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Wu JF, Tai CS, Chang KC, Chen YJ, Hsu CT, Chen HL, Ni YH, Chang MH. Predictors of Functional Cure of Chronic Hepatitis B Virus Infection: A Long-Term Follow-Up Study. Clin Gastroenterol Hepatol 2025; 23:583-590.e3. [PMID: 39209206 DOI: 10.1016/j.cgh.2024.07.036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 07/24/2024] [Accepted: 07/25/2024] [Indexed: 09/04/2024]
Abstract
BACKGROUND & AIMS A functional cure is an essential endpoint in the management of patients with chronic hepatitis B virus (HBV) infection. We evaluated the cumulative probability and predictors of functional cure in patients with chronic HBV infection after hepatitis B e antigen (HBeAg) seroconversion. METHODS We retrospectively analyzed 413 (249 males and 164 females) initially HBeAg-positive chronic HBV-infected patients who were followed up for a mean of 26.36 ± 0.53 years. All underwent HBeAg seroconversion during follow-up. A functional cure was defined as durable HBsAg and HBV DNA loss without antiviral treatment for more than 24 weeks. RESULTS After 10,888 person-years of follow-up, the cumulative probability of functional cure was 14.53% (n = 60). There were 24 (40%) subjects with functional cure after antiviral therapy. The annual functional cure rate was 0.55% per person-year, and increased to 0.96% per person-year after HBeAg seroconversion. In subjects with functional cure, the HBsAg and HBV DNA titers after HBeAg seroconversion were positively correlated with the time to functional cure (P < .001 and < .001, respectively). Multivariate Cox proportional hazards analysis of the cohort revealed that HBeAg seroconversion at <18 years of age, high-genetic-barrier nucleos(t)ide analogue(s) therapy before HBeAg seroconversion, and a serum HBsAg titer <1000 IU/mL at 18 months after HBeAg seroconversion were significant predictors of functional cure (P < .001, .001, and .001, respectively). CONCLUSIONS In a cohort of chronic HBV-infected patients with long-term follow-up, HBeAg seroconversion in childhood, high-genetic-barrier nucleos(t)ide analogue(s) therapy, and low HBsAg titers after HBeAg seroconversion were significant predictors of functional cure.
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Affiliation(s)
- Jia-Feng Wu
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan; Department of Pediatrics, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chi-San Tai
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Kai-Chi Chang
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Yuh-Jue Chen
- Department of Pediatrics, National Taiwan University Hospital Yunlin Branch, Yunlin County, Taiwan
| | - Chien-Ting Hsu
- Department of Pediatrics, National Taiwan University BioMedical Park Hospital, Hsinchu County, Taiwan
| | - Huey-Ling Chen
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan; Department of Medical Education, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan; Graduate Institute of Medical Education and Bioethics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Yen-Hsuan Ni
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan; Department of Pediatrics, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Mei-Hwei Chang
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
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Kouroumalis E, Tsomidis I, Voumvouraki A. Extracellular Vesicles in Viral Liver Diseases. Viruses 2024; 16:1785. [PMID: 39599900 PMCID: PMC11598962 DOI: 10.3390/v16111785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 11/12/2024] [Accepted: 11/15/2024] [Indexed: 11/29/2024] Open
Abstract
Extracellular vesicles (EVs) are bilayer vesicles released by cells in the microenvironment of the liver including parenchymal and non-parenchymal cells. They are the third important mechanism in the communications between cells, besides the secretion of cytokines and chemokines and the direct cell-to-cell contact. The aim of this review is to discuss the important role of EVs in viral liver disease, as there is increasing evidence that the transportation of viral proteins, all types of RNA, and viral particles including complete virions is implicated in the pathogenesis of both viral cirrhosis and viral-related hepatocellular carcinoma. The biogenesis of EVs is discussed and their role in the pathogenesis of viral liver diseases is presented. Their use as diagnostic and prognostic biomarkers is also analyzed. Most importantly, the significance of possible novel treatment strategies for liver fibrosis and hepatocellular carcinoma is presented, although available data are based on experimental evidence and clinical trials have not been reported.
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Affiliation(s)
- Elias Kouroumalis
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Greece;
| | - Ioannis Tsomidis
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Greece;
| | - Argyro Voumvouraki
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Greece;
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Cross A, Harris JM, Arbe-Barnes E, Nixon C, Dhairyawan R, Hall A, Quaglia A, Issa F, Kennedy PTF, McKeating JA, Gill US, Peppa D. Characterisation of HBV and co-infection with HDV and HIV through spatial transcriptomics. EGASTROENTEROLOGY 2024; 2:e100067. [PMID: 39149129 PMCID: PMC11326438 DOI: 10.1136/egastro-2024-100067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 08/17/2024]
Abstract
Background and aims The intrahepatic processes associated with chronic hepatitis B (CHB), especially in the context of hepatitis delta virus (HDV) and HIV co-infection, require a better understanding. Spatial transcriptomics can provide new insights into the complex intrahepatic biological processes, guiding new personalised treatments. Our aim is to evaluate this method characterising the intrahepatic transcriptional landscape, cellular composition and biological pathways in liver biopsy samples from patients with hepatitis B virus (HBV) and HDV or HIV co-infection. Method The NanoString GeoMx digital spatial profiling platform was employed to assess expression of HBV surface antigen and CD45 in formalin-fixed paraffin-embedded (FFPE) biopsies from three treatment-naïve patients with chronic HBV and HDV or HIV co-infection. The GeoMx Human Whole Transcriptome Atlas assay quantified the expression of genes enriched in specific regions of interest (ROIs). Cell type proportions within ROIs were deconvoluted using a training matrix from the human liver cell atlas. A weighted gene correlation network analysis evaluated transcriptomic signatures across sampled regions. Results Spatially discrete transcriptomic signatures and distinct biological pathways were associated with HBV infection/disease status and immune responses. Shared features including 'cytotoxicity' and 'B cell receptor signalling' were consistent across patients, suggesting common elements alongside individual traits. HDV/HBV co-infection exhibited upregulated genes linked to apoptosis and immune cell recruitment, whereas HIV/HBV co-infection featured genes related to interferon response regulation. Varied cellular characteristics and immune cell populations, with an abundance of γδT cells in the HDV/HBV sample, were observed within analysed regions. Transcriptional differences in hepatocyte function suggest disrupted metabolic processes in HDV/HBV co-infection potentially impacting disease progression. Conclusion This proof-of-principle study shows the value of this platform in investigating the complex immune landscape, highlighting relevant host pathways to disease pathogenesis.
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Affiliation(s)
- Amy Cross
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - James M Harris
- Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Edward Arbe-Barnes
- Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, London, UK
| | - Colin Nixon
- Cancer Research UK, Scotalnd Institute, Glasgow, UK
| | - Rageshri Dhairyawan
- Division of Infection and Immunity, Barts Health NHS Trust, London, UK
- Centre for Immunobiology, Barts & The London School of Medicine & Dentistry, QMUL, London, UK
| | - Andrew Hall
- UCL Cancer Institute, Royal Free London NHS Foundation Trust, London, UK
| | - Alberto Quaglia
- UCL Cancer Institute, Royal Free London NHS Foundation Trust, London, UK
| | - Fadi Issa
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Patrick T F Kennedy
- Centre for Immunobiology, Barts & The London School of Medicine & Dentistry, QMUL, London, UK
| | - Jane A McKeating
- Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford, UK
| | - Upkar S Gill
- Centre for Immunobiology, Barts & The London School of Medicine & Dentistry, QMUL, London, UK
| | - Dimitra Peppa
- Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, London, UK
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Basimane Bisimwa P, Koyaweda GW, Bihehe Masemo D, Ayagirwe RBB, Birindwa AB, Bisimwa PN, Kikuni Besulani G, Kashosi TM, Mugisho Matabishi C, Mitima Misuka B, Mukonkole JPM, Bisimwa Nachega J, Mukwege Mukengere D, Komas NPJ. High prevalence of hepatitis B and HIV among women survivors of sexual violence in South Kivu province, eastern Democratic Republic of Congo. PLoS One 2024; 19:e0292473. [PMID: 38959256 PMCID: PMC11221749 DOI: 10.1371/journal.pone.0292473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 05/08/2024] [Indexed: 07/05/2024] Open
Abstract
INTRODUCTION Limited data are available on the prevalence rates of hepatitis B and acquired immunodeficiency syndrome (AIDS) among women survivors of sexual violence (WSSV) in South Kivu province, in the eastern part of the Democratic Republic of Congo (DRC), where armed conflicts persist. Here, we aimed to assess the prevalence of these two infections in this vulnerable local population. METHODS A total of 1002 WSSV, aged from 18 to 70 years old were enrolled from May 2018 to May 2020 at three healthcare facilities (Panzi, Mulamba and Bulenga hospitals), which are called "The One-Stop Centre Care Model" for the management of sexual violence in South Kivu. Blood samples were collected and tested for hepatitis B virus (HBV) and human immunodeficiency virus (HIV) antigens and antibodies using enzyme-linked immunoassay (ELISA) methods. Subsequently, viral load quantification for HBV and HIV were performed using the GeneXpert. Univariate and multivariate logistic regression models were used to assess factors associated with HIV-positive and HBV-positive status. RESULTS For HBV, overall prevalence was 8.9% (95% CI; 7.2-10.8%), 32.1% (95% CI; 29.3-35.0%), and 14.5% (95% CI; 12.3-16.8%) for HBsAg, anti-HBc and anti-HBs antibodies, respectively. Among the 89 HBsAg-positive patients, 17 (19.1%) were HBeAg-positive. The median age of individuals with a positive HBsAg test was higher than those with a negative test (median: 40 years (IQR 30-52) compared to 36 years (IQR 24-48)). Risk factors for HBV infection were age (≥35 years) (AOR = 1.83 [1.02-3.32]; p = 0.041), having no schooling (AOR = 4.14 [1.35-12.62]; p = 0.012) or only primary school-level (AOR = 4.88 [1.61-14.75]; p = 0.005), and multiple aggressors (AOR = 1.76 [1.09-2.84], p = 0.019). The prevalence of HIV was 4.3% [95% CI: 3.1-5.7%]. HIV/HBV co-infection occurred only in 5 individuals (0.5%). The HBV viral load was detectable (> 1 log10 UI/mL) in 61.8% of HBsAg-positive subjects and 64.8% HIV-positive subjects had a high viral load (≥ 3 log10 copies/mL). CONCLUSION This study revealed a high prevalence of HBV and HIV infections among WSSV in South Kivu. The results generated highlight the urgent need for systematic screening of HBV and HIV by integrating fourth-generation ELISA tests in HIV and HBV control programs.
