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Naully PG, Tan MI, Agustiningsih A, Sukowati C, Giri-Rachman EA. cccDNA epigenetic regulator as target for therapeutical vaccine development against hepatitis B. Ann Hepatol 2024; 30:101533. [PMID: 39147134 DOI: 10.1016/j.aohep.2024.101533] [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: 04/23/2024] [Revised: 07/21/2024] [Accepted: 08/01/2024] [Indexed: 08/17/2024]
Abstract
Chronic hepatitis B virus infection (CHB) remains a global health concern, with currently available antiviral therapies demonstrating limited effectiveness in preventing hepatocellular carcinoma (HCC) development. Two primary challenges in CHB treatment include the persistence of the minichromosome, covalently closed circular DNA (cccDNA) of the hepatitis B virus (HBV), and the failure of the host immune response to eliminate cccDNA. Recent findings indicate several host and HBV proteins involved in the epigenetic regulation of cccDNA, including HBV core protein (HBc) and HBV x protein (HBx). Both proteins might contribute to the stability of the cccDNA minichromosome and interact with viral and host proteins to support transcription. One potential avenue for CHB treatment involves the utilization of therapeutic vaccines. This paper explores HBV antigens suitable for epigenetic manipulation of cccDNA, elucidates their mechanisms of action, and evaluates their potential as key components of epigenetically-driven vaccines for CHB therapy. Molecular targeted agents with therapeutic vaccines offer a promising strategy for addressing CHB by targeting the virus and enhancing the host's immunological response. Despite challenges, the development of these vaccines provides new hope for CHB patients by emphasizing the need for HBV antigens that induce effective immune responses without causing T cell exhaustion.
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Affiliation(s)
- Patricia Gita Naully
- School of Life Science and Technology, Institut Teknologi Bandung, Bandung 40132, Indonesia; Faculty of Health Sciences and Technology, Jenderal Achmad Yani University, Cimahi 40525, Indonesia
| | - Marselina Irasonia Tan
- School of Life Science and Technology, Institut Teknologi Bandung, Bandung 40132, Indonesia
| | - Agustiningsih Agustiningsih
- Eijkman Research Center for Molecular Biology, Research Organization for Health, National Research and Innovation Agency of Indonesia (BRIN), Jakarta Pusat 10340, Indonesia
| | - Caecilia Sukowati
- Eijkman Research Center for Molecular Biology, Research Organization for Health, National Research and Innovation Agency of Indonesia (BRIN), Jakarta Pusat 10340, Indonesia; Liver Cancer Unit, Fondazione Italiana Fegato ONLUS, AREA Science Park, Basovizza 34049, Trieste, Italy
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Forna L, Bozomitu L, Lupu A, Lupu VV, Cojocariu C, Anton C, Girleanu I, Singeap AM, Muzica CM, Trifan A. Insights into the Natural and Treatment Courses of Hepatitis B in Children: A Retrospective Study. Biomedicines 2024; 12:1585. [PMID: 39062157 PMCID: PMC11274914 DOI: 10.3390/biomedicines12071585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 07/09/2024] [Accepted: 07/15/2024] [Indexed: 07/28/2024] Open
Abstract
Chronic Hepatitis B virus (HBV) infection in children remains a significant public health challenge. The natural history and treatment outcomes of HBV can vary widely, influencing management strategies. This retrospective study was conducted in Northeast Romania and involved a cohort of 148 pediatric patients diagnosed with chronic viral Hepatitis B. Of these, 59 children underwent antiviral treatment while 89 were not treated. One of the main objectives was the rate of HBeAg (Hepatitis B-e antigen) seroconversion, a marker of disease progression and response to therapy. Among the treated group, 26 children (44%) achieved HBeAg seroconversion following therapy. In contrast, 44 of the untreated children (49%) experienced spontaneous HBeAg seroconversion, indicating a substantial rate of natural resolution within this population subset. The findings highlight a significant proportion of spontaneous seroconversion in untreated pediatric patients, suggesting a potential re-evaluation of treatment criteria and timing for children with chronic HBV infection. The comparable rates of seroconversion between treated and untreated cohorts underscore the need for individualized treatment approaches based on a combination of virological, biochemical, and clinical parameters. Further studies are required to refine management strategies to optimize long-term outcomes in pediatric HBV infections.
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Affiliation(s)
- Lorenza Forna
- Pediatrics–“Sf. Maria” Clinical Emergency Children’s Hospital, 700309 Iași, Romania; (L.F.); (L.B.); (A.L.); (V.V.L.)
- Faculty of General Medicine, University of Medicine and Pharmacy “Gr. T. Popa”, 700115 Iași, Romania; (C.C.); (C.A.); (I.G.); (A.M.S.); (A.T.)
| | - Laura Bozomitu
- Pediatrics–“Sf. Maria” Clinical Emergency Children’s Hospital, 700309 Iași, Romania; (L.F.); (L.B.); (A.L.); (V.V.L.)
- Faculty of General Medicine, University of Medicine and Pharmacy “Gr. T. Popa”, 700115 Iași, Romania; (C.C.); (C.A.); (I.G.); (A.M.S.); (A.T.)
| | - Ancuta Lupu
- Pediatrics–“Sf. Maria” Clinical Emergency Children’s Hospital, 700309 Iași, Romania; (L.F.); (L.B.); (A.L.); (V.V.L.)
- Faculty of General Medicine, University of Medicine and Pharmacy “Gr. T. Popa”, 700115 Iași, Romania; (C.C.); (C.A.); (I.G.); (A.M.S.); (A.T.)
| | - Vasile Valeriu Lupu
- Pediatrics–“Sf. Maria” Clinical Emergency Children’s Hospital, 700309 Iași, Romania; (L.F.); (L.B.); (A.L.); (V.V.L.)
- Faculty of General Medicine, University of Medicine and Pharmacy “Gr. T. Popa”, 700115 Iași, Romania; (C.C.); (C.A.); (I.G.); (A.M.S.); (A.T.)
| | - Camelia Cojocariu
- Faculty of General Medicine, University of Medicine and Pharmacy “Gr. T. Popa”, 700115 Iași, Romania; (C.C.); (C.A.); (I.G.); (A.M.S.); (A.T.)
- Department of Clinical Gastroenterology, “Sf. Spiridon” Clinical Emergency Hospital, 700111 Iași, Romania
| | - Carmen Anton
- Faculty of General Medicine, University of Medicine and Pharmacy “Gr. T. Popa”, 700115 Iași, Romania; (C.C.); (C.A.); (I.G.); (A.M.S.); (A.T.)
- Department of Clinical Gastroenterology, “Sf. Spiridon” Clinical Emergency Hospital, 700111 Iași, Romania
| | - Irina Girleanu
- Faculty of General Medicine, University of Medicine and Pharmacy “Gr. T. Popa”, 700115 Iași, Romania; (C.C.); (C.A.); (I.G.); (A.M.S.); (A.T.)
- Department of Clinical Gastroenterology, “Sf. Spiridon” Clinical Emergency Hospital, 700111 Iași, Romania
| | - Ana Maria Singeap
- Faculty of General Medicine, University of Medicine and Pharmacy “Gr. T. Popa”, 700115 Iași, Romania; (C.C.); (C.A.); (I.G.); (A.M.S.); (A.T.)
- Department of Clinical Gastroenterology, “Sf. Spiridon” Clinical Emergency Hospital, 700111 Iași, Romania
| | - Cristina Maria Muzica
- Faculty of General Medicine, University of Medicine and Pharmacy “Gr. T. Popa”, 700115 Iași, Romania; (C.C.); (C.A.); (I.G.); (A.M.S.); (A.T.)
- Department of Clinical Gastroenterology, “Sf. Spiridon” Clinical Emergency Hospital, 700111 Iași, Romania
| | - Anca Trifan
- Faculty of General Medicine, University of Medicine and Pharmacy “Gr. T. Popa”, 700115 Iași, Romania; (C.C.); (C.A.); (I.G.); (A.M.S.); (A.T.)
- Department of Clinical Gastroenterology, “Sf. Spiridon” Clinical Emergency Hospital, 700111 Iași, Romania
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Chinese Society of Infectious Diseases, Chinese Medical Association, Chinese Society of Hepatology, Chinese Medical Association, Group of Infectious Diseases, Chinese Pediatric Society, Chinese Medical Association, National Clinical Research Center for Infectious Diseases (Beijing). Expert Consensus on the Prevention and Treatment of Chronic Hepatitis B in Children. INFECTIOUS DISEASES & IMMUNITY 2024; 4:106-120. [DOI: 10.1097/id9.0000000000000122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/27/2024]
Abstract
Abstract
The aim of this consensus is to standardize the prevention, diagnosis, and treatment of chronic hepatitis B in children and to achieve the goal of “eliminating viral hepatitis as a major public health threat by 2030” issued by the World Health Organization. Formulated by organized experts of the Chinese Society of Infectious Diseases and Chinese Society of Hepatology, Chinese Medical Association; Group of Infectious Diseases, Chinese Pediatric Society, Chinese Medical Association; and the National Clinical Research Center for Infectious Diseases (Beijing), the consensus provides the latest evidence and recommendations for the prevention, diagnosis, and treatment of chronic hepatitis B in children.
