ongoing selection of mutations, including further compensatory mutations as well as potential cross-resistance mutations.
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Affiliation(s)
- Chen Wei
- Medical Research Center, The Third Affiliated Hospital of Sun Yat-sen University, No 600, Tianhe Road, Guangzhou, Guangdong, China.
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39
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Strasfeld L, Chou S. Antiviral drug resistance: mechanisms and clinical implications. Infect Dis Clin North Am 2010; 24:413-37. [PMID: 20466277 DOI: 10.1016/j.idc.2010.01.001] [Citation(s) in RCA: 119] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Antiviral drug resistance is an increasing concern in immunocompromised patient populations, where ongoing viral replication and prolonged drug exposure lead to the selection of resistant strains. Rapid diagnosis of resistance can be made by associating characteristic viral mutations with resistance to various drugs as determined by phenotypic assays. Management of drug resistance includes optimization of host factors and drug delivery, selection of alternative therapies based on knowledge of mechanisms of resistance, and the development of new antivirals. This article discusses drug resistance in herpesviruses and hepatitis B.
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Affiliation(s)
- Lynne Strasfeld
- Division of Infectious Diseases, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, mail code L457, Portland, OR 97239, USA.
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40
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Martin CM, Welge JA, Shire NJ, Rouster SD, Shata MT, Sherman KE, Blackard JT. Genomic variability associated with the presence of occult hepatitis B virus in HIV co-infected individuals. J Viral Hepat 2010; 17:588-97. [PMID: 19889143 PMCID: PMC3032083 DOI: 10.1111/j.1365-2893.2009.01214.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Occult hepatitis B virus (O-HBV) infection is characterized by the presence of HBV DNA without detectable hepatitis B surface antigen (HBV DNA+/HBsAg-) in the serum. Although O-HBV is more prevalent during HBV/HIV co-infection, analysis of HBV mutations in co-infected patients is limited. In this preliminary study, HBV PreSurface (PreS) and surface (S) regions were amplified from 33 HIV-positive patient serum samples - 27 chronic HBV (C-HBV) and six O-HBV infections. HBV genotype was determined by phylogenetic analysis, while quasispecies diversity was quantified for the PreS, S and overlapping polymerase regions. C-HBV infections harboured genotypes A, D and G, compared to A, E, G and one mixed A/G infection for O-HBV. Interestingly, nonsynonymous-synonymous mutation values indicated positive immune selection in three regions for O-HBV vs one for C-HBV. Sequence analysis further identified new O-HBV mutations, in addition to several previously reported mutations within the HBsAg antigenic determinant. Several of these O-HBV mutations likely contribute to the lack of detectable HBsAg in O-HBV infection by interfering with detection in serologic assays, altering antigen secretion and/or decreasing replicative fitness.
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Affiliation(s)
- C. M. Martin
- Department of Internal Medicine, Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - J. A. Welge
- Departments of Psychiatry and Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - N. J. Shire
- Department of Internal Medicine, Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - S. D. Rouster
- Department of Internal Medicine, Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - M. T. Shata
- Department of Internal Medicine, Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - K. E. Sherman
- Department of Internal Medicine, Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - J. T. Blackard
- Department of Internal Medicine, Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, OH, USA
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41
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Chun J, Kim W, Kim BG, Lee KL, Suh KS, Yi NJ, Park KU, Kim YJ, Yoon JH, Lee HS. High viremia, prolonged Lamivudine therapy and recurrent hepatocellular carcinoma predict posttransplant hepatitis B recurrence. Am J Transplant 2010; 10:1649-59. [PMID: 20642687 DOI: 10.1111/j.1600-6143.2010.03162.x] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Hepatitis B virus (HBV) recurrence following orthotopic liver transplantation (OLT) is generally preventable by prophylaxis with hepatitis B immunoglobulin (HBIG) and lamivudine (LAM). However, HBV recurrence sometimes develops despite prophylaxis. This study assessed posttransplant outcomes and identified predictors of HBV recurrence. We analyzed the outcomes of 209 consecutive patients positive for hepatitis B surface antigen who underwent OLT, who received either combination prophylaxis with HBIG and LAM (89.0%) or HBIG monoprophylaxis (11.0%). The median follow-up was 36.8 months (range, 1.0-84.4). Posttransplant HBV recurrence occurred in 22 patients (10.5%), including 13 patients with drug-resistant mutations. HBV recurrence was observed in six patients after hepatocellular carcinoma (HCC) recurrence. Independent predictors of HBV recurrence were recurrent HCC (p < 0.001), LAM therapy >1.5 years (p = 0.001) and high HBV DNA titers (> or =10(5) copies/mL) at OLT (p = 0.036). In conclusion, high viremia at OLT and prolonged exposure to LAM should be further stressed as main predictors of HBV recurrence.