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Affiliation(s)
- Parvine Basimane Bisimwa
- Viral Hepatitis Laboratory, Institut Pasteur de Bangui, Bangui, Central African Republic
- Faculty of Medecine, Université Evangélique en Afrique (UEA), Bukavu, Democratic Republic of Congo
- Panzi General Referral Hospital, Internal Medicine, Bukavu, Democratic Republic of Congo
- Molecular Biology Laboratory, Université Evangélique en Afrique (UEA), Bukavu, Democratic Republic of Congo
- International Center Advanced for Research and Training (ICART)/Panzi Fondation, Bukavu, Democratic Republic of Congo
| | | | - Dieudonné Bihehe Masemo
- Faculty of Medecine, Université Evangélique en Afrique (UEA), Bukavu, Democratic Republic of Congo
- Panzi General Referral Hospital, Internal Medicine, Bukavu, Democratic Republic of Congo
| | | | - Ahadi Bwihangane Birindwa
- Molecular Biology Laboratory, Université Evangélique en Afrique (UEA), Bukavu, Democratic Republic of Congo
| | - Patrick Ntagereka Bisimwa
- Molecular Biology Laboratory, Université Evangélique en Afrique (UEA), Bukavu, Democratic Republic of Congo
| | - Georges Kikuni Besulani
- Faculty of Medecine, Université Evangélique en Afrique (UEA), Bukavu, Democratic Republic of Congo
- Panzi General Referral Hospital, Internal Medicine, Bukavu, Democratic Republic of Congo
| | - Théophile Mitima Kashosi
- Faculty of Medecine, Université Evangélique en Afrique (UEA), Bukavu, Democratic Republic of Congo
| | | | - Bienfait Mitima Misuka
- Faculty of Medecine, Université Evangélique en Afrique (UEA), Bukavu, Democratic Republic of Congo
| | - Jean Paulin Mbo Mukonkole
- Faculty of Medecine, Université Evangélique en Afrique (UEA), Bukavu, Democratic Republic of Congo
- Panzi General Referral Hospital, Internal Medicine, Bukavu, Democratic Republic of Congo
| | - Jean Bisimwa Nachega
- Departments of Epidemiology, Infectious Diseases and Microbiology, University of Pittsburgh School of Public Health, Pittsburgh, Pennsylvania, United States of America
- Departments of Epidemiology and International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America
- Department of Medicine, Stellenbosch University Faculty of Medicine and Health Sciences, Cape Town, South Africa
| | - Denis Mukwege Mukengere
- Faculty of Medecine, Université Evangélique en Afrique (UEA), Bukavu, Democratic Republic of Congo
- Panzi General Referral Hospital, Internal Medicine, Bukavu, Democratic Republic of Congo
- Molecular Biology Laboratory, Université Evangélique en Afrique (UEA), Bukavu, Democratic Republic of Congo
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Wu JF, Tai CS, Chang KC, Chen TW, Chen HL, Ni YH, Hsu HY, Chang MH. CTLA-4 haplotype predicts HBsAg and HBcrAg levels and HBeAg seroconversion age in children with chronic HBV infection. JHEP Rep 2024; 6:101061. [PMID: 38601477 PMCID: PMC11002868 DOI: 10.1016/j.jhepr.2024.101061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 02/28/2024] [Accepted: 03/05/2024] [Indexed: 04/12/2024] Open
Abstract
Background & Aim Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) attenuates cytotoxic T lymphocyte (CTL) activation. This study was performed to examine the relationships between CTLA-4 genotypes/haplotypes, hepatitis B surface antigen (HBsAg), and hepatitis B core-related antigen (HBcrAg) levels, and their potential impact on the clinical course of chronic HBV infection. Methods We recruited 145 treatment-naïve patients with genotype B or C chronic HBV infection who were initially hepatitis B e-antigen (HBeAg)-positive and had been followed from a mean age of 7.08 years for a total of 4,787 person-years in the study cohort. We also recruited another 69 treatment-naïve adults with genotype B or C chronic HBV infection as a validation cohort. We assessed the CTLA-4 gene single nucleotide polymorphisms rs4553808 (-A1661G)/rs5742909 (-C318T) in both cohorts, and the serum HBsAg and HBcrAg levels in the study cohort. Results CTLA-4 promoter haplotypes were associated with HBsAg and HBcrAg levels at 10 and 15 years of age in the study cohort. Patients with the CTLA-4 AA/CC haplotype showed earlier spontaneous HBeAg seroconversion (hazard ratio = 1.58; p = 0.02), and a more rapid annual decline in the serum HBsAg level than other patients (0.09 vs. 0.03 log10 IU/ml/year, p = 0.02). The CTLA-4 AA/CC haplotype was also predictive of HBeAg seroconversion in the validation cohort (p = 0.01). Conclusions Chronic HBV-infected patients with a CTLA-4 AA/CC haplotype had lower serum HBsAg and HBcrAg levels in childhood and earlier spontaneous HBeAg seroconversion. Impact and implications The role of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) in chronic HBV-infected children has not been studied previously. In a very long-term cohort followed from childhood to adulthood, we showed that CTLA-4 haplotypes are associated with HBV biomarker levels in childhood and are correlated with the clinical course of chronic HBV infection. CTLA-4 pathway may serve as a future target for the development of therapeutic agents against HBV infection.
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Affiliation(s)
- Jia-Feng Wu
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Chi-San Tai
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Kai-Chi Chang
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Ting-Wei Chen
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Huey-Ling Chen
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
- Department of Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Yen-Hsuan Ni
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
- Department of Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Hong-Yuan Hsu
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Mei-Hwei Chang
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
- Department of Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
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Sonderup MW, Spearman CW. HBV elimination in Africa-Current status and challenges. Clin Liver Dis (Hoboken) 2024; 23:e0166. [PMID: 38707243 PMCID: PMC11068139 DOI: 10.1097/cld.0000000000000166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 03/15/2024] [Indexed: 05/07/2024] Open
Abstract
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Lazarevic I, Svicher V, Cupic M. Editorial: The role of novel hepatitis B biomarkers in solving therapeutic dilemmas. Front Med (Lausanne) 2023; 10:1256109. [PMID: 37564046 PMCID: PMC10411176 DOI: 10.3389/fmed.2023.1256109] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 07/17/2023] [Indexed: 08/12/2023] Open
Affiliation(s)
- Ivana Lazarevic
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | | | - Maja Cupic
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
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Baseline Hepatitis B Virus Surface Antigen Titers in Childhood Predict the Risk of Advanced Liver Fibrosis in Adulthood. Clin Gastroenterol Hepatol 2023; 21:663-669.e1. [PMID: 35240329 DOI: 10.1016/j.cgh.2022.02.046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/31/2022] [Accepted: 02/21/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Hepatitis B virus (HBV) surface antigen (HBsAg) is a marker of both HBV covalently closed circular DNA and integrated HBV genome, whereas the HBV core-related antigen (HBcrAg) indicates the transcriptional activity of covalently closed circular DNA. This study examined the relationship between HBsAg and HBcrAg titers in childhood and advanced fibrosis in adulthood. METHODS We recruited 214 initially hepatitis B e antigen-positive chronic HBV-infected patients who were followed for a total of 6371 person-years. None of the patients were co-infected with hepatitis C or D virus. Serum HBsAg and HBcrAg titers were assessed at 10 and 15 years of age. Transient elastography was performed at a mean final age of 38.21 years to identify advanced fibrosis. RESULTS Patients with advanced fibrosis in adulthood had a higher rate of genotype C HBV infection and a higher HBsAg titer at 10 and 15 years of age (P = .003, P = .03, and P = .005, respectively). The HBcrAg titer was not correlated with advanced fibrosis (P > .05). Receiver operating characteristic curve analysis showed that HBsAg cutoffs of >4.23 and >4.44 log10 IU/mL at 10 and 15 years of age, respectively, best predicted advanced fibrosis in the fourth decade of life (P = .001 and P < .001, respectively). In a multivariate analysis, both an HBsAg titer >4.44 log10 IU/mL at 15 years of age and HBV genotype C were predictors of advanced fibrosis (odds ratios, 15.43 and 4.77; P = .01 and P = .02, respectively). CONCLUSIONS HBsAg titers in childhood predict the progression to liver fibrosis in adulthood.
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Coffin CS, Haylock-Jacobs S, Doucette K, Ramji A, Ko HH, Wong DK, Elkhashab M, Bailey R, Uhanova J, Minuk G, Tsoi K, Wong A, Ma MM, Tam E, Brahmania M, Nudo C, Zhu J, Lowe CF, Osiowy C, Lethebe BC, Congly SE, Chan EKH, Villasis-Keever A, Sbarigia U, Cooper CL, Fung S. Clinical Outcomes and Quantitative HBV Surface Antigen Levels in Diverse Chronic Hepatitis B Patients in Canada: A Retrospective Real-World Study of CHB in Canada (REVEAL-CANADA). Viruses 2022; 14:2668. [PMID: 36560672 PMCID: PMC9781785 DOI: 10.3390/v14122668] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 11/16/2022] [Accepted: 11/18/2022] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND Hepatitis B surface antigen (HBsAg) loss is associated with improved clinical outcomes for individuals with chronic hepatitis B (CHB); however, the effects of varying HBsAg levels on clinical outcomes in diverse cohorts are understudied. METHODS In this cross-sectional, multicentre, retrospective study, the data on adult subjects enrolled in the Canadian HBV Network with CHB seen from 1 January 2012 to 30 January 2021 with the treatment and virologic data within 1 year of HBsAg testing were analyzed. Patients were tested for HBsAg using qualitative (for HBsAg-negative samples) and/or commercial quantitative assays. Fibrosis or hepatic necroinflammation was determined by the liver stiffness measurement (LSM). The baseline data were summarized using descriptive statistics and compared by using univariable/multivariable analyses. RESULTS This study included 844 CHB patients, with a median age of 49.6 years (IQR 40.1-60.5), and 37% were female. In total, 751 patients (78.6%) had known ethnicity data, and 76.7% self-reported as Asian, 11.4% as Black, 6.8% as White, and 4.8% as other. Among the 844 patients, 237 (28.0%) were HBsAg (-) (1000 IU/mL. Overall, 80% (682) had known HBeAg status at the last follow-up, and the majority (87.0%) were HBeAg-negative. In addition, 54% (461/844) had prior antiviral therapy, 19.7% of which (16.3, 23.7, n = 91) were HBsAg (-). The treated patients had a lower risk of cirrhosis (16.46, 95% CI 1.89-143.39, p = 0.01) or HCC (8.23, 95% CI 1.01-67.39, p = 0.05) than the untreated patients. A lower proportion of the HBsAg-loss group had cirrhosis (5.7% vs. 10.9%, p = 0.021) and HCC (0.9% vs. 6.2%, p = 0.001). CONCLUSION In this retrospective, ethnically diverse cohort study, CHB patients who received antiviral therapy and/or had HBsAg loss were less likely to develop cirrhosis and HCC, confirming the results of the studies in less diverse cohorts. No association was found between the qHBsAg level and fibrosis determined with LSM. Individuals who achieved HBsAg loss had low-level qHBsAg within 1 year of seroclearance.
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Affiliation(s)
- Carla S. Coffin
- Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada
| | | | - Karen Doucette
- Department of Medicine, University of Alberta, Edmonton, AB T6G 2R3, Canada
| | - Alnoor Ramji
- Department of Medicine, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
| | - Hin Hin Ko
- Department of Medicine, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
| | - David K. Wong
- Department of Medicine, University of Toronto, Toronto, ON M5G 2CV, Canada
| | | | | | - Julia Uhanova
- Department of Internal Medicine, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
| | - Gerald Minuk
- Department of Internal Medicine, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
| | - Keith Tsoi
- Department of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada
| | - Alexander Wong
- Department of Medicine, University of Saskatchewan, Regina, SK S7N 5A2, Canada
| | - Mang M. Ma
- Department of Medicine, University of Alberta, Edmonton, AB T6G 2R3, Canada
| | - Edward Tam
- Pacific Gastroenterology Associates, Vancouver, BC V6Z 2K5, Canada
| | - Mayur Brahmania
- Multi Organ Transplant Unit, Department of Medicine, Division of Gastroenterology, Western University, London, ON N6A 3K7, Canada
| | - Carmine Nudo
- Cité-de-la-Santé de Laval, Laval, QC H7M 3L9, Canada
| | - Julie Zhu
- Faculty of Medicine, Dalhousie University, Halifax, NS B3H 4R2, Canada
| | - Christopher F. Lowe
- Division of Medical Microbiology, Providence Health Care, Vancouver, BC V6Z 1Y6, Canada
| | - Carla Osiowy
- National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3R2, Canada
| | - B. Cord Lethebe
- Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada
| | - Stephen E. Congly
- Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada
| | | | | | | | - Curtis L. Cooper
- Department of Medicine, Division of infectious Diseases, University of Ottawa, Ottawa, ON K1N 6N5, Canada
| | - Scott Fung
- Department of Medicine, University of Toronto, Toronto, ON M5G 2CV, Canada
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Mohareb AM, Liu AF, Kim AY, Coffie PA, Kouamé MG, Freedberg KA, Boyd A, Hyle EP. Clearance of Hepatitis B e Antigen in Untreated Chronic Hepatitis B Virus Infection: A Systematic Review and Meta-analysis. J Infect Dis 2022; 226:1761-1770. [PMID: 35511194 DOI: 10.1093/infdis/jiac168] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 04/29/2022] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND In people with hepatitis B virus (HBV) infection, persistence of hepatitis B e antigen (HBeAg) is associated with clinical progression and need for treatment. HBeAg loss represents partial immune control and is a critical event in the natural history of chronic HBV. METHODS We conducted a systematic review and meta-analysis of cohort studies that report HBeAg loss among people with untreated chronic HBV. We evaluated HBeAg loss using a random-effects model and conducted subanalysis on region. RESULTS We screened 10 560 publications, performed 196 full-text analyses, and included 26 studies for meta-analysis. The pooled rate of HBeAg loss was 6.46/100 person-years (PYs) (95% confidence interval, 5.17-8.08). Meta-regression showed that older age of participants and studies in Europe were associated with higher rate of HBeAg loss. Rates per 100 PYs were 7.43 (95% confidence interval, 6.30-8.75; 1 study) in Africa, 3.24 (2.61--4.02; 1 study) in the Eastern Mediterranean, 13.67 (11.21-16.66; 4 studies) in Europe, 7.34 (4.61--11.70; 5 studies) in North America, and 5.53 (4.05--7.55; 15 studies) in the Western Pacific. CONCLUSIONS Spontaneous HBeAg loss occurs at a rate of 6.46/100 PYs. Variations by region and age group may reflect epidemiological, immunological, or HBV genotype-related differences.