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Hofmann S, Luther J, Plank V, Oswald A, Mai J, Simons I, Miller J, Falcone V, Hansen-Palmus L, Hengel H, Nassal M, Protzer U, Schreiner S. Arsenic trioxide impacts hepatitis B virus core nuclear localization and efficiently interferes with HBV infection. Microbiol Spectr 2024; 12:e0378823. [PMID: 38567974 PMCID: PMC11064512 DOI: 10.1128/spectrum.03788-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Accepted: 03/14/2024] [Indexed: 05/03/2024] Open
Abstract
The key to a curative treatment of hepatitis B virus (HBV) infection is the eradication of the intranuclear episomal covalently closed circular DNA (cccDNA), the stable persistence reservoir of HBV. Currently, established therapies can only limit HBV replication but fail to tackle the cccDNA. Thus, novel therapeutic approaches toward curative treatment are urgently needed. Recent publications indicated a strong association between the HBV core protein SUMOylation and the association with promyelocytic leukemia nuclear bodies (PML-NBs) on relaxed circular DNA to cccDNA conversion. We propose that interference with the cellular SUMOylation system and PML-NB integrity using arsenic trioxide provides a useful tool in the treatment of HBV infection. Our study showed a significant reduction in HBV-infected cells, core protein levels, HBV mRNA, and total DNA. Additionally, a reduction, albeit to a limited extent, of HBV cccDNA could be observed. Furthermore, this interference was also applied for the treatment of an established HBV infection, characterized by a stably present nuclear pool of cccDNA. Arsenic trioxide (ATO) treatment not only changed the amount of expressed HBV core protein but also induced a distinct relocalization to an extranuclear phenotype during infection. Moreover, ATO treatment resulted in the redistribution of transfected HBV core protein away from PML-NBs, a phenotype similar to that previously observed with SUMOylation-deficient HBV core. Taken together, these findings revealed the inhibition of HBV replication by ATO treatment during several steps of the viral replication cycle, including viral entry into the nucleus as well as cccDNA formation and maintenance. We propose ATO as a novel prospective treatment option for further pre-clinical and clinical studies against HBV infection. IMPORTANCE The main challenge for the achievement of a functional cure for hepatitis B virus (HBV) is the covalently closed circular DNA (cccDNA), the highly stable persistence reservoir of HBV, which is maintained by further rounds of infection with newly generated progeny viruses or by intracellular recycling of mature nucleocapsids. Eradication of the cccDNA is considered to be the holy grail for HBV curative treatment; however, current therapeutic approaches fail to directly tackle this HBV persistence reservoir. The molecular effect of arsenic trioxide (ATO) on HBV infection, protein expression, and cccDNA formation and maintenance, however, has not been characterized and understood until now. In this study, we reveal ATO treatment as a novel and innovative therapeutic approach against HBV infections, repressing viral gene expression and replication as well as the stable cccDNA pool at low micromolar concentrations by affecting the cellular function of promyelocytic leukemia nuclear bodies.
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Affiliation(s)
- Samuel Hofmann
- Institute of Virology, School of Medicine, Technical University of Munich, Munich, Germany
- Institute of Virology, Hannover Medical School, Hannover, Germany
- Cluster of Excellence RESIST (Resolving Infection Susceptibility, EXC 2155), Hannover Medical School, Hannover, Germany
- Division of Pediatric Neurology and Metabolic Medicine, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany
| | - Julius Luther
- Institute of Virology, Hannover Medical School, Hannover, Germany
- Cluster of Excellence RESIST (Resolving Infection Susceptibility, EXC 2155), Hannover Medical School, Hannover, Germany
| | - Verena Plank
- Institute of Virology, School of Medicine, Technical University of Munich, Munich, Germany
| | - Andreas Oswald
- Institute of Virology, School of Medicine, Technical University of Munich, Munich, Germany
| | - Julia Mai
- Institute of Virology, Hannover Medical School, Hannover, Germany
- Cluster of Excellence RESIST (Resolving Infection Susceptibility, EXC 2155), Hannover Medical School, Hannover, Germany
- Department of Internal Medicine II/Molecular Biology, University Hospital Freiburg, Freiburg, Germany
| | - Ilka Simons
- Institute of Virology, Hannover Medical School, Hannover, Germany
- Cluster of Excellence RESIST (Resolving Infection Susceptibility, EXC 2155), Hannover Medical School, Hannover, Germany
| | - Julija Miller
- Department of Internal Medicine II/Molecular Biology, University Hospital Freiburg, Freiburg, Germany
| | - Valeria Falcone
- Institute of Virology, Medical Center – University of Freiburg, Freiburg, Germany
| | - Lea Hansen-Palmus
- Institute of Virology, School of Medicine, Technical University of Munich, Munich, Germany
| | - Hartmut Hengel
- Institute of Virology, Medical Center – University of Freiburg, Freiburg, Germany
| | - Michael Nassal
- Department of Internal Medicine II/Molecular Biology, University Hospital Freiburg, Freiburg, Germany
| | - Ulrike Protzer
- Institute of Virology, School of Medicine, Technical University of Munich, Munich, Germany
- Institute of Virology, Helmholtz Zentrum München, Munich, Germany
- German Center for Infection Research (DZIF), Munich, Germany
| | - Sabrina Schreiner
- Institute of Virology, School of Medicine, Technical University of Munich, Munich, Germany
- Institute of Virology, Hannover Medical School, Hannover, Germany
- Cluster of Excellence RESIST (Resolving Infection Susceptibility, EXC 2155), Hannover Medical School, Hannover, Germany
- Institute of Virology, Medical Center – University of Freiburg, Freiburg, Germany
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Varghese N, Majeed A, Nyalakonda S, Boortalary T, Halegoua-DeMarzio D, Hann HW. Review of Related Factors for Persistent Risk of Hepatitis B Virus-Associated Hepatocellular Carcinoma. Cancers (Basel) 2024; 16:777. [PMID: 38398168 PMCID: PMC10887172 DOI: 10.3390/cancers16040777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2023] [Revised: 01/30/2024] [Accepted: 02/05/2024] [Indexed: 02/25/2024] Open
Abstract
Chronic hepatitis B virus (HBV) infection is the largest global cause of hepatocellular carcinoma (HCC). Current HBV treatment options include pegylated interferon-alpha and nucleos(t)ide analogues (NAs), which have been shown to be effective in reducing HBV DNA levels to become undetectable. However, the literature has shown that some patients have persistent risk of developing HCC. The mechanism in which this occurs has not been fully elucidated. However, it has been discovered that HBV's covalently closed circular DNA (cccDNA) integrates into the critical HCC driver genes in hepatocytes upon initial infection; additionally, these are not targets of current NA therapies. Some studies suggest that HBV undergoes compartmentalization in peripheral blood mononuclear cells that serve as a sanctuary for replication during antiviral therapy. The aim of this review is to expand on how patients with HBV may develop HCC despite years of HBV viral suppression and carry worse prognosis than treatment-naive HBV patients who develop HCC. Furthermore, HCC recurrence after initial surgical or locoregional treatment in this setting may cause carcinogenic cells to behave more aggressively during treatment. Curative novel therapies which target the life cycle of HBV, modulate host immune response, and inhibit HBV RNA translation are being investigated.
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Affiliation(s)
- Nevin Varghese
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (N.V.); (A.M.); (S.N.); (T.B.); (D.H.-D.)
| | - Amry Majeed
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (N.V.); (A.M.); (S.N.); (T.B.); (D.H.-D.)
| | - Suraj Nyalakonda
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (N.V.); (A.M.); (S.N.); (T.B.); (D.H.-D.)
| | - Tina Boortalary
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (N.V.); (A.M.); (S.N.); (T.B.); (D.H.-D.)
- Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Dina Halegoua-DeMarzio
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (N.V.); (A.M.); (S.N.); (T.B.); (D.H.-D.)
- Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Hie-Won Hann
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (N.V.); (A.M.); (S.N.); (T.B.); (D.H.-D.)
- Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
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Harris AM, Schillie S. Hepatitis B and Hepatitis D Viruses. PRINCIPLES AND PRACTICE OF PEDIATRIC INFECTIOUS DISEASES 2023:1125-1133.e4. [DOI: 10.1016/b978-0-323-75608-2.00213-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Wu Y, Wen J, Tang G, Zhang J, Xin J. On-treatment HBV RNA dynamic predicts entecavir-induced HBeAg seroconversion in children with chronic hepatitis B. J Infect 2021; 83:594-600. [PMID: 34474058 DOI: 10.1016/j.jinf.2021.08.044] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 08/08/2021] [Accepted: 08/28/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Hepatitis B e antigen (HBeAg) seroconversion is an important intermediate outcome in HBeAg-positive chronic hepatitis B patients. This study aimed to explore whether hepatitis B virus (HBV) RNA serum levels can predict HBeAg seroconversion treated with entecavir. METHODS Serum samples from HBeAg-positive children previously treated with entecavir were retrospectively analyzed. HBV RNA levels were measured at baseline, weeks 12, 24, 48, 72 of therapy. Ability of individual biomarkers to predict HBeAg seroconversion was evaluated using receiver operating characteristics (ROC) analyzes. RESULTS Serum HBV RNA was detectable in 51 children with a median of 6.05 (4.04-8.29) log10 IU/mL at baseline. Patients with subsequent HBeAg seroconversion showed a significantly larger decline in median HBV RNA levels during treatment from baseline to week 12 of 1.96 (0.30-3.38) and to week 24 of 2.27 (1.20-3.38) log10 IU/mL, respectively, in comparison to HBeAg-positive patients without HBeAg seroconversion (P < 0.001). Levels of HBV RNA at treatment weeks 12 and 24 showed good ability to predict HBeAg seroconversion (area under ROC scores > 0.85, P < 0.001). CONCLUSION On-treatment HBV RNA dynamic predicts entecavir-induced HBeAg seroconversion in children with chronic hepatitis B living in China.
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Key Words
- ALT,alanine aminotransferase
- AUC, area under the ROC curve
- Abbreviations
- Anti-HBe, hepatitis B e antibody
- BMI, body mass index
- CHB, chronic hepatitis B
- CccDNA, covalently closed circular DNA
- Children
- Chronic hepatitis B
- ETV, entecavir
- GEE, generalized estimating equation
- HBV RNA
- HBV, hepatitis B virus
- HBeAg seroconversion
- HBeAg, hepatitis B e antigen
- HBsAg, hepatitis B surface antigen
- HCC, hepatocellular carcinoma
- LoD, limit of detection
- Marker
- NUC, nucleos/tide
- PEI, Paul-Ehrlich Institute
- PgRNA, pregenomic RNA
- ROC, receiver operating characteristics
- RcDNA, relaxed circular DNA
- ULN, upper limit of normal
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Affiliation(s)
- Yongbin Wu
- Department of Laboratory Medicine, Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin, China; Institute of Translational Medicine, Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin, China.
| | - Jian Wen
- Department of Infectious Diseases, Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin, China
| | - Guifang Tang
- Department of Infectious Diseases, Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin, China
| | - Jing Zhang
- Department of Laboratory Medicine, Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin, China
| | - Jie Xin
- Department of Laboratory Medicine, Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin, China
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Zhang KL, Chen XQ, Lv ZL, Tang Q, Shan QW. A simple noninvasive model to predict significant fibrosis in children with chronic hepatitis B. Medicine (Baltimore) 2021; 100:e26462. [PMID: 34160448 PMCID: PMC8238263 DOI: 10.1097/md.0000000000026462] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 05/17/2021] [Accepted: 06/06/2021] [Indexed: 01/04/2023] Open
Abstract
To develop a noninvasive model to predict significant fibrosis in children with chronic hepatitis B (CHB).A total of 116 CHB pediatric patients who underwent liver biopsy were included in the study. Liver histology, which is the gold standard for assessing fibrosis, was performed. Blood routine examination, coagulation function, liver biochemistry, viral serology, and viral load were analyzed. Receiver operating characteristic curve analysis was used to analyze the sensitivity and specificity of all possible cut-off values.Based on the correlation and difference analyses, 7 available clinical parameters (total bile acid, gamma-glutamyl transpeptidase [GGT], aspartate transaminase, direct bilirubin to total bilirubin ratio, alanine aminotransferase, prealbumin [PA], and cholinesterase) were included in the modeling analysis. A model to predict significant liver fibrosis was derived using the 2 best parameters (PA and GGT). The original model was . After the mathematical calculation, the G index=600 × GGT/PA2 predicted significant fibrosis, with an area under the receiving operating characteristics (AUROC) curve of 0.733, 95% confidence interval (0.643-0.811). The AUROC of the G index (0.733) was higher than that of aminotransferase to platelet ratio index (APRI) (0.680) and Fibrosis index based on 4 factors (FIB-4) (0.601) in predicting significant fibrosis in children with CHB. If the values of the G index were outside the range of 0.28 to 1.16, 52% of children with CHB could avoid liver biopsy, with an overall accuracy of 75%.The G index can predict and exclude significant fibrosis in children with CHB, and it may reduce the need for liver biopsy in children with CHB.
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Affiliation(s)
- Kang-Ling Zhang
- Department Of Pediatrics
- Child Health Section, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | | | - Zi-Li Lv
- Department Of Pathology, The First Affiliated Hospital Of Guangxi Medical University, Nanning
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Komatsu H, Inui A, Yoshio S, Fujisawa T. Pharmacotherapy options for managing hepatitis B in children. Expert Opin Pharmacother 2021; 22:449-467. [PMID: 33090882 DOI: 10.1080/14656566.2020.1841165] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION To eliminate viral hepatitis by 2030, the World Health Organization (WHO) launched the first global health sector strategy on viral hepatitis, with particular focus given to hepatitis B and C in 2016. To achieve the reduction of mortality in children, it is indispensable to know which children should be treated and how to treat them. AREA COVERED In this article, the authors review the antiviral treatment of children with chronic hepatitis B virus (HBV) infection including antivirals available for children with chronic HBV infection. EXPERT OPINION The approvals of nucleos(t)ide analogues (NAs) and pegylated interferon (PEG-IFN) for children have lowered a hurdle to the initiation of antiviral treatment in children. The international guidelines use nearly the same criteria of antiviral treatment for children with chronic HBV infection, but the WHO guidelines provide a cautious stance on the antiviral treatment of children. Not only PEG-IFN but also NAs with a high genetic barrier to drug resistance should be the first-line treatment for children. In settings with limited medical resources, NAs can be the first-line treatment for children. Although the concept of an 'immune-tolerant phase' is challenged, evidence is not sufficient to recommend the treatment of HBeAg-positive immune-tolerant children.
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Affiliation(s)
- Haruki Komatsu
- Department of Pediatrics, Toho University, Sakura Medical Center, Chiba, Japan
| | - Ayano Inui
- Department of Pediatric Hepatology and Gastroenterology, Eastern Yokohama Hospital, Kanagawa, Japan
| | - Sachiyo Yoshio
- Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
| | - Tomoo Fujisawa
- Department of Pediatric Hepatology and Gastroenterology, Eastern Yokohama Hospital, Kanagawa, Japan
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Efficacy and safety of interferon alpha-2b versus pegylated interferon alpha-2a monotherapy in children with chronic hepatitis B: a real-life cohort study from Shanghai, China. World J Pediatr 2019; 15:595-600. [PMID: 31487005 DOI: 10.1007/s12519-019-00303-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 08/01/2019] [Indexed: 12/26/2022]
Abstract
BACKGROUND Interferon alpha (IFN-α) is a preferred therapy for antiviral treatment of children with chronic hepatitis B (CHB) aged > 1 year currently. Peginterferon alpha-2a (Peg-IFN α-2a) is a recommended international guideline for treatment of CHB children, which is limited to children aged > 3 years. But the exact efficacy and safety of IFN-α and Peg-IFN α-2a for treating CHB are not sufficient. METHODS Clinical manifestations, baseline characteristics, related laboratory tests and adverse events were retrospectively analyzed in children with CHB, who visited Children's Hospital of Fudan University and were treated with IFN α-2b or Peg-IFN α-2a monotherapy and followed up from January 2003 to October 2018. RESULTS A total of 36 immune-active patients without advanced fibrosis were enrolled to be treated with IFN α-2b (group A, n = 18) or Peg-IFN α-2a (group B, n = 18). IFN α-2b or Peg-IFN α-2a was administered for a median of 48 weeks subcutaneously by body surface area (BSA) category at a dose of 3 MU/m2 or 104 μg/m2, respectively. HBV e antigen (HBeAg) seroconversion rates at 48 weeks post-treatment were higher in group A than group B (92.9% vs. 87.5%), so as the rates of HBsAg clearance (22.2% vs. 11.1%), and hepatitis B virus (HBV)-DNA < 1000 IU/mL (88.9% vs. 83.3%). Only mild flu-like symptoms and transient neutropenia appeared in some children at the early stage of treatment. No severe abnormal results was observed in other laboratory assessments. CONCLUSION The antiviral monotherapy of 48-week IFN α-2b or Peg-IFN α-2a in children with CHB is well tolerated and effective, which is associated with higher rates of HBeAg seroconversion and HBsAg clearance than in adults and previously pediatric patients.