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Affiliation(s)
- J Chun
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Korea
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42
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Oh YJ, Park YM, Hong SP, Shin SK, Ji SI, Kim BH, Park SJ, Hong Z. A YIDD Mutation in a Case of Recurrent Hepatitis B after Liver Transplantation Induced by an S-escape Mutant. Gut Liver 2010; 4:253-7. [PMID: 20559531 DOI: 10.5009/gnl.2010.4.2.253] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2009] [Accepted: 10/12/2009] [Indexed: 12/13/2022] Open
Abstract
A 47-year-old woman underwent orthotopic liver transplantation (OLT) for hepatitis B virus (HBV)-related end-stage liver cirrhosis. The patient received hepatitis B immunoglobulin prophylaxis after OLT. Despite the protective level of the serum anti-hepatitis-B surface antibody, HBV recurred at 22 months post-OLT and induced subacute hepatic failure. The pre-OLT HBV genome contained a complex mutation pattern in overlapping frame regions of the surface (S) and polymerase (P) genes, which is the same mutation pattern as seen in post-OLT HBV DNA. G145R and K141R mutations in the "a" determinant were detected only in the post-OLT sample. Clevudine (30 mg once daily) was administered for recurrent hepatitis B. Hepatitis B was reactivated with a flare-up, and a M204I mutation (YIDD mutant type) appeared with a higher viral load at 9 months after clevudine treatment. We report here a case of a YIDD mutation that developed in recurrent hepatitis B after OLT induced by an S-escape mutant.
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Affiliation(s)
- Yun-Jung Oh
- Department of Internal Medicine, Bundang Jesang General Hospital, Daejin Medical Center, Seongnam, Korea
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43
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Gao Z, Liu FJ, Liu L, Zhou TY, Lei J, Xu L, Liu C, Dai J, Chen EQ, Tang H. Application of hepatitis B virus replication mouse model. World J Gastroenterol 2010; 16:1979-85. [PMID: 20419834 PMCID: PMC2860074 DOI: 10.3748/wjg.v16.i16.1979] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the value of the hepatitis B virus (HBV) replication mouse model with regard to several aspects of the study of HBV biology.
METHODS: To evaluate the HBV replication mouse model in detecting the efficacy of anti-HBV agents, the interferon inducer polyinosinic-polytidylin acid (polyIC) and nucleotide analogues adefovir and entecavir were administered to mice injected with wild type pHBV4.1, and the inhibiting effect of these agents on HBV DNA replication was evaluated. To identify the model’s value in a replication ability study of HBV drug-resistant mutants and a HBx-minus mutant, telbivudine resistance mutants (rtM204I, ayw subtype), adefovir resistance mutants (rtA181V + rtN236T, ayw subtype) and HBx-minus mutants were injected respectively, and their corresponding HBV DNA replication intermediates in mouse liver were assessed.
RESULTS: Compared with the wild type HBV replication mouse model without antiviral agent treatment, the HBV DNA replication intermediates of the polyIC-treated group were decreased 1-fold; while in the entecavir- and adefovir-treated groups, the levels of HBV DNA replication intermediates were inhibited 13.6-fold and 1.4-fold, respectively. For the mouse models injected with telbivudine resistance mutant, adefovir resistance mutant and HBx-minus mutant, HBV DNA replication intermediates could still be detected, but the levels of HBV DNA replication intermediates of these mutants decreased 4.5-fold, 5.6-fold and 2.9-fold respectively, compared with the mouse model with wild type HBV plasmid.
CONCLUSION: The HBV replication mouse model we established was a useful and convenient tool to detect the efficacy of antiviral agents and to study the replication ability of HBV mutants in vivo.