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Affiliation(s)
- Amir M Mohareb
- Medical Practice Evaluation Center, Massachusetts General Hospital, Boston, Massachusetts, USA.,Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA.,Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - Anne F Liu
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.,Division of Gastroenterology, Hepatology, and Endoscopy, Brigham & Women's Hospital, Boston, Massachusetts, USA
| | - Arthur Y Kim
- Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA.,Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - Patrick A Coffie
- Department of Dermatology and Infectious Diseases, UFR des Sciences Médicales, Université Félix Houphouët-Boigny, Abidjan, Côte d'Ivoire.,Programme PAC-CI, ANRS Research site, Abidjan, Côte d'Ivoire
| | | | - Kenneth A Freedberg
- Medical Practice Evaluation Center, Massachusetts General Hospital, Boston, Massachusetts, USA.,Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA.,Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.,Division of General Internal Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Anders Boyd
- Stiching hiv monitoring, Amsterdam, the Netherlands.,Department of Infectious Diseases, Research and Prevention, Public Health Service of Amsterdam, Amsterdam, the Netherlands
| | - Emily P Hyle
- Medical Practice Evaluation Center, Massachusetts General Hospital, Boston, Massachusetts, USA.,Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA.,Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
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11
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Taye BW, Valery PC, Clark PJ. Targeted antiviral treatment of hepatitis B virus in culturally and linguistically diverse populations to achieve elimination targets in Australia. J Viral Hepat 2022; 29:868-878. [PMID: 35748684 PMCID: PMC9544141 DOI: 10.1111/jvh.13727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 06/03/2022] [Accepted: 06/09/2022] [Indexed: 12/09/2022]
Abstract
The majority of Australia's hepatitis B virus (HBV) burden is borne by culturally and linguistically diverse (CALD) populations, and antiviral treatment is the mainstay of intervention. Using modelling, we estimated the impact of targeted antiviral treatment scale-up and changes in migration on HBV-related mortality and HBV elimination in CALD populations in Australia. We fitted a deterministic mathematical model based on the natural history of HBV and the Australian migration effect in four CALD population groups according to country of birth. We used three antiviral treatment scale-up scenarios: baseline (9.3% coverage); intermediate (coverage of 80% of patients eligible for antiviral therapy by 2030); and optimistic (coverage of 20% of all patients living with HBV by 2022). Our model predicted that if the baseline treatment is followed between 2015 and 2030, the number of chronic HBV cases and HBV-related mortality will increase. Following the optimistic scale-up, the number of new HBV cases could be reduced by 78%, 73%, 74% and 83% in people born in Asia-Pacific, Europe, Africa and the Middle East, and Americas, respectively, between 2015 and 2030. An optimistic treatment scale-up could result in a 19.2%-24.5% reduction in HBV-related mortality and a 15%-25% reduction in HCC-related mortality in CALD populations between 2015 and 2030. In conclusion, our findings highlight that targeted antiviral treatment for CALD populations provides significant health system benefits by reducing HBV-related complications from cirrhosis and HCC. Expanded antiviral treatment programmes focusing on high-prevalence CALD populations may be an effective strategy to reduce HBV-related morbidity and mortality.
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Affiliation(s)
- Belaynew W. Taye
- Faculty of MedicineThe University of QueenslandBrisbaneQueenslandAustralia,Mater Research Institute‐University of QueenslandBrisbaneQueenslandAustralia,Population HealthQIMR Berghofer Medical Research InstituteBrisbaneQueenslandAustralia,Department of EpidemiologyBahir Dar UniversityBahir DarEthiopia
| | - Patricia C. Valery
- Faculty of MedicineThe University of QueenslandBrisbaneQueenslandAustralia,Population HealthQIMR Berghofer Medical Research InstituteBrisbaneQueenslandAustralia
| | - Paul J. Clark
- Faculty of MedicineThe University of QueenslandBrisbaneQueenslandAustralia,Mater Research Institute‐University of QueenslandBrisbaneQueenslandAustralia,Population HealthQIMR Berghofer Medical Research InstituteBrisbaneQueenslandAustralia,Department of Gastroenterology and HepatologyMater HospitalsBrisbaneQueenslandAustralia,Department of Gastroenterology and HepatologyPrincess Alexandra HospitalBrisbaneQueenslandAustralia
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12
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Zhang Z, Lu W, Huang D, Zhou X, Ding R, Li X, Wang Y, Lin W, Zeng D, Feng Y. Capabilities of hepatitis B surface antigen are divergent from hepatitis B virus DNA in delimiting natural history phases of chronic hepatitis B virus infection. Front Immunol 2022; 13:944097. [PMID: 35958621 PMCID: PMC9359073 DOI: 10.3389/fimmu.2022.944097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 06/29/2022] [Indexed: 11/13/2022] Open
Abstract
ObjectiveQuantitative hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA in the natural history of chronic HBV infection have not been rationally evaluated. This study aimed to re-characterize quantitative HBsAg and HBV DNA in the natural history phases.MethodsA total of 595 and 651 hepatitis B e antigen (HBeAg)-positive patients and 485 and 705 HBeAg-negative patients were assigned to the early and late cohorts, respectively. Based on the ‘S-shape’ receiver operating characteristic (ROC) curves, the HBeAg-positive sub-cohorts with possibly high HBV replication (PHVR) and possibly low HBV replication (PLVR) and the HBeAg-negative sub-cohorts with possibly high HBsAg expression (PHSE) and possibly low HBsAg expression (PLSE) were designated.ResultsThe areas under the ROC curve (AUCs) of HBsAg and HBV DNA in predicting HBeAg-positive significant hepatitis activity (SHA) in the early cohort, sub-cohort with PHVR, and sub-cohort with PLVR were 0.655 and 0.541, 0.720 and 0.606, and 0.553 and 0.725, respectively; those in the late cohort, sub-cohort with PHVR, and sub-cohort with PLVR were 0.646 and 0.501, 0.798 and 0.622, and 0.603 and 0.674, respectively. The AUCs of HBsAg and HBV DNA in predicting HBeAg-negative SHA in the early cohort, sub-cohort with PHSE, and sub-cohort with PLSE were 0.508 and 0.745, 0.573 and 0.780, and 0.577 and 0.729, respectively; those in the late cohort, sub-cohort with PHSE, and sub-cohort with PLSE were 0.503 and 0.761, 0.560 and 0.814, and 0.544 and 0.722, respectively. The sensitivity and specificity of HBsAg ≤4.602 log10 IU/ml in predicting HBeAg-positive SHA in the early cohort were 82.6% and 45.8%, respectively; those in the late cohort were 87.0% and 44.1%, respectively. The sensitivity and specificity of HBV DNA >3.301 log10 IU/ml in predicting HBeAg-negative SHA in the early cohort were 73.4% and 60.8%, respectively; those in the late cohort were 73.6% and 64.1%, respectively.ConclusionQuantitative HBsAg and HBV DNA are valuable, but their capabilities are divergent in delimiting the natural history phases.
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Affiliation(s)
- Zhanqing Zhang
- Department of Hepatobiliary Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
- *Correspondence: Zhanqing Zhang,
| | - Wei Lu
- Department of Hepatobiliary Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Dan Huang
- Department of Hepatobiliary Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Xinlan Zhou
- Department of Hepatobiliary Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Rongrong Ding
- Department of Hepatobiliary Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Xiufen Li
- Department of Hepatobiliary Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Yanbing Wang
- Department of Hepatobiliary Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Weijia Lin
- Department of Hepatobiliary Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Dong Zeng
- Department of Clinical Pathology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Yanling Feng
- Department of Clinical Pathology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
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13
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Circulating IL-1β, IL-17, and IP-10 as Potential Predictors of Hepatitis B Virus Infection Prognosis. J Immunol Res 2022; 2022:5202898. [PMID: 35785033 PMCID: PMC9242762 DOI: 10.1155/2022/5202898] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 06/08/2022] [Indexed: 02/05/2023] Open
Abstract
Circulating cytokines and chemokines play critical roles in hepatitis B virus (HBV) infection. Here, we explored the effects of proinflammatory and anti-inflammatory effector molecules on HBV progression, e antigen seroconversion, and liver function. Our results showed that circulating interleukin (IL)-17 may be helpful in HBV spontaneous clearance [odds ratio (OR) = 1.468, 95%confidence interval (CI) = 1.080–1.995, P = 0.014] and protective against HBV-related hepatoma development (OR = 0.933, 95%CI = 0.910–0.957, P < 0.001). IL-1β negatively affected HBV clearance (OR = 0.052, 95%CI = 0.005–0.534, P = 0.013). In patients with chronic hepatitis B, interferon-γ-inducible protein-10 (IP-10) levels significantly increased in the group of abnormal liver function (P = 0.006). Furthermore, positive correlations of IP-10 with alanine aminotransferase and aspartate aminotransferase levels were observed (rs = 0.546 and 0.644, respectively; P < 0.001). In conclusion, inflammatory cytokines and chemokines may be a “double-edged sword” for HBV clearance and progression. Further exploration of the roles of IL-17, IL-1β, and IP-10 in chronic HBV infection is needed.
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14
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Wildum S, Korolowicz KE, Suresh M, Steiner G, Dai L, Li B, Yon C, De Vera Mudry MC, Regenass-Lechner F, Huang X, Hong X, Murreddu MG, Kallakury BV, Young JAT, Menne S. Toll-Like Receptor 7 Agonist RG7854 Mediates Therapeutic Efficacy and Seroconversion in Woodchucks With Chronic Hepatitis B. Front Immunol 2022; 13:884113. [PMID: 35677037 PMCID: PMC9169629 DOI: 10.3389/fimmu.2022.884113] [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: 02/25/2022] [Accepted: 04/22/2022] [Indexed: 01/04/2023] Open
Abstract
Conventional treatment of chronic hepatitis B (CHB) is rarely curative due to the immunotolerant status of patients. RG7854 is an oral double prodrug of a toll-like receptor 7 (TLR7) agonist that is developed for the treatment of CHB. The therapeutic efficacy, host immune response, and safety of RG7854 were evaluated in the woodchuck model of CHB. Monotreatment with the two highest RG7854 doses and combination treatment with the highest RG7854 dose and entecavir (ETV) suppressed viral replication, led to loss of viral antigens, and induced seroconversion in responder woodchucks. Since viral suppression and high-titer antibodies persisted after treatment ended, this suggested that a sustained antiviral response (SVR) was induced by RG7854 in a subset of animals. The SVR rate, however, was comparable between both treatment regimens, suggesting that the addition of ETV did not enhance the therapeutic efficacy of RG7854 although it augmented the proliferation of blood cells in response to viral antigens and magnitude of antibody titers. The induction of interferon-stimulated genes in blood by RG7854/ETV combination treatment demonstrated on-target activation of TLR7. Together with the virus-specific blood cell proliferation and the transient elevations in liver enzymes and inflammation, this suggested that cytokine-mediated non-cytolytic and T-cell mediated cytolytic mechanisms contributed to the SVR, in addition to the virus-neutralizing effects by antibody-producing plasma cells. Both RG7854 regimens were not associated with treatment-limiting adverse effects but accompanied by dose-dependent, transient neutropenia and thrombocytopenia. The study concluded that finite, oral RG7854 treatment can induce a SVR in woodchucks that is based on the retrieval of antiviral innate and adaptive immune responses. This supports future investigation of the TLR7 agonist as an immunotherapeutic approach for achieving functional cure in patients with CHB.
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Affiliation(s)
- Steffen Wildum
- Roche Pharma, Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
| | - Kyle E Korolowicz
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Manasa Suresh
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Guido Steiner
- Roche Pharma, Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
| | - Lue Dai
- Roche Pharma, Research and Early Development, Roche Innovation Center Shanghai, Shanghai, China
| | - Bin Li
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Changsuek Yon
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, United States
| | | | | | - Xu Huang
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Xupeng Hong
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Marta G Murreddu
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Bhaskar V Kallakury
- Department of Pathology, Georgetown University Medical Center, Washington, DC, United States
| | - John A T Young
- Roche Pharma, Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
| | - Stephan Menne
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, United States
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15
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Li M, Zhang L, Xie S, Sun F, Zeng Z, Deng W, Jiang T, Bi X, Lin Y, Yang L, Lu Y, Shen G, Liu R, Wu S, Chang M, Hu L, Dong J, Yi W, Xie Y. Dynamic Changes of Cytokine Profiles and Virological Markers Associated With HBsAg Loss During Peginterferon Alpha-2a Treatment in HBeAg-Positive Chronic Hepatitis B Patients. Front Immunol 2022; 13:892031. [PMID: 35603222 PMCID: PMC9114800 DOI: 10.3389/fimmu.2022.892031] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 04/11/2022] [Indexed: 11/13/2022] Open
Abstract
Objective To explore dynamic changes of cytokines and virological markers associated with hepatitis B surface antigen (HBsAg) loss during peginterferon alpha-2a (PEG-IFN α-2a) treatment in hepatitis B e antigen (HBeAg) positive chronic hepatitis B (CHB) patients. Methods It was a single-center prospective cohort study. HBeAg-positive CHB patients were prospectively and consecutively enrolled. Cytokines were detected at baseline, week 12 and 24 of PEG-IFN treatment. HBsAg disappearance rate was the primary evaluation index at 48 weeks of PEG-IFN treatment. Results Among 100 patients who completed the 48-week PEG-IFN α-2a treatment, 38 patients achieved serum HBeAg disappearance, 25 patients achieved HBeAg seroconversion, 9 patients achieved functional cure, 37 patients had HBsAg decline of ≥1 log IU/ml, and 8 patients produced hepatitis B surface antibody (HBsAb). Albumin (ALB), fms-like tyrosine kinase 3 ligand (FLT3-L) and interferon-alpha2 (IFN-α2) in the clinical cure group were significantly lower than those in the non-clinical-cure group at baseline. After 12 weeks of treatment, HBsAg in the clinical cure group was significantly lower than that in the non-clinical-cure group (median 1.14 vs. 3.45 log10IU/ml, Z=-4.355, P < 0.001). The decrease of HBsAg and hepatitis B virus desoxyribose nucleic acid (HBV DNA) in the clinical cure group was significantly higher than that in non-clinical-cure group (median: HBsAg 1.96 vs. 0.33 log10IU/ml, Z=-4.703, P< 0.001; HBV DNA 4.49 vs.3.13 log10IU/ml, Z=-3.053, P=0.002). The increase of IFN-α2 in the cure group was significantly higher than that in the non-clinical-cure group (497.89 vs. 344.74, Z=-2.126, P=0.034). After 24 weeks of treatment, HBsAg, HBeAg, Flt3-L, and IL-10 in the clinical cure group were significantly lower than those in the non-clinical-cure group (median: HBsAg 0.70 vs. 3.15 log10IU/ml, Z=-4.535, P< 0.001; HBeAg 1.48 vs. 13.72 S/CO, Z = 2.512, P = 0.012; Flt3-l 0.00 vs 2.24 pg/ml, Z = 3.137, P=0.002; IL-10 0.70 vs. 2.71 pg/ml, Z=-4.067, P < 0.001). HBsAg decreased significantly in the clinical cure group compared with non-clinical-cure group (median 3.27 vs. 0.45, Z=-4.463, P < 0.001). Conclusion Dynamic changes of cytokines and virology markers during early PEG IFN α-2a treatment were associated with HBsAg loss in HBeAg-positive CHB patients.