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Chen HS, Wu JF, Su TH, Chen HL, Hsu HY, Xia NS, Chen PJ, Chang MH. Baseline Level of Hepatitis B Core Antibody Predicts Spontaneous Hepatitis B e Antigen (HBeAg) Seroconversion in HBeAg-Positive Children With a Normal Alanine Aminotransferase Level. Hepatology 2019; 70:1903-1912. [PMID: 31121067 DOI: 10.1002/hep.30788] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Accepted: 05/19/2019] [Indexed: 12/11/2022]
Abstract
It is not clear whether baseline hepatitis B core antibody (anti-HBc) level in hepatitis B e antigen (HBeAg)-positive children with a normal alanine aminotransferase (ALT) level is predictive of spontaneous HBeAg seroconversion. We investigated the correlation between anti-HBc level and the natural course of chronic hepatitis B (CHB) virus (HBV) infection in children, particularly the ability of baseline anti-HBc level to predict spontaneous HBeAg seroconversion during long-term follow-up. HBeAg-positive children with untreated CHB and a normal ALT level were followed longitudinally. Anti-HBc level was determined by double-sandwich immunoassay. Effects of anti-HBc levels and other parameters on spontaneous HBeAg seroconversion and the natural course of CHB were assessed. A total of 182 children (106 males) with a median age at enrollment of 10.6 years (interquartile range [IQR], 10.3-15.3) were followed for a median of 19.8 years (IQR, 11.9-21.9). Spontaneous HBeAg seroconversion occurred in 85 children (46.7%) during the follow-up. A baseline anti-HBc titer of >500 IU/mL (hazard ratio [HR] = 2.81), HBV genotype B and B + C (HR = 3.46), and a baseline hepatitis B surface antigen titer of ≤4.8 log10 IU/mL (HR = 3.09) were predictive of spontaneous HBeAg seroconversion, based on multivariable survival analysis (P < 0.001). In cases remaining HBeAg positive, their anti-HBc levels increased gradually during follow-up because of ongoing inflammation. Conclusion: Baseline anti-HBc level is predictive of spontaneous HBeAg seroconversion in HBeAg-positive children with a normal ALT level. Anti-HBc level reflects anti-HBV immune response in the HBeAg-positive normal ALT phase of CHB.
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Affiliation(s)
- Ho-Sheng Chen
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.,Department of Pediatrics, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu City, Taiwan
| | - Jia-Feng Wu
- Department of Pediatrics, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan
| | - Tung-Hung Su
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan
| | - Huey-Ling Chen
- Department of Pediatrics, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan
| | - Hong-Yuan Hsu
- Department of Pediatrics, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan
| | - Ning-Shao Xia
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China
| | - Pei-Jer Chen
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan
| | - Mei-Hwei Chang
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.,Department of Pediatrics, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan
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12
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Abstract
OBJECTIVE The aim of the study was to define chronic HBV phenotypes in a large, cohort of United States and Canadian children utilizing recently published population-based upper limit of normal alanine aminotransferase levels (ULN ALT), compared with local laboratory ULN; identify relationships with host and viral factors. BACKGROUND Chronic hepatitis B virus (HBV) infection has been characterized by phases or phenotypes, possibly associated with prognosis and indications for therapy. METHODS Baseline enrollment data of children in the Hepatitis B Research Network were examined. Phenotype definitions were inactive carrier: HBeAg-negative with low HBV DNA and normal ALT levels; immune-tolerant: HBeAg-positive with high HBV DNA but normal ALT levels; or chronic hepatitis B: HBeAg-positive or -negative with high HBV DNA and abnormal ALT levels. RESULTS Three hundred seventy-one participants were analyzed of whom 274 were HBeAg-positive (74%). Younger participants were more likely be HBeAg-positive with higher HBV DNA levels. If local laboratory ULN ALT levels were used, 35% were assigned the immune tolerant phenotype, but if updated ULN were applied, only 12% could be so defined, and the remaining 82% would be considered to have chronic hepatitis B. Among HBeAg-negative participants, only 21 (22%) were defined as inactive carriers and 14 (14%) as HBeAg-negative chronic hepatitis B; the majority (61%) had abnormal ALT and low levels of HBV DNA, thus having an indeterminant phenotype. Increasing age was associated with smaller proportions of HBeAg-positive infection. CONCLUSIONS Among children with chronic HBV infection living in North America, the immune tolerant phenotype is uncommon and HBeAg positivity decreases with age.
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13
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Zhu S, Dong Y, Wang L, Liu W, Zhao P. Early initiation of antiviral therapy contributes to a rapid and significant loss of serum HBsAg in infantile-onset hepatitis B. J Hepatol 2019; 71:871-875. [PMID: 31228491 DOI: 10.1016/j.jhep.2019.06.009] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2019] [Revised: 05/30/2019] [Accepted: 06/11/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIM There is a paucity of data regarding antiviral therapy in hepatitis B virus (HBV)-infected infants aged <1 year who have elevated alanine aminotransferase. This study aims to assess the efficacy and safety of antiviral therapy initiated in infancy. METHODS A real-world cohort study was conducted from January 2010 to December 2017. HBV-infected infants under 1 year of age, with persistent elevation of alanine aminotransferase and high viral load, were recruited and divided into 2 groups. Group I included 18 infants whose parents chose to initiate antiviral therapy with lamivudine before 1 year of age. Group II included 11 infants whose parents chose to initiate antiviral therapy with interferon-α after 1 year of age and not to receive any antiviral therapies before 1 year of age. The main outcome measure was rate of serum HBV surface antigen (HBsAg) loss at month 12 of treatment. RESULTS There were no statistical differences between Groups I and II regarding baseline characteristics. No infants in Group II developed spontaneous HBsAg loss before 1 year of age. In Group I, the cumulative rates of HBsAg loss at month 3, 6, 9 and 12 of treatment were 39%, 67%, 78% and 83%, respectively. In Group II, the cumulative rates of HBsAg loss at month 3, 6, 9 and 12 of treatment were 18%, 27%, 27% and 36%, respectively. Statistical differences existed in the cumulative rates of HBsAg loss between the 2 groups (log-rank test, p = 0.0023). No serious adverse events occurred in the study. CONCLUSION Early initiation of antiviral therapy for infantile-onset hepatitis B contributes to a rapid and significant loss of HBsAg. Further trials with larger cohorts are needed to verify our results. LAY SUMMARY Chronicity is a serious threat to infants infected with hepatitis B. However, no treatment measure has been recommended for infantile-onset hepatitis B in current guidelines. In order to evaluate the benefit and safety of antiviral therapy in infantile-onset hepatitis B, a real-world cohort study was conducted. Long-term follow-up results showed that early initiation of antiviral therapy with lamivudine safely led to a rapid and significant loss of serum hepatitis B surface antigen in the present subset of infants with alanine aminotransferase ≥2× upper limit of normal. Further trials with larger cohorts are needed.
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Affiliation(s)
- Shishu Zhu
- The Fifth Medical Center (formerly Beijing 302 Hospital), Chinese PLA General Hospital, Beijing 100039, China
| | - Yi Dong
- The Fifth Medical Center (formerly Beijing 302 Hospital), Chinese PLA General Hospital, Beijing 100039, China
| | - Limin Wang
- The Fifth Medical Center (formerly Beijing 302 Hospital), Chinese PLA General Hospital, Beijing 100039, China
| | - Weiwei Liu
- Medical Statistics Section, Academy of Military Medical Sciences, Beijing 100850, China
| | - Pan Zhao
- The Fifth Medical Center (formerly Beijing 302 Hospital), Chinese PLA General Hospital, Beijing 100039, China; The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, China.