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44
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Sayan M, Sentürk O, Akhan SÇ, Hülagü S, Cekmen MB. Monitoring of hepatitis B virus surface antigen escape mutations and concomitantly nucleos(t)ide analog resistance mutations in Turkish patients with chronic hepatitis B. Int J Infect Dis 2010; 14 Suppl 3:e136-41. [PMID: 20382061 DOI: 10.1016/j.ijid.2009.11.039] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2009] [Revised: 10/30/2009] [Accepted: 11/25/2009] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND The hepatitis B virus (HBV) polymerase gene completely overlaps with the envelope gene. In the present study we aimed to monitor the prevalence and pattern of the typical mutations for hepatitis B surface antigen (HBsAg) escape, and concomitantly nucleos(t)ide analog (NUC) resistance mutations, in Turkish patients undergoing different antiviral therapies and in treatment-naïve patients with chronic hepatitis B (CHB). METHODS The investigation was undertaken between March 2007 and August 2009 and involved a total of 142 patients under NUC therapy (88 males; mean age 42 years (range 13-68); hepatitis B e antigen (HBeAg) negativity in 94 patients; HBV DNA median log 4.3 log(10) IU/ml (range 2.0->6.0); alanine aminotransferase (ALT) median level 76.1 IU/ml (range 12-1082)) and 185 treatment-naïve CHB patients (120 males; mean age 39 years (range 1-76 years); HBeAg negativity in 132 patients; HBV DNA median log 3.5 log(10) IU/ml (range 2.0-6.0); ALT median level 60.7 IU/l (range 8-874)). RESULTS The overall prevalence of typical HBsAg escape mutations found in the CHB patients was 8.3% (27/327). In the NUC therapy group the prevalence was 8.5% (12/142), with the following patterns: sY100C+sI110V, sL109I, sP120T, sP127T, sG130R+sG145X, sS132A+sY134N, sY134N+sG145R, sC137G, sD144E, sG145R. In the treatment-naïve group the prevalence was 8.1% (15/185), with the following patterns: sL109I, sI110V, sS117INST, sP120T, sP127T, sM133I, sC137L+sG145R, sS143L. However, NUC resistance mutations were found in 7.7% (11/142) of the patients on NUC therapy and 3.8% (7/185) of the treatment-naïve group patients. Interestingly, the treatment-naïve patients had preexisting drug resistance mutations related to lamivudine (rtL180M+rtM204I), adefovir (rtA181V, rtQ215S, rtI233V), entecavir (intermediate susceptibility with rtL180M+rtM204IHBV variant), telbivudine (rtL180M+rtM204I), and tenofovir (rtA194T). CONCLUSIONS The findings of this study show preexisting typical HBsAg escape and NUC resistance mutations are possible. The genetic arrangement of the HBV genome with polymerase and surface genes overlapping has substantial public health and diagnostic implications and relevance.
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Affiliation(s)
- M Sayan
- Clinical Laboratory, PCR Unit, Faculty of Medicine, University of Kocaeli, İzmit-Kocaeli, Turkey.
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45
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Coinfection of hepatic cell lines with human immunodeficiency virus and hepatitis B virus leads to an increase in intracellular hepatitis B surface antigen. J Virol 2010; 84:5860-7. [PMID: 20357083 DOI: 10.1128/jvi.02594-09] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Liver-related mortality is increased in the setting of HIV-hepatitis B virus (HBV) coinfection. However, interactions between HIV and HBV to explain this observation have not been described. We hypothesized that HIV infection of hepatocytes directly affects the life cycle of HBV. We infected human hepatic cell lines expressing HBV (Hep3B and AD38 cells) or not expressing HBV (Huh7, HepG2, and AD43 cells) with laboratory strains of HIV (NL4-3 and AD8), as well as a vesicular stomatitis virus (VSV)-pseudotyped HIV expressing enhanced green fluorescent protein (EGFP). Following HIV infection with NL4-3 or AD8 in hepatic cell lines, we observed a significant increase in HIV reverse transcriptase activity which was infectious. Despite no detection of surface CD4, CCR5, and CXCR4 by flow cytometry, AD8 infection of AD38 cells was inhibited by maraviroc and NL4-3 was inhibited by AMD3100, demonstrating that HIV enters AD38 hepatic cell lines via CCR5 or CXCR4. High-level infection of AD38 cells (50%) was achieved using VSV-pseudotyped HIV. Coinfection of the AD38 cell line with HIV did not alter the HBV DNA amount or species as determined by Southern blotting or nucleic acid signal amplification. However, coinfection with HIV was associated with a significant increase in intracellular HBsAg when measured by Western blotting, quantitative HBsAg, and fluorescence microscopy. We conclude that HIV infection of HBV-infected hepatic cell lines significantly increased intracellular HBsAg but not HBV DNA synthesis and that increased intrahepatic HBsAg secondary to direct infection by HIV may contribute to accelerated liver disease in HIV-HBV-coinfected individuals.