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Affiliation(s)
- Minghui Li
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China.,Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
| | - Luxue Zhang
- Infectious Disease Department, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Si Xie
- Division of Hepatology, Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Fangfang Sun
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Zhan Zeng
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
| | - Wen Deng
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Tingting Jiang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xiaoyue Bi
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yanjie Lin
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
| | - Liu Yang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yao Lu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Ge Shen
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Ruyu Liu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Shuling Wu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Min Chang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Leiping Hu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Jianping Dong
- Department of Infectious Diseases, Haidian Hospital, Beijing Haidian Section of Peking University Third Hospital, Beijing, China
| | - Wei Yi
- Department of Gynecology and Obstetrics, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yao Xie
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China.,Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
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16
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Asai A, Hirai S, Yokohama K, Nishikawa T, Nishikawa H, Higuchi K. Effect of an Electronic Alert System on Hepatitis B Virus Reactivation in Patients Receiving Immunosuppressive Drug Therapy. J Clin Med 2022; 11:jcm11092446. [PMID: 35566572 PMCID: PMC9104084 DOI: 10.3390/jcm11092446] [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: 03/10/2022] [Revised: 04/19/2022] [Accepted: 04/23/2022] [Indexed: 02/04/2023] Open
Abstract
Hepatitis B virus (HBV) reactivation (HBVr) can occur in patients receiving immunosuppressive drug therapies, causing significant morbidity and mortality. Although the guidelines for HBVr have been proposed by several academic societies, some providers do not follow them, resulting in HBVr and death. As HBV-DNA levels increase before liver enzyme levels do, we previously constructed an electronic alert system that recommends the measurement of HBV-DNA. Here, we investigated whether this alert system improves the HBV-DNA measurement rate and elicits responses according to guidelines. A total of 5329 patients were divided into two groups, before and after the introduction of the alert system, and the HBV-DNA measurement rates in both groups were compared. Because of the introduction of the alert system, the HBV-DNA measurement rate among HBsAg-negative patients with anti-HBs and/or anti-HBc before immunosuppressive drug therapy improved significantly. The HBV-DNA monitoring rate within 3 months also improved significantly (p = 0.0034) in HBV-remission phase patients. HBVr was detected immediately, and the affected patients were treated with nucleotide analogs before severe hepatitis onset. The introduction of the alert system for HBVr improved the HBV-DNA measurement rates in patients receiving immunosuppressive drug therapy, leading to the rapid treatment of patients with HBVr.
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Affiliation(s)
- Akira Asai
- The Second Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki 569-8686, Japan; (K.Y.); (T.N.); (H.N.); (K.H.)
- Correspondence: ; Tel.: +81-(726)-83-1221
| | - Saho Hirai
- Faculty of Medicine, Osaka Medical and Pharmaceutical University, Takatsuki 569-8686, Japan;
| | - Keisuke Yokohama
- The Second Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki 569-8686, Japan; (K.Y.); (T.N.); (H.N.); (K.H.)
| | - Tomohiro Nishikawa
- The Second Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki 569-8686, Japan; (K.Y.); (T.N.); (H.N.); (K.H.)
| | - Hiroki Nishikawa
- The Second Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki 569-8686, Japan; (K.Y.); (T.N.); (H.N.); (K.H.)
| | - Kazuhide Higuchi
- The Second Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki 569-8686, Japan; (K.Y.); (T.N.); (H.N.); (K.H.)
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17
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Fainboim H, Di Benedetto N, Paz S, Mendizabal M, Campuzano S, Elizalde M, Tadey L, Deluchi G, Bouzas MB, Mammana L, Flichman D. Quantitative HBsAg an unreliable marker for diagnosis and disease progression in genotype F chronic HBeAg-negative infections. J Viral Hepat 2022; 29:298-301. [PMID: 35152530 DOI: 10.1111/jvh.13657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 02/01/2022] [Indexed: 12/09/2022]
Affiliation(s)
- Hugo Fainboim
- Unidad de Hepatopatías Infecciosas, Hospital de Infecciosas F. J. Muñiz, Buenos Aires, Argentina
| | | | - Silvia Paz
- Unidad de Hepatopatías Infecciosas, Hospital de Infecciosas F. J. Muñiz, Buenos Aires, Argentina
| | | | - Soledad Campuzano
- Unidad de Hepatopatías Infecciosas, Hospital de Infecciosas F. J. Muñiz, Buenos Aires, Argentina
| | - Mercedes Elizalde
- Instituto de Investigaciones Biomédicas en Retrovirus y Síndrome de Inmunodeficiencia Adquirida (INBIRS), Buenos Aires, Argentina.,Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Luciana Tadey
- Unidad de Virología, Hospital de Infecciosas "Francisco J. Muñiz", Buenos Aires, Argentina
| | - Gabriel Deluchi
- Unidad de Virología, Hospital de Infecciosas "Francisco J. Muñiz", Buenos Aires, Argentina
| | - María Belén Bouzas
- Unidad de Virología, Hospital de Infecciosas "Francisco J. Muñiz", Buenos Aires, Argentina
| | - Lilia Mammana
- Unidad de Virología, Hospital de Infecciosas "Francisco J. Muñiz", Buenos Aires, Argentina
| | - Diego Flichman
- Instituto de Investigaciones Biomédicas en Retrovirus y Síndrome de Inmunodeficiencia Adquirida (INBIRS), Buenos Aires, Argentina.,Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
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18
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Nkongolo S, Hollnberger J, Urban S. [Bulevirtide as the first specific agent against hepatitis D virus infections-mechanism and clinical effect]. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2022; 65:254-263. [PMID: 35028672 PMCID: PMC8813823 DOI: 10.1007/s00103-022-03486-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 12/22/2021] [Indexed: 12/19/2022]
Abstract
Die Blockade des Zelleintritts von Krankheitserregern ist ein geeigneter Ansatz, um Neuinfektionen zu verhindern. Der therapeutische Einsatz von Eintrittsinhibitoren bei chronisch infizierten Patienten war jedoch bisher nur begrenzt erfolgreich. Zur Behandlung von chronischen Hepatitis-D-Virus-(HDV-)Infektionen wurde im Juli 2020 mit Bulevirtide (BLV) ein vielversprechender Wirkstoff bedingt zugelassen, der auf diesem Wirkprinzip beruht. Zuvor hatten für HDV keine gezielte Medikation zur Verfügung gestanden und die Behandlung beruhte auf dem Off-Label-Einsatz von Interferon-Alpha/Peginterferon-Alpha (IFNα/Peg-IFNα). In diesem Beitrag wird ein Überblick über die Grundlagen des Wirkmechanismus von BLV gegeben und bisher vorliegende klinische Daten werden zusammengefasst. Eine HDV-Infektion manifestiert sich als Ko- oder Superinfektion bei Hepatitis-B-Virus-(HBV-)Infektionen und betrifft 4,5–15 % der HBV-Patienten weltweit. HDV nutzt die Hüllproteine von HBV zur Verbreitung. BLV wirkt, indem es den HBV/HDV-Rezeptor natriumtaurocholat-co-transportierendes Polypeptid (NTCP) blockiert und so den Eintritt von HBV/HDV in Hepatozyten verhindert. BLV senkt die HDV-Serum-RNA-Spiegel und führt bei HBV/HDV-infizierten Personen zur Normalisierung der Alanin-Aminotransferase-(ALT-)Werte. Es hat ein ausgezeichnetes Sicherheitsprofil, selbst wenn es über 48 Wochen in hohen Dosen (10 mg täglich) verabreicht wird. In Kombination mit Peg-IFNα zeigt BLV synergistische Effekte auf die Senkung der HDV-RNA im Serum, aber auch auf die Hepatitis-B-Oberflächenantigen-(HBsAg‑)Spiegel. Dies führte bei einer Untergruppe von Patienten zu einer funktionellen Heilung, wenn 2 mg BLV plus Peg-IFNα verabreicht wurden. Der Mechanismus dieser wahrscheinlich immunvermittelten Eliminierung wird in Folgestudien untersucht.
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Affiliation(s)
- Shirin Nkongolo
- Molekulare Virologie, Translationale Virologie, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 344, 69120, Heidelberg, Deutschland.,Deutsches Zentrum für Infektionsforschung (DZIF), Partnerstandort Heidelberg, Deutschland.,Toronto Centre for Liver Disease, University Health Network, Toronto, Kanada
| | - Julius Hollnberger
- Molekulare Virologie, Translationale Virologie, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 344, 69120, Heidelberg, Deutschland.,Deutsches Zentrum für Infektionsforschung (DZIF), Partnerstandort Heidelberg, Deutschland
| | - Stephan Urban
- Molekulare Virologie, Translationale Virologie, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 344, 69120, Heidelberg, Deutschland. .,Deutsches Zentrum für Infektionsforschung (DZIF), Partnerstandort Heidelberg, Deutschland.
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19
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A Prospective Five-Year Follow-up After peg-Interferon Plus Nucleotide Analogue Treatment or no Treatment in HBeAg Negative Chronic Hepatitis B Patients. J Clin Exp Hepatol 2022; 12:735-744. [PMID: 35677522 PMCID: PMC9168707 DOI: 10.1016/j.jceh.2021.12.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 12/16/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Currently available treatment options for chronic hepatitis B (CHB) are not recommended for HBeAg-negative patients with a low viral load. These patients may however benefit from treatment by achieving a functional cure, defined by HBsAg-loss and undetectable HBV DNA. This study evaluated the long-term effect of combination treatment with peg-interferon-alpha-2a (peg-IFN) and adefovir or tenofovir compared to no treatment in these patients. METHODS HBeAg-negative CHB patients with HBV-DNA levels < 20,000 IU/mL (n = 151) were previously randomised 1:1:1 for peg-IFN 180 μg/week plus either adefovir 10 mg/day or tenofovir 245 mg/day, or no treatment and treated for 48 weeks in an open-label study. In this prospective long-term follow-up study, patients were monitored yearly up to five years after end of treatment (week 308). The primary outcome was sustained HBsAg-loss and secondary outcome the dynamics of HBsAg and HBV-DNA levels over time. RESULTS Of the 131 followed patients, the HBsAg-status was known for 118 patients after five-year follow-up. HBsAg-loss occurred similarly (P = 0.703) in all arms: 8/43 (18.6%) peg-IFN + adefovir, 4/34 (11.7%) peg-IFN + tenofovir, and 6/41 (14.6%) among the untreated patients. The time to HBsAg-loss did not differ between groups (P = 0.641). Low baseline HBsAg levels and genotype A were independently associated with HBsAg-loss irrespective of allocation. HBsAg and HBV-DNA levels declined similarly during follow-up in all patient groups. CONCLUSIONS This prospective randomised controlled study showed that HBsAg-loss overtime was not influenced by treatment with a combination of nucleotide analogue and Peg-IFN. Low baseline HBsAg levels can predict HBsAg-loss irrespective of treatment allocation.