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14
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Fan H, Lin L, Jia S, Xie M, Luo C, Tan X, Ying R, Guan Y, Li F. Interferon alpha treatment leads to a high rate of hepatitis B surface antigen seroconversion in Chinese children with chronic hepatitis B. J Viral Hepat 2019; 26 Suppl 1:77-84. [PMID: 31380586 DOI: 10.1111/jvh.13165] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Accepted: 05/15/2019] [Indexed: 12/24/2022]
Abstract
Chronic hepatitis B virus (HBV) infection (CHB) in children remains a public health challenge despite significant success in programme is established to prevent mother-to-child transmission. In particular, CHB in Chinese children are mostly acquired through vertical transmission, which differs from the common infection route reported in other countries and regions. This situation has resulted in a high endemic prevalence of CHB in Chinese adults. Thus, successful treatment of children with CHB will prevent the development of advanced liver diseases in late adulthood. However, there is still no consensus on the clinical guideline to treat paediatric CHB. In this study, we evaluated the potential of interferon alpha (IFNa) treatment for Chinese children with CHB. A total of 41 patients with CHB aged 3-17 years were enrolled in this retrospective study: 21 patients were treated with pegylated (PEG)-IFNa and 20 patients without treatment served as the control group. The rates of HBV DNA suppression, hepatitis B e antigen (HBeAg) clearance and hepatitis B surface antigen (HBsAg) clearance were significantly higher in the PEG-IFNa treatment group than in the control group (P < 0.05 at 48 weeks). Unexpectedly, PEG-IFNa treatment achieved a high rate of HBsAb production, far exceeding the clinical outcome in documented PEG-IFNa-treated CHB adults. Further analysis revealed that younger children (3-6 years old) were more responsive to PEG-IFNa treatment with respect to achieving a protective level of HBsAb in a short treatment cycle than adolescents (10-17 years old). Overall, these results indicate that the immune system of children might have a preserved PEG-IFNa-mediated mechanism to completely control HBV, which can help to design new strategies to treat CHB patients.
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Affiliation(s)
- Huimin Fan
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Luping Lin
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Shijie Jia
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Min Xie
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Chun Luo
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Xinghua Tan
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Ruosu Ying
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Yujuan Guan
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Feng Li
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
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15
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KASL clinical practice guidelines for management of chronic hepatitis B. Clin Mol Hepatol 2019; 25:93-159. [PMID: 31185710 PMCID: PMC6589848 DOI: 10.3350/cmh.2019.1002] [Citation(s) in RCA: 165] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Accepted: 03/25/2019] [Indexed: 02/06/2023] Open
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16
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Rosenthal P, Ling SC, Belle SH, Murray KF, Rodriguez-Baez N, Schwarzenberg SJ, Teckman J, Lin HHS, Schwarz KB, for the Hepatitis B Research Network (HBRN). Combination of Entecavir/Peginterferon Alfa-2a in Children With Hepatitis B e Antigen-Positive Immune Tolerant Chronic Hepatitis B Virus Infection. Hepatology 2019; 69:2326-2337. [PMID: 30318613 PMCID: PMC6465180 DOI: 10.1002/hep.30312] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Accepted: 10/10/2018] [Indexed: 12/17/2022]
Abstract
The optimal management strategy for children with immune-tolerant chronic hepatitis B virus (HBV) infection remains unknown. The purpose of this clinical trial was to determine the safety and efficacy of therapy with entecavir and peginterferon in a group of children in the immune-tolerant phase of HBV infection. Children with immune-tolerant features of chronic hepatitis B (CHB) received entecavir once-daily in a dose of 0.015 mg/kg (0.5 mg maximum) for 48 weeks; peginterferon alfa-2a (180 µg/1.73m2 subcutaneously) once-weekly was added at the end of week 8 and continued until week 48. The primary endpoint was lack of detectable hepatitis B e antigen (HBeAg) with HBV DNA levels ≤1,000 IU/mL 48 weeks after stopping therapy. Sixty children (75% female), median age 10.9 (range, 3.4-17.9) years, were enrolled. All were positive for hepatitis B surface antigen (HBsAg) and HBeAg and had high levels of HBV DNA with normal or minimally elevated levels of alanine aminotransferase (ALT). Fifty-five children completed the entire 48-week course of therapy. At 48 weeks after treatment ended (week 96), 2 children (3%) achieved the primary endpoint and were also HBsAg negative and anti-hepatitis B surface antigen antibody (anti-HBs) positive. One child was HBeAg positive but HBsAg negative at week 60; another was HBeAg negative but HBsAg positive at week 72, which were their last clinic visits. In the remaining children, serum ALT and HBV DNA levels at week 96 were similar to baseline. Thirty-seven children experienced adverse events (AEs), and 1 had a serious AE (SAE). Conclusion: The combination of entecavir and peginterferon for up to 48 weeks rarely led to loss of HBeAg with sustained suppression of HBV DNA levels in children in the immune-tolerant phase of HBV infection, and treatment was associated with frequent AEs.
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Affiliation(s)
- Philip Rosenthal
- Pediatrics, University of California, San Francisco, San Francisco, CA, United States
| | - Simon C. Ling
- The Hospital for Sick Children, and Department of Pediatrics, University of Toronto, Toronto, ON, Canada
| | - Steven H. Belle
- Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States
| | - Karen F. Murray
- Pediatrics, University of Washington School of Medicine and Seattle Children’s Hospital, Seattle, WA, United States
| | - Norberto Rodriguez-Baez
- Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Sarah J. Schwarzenberg
- Pediatrics, University of Minnesota Masonic Children’s Hospital, Minneapolis, MN, United States
| | - Jeffrey Teckman
- Pediatrics, Saint Louis University, Saint Louis, MO, United States
| | - Hsing-Hua S. Lin
- Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States
| | - Kathleen B. Schwarz
- Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, United States
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17
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El-Raziky MES, Fouad HM, Abd Elkhalak NS, Ghobrial CM, El-Karaksy HM. Paediatric chronic hepatitis B virus infection: are children too tolerant to treat? Acta Paediatr 2019; 108:1144-1150. [PMID: 30362178 DOI: 10.1111/apa.14626] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Revised: 05/27/2018] [Accepted: 10/23/2018] [Indexed: 12/22/2022]
Abstract
AIM Guidelines for managing the hepatitis B (HB) virus infection in children are still evolving. We aimed to assess the eligibility of children with HB virus infections for treatment based on the current guidelines. METHODS This observational study took place in 2016 and focused on children with isolated chronic HB infections, who attended the paediatric hepatology units at two centres in Egypt. We recruited all treatment-naïve children aged one year to 18 years who had completed at least 12 months of follow-up. RESULTS The study comprised 103 children aged between 1.5-18 years. Of these, 51 (50%) had the HB e antigen-positive chronic infection, 28 (27%) had the HB-negative chronic infection, 11 (11%) had the HB e antigen-positive chronic hepatitis and none had the HB e antigen-negative chronic hepatitis. The remaining 13 (12%) children did not fulfil the criteria for chronic HB definitions. Only two of the children were candidates for treatment: both had HB e antigen-positive chronic hepatitis and had undergone liver biopsies. CONCLUSION Only two of the 103 children with chronic HB were eligible for treatment according to the current guidelines and every measure should be taken to prevent the HB virus infection in children.
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Affiliation(s)
- Mona El-Said El-Raziky
- The Department of Paediatrics, Kasr Alainy Medical School, Cairo University, Cairo, Egypt
| | - Hanan Mina Fouad
- The Department of Paediatrics, Faculty of Medicine, Helwan University, Cairo, Egypt
- The National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt
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Association between IL-37 gene polymorphisms and risk of HBV-related liver disease in a Saudi Arabian population. Sci Rep 2019; 9:7123. [PMID: 31073186 PMCID: PMC6509272 DOI: 10.1038/s41598-019-42808-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Accepted: 03/13/2019] [Indexed: 12/26/2022] Open
Abstract
Interleukin-37 (IL-37) has recently been recognized as a strong anti-inflammatory cytokine having anti-tumor activity against hepatocellular carcinoma (HCC) in hepatitis B virus (HBV)-infected patients. HCC is a typical inflammation-related cancer, and genetic variations within the IL-37 gene may be associated with the risk of HBV infection. Identification of the allelic patterns that genetically have a high disease risk is essential for the development of preventive diagnostics for HBV-mediated liver disease pathogenesis. In this study, we aimed to investigate the association between single nucleotide polymorphisms (SNPs) within the IL-37 gene and disease sequelae associated with HBV infection. We genotyped ten IL-37 SNPs in 1274 patients infected with HBV and 599 healthy controls from a Saudi Arabian population. Among the selected SNPs, two SNPs (rs2723175 and rs2708973) were strongly associated with HBV infection, and six SNPs (rs2723176, rs2723175, rs2723186, rs364030, rs28947200, rs4392270) were associated with HBV clearance, comparing healthy controls and HBV infected-patients respectively. A suggestive association of rs4849133 was identified with active HBV surface antigen (HBsAg) carrier and HBV-related liver disease progression. In conclusion, our findings suggest that variations at the IL-37 gene may be useful as genetic predictive risk factors for HBV infection and HBV-mediated liver disease progression in the Saudi Arabian population.