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46
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Differential impact of immune escape mutations G145R and P120T on the replication of lamivudine-resistant hepatitis B virus e antigen-positive and -negative strains. J Virol 2009; 84:1026-33. [PMID: 19889778 DOI: 10.1128/jvi.01796-09] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Immune escape variants of the hepatitis B virus (HBV) represent an emerging clinical challenge, because they can be associated with vaccine escape, HBV reactivation, and failure of diagnostic tests. Recent data suggest a preferential selection of immune escape mutants in distinct peripheral blood leukocyte compartments of infected individuals. We therefore systematically analyzed the functional impact of the most prevalent immune escape variants, the sG145R and sP120T mutants, on the viral replication efficacy and antiviral drug susceptibility of common treatment-associated mutants with resistance to lamivudine (LAM) and/or HBeAg negativity. Replication-competent HBV strains with sG145R or sP120T and LAM resistance (rtM204I or rtL180M/rtM204V) were generated on an HBeAg-positive and an HBeAg-negative background with precore (PC) and basal core promoter (BCP) mutants. The sG145R mutation strongly reduced HBsAg levels and was able to fully restore the impaired replication of LAM-resistant HBV mutants to the levels of wild-type HBV, and PC or BCP mutations further enhanced viral replication. Although the sP120T substitution also impaired HBsAg secretion, it did not enhance the replication of LAM-resistant clones. However, the concomitant occurrence of HBeAg negativity (PC/BCP), sP120T, and LAM resistance resulted in the restoration of replication to levels of wild-type HBV. In all clones with combined immune escape and LAM resistance mutations, the nucleotide analogues adefovir and tenofovir remained effective in suppressing viral replication in vitro. These findings reveal the differential impact of immune escape variants on the replication and drug susceptibility of complex HBV mutants, supporting the need of close surveillance and treatment adjustment in response to the selection of distinct mutational patterns.
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47
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Yim HJ. [Hepatitis B virus genetic diversity and mutant]. THE KOREAN JOURNAL OF HEPATOLOGY 2009; 14:446-64. [PMID: 19119240 DOI: 10.3350/kjhep.2008.14.4.446] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatitis B virus (HBV) is a partially double stranded DNA virus with genetic diversity represented by eight genotypes (A to H). Natural course and response to treatment could be affected by HBV genotypes. HBV shows high rates of turn over in the absence of proof-reading ability. As a result, large amounts of quasispecies are produced naturally or antiviral-associated. HBV consists of four open reading frames, namely preS/S gene, precore/core gene, polymerase gene, and X gene. Mutations on preS gene can result in undetectable HBsAg even in case that HBV is replicating. Surface gene mutation leads to decreased binding affinity to anti-HBs, which is associated with a vaccine escape mutant. Precore mutation abolishes HBeAg whereas mutations on basal core promoter gene down-regulate the HBeAg production. Mutations on basal core promoter are associated with increased HBV replication and high incidence of progressive liver diseases such as liver cirrhosis and hepatocellular carcinoma. Mutations on polymerase genes are often induced by antiviral therapy. Emergence of antiviral-resistant mutation is the major cause of treatment failure. Furthermore, existence of prior antiviral-resistant mutations limits the options of subsequent antiviral agents. Therefore, judicious use of antivirals and selection of the most potent drug with the lowest resistance rate are of the utmost importance for the prevention of antiviral-associated mutants. Detailed knowledge and understanding of HBV genetic diversity and mutant would be critical to establish strategies for the diagnosis and management of HBV infection.
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Affiliation(s)
- Hyung Joon Yim
- Department of Internal Medicine, Korea University College of Medicine, Ansan, Korea.