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Key Words
- ADV, Adefovir dipivoxil
- ALT, Alanine aminotransferase
- CHB, Chronic hepatitis B
- EOT, End of treatment
- GZ, Grey zone
- HBeAg, Hepatitis B e antigen
- HBsAg, Hepatitis B surface antigen
- HCC, Hepatocellular Carcinoma
- HNCH, HBeAg-negative chronic infection
- NA, Nucleot(s)ide analogue
- ROC, Receiver operating characteristic
- TAF, Tenofovir alafenamide fumarateor
- TDF, Tenofovir disoproxil fumarate
- ULN, Upper limit of normal
- UMC, University Medical Centers
- combination therapy
- functional cure
- hepatitis B virus
- inactive carrier
- low viral load
- peg-IFN, Pegylated-interferon
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20
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González Grande R, Santaella Leiva I, López Ortega S, Jiménez Pérez M. Present and future management of viral hepatitis. World J Gastroenterol 2021; 27:8081-8102. [PMID: 35068856 PMCID: PMC8704279 DOI: 10.3748/wjg.v27.i47.8081] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 04/08/2021] [Accepted: 12/07/2021] [Indexed: 02/06/2023] Open
Abstract
Viral hepatitis can result in important morbidity and mortality, with its impact on health conditioned by the specific type of hepatitis, the geographical region of presentation and the development and access to new drugs, among other factors. Most acute presentation forms are self-limiting and may even go unnoticed, with just a small percentage of cases leading to acute liver failure that may necessitate transplantation or even cause the death of the patient. However, when they become chronic, as in the case of hepatitis B virus and C virus, unless they are diagnosed and treated adequately they may have severe consequences, like cirrhosis or hepatocarcinoma. Understanding of the mechanisms of transmission, the pathogenesis, the presence of vaccinations and the development over recent years of new highly-efficient, potent drugs have meant that we are now faced with a new scenario in the management of viral hepatitis, particularly hepatitis B virus and hepatitis C virus. The spectacular advances in hepatitis C virus treatment have led the World Health Organization to propose the objective of its eradication by 2030. The key aspect to achieving this goal is to ensure that these treatments reach all the more vulnerable population groups, in whom the different types of viral hepatitis have a high prevalence and constitute a niche that may perpetuate infection and hinder its eradication. Accordingly, micro-elimination programs assume special relevance at the present time.
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Affiliation(s)
- Rocío González Grande
- UGC de Aparato Digestivo. Unidad de Hepatología-Trasplante Hepático, Hospital Regional Universitario de Málaga, Málaga 29010, Spain
| | - Inmaculada Santaella Leiva
- UGC de Aparato Digestivo. Unidad de Hepatología-Trasplante Hepático, Hospital Regional Universitario de Málaga, Málaga 29010, Spain
| | - Susana López Ortega
- UGC de Aparato Digestivo. Unidad de Hepatología-Trasplante Hepático, Hospital Regional Universitario de Málaga, Málaga 29010, Spain
| | - Miguel Jiménez Pérez
- UGC de Aparato Digestivo. Unidad de Hepatología-Trasplante Hepático, Hospital Regional Universitario de Málaga, Málaga 29010, Spain
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21
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Du Y, Broering R, Li X, Zhang X, Liu J, Yang D, Lu M. In Vivo Mouse Models for Hepatitis B Virus Infection and Their Application. Front Immunol 2021; 12:766534. [PMID: 34777385 PMCID: PMC8586444 DOI: 10.3389/fimmu.2021.766534] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Accepted: 10/14/2021] [Indexed: 12/19/2022] Open
Abstract
Despite the availability of effective vaccination, hepatitis B virus (HBV) infection continues to be a major challenge worldwide. Research efforts are ongoing to find an effective cure for the estimated 250 million people chronically infected by HBV in recent years. The exceptionally limited host spectrum of HBV has limited the research progress. Thus, different HBV mouse models have been developed and used for studies on infection, immune responses, pathogenesis, and antiviral therapies. However, these mouse models have great limitations as no spread of HBV infection occurs in the mouse liver and no or only very mild hepatitis is present. Thus, the suitability of these mouse models for a given issue and the interpretation of the results need to be critically assessed. This review summarizes the currently available mouse models for HBV research, including hydrodynamic injection, viral vector-mediated transfection, recombinant covalently closed circular DNA (rc-cccDNA), transgenic, and liver humanized mouse models. We systematically discuss the characteristics of each model, with the main focus on hydrodynamic injection mouse model. The usefulness and limitations of each mouse model are discussed based on the published studies. This review summarizes the facts for considerations of the use and suitability of mouse model in future HBV studies.
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Affiliation(s)
- Yanqin Du
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Ruth Broering
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Xiaoran Li
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaoyong Zhang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jia Liu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dongliang Yang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Mengji Lu
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
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22
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Philips CA, Ahamed R, Abduljaleel JK, Rajesh S, Augustine P. Critical Updates on Chronic Hepatitis B Virus Infection in 2021. Cureus 2021; 13:e19152. [PMID: 34733599 PMCID: PMC8557099 DOI: 10.7759/cureus.19152] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/30/2021] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection is a global healthcare burden in the form of chronic liver disease, cirrhosis, liver failure and liver cancer. There is no definite cure for the virus and even though extensive vaccination programs have reduced the burden of liver disease in the future population, treatment options to eradicate the virus from the host are still lacking. In this review, we discuss in detail current updates on the structure and applied biology of the virus in the host, examine updates to current treatment and explore novel and state-of-the-art therapeutics in the pipeline for management of chronic HBV. Furthermore, we also specifically review clinical updates on HBV-related acute on chronic liver failure (ACLF). Current treatments for chronic HBV infection have seen important updates in the form of considerations for treating patients in the immune tolerant phase and some clarity on end points for treatment and decisions on finite therapy with nucleos(t)ide inhibitors. Ongoing cutting-edge research on HBV biology has helped us identify novel target areas in the life cycle of the virus for application of new therapeutics. Due to improvements in the area of genomics, the hope for therapeutic vaccines, vector-based treatments and focused management aimed at targeting host integration of the virus and thereby a total cure could become a reality in the near future. Newer clinical prognostic tools have improved our understanding of timing of specific treatment options for the catastrophic syndrome of ACLF secondary to reactivation of HBV. In this review, we discuss in detail pertinent updates regarding virus biology and novel therapeutic targets with special focus on the appraisal of prognostic scores and treatment options in HBV-related ACLF.
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Affiliation(s)
- Cyriac A Philips
- Clinical and Translational Hepatology, The Liver Institute, Rajagiri Hospital, Aluva, IND
| | - Rizwan Ahamed
- Gastroenterology and Advanced Gastrointestinal Endoscopy, Center of Excellence in Gastrointestinal Sciences, Rajagiri Hospital, Aluva, IND
| | - Jinsha K Abduljaleel
- Gastroenterology and Advanced Gastrointestinal Endoscopy, Center of Excellence in Gastrointestinal Sciences, Rajagiri Hospital, Aluva, IND
| | - Sasidharan Rajesh
- Diagnostic and Interventional Radiology, Center of Excellence in Gastrointestinal Sciences, Rajagiri Hospital, Aluva, IND
| | - Philip Augustine
- Gastroenterology and Advanced Gastrointestinal Endoscopy, Center of Excellence in Gastrointestinal Sciences, Rajagiri Hospital, Aluva, IND
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23
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Piermatteo L, Alkhatib M, D’Anna S, Malagnino V, Bertoli A, Andreassi E, Basile E, Iuvara A, De Cristofaro M, Cappiello G, Cerva C, Minichini C, Pisaturo M, Starace M, Coppola N, Fontana C, Grelli S, Ceccherini-Silberstein F, Andreoni M, Gill US, Kennedy PTF, Sarmati L, Salpini R, Svicher V. HBeAg Levels Vary across the Different Stages of HBV Infection According to the Extent of Immunological Pressure and Are Associated with Therapeutic Outcome in the Setting of Immunosuppression-Driven HBV Reactivation. Biomedicines 2021; 9:biomedicines9101352. [PMID: 34680469 PMCID: PMC8533134 DOI: 10.3390/biomedicines9101352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 09/21/2021] [Accepted: 09/24/2021] [Indexed: 11/16/2022] Open
Abstract
HBeAg is a marker of HBV-activity, and HBeAg-loss predicts a favorable clinical outcome. Here, we characterize HBeAg-levels across different phases of HBV infection, their correlation with virological/biochemical markers and the virological response to anti-HBV therapy. Quantitative HBeAg (qHBeAg, DiaSorin) is assessed in 101 HBeAg+ patients: 20 with acute-infection, 20 with chronic infection, 32 with chronic hepatitis and 29 with immunosuppression-driven HBV-reactivation (HBV-R). A total of 15/29 patients with HBV-R are monitored for >12 months after starting TDF/ETV. qHBeAg is higher in immunosuppression-driven HBV-R (median[IQR]:930[206-1945]PEIU/mL) and declines in chronic hepatitis (481[28-1393]PEIU/mL, p = 0.03), suggesting HBeAg production, modulated by the extent of immunological pressure. This is reinforced by the negative correlation between qHBeAg and ALT in acute infection (Rho = -0.66, p = 0.006) and chronic hepatitis (Rho = -0.35; p = 0.05). Interestingly, qHBeAg strongly and positively correlates with qHBsAg across the study groups, suggesting cccDNA as a major source of both proteins in the setting of HBeAg positivity (with limited contribution of integrated HBV-DNA to HBsAg production). Focusing on 15 patients with HBV-R starting TDF/ETV, virological suppression and HBeAg-loss are achieved in 60% and 53.3%. Notably, the combination of qHBeAg > 2000 PEIU/mL + qHBsAg > 52,000 IU/mL at HBV-R is the only factor predicting no HBeAg loss (HBeAg loss: 0% with vs. 72.7% without qHBeAg > 2000 PEIU/mL + qHBsAg > 52,000 IU/mL, p = 0.03). In conclusion, qHBeAg varies over the natural course of HBV infection, according to the extent of immunological pressure. In the setting of HBV-R, qHBeAg could be useful in predicting the treatment response under immunosuppression.
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Affiliation(s)
- Lorenzo Piermatteo
- Department of Experimental Medicine, University of Rome Tor Vergata, 00133 Rome, Italy; (L.P.); mohammad-- (M.A.); (S.D.); (A.B.); (E.A.); (S.G.); (F.C.-S.); (V.S.)
| | - Mohammad Alkhatib
- Department of Experimental Medicine, University of Rome Tor Vergata, 00133 Rome, Italy; (L.P.); mohammad-- (M.A.); (S.D.); (A.B.); (E.A.); (S.G.); (F.C.-S.); (V.S.)
| | - Stefano D’Anna
- Department of Experimental Medicine, University of Rome Tor Vergata, 00133 Rome, Italy; (L.P.); mohammad-- (M.A.); (S.D.); (A.B.); (E.A.); (S.G.); (F.C.-S.); (V.S.)
| | - Vincenzo Malagnino
- Infectious Disease Unit, University Hospital of Rome Tor Vergata, 00133 Rome, Italy; (V.M.); (C.C.); (M.A.); (L.S.)
| | - Ada Bertoli
- Department of Experimental Medicine, University of Rome Tor Vergata, 00133 Rome, Italy; (L.P.); mohammad-- (M.A.); (S.D.); (A.B.); (E.A.); (S.G.); (F.C.-S.); (V.S.)
- Microbiology and Virology Unit, University Hospital of Rome Tor Vergata, 00133 Rome, Italy; (E.B.); (A.I.); (C.F.)
| | - Eleonora Andreassi
- Department of Experimental Medicine, University of Rome Tor Vergata, 00133 Rome, Italy; (L.P.); mohammad-- (M.A.); (S.D.); (A.B.); (E.A.); (S.G.); (F.C.-S.); (V.S.)
| | - Elisa Basile
- Microbiology and Virology Unit, University Hospital of Rome Tor Vergata, 00133 Rome, Italy; (E.B.); (A.I.); (C.F.)
| | - Alessandra Iuvara
- Microbiology and Virology Unit, University Hospital of Rome Tor Vergata, 00133 Rome, Italy; (E.B.); (A.I.); (C.F.)
| | - Maria De Cristofaro
- Microbiology Unit, “Sandro Pertini” Hospital, 00133 Rome, Italy; (M.D.C.); (G.C.)
| | - Giuseppina Cappiello
- Microbiology Unit, “Sandro Pertini” Hospital, 00133 Rome, Italy; (M.D.C.); (G.C.)
| | - Carlotta Cerva
- Infectious Disease Unit, University Hospital of Rome Tor Vergata, 00133 Rome, Italy; (V.M.); (C.C.); (M.A.); (L.S.)
| | - Carmine Minichini
- Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, University of Campania Luigi Vanvitelli, 80138 Naples, Italy; (C.M.); (M.P.); (M.S.); (N.C.)
| | - Mariantonietta Pisaturo
- Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, University of Campania Luigi Vanvitelli, 80138 Naples, Italy; (C.M.); (M.P.); (M.S.); (N.C.)
| | - Mario Starace
- Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, University of Campania Luigi Vanvitelli, 80138 Naples, Italy; (C.M.); (M.P.); (M.S.); (N.C.)
| | - Nicola Coppola
- Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, University of Campania Luigi Vanvitelli, 80138 Naples, Italy; (C.M.); (M.P.); (M.S.); (N.C.)
| | - Carla Fontana
- Microbiology and Virology Unit, University Hospital of Rome Tor Vergata, 00133 Rome, Italy; (E.B.); (A.I.); (C.F.)
| | - Sandro Grelli
- Department of Experimental Medicine, University of Rome Tor Vergata, 00133 Rome, Italy; (L.P.); mohammad-- (M.A.); (S.D.); (A.B.); (E.A.); (S.G.); (F.C.-S.); (V.S.)