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19
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Antiviral Therapy for AECHB and Severe Hepatitis B (Liver Failure). ACUTE EXACERBATION OF CHRONIC HEPATITIS B 2019. [PMCID: PMC7498919 DOI: 10.1007/978-94-024-1603-9_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
This chapter describes the principles of antiviral therapy, treatment strategies, medications and recommendations for AECHB, HBV-ACLF, HBV-related liver cirrhosis, HBV-related HCC, and liver transplantation.
Severe exacerbation of chronic hepatitis B is closely related to continuous HBV replication. Therefore, inhibiting HBV replication to reduce viral load may block disease progression and improve the quality of life of these patients. ETV or TDF has been recommend first-line drug for the treatment of AECHB. A hyperactive immune response due to continuous HBV replication is the main mechanism for development of severe hepatitis B. In addition to comprehensive treatment, early administration of potent nucleoside analogs can rapidly reduce HBV DNA concentration, relieve immune injury induced by HBV, and reduce liver inflammation and patient mortality. Antiviral agents have become important in the treatment of severe exacerbation of chronic hepatitis B. Long-term antiviral treatment with nucleoside analogs can delay or reverse the progress of liver cirrhosis. Virologic response, viral resistance and adverse drug reactions should be closely monitored during treatment. The treatment should be optimized for maximum effect based on each patient’s responses. Effective antiviral therapy can suppress HBV replication and reduce the incidence of HBV-related HCC. Patients with HBV-related HCC should receive individualized and optimal multidisciplinary comprehensive treatment. Anti-viral drugs with high efficacy, low resistance and low adverse drug reactions should be selected to improve the patient’s quality of life and prolong survival time. Methods to prevent HBV reinfection after liver transplantation include passive immunization (HBIG), antiviral treatment (nucleoside analogs) and active immunization (hepatitis B vaccine). Clinical trials involving sequential combination therapy with NUC and Peg-IFN have shown statistically significant decline in HBsAg levels on treatment and high rates of sustained post-treatment serologic response. Combination therapy with novel DAA and immunotherapeutic approach may hold promise to overcome both cccDNA persistence and immune escape, representing a critical step towards HBV cure.
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20
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Mogul DB, Brereton N, Carson KA, Pittarelli M, Daniel H, Torbenson M, Schwarz KB. Development of a Dietary Methyl Donor Food Frequency Questionnaire to Assess Folate and Vitamin B 12 Status in Children with Chronic Hepatitis B Virus Infection. J Pediatr 2018; 203:41-46.e2. [PMID: 30243534 DOI: 10.1016/j.jpeds.2018.07.088] [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: 04/04/2018] [Revised: 07/10/2018] [Accepted: 07/26/2018] [Indexed: 10/28/2022]
Abstract
OBJECTIVE To develop a dietary methyl donor food frequency questionnaire (DMD-FFQ) that is validated in a cohort of US children and to determine whether the consumption of folate and vitamin B12, principal DMDs, correlates with HBV DNA levels and its methylation density. STUDY DESIGN We developed a semiquantitative DMD-FFQ to estimate intake of folate and vitamin B12 and validated this instrument against a 24-hour dietary recall and biomarkers-red blood cell folate, serum vitamin B12, and homocysteine-in 35 children with chronic HBV infection without other medical comorbidities. Estimates of DMD, as well as the serum biomarkers, were correlated with the methylation density of HBV CpG island 2 and HBV DNA levels. RESULTS Folate per kilogram of body weight by the DMD-FFQ correlated positively with 24-hour recall (r = 0.60; P < .001) and red blood cell folate (r = 0.40; P = .02), and negatively with homocysteine (r = -0.54; P < .001). Vitamin B12 per kilogram by DMD-FFQ also correlated positively with 24-hour recall (r = 0.57; P < .001) and serum vitamin B12 (r = 0.36, P = .04), and negatively with homocysteine (r = -0.44; P = .008). Neither DMD intake (from DMD-FFQ or 24-hour recall) nor serum biomarkers correlated with HBV DNA levels or its methylation density. CONCLUSIONS Our DMD-FFQ correlates well with a 24-hour recall and circulating biomarkers. Although little evidence existed that consumption of these micronutrients correlated with HBV replication, this tool could prove useful for investigating epigenetic modification by diet for several pediatric diseases.
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Affiliation(s)
- Douglas B Mogul
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Johns Hopkins University School of Medicine, Baltimore, MD.
| | - Nga Brereton
- Institute for Clinical and Translational Research, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Kathryn A Carson
- Institute for Clinical and Translational Research, Johns Hopkins University School of Medicine, Baltimore, MD; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
| | - Maria Pittarelli
- Institute for Clinical and Translational Research, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Hubert Daniel
- Department of Pathology, Johns Hopkins Hospital, Baltimore, MD
| | | | - Kathleen B Schwarz
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Johns Hopkins University School of Medicine, Baltimore, MD
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Tajiri H, Takano T, Tanaka Y, Murakami J, Brooks S. Suppression of hepatitis B surface antigen production by combination therapy with nucleotide analogues and interferon in children with genotype C hepatitis B virus infection. Hepatol Res 2018; 48:1172-1177. [PMID: 29981262 DOI: 10.1111/hepr.13227] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Revised: 04/27/2018] [Accepted: 07/02/2018] [Indexed: 02/08/2023]
Abstract
AIM Sustained suppression of hepatitis B surface antigen (HBsAg) production after interferon (IFN) treatment has not been reported for children with genotype C chronic hepatitis B virus (HBV) infection, which is prevalent in Asia. Among children with hepatitis B envelope antigen-positive genotype C chronic HBV infection, we compared the efficacy of combination therapy with nucleotide analogues and IFN-α in 11 children with 12 historical cases treated with IFN monotherapy. METHODS The combination of lamivudine and conventional IFN-α was introduced for the first three patients; the other eight patients were treated with entecavir and pegylated IFN. RESULTS Demographic factors as well as baseline HBsAg titers and HBV-DNA levels were similar between the two groups. In the combination therapy group, viral loads were suppressed in 9/11 to below 4.0 log copies/mL both at the end of the therapy (EOT) and at 6 months after EOT. In contrast, in the IFN monotherapy group, suppression of viral loads was observed in 2/12 and 3/12 at EOT and at 6 months after EOT, respectively. In the combination therapy group, HBsAg titers dropped from 4.03 at pretreatment to 2.91 log IU/mL at 6 months after EOT with 4/11 showing a drop to below 1000 IU/mL (one patient achieved HBsAg clearance). In contrast, the amount of HBsAg did not change during the corresponding periods in the IFN monotherapy group. CONCLUSIONS Our preliminary results suggest that combination therapy might be effective in the suppression of HBsAg production as well as HBV-DNA production for children with genotype C chronic HBV infection.
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Affiliation(s)
- Hitoshi Tajiri
- Department of Pediatrics, Osaka General Medical Center, Osaka
| | - Tomoko Takano
- Department of Pediatrics, Osaka General Medical Center, Osaka
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya
| | - Jun Murakami
- Division of Pediatrics and Perinatology, Tottori University, Yonago, Japan
| | - Stephen Brooks
- Department of Microbiology/Immunology, State University of New York at Buffalo, Buffalo, New York, USA
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Wirth S, Zhang H, Hardikar W, Schwarz KB, Sokal E, Yang W, Fan H, Morozov V, Mao Q, Deng H, Huang Y, Yang L, Frey N, Nasmyth-Miller C, Pavlovic V, Wat C. Efficacy and Safety of Peginterferon Alfa-2a (40KD) in Children With Chronic Hepatitis B: The PEG-B-ACTIVE Study. Hepatology 2018; 68:1681-1694. [PMID: 29689122 DOI: 10.1002/hep.30050] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Revised: 03/07/2018] [Accepted: 04/18/2018] [Indexed: 02/06/2023]
Abstract
Children with chronic hepatitis B (CHB) represent an area of unmet medical need, attributed to increased lifetime risk of CHB sequelae and limited therapeutic options compared with adult CHB patients. The PEG-B-ACTIVE (NCT01519960) phase III study evaluated peginterferon (PegIFN) alfa-2a treatment in children aged 3 to <18 years with CHB. A total of 161 hepatitis B e antigen (HBeAg)-positive immune-active patients without advanced fibrosis (AF)/cirrhosis were randomized (2:1) to PegIFN alfa-2a (Group A, n = 101) or no treatment (Group B, n = 50); patients with AF were assigned to PegIFN alfa-2a (Group C, n = 10). PegIFN alfa-2a was administered for 48 weeks by body surface area (BSA) category, based on 180 μg/1.73 m2 . HBeAg seroconversion rates at 24 weeks posttreatment were significantly higher in Group A (25.7% vs. 6%; P = 0.0043), as were the rates of hepatitis B surface antigen (HBsAg) clearance (8.9% vs. 0%; P = 0.03), hepatitis B virus (HBV) DNA <2,000 IU/mL (28.7% vs. 2.0%; P < 0.001) or undetectable (16.8% vs. 2.0%; P = 0.0069), and alanine aminotransferase (ALT) normalization (51.5% vs. 12%; P < 0.001). Safety, including incidence of ALT flares and neutropenia, was comparable to the established PegIFN alfa-2a profile in HBV-infected adults or hepatitis C virus-infected children. Changes in growth parameters were minimal during treatment and comparable to those in untreated patients. Safety and efficacy outcomes in Group C were in line with Group A. Conclusion: PegIFN alfa-2a treatment of children in the immune-active phase of CHB was efficacious and well tolerated, and associated with higher incidence of HBsAg clearance than in adults. This represents an important advance to the treatment options for children with CHB.