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48
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Lai MW, Huang SF, Hsu CW, Chang MH, Liaw YF, Yeh CT. Identification of nonsense mutations in hepatitis B virus S gene in patients with hepatocellular carcinoma developed after lamivudine therapy. Antivir Ther 2009; 14:249-261. [PMID: 19430100 DOI: 10.1177/135965350901400216] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
BACKGROUND Lamivudine is widely used in patients with chronic hepatitis B virus (HBV) infection. In cirrhotic patients, long-term lamivudine therapy significantly reduced the risk of hepatocellular carcinoma (HCC). However, in a small but substantial portion of patients, HCC still developed despite lamivudine therapy. Prolonged usage of lamivudine led to mutations in the polymerase gene, where concurrent nonsense mutations in the HBV S gene occasionally occurred. The significance of such mutations in hepatocarcinogenesis remains elusive. Here, we aimed to understand the oncogenicity of HBV pre-S/S nonsense mutations identified in patients with HCC that developed after lamivudine therapy. METHODS Of 141 consecutive hepatitis B surface antigen-positive HCC patients, 8 developed HCC after receiving lamivudine therapy. The HBV pre-S/S sequences in their serum and tissue samples were analysed. A sex- and age-matched group of HCC patients who never received lamivudine therapy were included as controls. Site-directed mutagenesis experiments were performed to generate identified pre-S/S nonsense mutations in expression vectors for tumourigenicity analysis. RESULTS Seven of eight patients in the lamivudine-treated group harboured nonsense mutations in the S gene compared with none in the control group (P<0.001). Site-directed mutagenesis and transient transfection experiments revealed that these mutants could transactivate oncogene promoters. NIH3T3 cells stably expressing sL21*, sW156* and sW172* pre-S/S mutants had increased tumourigenicity in nude mice. CONCLUSIONS HCCs developed in lamivudine-treated patients who frequently carried nonsense mutations in the S gene. Such pre-S/S mutants are potentially oncogenic and might counteract the effect of lamivudine in preventing hepatocarcinogenesis.
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Affiliation(s)
- Ming-Wei Lai
- Liver Research Unit, Chang Gung Medical Center, Taipei, Taiwan
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49
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Fujimoto M, Ichikawa T, Nakao K, Miyaaki H, Shibata H, Eguchi S, Takatsuki M, Nagaoka S, Yatsuhashi H, Kanematsu T, Eguchi K. The significance of enzyme immunoassay for the assessment of hepatitis B virus core-related antigen following liver transplantation. Intern Med 2009; 48:1577-83. [PMID: 19755758 DOI: 10.2169/internalmedicine.48.2000] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
PURPOSE Recently, a new enzyme immunoassay for the detection of hepatitis B virus (HBV) core-related antigen (HBcrAg) has been reported. In this study, we proposed to account for feasibility of HBcrAg assay, and discuss the dynamics of HBV seen in patients following HBV-related living donor liver transplantation (LDLT). METHODS AND RESULTS This study involved 12 patients; 11 patients had positive serum HBcrAg, and 6 patients had negative HBV-DNA. In the post-operation period, all cases were negative for HBV-DNA and HBsAg in sera under prophylaxis therapy. At post-operation, 5 of the 12 had positive serum HBcrAg, and at stable state, 6 had positive serum HBcrAg postoperatively. The mean levels of HBcrAg following LDLT were significantly lower than those seen in the preoperative-operation stage. CONCLUSION This enzyme immunoassay is a readily utilizable marker of HBV replication in the post transplantation stage. Furthermore, the evaluation of HBV activity by HBcrAg assay must be studied to determine the appropriate prophylaxis for controlling replication of HBV following LDLT.
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Affiliation(s)
- Masumi Fujimoto
- The First Department of Internal Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
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50
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Roche B, Samuel D. Liver transplantation in viral hepatitis: prevention of recurrence. Best Pract Res Clin Gastroenterol 2008; 22:1153-69. [PMID: 19187873 DOI: 10.1016/j.bpg.2008.12.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
End-stage liver disease caused by the hepatitis B and C viruses (HBV and HCV) are major indications for liver transplantation. Outcome depends largely on the prevention of allograft reinfection. The advent of long-term hepatitis B immune globulin administration and the introduction of new antiviral agents were a major breakthrough in the management of these patients. Today, survival after orthotopic liver transplantation (OLT) is similar to that of patients transplanted for HBsAg-negative liver disease, and the risk of recurrence is below 10%. In contrast, HCV reinfection is almost constant and significantly impairs patient and graft survival. Factors that may influence disease severity and consequently progression of HCV graft injury remain unclear. Pre-transplantation and prophylactic post-transplantation antiviral treatments are limited by low applicability and poor tolerance. Treatment of established graft lesions with combination therapy gave promising results, with sustained virological response in 25-45% of patients, but indications, modality and duration of treatment should be assessed.
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Affiliation(s)
- Bruno Roche
- Assistance Publique-Hopitaux de Paris, Hopital Paul Brousse, Centre Hepato-Biliaire, Villejuif, France
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