- Microbiology and Virology Unit, University Hospital of Rome Tor Vergata, 00133 Rome, Italy; (E.B.); (A.I.); (C.F.)
| | - Francesca Ceccherini-Silberstein
- Department of Experimental Medicine, University of Rome Tor Vergata, 00133 Rome, Italy; (L.P.); mohammad-- (M.A.); (S.D.); (A.B.); (E.A.); (S.G.); (F.C.-S.); (V.S.)
| | - Massimo Andreoni
- Infectious Disease Unit, University Hospital of Rome Tor Vergata, 00133 Rome, Italy; (V.M.); (C.C.); (M.A.); (L.S.)
| | - Upkar S. Gill
- Barts Liver Centre, Immunobiology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK; (U.S.G.); (P.T.F.K.)
| | - Patrick T. F. Kennedy
- Barts Liver Centre, Immunobiology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK; (U.S.G.); (P.T.F.K.)
| | - Loredana Sarmati
- Infectious Disease Unit, University Hospital of Rome Tor Vergata, 00133 Rome, Italy; (V.M.); (C.C.); (M.A.); (L.S.)
| | - Romina Salpini
- Department of Experimental Medicine, University of Rome Tor Vergata, 00133 Rome, Italy; (L.P.); mohammad-- (M.A.); (S.D.); (A.B.); (E.A.); (S.G.); (F.C.-S.); (V.S.)
- Correspondence:
| | - Valentina Svicher
- Department of Experimental Medicine, University of Rome Tor Vergata, 00133 Rome, Italy; (L.P.); mohammad-- (M.A.); (S.D.); (A.B.); (E.A.); (S.G.); (F.C.-S.); (V.S.)
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24
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Korolowicz KE, Suresh M, Li B, Huang X, Yon C, Kallakury BV, Lee KP, Park S, Kim YW, Menne S. Combination Treatment with the Vimentin-Targeting Antibody hzVSF and Tenofovir Suppresses Woodchuck Hepatitis Virus Infection in Woodchucks. Cells 2021; 10:2321. [PMID: 34571970 PMCID: PMC8466705 DOI: 10.3390/cells10092321] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 08/24/2021] [Accepted: 08/27/2021] [Indexed: 02/07/2023] Open
Abstract
Current treatment options for patients infected with hepatitis B virus (HBV) are suboptimal, because the approved drugs rarely induce cure due to the persistence of the viral DNA genome in the nucleus of infected hepatocytes, and are associated with either severe side effects (pegylated interferon-alpha) or require life-long administration (nucleos(t)ide analogs). We report here the evaluation of the safety and therapeutic efficacy of a novel, humanized antibody (hzVSF) in the woodchuck model of HBV infection. hzVSF has been shown to act as a viral entry inhibitor, most likely by suppressing vimentin-mediated endocytosis of virions. Targeting the increased vimentin expression on liver cells by hzVSF after infection with HBV or woodchuck hepatitis virus (WHV) was demonstrated initially. Thereafter, hzVSF safety was assessed in eight woodchucks naïve for WHV infection. Antiviral efficacy of hzVSF was evaluated subsequently in 24 chronic WHV carrier woodchucks by monotreatment with three ascending doses and in combination with tenofovir alafenamide fumarate (TAF). Consistent with the proposed blocking of WHV reinfection, intravenous hzVSF administration for 12 weeks resulted in a modest but transient reduction of viral replication and associated liver inflammation. In combination with oral TAF dosing, the antiviral effect of hzVSF was enhanced and sustained in half of the woodchucks with an antibody response to viral proteins. Thus, hzVSF safely but modestly alters chronic WHV infection in woodchucks; however, as a combination partner to TAF, its antiviral efficacy is markedly increased. The results of this preclinical study support future evaluation of this novel anti-HBV drug in patients.
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Affiliation(s)
- Kyle E. Korolowicz
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA; (K.E.K.); (M.S.); (B.L.); (X.H.); (C.Y.)
| | - Manasa Suresh
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA; (K.E.K.); (M.S.); (B.L.); (X.H.); (C.Y.)
| | - Bin Li
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA; (K.E.K.); (M.S.); (B.L.); (X.H.); (C.Y.)
| | - Xu Huang
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA; (K.E.K.); (M.S.); (B.L.); (X.H.); (C.Y.)
| | - Changsuek Yon
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA; (K.E.K.); (M.S.); (B.L.); (X.H.); (C.Y.)
| | - Bhaskar V. Kallakury
- Department of Pathology, Georgetown University Medical Center, Washington, DC 20057, USA;
| | - Kyoung-pil Lee
- ImmuneMed, Inc., Chuncheon BioTown, Soyanggang ro 32, Chuncheon-si 24232, Gangwon-do, Korea; (K.-p.L.); (S.P.); (Y.-W.K.)
| | - Sungman Park
- ImmuneMed, Inc., Chuncheon BioTown, Soyanggang ro 32, Chuncheon-si 24232, Gangwon-do, Korea; (K.-p.L.); (S.P.); (Y.-W.K.)
| | - Yoon-Won Kim
- ImmuneMed, Inc., Chuncheon BioTown, Soyanggang ro 32, Chuncheon-si 24232, Gangwon-do, Korea; (K.-p.L.); (S.P.); (Y.-W.K.)
| | - Stephan Menne
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA; (K.E.K.); (M.S.); (B.L.); (X.H.); (C.Y.)
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25
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Axiaris G, Zampeli E, Michopoulos S, Bamias G. Management of hepatitis B virus infection in patients with inflammatory bowel disease under immunosuppressive treatment. World J Gastroenterol 2021; 27:3762-3779. [PMID: 34321842 PMCID: PMC8291024 DOI: 10.3748/wjg.v27.i25.3762] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 04/26/2021] [Accepted: 05/27/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B remains a significant global clinical problem, despite the implementation of safe and effective vaccination programs. The prevalence of hepatitis B virus (HBV) in patients with inflammatory bowel disease (IBD) largely follows the regional epidemiologic status. Serological screening with hepatitis B surface antigen (HBsAg), and antibodies to hepatitis B surface (anti-HBs) and core (anti-HBc) proteins is a key element in the management of IBD patients and, ideally, should be performed at IBD diagnosis. Stratification of individual cases should be done according to the serologic profile and the IBD-specific treatment, with particular emphasis in patients receiving immunosuppressive regimens. In patients who have not contracted HBV, vaccination is indicated to accomplish protective immunity. Vaccination in immunosuppressed patients, however, is a challenging issue and several strategies for primary and revaccination have been proposed. The risk of HBV reactivation in patients with IBD should be considered in both HBsAg-positive and HBsAg-negative/anti-HBc-positive patients, when immunosuppressive therapies are administered. HBV reactivation is preventable via the administration of prophylactic nucleot(s)ide analogues and should be the standard approach in HBsAg-positive patients. HBsAg-negative/anti-HBc-positive patients represent a non-homogeneous group and bear a significantly lower risk of HBV reactivation. Biochemical, serological and molecular monitoring is currently the recommended approach for anti-HBc patients. Acute HBV infection is rarely reported in IBD patients. In the present review, we outline the problems associated with HBV infection in patients with IBD and present updated evidence for their management.
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Affiliation(s)
- Georgios Axiaris
- Gastroenterology Department, "Alexandra" Hospital, Athens 11528, Greece
| | - Evanthia Zampeli
- Gastroenterology Department, "Alexandra" Hospital, Athens 11528, Greece
| | | | - Giorgos Bamias
- GI Unit, 3rd Academic Department of Internal Medicine, National and Kapodistrian University of Athens, Sotiria Hospital, Athens 11526, Greece
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Campos-Valdez M, Monroy-Ramírez HC, Armendáriz-Borunda J, Sánchez-Orozco LV. Molecular Mechanisms during Hepatitis B Infection and the Effects of the Virus Variability. Viruses 2021; 13:v13061167. [PMID: 34207116 PMCID: PMC8235420 DOI: 10.3390/v13061167] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 06/10/2021] [Accepted: 06/11/2021] [Indexed: 12/16/2022] Open
Abstract
The immunopathogenesis and molecular mechanisms involved during a hepatitis B virus (HBV) infection have made the approaches for research complex, especially concerning the patients’ responses in the course of the early acute stage. The study of molecular bases involved in the viral clearance or persistence of the infection is complicated due to the difficulty to detect patients at the most adequate points of the disease, especially in the time lapse between the onset of the infection and the viral emergence. Despite this, there is valuable data obtained from animal and in vitro models, which have helped to clarify some aspects of the early immune response against HBV infection. The diversity of the HBV (genotypes and variants) has been proven to be associated not only with the development and outcome of the disease but also with the response to treatments. That is why factors involved in the virus evolution need to be considered while studying hepatitis B infection. This review brings together some of the published data to try to explain the immunological and molecular mechanisms involved in the different stages of the infection, clinical outcomes, viral persistence, and the impact of the variants of HBV in these processes.
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Affiliation(s)
- Marina Campos-Valdez
- Centro Universitario de Ciencias de la Salud, Departamento de Biología Molecular y Genómica, Instituto de Biología Molecular en Medicina, Universidad de Guadalajara, Guadalajara 44340, Jalisco, México; (M.C.-V.); (H.C.M.-R.); (J.A.-B.)
| | - Hugo C. Monroy-Ramírez
- Centro Universitario de Ciencias de la Salud, Departamento de Biología Molecular y Genómica, Instituto de Biología Molecular en Medicina, Universidad de Guadalajara, Guadalajara 44340, Jalisco, México; (M.C.-V.); (H.C.M.-R.); (J.A.-B.)
| | - Juan Armendáriz-Borunda
- Centro Universitario de Ciencias de la Salud, Departamento de Biología Molecular y Genómica, Instituto de Biología Molecular en Medicina, Universidad de Guadalajara, Guadalajara 44340, Jalisco, México; (M.C.-V.); (H.C.M.-R.); (J.A.-B.)
- Escuela de Medicina y Ciencias de la Salud, Tecnológico de Monterrey, Campus Guadalajara, Zapopan 45201, Jalisco, México
| | - Laura V. Sánchez-Orozco
- Centro Universitario de Ciencias de la Salud, Departamento de Biología Molecular y Genómica, Instituto de Biología Molecular en Medicina, Universidad de Guadalajara, Guadalajara 44340, Jalisco, México; (M.C.-V.); (H.C.M.-R.); (J.A.-B.)
- Correspondence: ; Tel.: +52-33-3954-5677
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27
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Hepatitis Flare During Immunotherapy in Patients With Current or Past Hepatitis B Virus Infection. Am J Gastroenterol 2021; 116:1274-1283. [PMID: 33560651 DOI: 10.14309/ajg.0000000000001142] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 12/16/2020] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Immunotherapy has dramatically improved the survival of patients with advanced or metastatic malignancies. Recent studies suggest that immunotherapy may increase the risk of hepatitis, whereas it may also induce functional cure of chronic hepatitis B virus (HBV) infection. We evaluated the incidence of hepatitis flare, HBV reactivation, hepatitis B surface antigen (HBsAg) seroclearance or seroreversion in patients with current or past HBV infection who had received immunotherapy. METHODS This was a territory-wide observational cohort study in Hong Kong. We identified patients through electronic medical records based on the prescriptions of immune checkpoint inhibitors from July 1, 2014, to December 31, 2019. Patients who were HBsAg positive or HBsAg negative with results for antibody to hepatitis B surface or core antigen (anti-HBs or anti-HBc) were included. RESULTS A total of 990 patients (397 HBsAg-positive, 593 HBsAg-negative with 482 anti-HBc and/or anti-HBs positive, and 111 both anti-HBc and anti-HBs negative) were identified. All of HBsAg-positive and 15.9% HBsAg-negative patients were put on oral antiviral treatment. Hepatitis flare (alanine aminotransferase >2 times of the upper limit of normal) occurred in 39.3% HBsAg-positive and 30.4% HBsAg-negative patients. High baseline alanine aminotransferase and combination of immunotherapy increased the risk of hepatitis. HBV reactivation (≥2 log increase in HBV DNA from baseline) occurred in 2 HBsAg-positive patients; HBsAg seroclearance and seroreversion was observed in 1 HBsAg-positive and 1 HBsAg-negative patient, respectively (<1%). DISCUSSION Hepatitis flare occurs in approximately 40% of HBsAg-positive patients and 30% of HBsAg-negative patients during immunotherapy. HBV reactivation, HBsAg seroclearance, and HBsAg seroreversion are rare. Current or past HBV infection has no impact on the emergence of hepatic flare associated with immunotherapy.
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Korolowicz KE, Suresh M, Li B, Huang X, Yon C, Leng X, Kallakury BV, Tucker RD, Menne S. Treatment with the Immunomodulator AIC649 in Combination with Entecavir Produces Antiviral Efficacy in the Woodchuck Model of Chronic Hepatitis B. Viruses 2021; 13:v13040648. [PMID: 33918831 PMCID: PMC8069054 DOI: 10.3390/v13040648] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 04/06/2021] [Accepted: 04/07/2021] [Indexed: 12/12/2022] Open
Abstract
As current interventions for chronic hepatitis B (CHB) rarely induce cure, more effective drugs are needed. Short-term treatment of woodchucks with the novel immunomodulator AIC649, a parapoxvirus-based stimulator of toll-like receptor 9 dependent and independent pathways, has been shown to reduce viral DNA and surface antigen via a unique, biphasic response pattern. The present study evaluated long-term AIC649 treatment in combination with Entecavir for potency and safety in woodchucks. AIC649 monotreatment induced modest reductions in serum viral DNA and surface and e antigens that were associated with the same biphasic response pattern previously observed. Entecavir monotreatment reduced transiently viremia but not antigenemia, while AIC649/Entecavir combination treatment mediated superior viral control. Undetectability of viral antigens and elicitation of antibodies in AIC649/Entecavir-treated woodchucks correlated with the expression of interferons and suppression of viral replication in liver. Combination treatment was well tolerated, and liver enzyme elevations were minor and transient. It was concluded that the AIC649-mediated effects were most likely based on an improvement and/or reconstitution of antiviral immune responses that are typically deficient in CHB. As a combination partner to Entecavir, the antiviral efficacy of AIC649 was markedly enhanced. This preclinical study supports future evaluation of AIC649 for treatment of human CHB.