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Affiliation(s)
- Stefan Wirth
- Department of Pediatrics, Helios Medical Center Wuppertal, Witten-Herdecke University, Germany
| | | | | | | | - Etienne Sokal
- Cliniques Universitaires St Luc, Université Catholique de Louvain, Brussels, Belgium
| | - Weibo Yang
- First Affiliated Hospital of Kunming Medical College, Kunming, China
| | - Huimin Fan
- Eighth People's Hospital of Guangzhou, Guangzhou, China
| | | | - Qing Mao
- SouthWest Hospital, Third Military Medical University, Chongqing, China
| | - Hong Deng
- Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Yang Huang
- Roche (China) Holding Ltd, Shanghai, China
| | - Lei Yang
- Roche (China) Holding Ltd, Shanghai, China
| | - Nicolas Frey
- Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland
| | | | | | - Cynthia Wat
- Roche Products Limited, Welwyn Garden City, United Kingdom
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Goyal A, Romero-Severson EO. Screening for hepatitis D and PEG-Interferon over Tenofovir enhance general hepatitis control efforts in Brazil. PLoS One 2018; 13:e0203831. [PMID: 30192887 PMCID: PMC6128631 DOI: 10.1371/journal.pone.0203831] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Accepted: 08/28/2018] [Indexed: 11/30/2022] Open
Abstract
Background Hepatitis D virus (HDV), which requires the presence of hepatitis B virus (HBV), is a deadly yet neglected disease that rapidly leads to liver cancer and disease-induced mortality. This co-dependence creates complex transmission dynamics that make it difficult to predict the efficacy of interventions aimed at HBV and/or HDV control in endemic regions, such as certain municipalities of Brazil, where up to 65% of HBV-infected persons are co-infected. Methodology We created a mathematical model that captures the joint transmission dynamics of HBV and HDV, incorporating mother-to-child, sexual and household transmission. With an aim to minimize the number of total infections and disease-induced mortality in 2027, we then determined optimal strategies for Brazil and its sub-regions under a constrained budget, which was dynamically allocated among HBV and HDV screening, HBV and HDV treatment, HBV newborn and adult vaccination, and awareness programs. Three treatment options were considered, namely: Tenofovir, PEGylated-Interferon, and nucleic acid polymers (NAP). Results The additional cost of HDV screening and the use of a more expensive PEGylated-Interferon are offset by not wasting resources on treating co-infected persons with Tenofovir. The introductory price of NAP treatment must be less than $16,000 per course to become competitive with Tenofovir and PEGylated-Interferon in Brazil. Conclusion Additional screening for HDV is beneficial, even in a low HBV and HDV endemic regions of Brazil. We recommend PEGylated-Interferon, wherever possible, for both HBV and HDV. If PEGylated-Interferon is not available in abundance, PEGylated-Interferon for co-infections and 4-year Tenofovir treatment for mono-infections is recommended.
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Affiliation(s)
- Ashish Goyal
- Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America
- * E-mail:
| | - Ethan Obie Romero-Severson
- Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America
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Lee KJ, Choe BH, Choe JY, Kim JY, Jeong IS, Kim JW, Yang HR, Chang JY, Kim KM, Moon JS, Ko JS. A Multicenter Study of the Antiviral Efficacy of Entecavir Monotherapy Compared to Lamivudine Monotherapy in Children with Nucleos(t)ide-naïve Chronic Hepatitis B. J Korean Med Sci 2018; 33:e63. [PMID: 29441755 PMCID: PMC5809752 DOI: 10.3346/jkms.2018.33.e63] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Accepted: 12/18/2017] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND The aim of this study was to compare the long-term efficacy of entecavir (ETV) and lamivudine (LAM) therapy in children with chronic hepatitis B (CHB) who had not received nucleoside analogue treatment. METHODS In this multicenter, retrospective study, we included pediatric CHB patients younger than 20 years who received ETV or LAM treatment for at least 12 months and had no concomitant diseases. All of the patients were followed up every 1 to 3 months. At each visit, the patients underwent clinical evaluation and biochemical testing. RESULTS Eight (53.3%), 14 (93.3%), and 2 (15.4%) of the ETV-treated patients achieved virologic suppression, alanine aminotransferase (ALT) normalization and hepatitis B e antigen (HBeAg) seroconversion, respectively, at 1 year. In the ETV group, the cumulative rate of virologic suppression at 3 years was 91.7%, which was significantly higher than that in the LAM group (P < 0.001). The mean duration of treatment before virologic suppression was shorter in the ETV group than in the LAM group (P = 0.040). The cumulative rate of seroconversion in the ETV group at 3 years was 39.4%, which was not significantly different from that in the LAM group (P = 0.439). The ETV group showed lower cumulate rates of virologic breakthrough (33.3% at 6 years) and genotypic mutation than the LAM group (P = 0.033 and P = 0.011, respectively). CONCLUSION ETV is superior to LAM in pediatric CHB treatment because of its higher virologic suppression rate and lower cumulative rates of virologic breakthrough and genotypic mutation.
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Affiliation(s)
- Kyung Jae Lee
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Byung Ho Choe
- Department of Pediatrics, Kyungpook National University School of Medicine, Daegu, Korea
| | - Jae Young Choe
- Department of Pediatrics, Kyungpook National University School of Medicine, Daegu, Korea
| | - Ju Young Kim
- Department of Pediatrics, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - In Sook Jeong
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine Seoul, Korea
| | - Ju Whi Kim
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Hye Ran Yang
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Ju Yuong Chang
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Kyung Mo Kim
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine Seoul, Korea
| | - Jin Soo Moon
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Jae Sung Ko
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea.
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Zhou K, Terrault N. Immune tolerant HBV and HCC: time to revise our tolerance levels for therapy? ACTA ACUST UNITED AC 2018; 3. [PMID: 31058256 DOI: 10.21037/amj.2018.02.01] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Kali Zhou
- Department of Gastroenterology/Hepatology, University of California, San Francisco, San Francisco, CA, USA
| | - Norah Terrault
- Department of Gastroenterology/Hepatology, University of California, San Francisco, San Francisco, CA, USA
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Choe JY, Ko JS, Choe BH, Kim JE, Kang B, Lee KJ, Yang HR. Antiviral Efficacy of Tenofovir Monotherapy in Children with Nucleos(t)ide-naive Chronic Hepatitis B. J Korean Med Sci 2018; 33:e11. [PMID: 29215820 PMCID: PMC5729652 DOI: 10.3346/jkms.2018.33.e11] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Accepted: 10/14/2017] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The purpose was to compare the efficacy between tenofovir disoproxil fumarate (TDF) and lamivudine (LMV) in children with nucleos(t)ide-naive chronic hepatitis B (CHB) infection. Patients with CHB were treated with TDF in the immune-reactive phase and compared with a historical control group of patients treated with LMV before the TDF era. METHODS Hepatitis B virus (HBV) DNA titer decrements (> 3 log₁₀ IU/mL) were monitored after treatment initiation. The treatment duration for HBV DNA clearance (< 357 IU/mL) and complete response (HBeAg loss and HBV DNA clearance) were analyzed. The follow-up period was 96 weeks. RESULTS Sixteen patients were treated with TDF and compared with a historical control group of 24 patients treated with LMV. HBV DNA decrement (> 3 log₁₀ IU/mL) was achieved in 100% (16/16) of the TDF group but in only 62.5% (15/24) of the LMV group (P = 0.005) at 48 weeks. The HBV DNA clearance (< 357 IU/mL) in the TDF and LMV groups was, respectively, as follows: 62.5% (10/16) and 25.0% (6/24) at 12 weeks (P = 0.018), 81.3% (13/16) and 37.5% (9/24) at 24 weeks (P = 0.006), 93.8% (15/16) and 50.0% (12/24) at 48 weeks (P = 0.004), and 100% (16/16) and 54.2% (13/24) at 96 weeks (P = 0.001). Complete response occurred in 41.7% (5/12) of HBeAg-positive patients in the TDF group and 28.6% (6/21) of the LMV group at 96 weeks (P = 0.443). CONCLUSION TDF monotherapy for 96 weeks produced a significantly more effective virologic response than LMV monotherapy in children with nucleos(t)ide-naive CHB.