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Affiliation(s)
- Kyle E. Korolowicz
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA; (K.E.K.); (M.S.); (B.L.); (X.H.); (C.Y.); (X.L.)
| | - Manasa Suresh
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA; (K.E.K.); (M.S.); (B.L.); (X.H.); (C.Y.); (X.L.)
| | - Bin Li
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA; (K.E.K.); (M.S.); (B.L.); (X.H.); (C.Y.); (X.L.)
| | - Xu Huang
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA; (K.E.K.); (M.S.); (B.L.); (X.H.); (C.Y.); (X.L.)
| | - Changsuek Yon
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA; (K.E.K.); (M.S.); (B.L.); (X.H.); (C.Y.); (X.L.)
| | - Xuebing Leng
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA; (K.E.K.); (M.S.); (B.L.); (X.H.); (C.Y.); (X.L.)
| | - Bhaskar V. Kallakury
- Department of Pathology, Georgetown University Medical Center, Washington, DC 20057, USA;
| | - Robin D. Tucker
- Division of Comparative Medicine, Georgetown University Medical Center, Washington, DC 20057, USA;
| | - Stephan Menne
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA; (K.E.K.); (M.S.); (B.L.); (X.H.); (C.Y.); (X.L.)
- Correspondence: ; Tel.: +1-(202)-687-2949
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Traum D, Wang YJ, Schwarz KB, Schug J, Wong DK, Janssen HLA, Terrault NA, Khalili M, Wahed AS, Murray KF, Rosenthal P, Ling SC, Rodriguez-Baez N, Sterling RK, Lau DT, Block TM, Feldman MD, Furth EE, Lee WM, Kleiner DE, Lok AS, Kaestner KH, Chang KM. Highly multiplexed 2-dimensional imaging mass cytometry analysis of HBV-infected liver. JCI Insight 2021; 6:146883. [PMID: 33621209 PMCID: PMC8119221 DOI: 10.1172/jci.insight.146883] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 02/18/2021] [Indexed: 02/06/2023] Open
Abstract
Studies of human hepatitis B virus (HBV) immune pathogenesis are hampered by limited access to liver tissues and technologies for detailed analyses. Here, utilizing imaging mass cytometry (IMC) to simultaneously detect 30 immune, viral, and structural markers in liver biopsies from patients with hepatitis B e antigen+ (HBeAg+) chronic hepatitis B, we provide potentially novel comprehensive visualization, quantitation, and phenotypic characterizations of hepatic adaptive and innate immune subsets that correlated with hepatocellular injury, histological fibrosis, and age. We further show marked correlations between adaptive and innate immune cell frequencies and phenotype, highlighting complex immune interactions within the hepatic microenvironment with relevance to HBV pathogenesis.
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Affiliation(s)
- Daniel Traum
- Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.,Medical Research, The Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania, USA
| | - Yue J Wang
- Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.,Biomedical Sciences, College of Medicine, Florida State University, Tallahasee, Florida, USA
| | | | - Jonathan Schug
- Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - David Kh Wong
- Toronto Centre for Liver Disease, University of Toronto, Toronto, Ontario, Canada
| | - Harry LA Janssen
- Toronto Centre for Liver Disease, University of Toronto, Toronto, Ontario, Canada
| | - Norah A Terrault
- Department of Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA
| | - Mandana Khalili
- Department of Medicine, UCSF, San Francisco, California, USA
| | - Abdus S Wahed
- University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA
| | - Karen F Murray
- Cleveland Clinic Pediatric Institute, Cleveland, Ohio, USA
| | | | - Simon C Ling
- The Hospital for Sick Children and Department of Paediatrics and University of Toronto, Toronto, Canada
| | - Norberto Rodriguez-Baez
- Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Richard K Sterling
- Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Daryl Ty Lau
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | | | - Michael D Feldman
- Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Elizabeth E Furth
- Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - William M Lee
- Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - David E Kleiner
- Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland, USA
| | - Anna S Lok
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Klaus H Kaestner
- Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Kyong-Mi Chang
- Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.,Medical Research, The Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania, USA
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Öznur M, Topçu B, Çelikkol A. Predictive value of noninvasive indices in chronic hepatitis B virus-related fibrosis. Eur J Gastroenterol Hepatol 2021; 33:577-582. [PMID: 33657603 DOI: 10.1097/meg.0000000000002045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVES Despite being an invasive method, liver biopsy followed by pathological grading remains the gold standard in evaluating liver fibrosis resulting from chronic hepatitis B virus (HBV) infection. The present study aims to evaluate the utility of biochemical parameters and their derived indices in predicting development of fibrosis related to HBV infection. PATIENTS AND METHODS Pathology results and biochemical parameters of patients who underwent liver biopsy were retrieved from electronic archive records dated 2010-2019 and evaluated retrospectively. Pathological fibrosis grading was performed as per Ishak scoring, with scores of 1-2 considered as mild fibrosis and 3-6 as advanced fibrosis. RESULTS The mean age of 302 patients was 37.69 ± 11.33 years. Of the 302 patients, 230 (76.2%) had mild fibrosis and 72 (23.8%) had advanced fibrosis. Age-platelet index, aspartate aminotransferase/platelet ratio index, fibrosis-4 (FIB-4), modified fibrosis-4, platelets count, aspartate aminotransferase to alanine aminotransferase ratio/platelet ratio index, Goteborg University Cirrhosis Index and King's score were markedly and significantly higher in patients with advanced fibrosis than those with mild fibrosis. FIB-4, age-platelet index and King's score had higher (>80%) area under the curve values than other indices in the receiver operating characteristics analysis. Evaluation of sensitivity, specificity and accuracy of these indices with the specified cut-off values revealed 87% sensitivity with FIB-4, 70% specificity with King's score and 72% accuracy with the age-platelet index. CONCLUSION In this study, the highest rates of sensitivity, specificity and accuracy in distinguishing and predicting liver fibrosis were observed with the noninvasive indices FIB-4, King's score and the age-platelet index, respectively.
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Affiliation(s)
- Meltem Öznur
- Medical Pathology Department, Tekirdağ Namik Kemal University Faculty of Medicine
| | - Birol Topçu
- Biostatistics Department, Tekirdağ Namik Kemal University Faculty of Medicine
| | - Aliye Çelikkol
- Medical Biochemistry Department, Tekirdağ Namik Kemal University Faculty of Medicine,Tekirdağ, Turkey
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31
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Rehm J, Patra J, Brennan A, Buckley C, Greenfield TK, Kerr WC, Manthey J, Purshouse RC, Rovira P, Shuper PA, Shield KD. The role of alcohol use in the aetiology and progression of liver disease: A narrative review and a quantification. Drug Alcohol Rev 2021; 40:1377-1386. [PMID: 33783063 PMCID: PMC9389623 DOI: 10.1111/dar.13286] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 12/16/2020] [Accepted: 03/10/2021] [Indexed: 12/16/2022]
Abstract
Issues. Alcohol use has been shown to impact on various forms of liver disease, not restricted to alcoholic liver disease. Approach. We developed a conceptual framework based on a narrative review of the literature to identify causal associations between alcohol use and various forms of liver disease including the complex interactions of alcohol with other major risk factors. Based on this framework, we estimate the identified relations for 2017 for the USA. Key Findings. The following pathways were identified and modelled for the USA for the year 2017. Alcohol use caused 35 200 (95% uncertainty interval 32 800–37 800) incident cases of alcoholic liver cirrhosis. There were 1700 (uncertainty interval 1100–2500) acute hepatitis B and C virus (HBV and HCV) infections attributable to heavy-drinking occasions, and 14 000 (uncertainty interval 5900–19 500) chronic HBV and 1700 (uncertainty interval 700–2400) chronic HCV infections due to heavy alcohol use interfering with spontaneous clearance. Alcohol use and its interactions with other risk factors (HBV, HCV, obesity) led to 54 500 (uncertainty interval 50 900–58 400) new cases of liver cirrhosis. In addition, alcohol use caused 6600 (uncertainty interval 4200–9300) liver cancer deaths and 40 700 (uncertainty interval 36 600–44 600) liver cirrhosis deaths. Implications. Alcohol use causes a substantial number of incident cases and deaths from chronic liver disease, often in interaction with other risk factors. Conclusion. This additional disease burden is not reflected in the current alcoholic liver disease categories. Clinical work and prevention policies need to take this into consideration.
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Affiliation(s)
- Jürgen Rehm
- Institute for Mental Health Policy Research, Centre for Addiction and Mental Health, Toronto, Canada.,Dalla Lana School of Public Health, University of Toronto, Toronto, Canada.,Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Canada.,Institute of Clinical Psychology and Psychotherapy, Center of Clinical Epidemiology and Longitudinal Studies, Technische Universität Dresden, Dresden, Germany.,Department of Psychiatry, University of Toronto, Toronto, Canada.,Department of International Health Projects, Institute for Leadership and Health Management, I.M. Sechenov First Moscow State Medical University, Moscow, Russia.,Program on Substance Abuse, Public Health Agency of Catalonia, Barcelona, Spain.,Department of Psychiatry and Psychotherapy, Center for Interdisciplinary Addiction Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jayadeep Patra
- Institute for Mental Health Policy Research, Centre for Addiction and Mental Health, Toronto, Canada.,Dalla Lana School of Public Health, University of Toronto, Toronto, Canada
| | - Alan Brennan
- School of Health and Related Research, University of Sheffield, Sheffield, UK
| | - Charlotte Buckley
- Department of Automatic Control and Systems Engineering, University of Sheffield, Sheffield, UK
| | | | - William C Kerr
- Alcohol Research Group, Public Health Institute, Emeryville, USA
| | - Jakob Manthey
- Institute of Clinical Psychology and Psychotherapy, Center of Clinical Epidemiology and Longitudinal Studies, Technische Universität Dresden, Dresden, Germany.,Department of Psychiatry and Psychotherapy, Center for Interdisciplinary Addiction Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,Department of Psychiatry, Medical Faculty, University of Leipzig, Leipzig, Germany
| | - Robin C Purshouse
- Department of Automatic Control and Systems Engineering, University of Sheffield, Sheffield, UK
| | - Pol Rovira
- Program on Substance Abuse, Public Health Agency of Catalonia, Barcelona, Spain
| | - Paul A Shuper
- Institute for Mental Health Policy Research, Centre for Addiction and Mental Health, Toronto, Canada.,Dalla Lana School of Public Health, University of Toronto, Toronto, Canada.,Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Canada
| | - Kevin D Shield
- Institute for Mental Health Policy Research, Centre for Addiction and Mental Health, Toronto, Canada.,Dalla Lana School of Public Health, University of Toronto, Toronto, Canada.,Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Canada
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HBV-Integration Studies in the Clinic: Role in the Natural History of Infection. Viruses 2021; 13:v13030368. [PMID: 33652619 PMCID: PMC7996909 DOI: 10.3390/v13030368] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Revised: 02/21/2021] [Accepted: 02/22/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a major global health problem causing acute and chronic liver disease that can lead to liver cirrhosis and hepatocellular carcinoma (HCC). HBV covalently closed circular DNA (cccDNA) is essential for viral replication and the establishment of a persistent infection. Integrated HBV DNA represents another stable form of viral DNA regularly observed in the livers of infected patients. HBV DNA integration into the host genome occurs early after HBV infection. It is a common occurrence during the HBV life cycle, and it has been detected in all the phases of chronic infection. HBV DNA integration has long been considered to be the main contributor to liver tumorigenesis. The recent development of highly sensitive detection methods and research models has led to the clarification of some molecular and pathogenic aspects of HBV integration. Though HBV integration does not lead to replication-competent transcripts, it can act as a stable source of viral RNA and proteins, which may contribute in determining HBV-specific T-cell exhaustion and favoring virus persistence. The relationship between HBV DNA integration and the immune response in the liver microenvironment might be closely related to the development and progression of HBV-related diseases. While many new antiviral agents aimed at cccDNA elimination or silencing have been developed, integrated HBV DNA remains a difficult therapeutic challenge.
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Kim HN. Chronic Hepatitis B and HIV Coinfection: A Continuing Challenge in the Era of Antiretroviral Therapy. CURRENT HEPATOLOGY REPORTS 2020; 19:345-353. [PMID: 33796434 PMCID: PMC8011543 DOI: 10.1007/s11901-020-00541-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE OF REVIEW The burden of chronic hepatitis B (HBV) remains disproportionately high among people living with HIV (PLWH) despite the advent of HBV vaccination and HBV-active antiretroviral therapy (ART). This review summarizes new insights and evolving issues in HIV-HBV coinfection. RECENT FINDINGS HBV-HIV coinfection is still a leading cause of cirrhosis, hepatocellular carcinoma (HCC) and liver-related mortality more than a decade after the approval of tenofovir. While tenofovir-based ART has been shown to improve rates of HBV virologic suppression and halt fibrosis progression, the long-term benefits on the prevention of end-stage liver disease or HCC in HIV-HBV coinfection have yet to be convincingly demonstrated in PLWH. Missed opportunities for HBV vaccination persist despite evidence of ongoing risk for HBV infection in this population. SUMMARY Even as we work towards HBV elimination and functional cure, ongoing efforts should focus on optimizing risk stratification as well as uptake of HBV-active antiviral therapy and HBV immunization in this priority population.
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Affiliation(s)
- H. Nina Kim
- Department of Medicine, Division of Allergy & Infectious Diseases, University of Washington, Seattle, WA
- Center for AIDS Research, University of Washington, Seattle, WA
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Wang X, Tian S, Yu L, Lv X, Zhang Z. Rapid screening of hepatitis B using Raman spectroscopy and long short-term memory neural network. Lasers Med Sci 2020; 35:1791-1799. [PMID: 32285292 DOI: 10.1007/s10103-020-03003-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Accepted: 03/25/2020] [Indexed: 12/30/2022]
Abstract
This study presents a rapid method to screen hepatitis B patients using serum Raman spectroscopy combined with long short-term memory neural network (LSTM). The serum samples taken from 435 hepatitis B patients and 699 non-hepatitis B people were measured in this experiment. Specific biomolecular changes in three groups of serum samples could be seen in the tentative assignment of Raman peaks. First, principal component analysis (PCA) was used for extracting key features of spectral data, which reduces the dimension of the multidimensional spectrum. Then, LSTM is used to train the spectral data. Finally, the full connection layer completes the classification of HBV. The diagnostic accuracy of the first LSTM model is 97.32%, and the value of AUC is 0.995. The results from the study demonstrate that the combination of serum Raman spectroscopy technique and LSTM provides an effective technical approach to the screening of hepatitis B.
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Affiliation(s)
- Xin Wang
- College of Software Engineering, Xin Jiang University, Urumuqi, 830000, China
| | - Shengwei Tian
- College of Software Engineering, Xin Jiang University, Urumuqi, 830000, China
| | - Long Yu
- College of Network Center, Xin Jiang University, Urumuqi, 830046, China.
| | - Xiaoyi Lv
- College of Software Engineering, Xin Jiang University, Urumuqi, 830000, China.
| | - Zhaoxia Zhang
- Department of Laboratory Medicine, The First Affiliated Hospital of Xinjiang Medical University, Urumuqi, 830000, China
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35
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Yip TCF, Liang LY, Wong GLH. Assessment of HCC Risk in Patients with Chronic HBV (REACH, PAGE-B, and Beyond). CURRENT HEPATOLOGY REPORTS 2020; 19:285-292. [DOI: 10.1007/s11901-020-00526-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2025]
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36
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Yoo SH, Kwon JH. [New Potential Therapies for Chronic Hepatitis B]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2020; 74:267-273. [PMID: 31765555 DOI: 10.4166/kjg.2019.74.5.267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/12/2019] [Revised: 10/23/2019] [Accepted: 10/25/2019] [Indexed: 11/03/2022]
Abstract
A HBV infection is a dynamic disease and long-term liver inflammation contributes to the development of liver cirrhosis and hepatocellular carcinoma. Currently available nucleos(t)ide analogues and pegylated interferon are effective in inhibiting HBV replication but rarely achieve HBsAg clearance. The present article introduces a new definition of HBV cure and several emerging therapies for HBV cure, including direct acting antivirals and immune modulatory antivirals.
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Affiliation(s)
- Sun Hong Yoo
- Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Incheon, Korea
| | - Jung Hyun Kwon
- Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Incheon, Korea
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Menne S, Wildum S, Steiner G, Suresh M, Korolowicz K, Balarezo M, Yon C, Murreddu M, Hong X, Kallakury BV, Tucker R, Yang S, Young JAT, Javanbakht H. Efficacy of an Inhibitor of Hepatitis B Virus Expression in Combination With Entecavir and Interferon-α in Woodchucks Chronically Infected With Woodchuck Hepatitis Virus. Hepatol Commun 2020; 4:916-931. [PMID: 32490326 PMCID: PMC7262289 DOI: 10.1002/hep4.1502] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 02/13/2020] [Accepted: 02/18/2020] [Indexed: 12/16/2022] Open
Abstract
RG7834 is a small‐molecule inhibitor of hepatitis B virus (HBV) gene expression that significantly reduces the levels of hepatitis B surface antigen (HBsAg) and HBV DNA in a humanized liver HBV mouse model. In the current study, we evaluated the potency of RG7834 in the woodchuck model of chronic HBV infection, alone and in combination with entecavir (ETV) and/or woodchuck interferon‐α (wIFN‐α). RG7834 reduced woodchuck hepatitis virus (WHV) surface antigen (WHsAg) by a mean of 2.57 log10 from baseline and WHV DNA by a mean of 1.71 log10. ETV + wIFN‐α reduced WHsAg and WHV DNA by means of 2.40 log10 and 6.70 log10, respectively. The combination of RG7834, ETV, and wIFN‐α profoundly reduced WHsAg and WHV DNA levels by 5.00 log10 and 7.46 log10, respectively. However, both viral parameters rebounded to baseline after treatment was stopped and no antibody response against WHsAg was observed. Effects on viral RNAs were mainly seen with the triple combination treatment, reducing both pregenomic RNA (pgRNA) and WHsAg RNA, whereas RG7834 mainly reduced WHsAg RNA and ETV mainly affected pgRNA. When WHsAg was reduced by the triple combination, peripheral blood mononuclear cells (PBMCs) proliferated significantly in response to viral antigens, but the cellular response was diminished after WHsAg returned to baseline levels during the off‐treatment period. Consistent with this, Pearson correlation revealed a strong negative correlation between WHsAg levels and PBMC proliferation in response to peptides covering the entire WHsAg and WHV nucleocapsid antigen. Conclusion: A fast and robust reduction of WHsAg by combination therapy reduced WHV‐specific immune dysfunction in the periphery. However, the magnitude and/or duration of the induced cellular response were not sufficient to achieve a sustained antiviral response.
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Affiliation(s)
- Stephan Menne
- Department of Microbiology and Immunology Georgetown University Medical Center Washington DC
| | - Steffen Wildum
- Roche Pharma Research and Early Development Roche Innovation Center Basel Basel Switzerland
| | - Guido Steiner
- Roche Pharma Research and Early Development Roche Innovation Center Basel Basel Switzerland
| | - Manasa Suresh
- Department of Microbiology and Immunology Georgetown University Medical Center Washington DC
| | - Kyle Korolowicz
- Department of Microbiology and Immunology Georgetown University Medical Center Washington DC
| | - Maria Balarezo
- Department of Microbiology and Immunology Georgetown University Medical Center Washington DC
| | - Changsuek Yon
- Department of Microbiology and Immunology Georgetown University Medical Center Washington DC
| | - Marta Murreddu
- Department of Microbiology and Immunology Georgetown University Medical Center Washington DC
| | - Xupeng Hong
- Department of Microbiology and Immunology Georgetown University Medical Center Washington DC
| | | | - Robin Tucker
- Department of Pharmacology Georgetown University Medical Center Washington DC
| | - Song Yang
- Roche Pharma Research and Early Development Roche Innovation Center Shanghai Shanghai China
| | - John A T Young
- Roche Pharma Research and Early Development Roche Innovation Center Basel Basel Switzerland
| | - Hassan Javanbakht
- Roche Pharma Research and Early Development Roche Innovation Center Basel Basel Switzerland
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Genotyping of immune-related loci associated with delayed HBeAg seroconversion in immune-active chronic hepatitis B patients. Antiviral Res 2020; 176:104719. [PMID: 32004619 DOI: 10.1016/j.antiviral.2020.104719] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 12/26/2019] [Accepted: 01/23/2020] [Indexed: 02/07/2023]
Abstract
The progression of chronic hepatitis B (CHB) is associated with single-nucleotide polymorphisms (SNPs). In this study, we demonstrated the association between immune-related SNPs and delayed spontaneous HBeAg seroconversion in immune-active CHB patients. In addition, we investigated the impact of delayed spontaneous HBeAg seroconversion-related SNPs on HBeAg seroconversion within 3 years during antiviral treatment. We enrolled 332 CHB patients and genotyped 124 SNPs associated with HBV-infected clinical outcomes, including 32 interleukin-related genes, 62 HLA genes, 9 CD marker genes, 7 NK cell receptor genes, and 14 other genes, using ABI OpenArray as a platform. Comparing the immune-active CHB patients with delayed spontaneous HBeAg seroconversion (persistent HBeAg seropositivity, older than 40 years) to those with early inefficient HBeAg seroconversion (HBeAg seroconversion with high viremia, younger than 40 years), logistic analysis revealed that rs3820998 (TANK), rs2621377 (HLA-DOB), rs3130215 (HLA-DPB2), rs2255336 (KLRK1), and rs11614913 (MIR-196A2) were significantly associated with delayed spontaneous HBeAg seroconversion. Using multivariate analysis, we determined that high serum HBV DNA levels (OR = 1.66, 95% CI = 1.33-2.08), rs3820998 (CA, OR = 3.37, 95% CI = 1.24-9.12), rs2621377 (TC, OR = 4.96, 95% CI = 1.85-13.3), rs2255336 (TT, OR = 0.09, 95% CI = 0.01-0.86), and rs11614913 (TT, OR = 2.53, 95% CI = 1.05-6.11) were five independent risk factors for delayed spontaneous HBeAg seroconversion. After patients received nucleos(t)ide analogue treatment, rs3820998 heterozygous CA variant conversely became the only independent favorable factor for treatment-induced HBeAg seroconversion within 3 years (OR = 0.21, 95% CI = 0.06-0.78). These results indicate that distinct immune-related SNPs play a vital role in regulating HBeAg status in immune-active CHB patients with or without antiviral treatment.
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Attar BM. CON: All Patients With Immune-Tolerated Hepatitis B Virus Do Not Need to Be Treated. Clin Liver Dis (Hoboken) 2020; 15:25-30. [PMID: 32104574 PMCID: PMC7041959 DOI: 10.1002/cld.893] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Accepted: 10/11/2019] [Indexed: 02/04/2023] Open
Abstract
http://aasldpubs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2046-2484/video/15-1-reading-attar a video presentation of this article.
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Affiliation(s)
- Bashar M. Attar
- Division of Gastroenterology and HepatologyCook County HealthChicagoIL
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40
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Li N, Fan X, Wang X, Zhang X, Zhang K, Han Q, Lv Y, Liu Z. Genetic association of polymorphisms at the intergenic region between PRDM1 and ATG5 with hepatitis B virus infection in Han Chinese patients. J Med Virol 2019; 92:1198-1205. [PMID: 31729038 DOI: 10.1002/jmv.25629] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Accepted: 11/12/2019] [Indexed: 12/21/2022]
Abstract
Chronic hepatitis B virus (HBV) infection is related to chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC), and the interplay between the virus and host immune response leads to different outcomes of the infection. PR domain zinc finger protein 1 (PRDM1) and autophagy-related protein 5 (ATG5) are involved in immune response and HBV infection. An intergenic region between PRDM1 and ATG5 (PRDM1-ATG5 region) has been identified, and single-nucleotide polymorphisms (SNPs) in this region were shown to be involved in immune regulation. This study investigated the functionally relevant rs548234, rs6937876, and rs6568431 polymorphisms at the PRDM1-ATG5 region in a Han Chinese population (403 patients with chronic HBV infection [171 chronic hepatitis, 119 cirrhosis, and 113 HCC], 70 infection resolvers, and 196 healthy controls). The frequencies of the rs6568431 allele A in HBV patients (P = .005) and genotype CA in infection resolvers (P = .005) were significantly higher than in healthy controls. In the dominant model, HCC patients had significantly higher frequencies of rs548234 genotypes CC + TC than cirrhosis patients (P = .009). Rs548234 was an independent factor for HCC in comparison with either cirrhosis (P = .005) or all chronic HBV infection without HCC (P = .018). Functional annotation showed evidence of the role of the SNPs in gene regulation. In conclusion, through this study it is revealed for the first time that rs6568431 may be associated with susceptibility to HBV infection and that rs548234 may be associated with HCC risk in chronic HBV infection, supporting the presence of HBV-related disease-causing regulatory polymorphisms in the PRDM1-ATG5 intergenic region.
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Affiliation(s)
- Na Li
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Xiude Fan
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Xiaoyun Wang
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Xiaoge Zhang
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Kun Zhang
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Qunying Han
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Yi Lv
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.,Institute of Advanced Surgical Technology and Engineering, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Zhengwen Liu
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.,Institute of Advanced Surgical Technology and Engineering, Xi'an Jiaotong University, Xi'an, Shaanxi, China
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