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Affiliation(s)
- Jae Young Choe
- Department of Pediatrics, Kyungpook National University School of Medicine, Daegu, Korea
| | - Jae Sung Ko
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Byung Ho Choe
- Department of Pediatrics, Kyungpook National University School of Medicine, Daegu, Korea.
| | - Jung Eun Kim
- Department of Pediatrics, Kyungpook National University School of Medicine, Daegu, Korea
| | - Ben Kang
- Department of Pediatrics, Kyungpook National University School of Medicine, Daegu, Korea
| | - Kyung Jae Lee
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Hye Ran Yang
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
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Collier MG, Schillie S. Hepatitis B and Hepatitis D Viruses. PRINCIPLES AND PRACTICE OF PEDIATRIC INFECTIOUS DISEASES 2018:1107-1114.e4. [DOI: 10.1016/b978-0-323-40181-4.00213-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Kimberlin DW. Antiviral Agents. PRINCIPLES AND PRACTICE OF PEDIATRIC INFECTIOUS DISEASES 2018:1551-1567.e6. [DOI: 10.1016/b978-0-323-40181-4.00295-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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29
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Chen HL, Wen WH, Chang MH. Management of Pregnant Women and Children: Focusing on Preventing Mother-to-Infant Transmission. J Infect Dis 2017; 216:S785-S791. [PMID: 29156049 DOI: 10.1093/infdis/jix429] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Hepatitis B virus (HBV) immunization has been effectively preventing chronic HBV infection with >90% efficacy in countries with universal neonatal immunization. Perinatal mother-to-infant transmission of HBV remains the major cause of chronic HBV infection despite immunization. Maternal hepatitis B e-antigen (HBeAg) and high viral load have been noted to be the most important risk factors for transmission. In recent years, short-term antiviral therapy for pregnant women in the third trimester has been shown to be highly effective in reducing 90% of vaccine failure in children. It is important to monitor maternal aminotransferase elevations postpartum. Long-term outcome of mothers and children is needed and awaits further investigations. Despite the above-mentioned preventive measures, it is also important to monitor high-risk children at 1 year of age with hepatitis B surface antigen and anti-hepatitis B to identify those with chronic HBV infection. Most of the children with chronic HBV infection were in the immune-tolerant phase. The goals for antiviral treatment in children are to reduce severity of liver injury, achieve HBeAg seroconversion, and prevent development of liver fibrosis and cancer. Studies on antiviral therapy are undergoing to elucidate the optimal indication and drug treatment for children. The ideal future goal of treatment is to eradicate chronic HBV infection globally.
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Affiliation(s)
- Huey-Ling Chen
- Department of Pediatrics, National Taiwan University Children's Hospital and College of Medicine, National Taiwan University, Taipei.,Department of Medical Education and Bioethics, College of Medicine, National Taiwan University, Taipei
| | - Wan-Hsin Wen
- Department of Pediatrics, Cardinal Tien Hospital, New Taipei City, Taiwan.,School of Medicine, College of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan
| | - Mei-Hwei Chang
- Department of Pediatrics, National Taiwan University Children's Hospital and College of Medicine, National Taiwan University, Taipei
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Natural history of chronic hepatitis B virus infection in children in Japan: a comparison of mother-to-child transmission with horizontal transmission. J Gastroenterol 2017; 52:1041-1050. [PMID: 28184998 DOI: 10.1007/s00535-017-1315-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Accepted: 01/28/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND It is necessary to evaluate the natural history of children with hepatitis B virus (HBV) infection in each country to consider their long-term management. METHODS A multi-center observational study of children with chronic HBV infection who were diagnosed at age ≤15 years was carried out in 18 hospitals in Japan. RESULTS We reviewed children with HBV infection including 381 with mother-to-child transmission (MTCT) and 154 with horizontal transmission, genotype C being the most prevalent virus genotype (83%). Children with horizontal transmission were more frequently infected with HBV genotype A or B and more likely to receive interferon therapy than those infected by MTCT. The HBeAg seroconversion rate at 15 years of age was 42% in the MTCT group and 38% in the horizontal group. It was lower in children with genotype C infection than in those infected with other genotypes (33 versus 45%). Hepatitis developed at any age but before 4 years of age the incidence was high in the horizontal group. At 3 years after the onset of the hepatitis, 26% of children with MTCT and 30% of those with horizontal transmission became inactive carriers. The incidences of hepatocellular carcinoma (HCC) at 30 years of age were 6% in the MTCT group and 11% in the horizontal group. CONCLUSIONS Patients with childhood-onset HBV infection with MTCT and horizontal transmission developed hepatitis and seroconverted to anti-HBe at any age and had a lifetime risk of developing HCC.
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31
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Tolerance and immunity to pathogens in early life: insights from HBV infection. Semin Immunopathol 2017; 39:643-652. [PMID: 28685270 PMCID: PMC5711997 DOI: 10.1007/s00281-017-0641-1] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2017] [Accepted: 06/19/2017] [Indexed: 02/06/2023]
Abstract
Immunity is not static but varies with age. The immune system of a newborn infant is not "defective" or "immature." Rather, there are distinct features of innate and adaptive immunity from fetal life to adulthood, which may alter the susceptibility of newborn infants to infections compared to adults. Increased protection to certain infectious diseases during early life may benefit from a dampened immune response as a result of decreased immune pathology. This concept may offer an alternative interpretation of the different pathological manifestations clinically observed in hepatitis B virus (HBV)-infected patients during the natural history of infection. Herein, we review the immune pathological features of HBV infection from early life to adulthood and challenge the concept of a generic immune tolerant state in young people. We then discuss how the different clinical and virological manifestations during HBV infection may be related to the differential antiviral immunity and pro-inflammatory capacity generated at different ages. Lastly, we address the potential to consider earlier therapeutic intervention in HBV-infected young patients to achieve effective immune control leading to better outcomes.
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Abstract
Chronic viral hepatitis is a global health threat and financial burden. Hepatitis B and C viruses (HBV and HCV) are the most common causes of chronic viral hepatitis in the United States. Most cases are asymptomatic before adulthood. Research has resulted in effective therapy for HCV and the promise of effective therapies for HBV. For HCV, therapy is pegylated interferon and ribavirin. Clinical trials with effective direct-acting antiviral agents are underway in pediatrics. For HBV, approved agents are alpha-interferon, lamivudine, adefovir, tenofovir, and entecavir. However, treatment seldom results in functional cure and more effective therapies are urgently needed.
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Affiliation(s)
- Wikrom Karnsakul
- Pediatric Liver Center, Department of Pediatrics, Johns Hopkins University School of Medicine, 600 North Wolfe Street, CMSC 2-117, Baltimore, MD 21287, USA.
| | - Kathleen B Schwarz
- Professor, Pediatric Liver Center, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Abstract
The therapeutic goal which is currently unfrequent but realistic in HBV infected patients is sustained HBsAg clearance. It is preceded by the loss or significant suppression of HBV replication and leads to inhibition of the progression of liver fibrosis, normalization of biochemical indicators of liver damage, reduction in the risk of hepatocellular carcinoma, prolongation of survival, prevention of HBV infection in the transplanted organ in post-transplant patients, enhancement of the quality of life, inhibition or reversal of extrahepatic changes associated with HBV infection, and halting of the spread of HBV infections. Recommendations of Polish Group of Experts for HBV for 2017 provide guidelines to assess treatment eligibility, choice of the first-line drug, monitoring and duration of treatment, management of treatment failure as well as therapy of HBV associated cirrhosis or hepatocellular carcinoma. Moreover it contains advice for treatment of HBV infection in children, females planning pregnancy or pregnant. We also included recommendations for pre- and post-exposure prophylaxis, prevention of HBV transmission from mother to infant, after liver transplantation, on immunosuppressive therapy and during HCV treatment.
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Rifai G, Anani A, Hanouneh IA, Mohamad B, Matloob A, Lopez R, Zein NN, Alkhouri N. Liver Transplantation for Hepatitis B in Early Adulthood: Analysis of the United Network for Organ Sharing Database. Transplant Proc 2017; 48:3362-3367. [PMID: 27931582 DOI: 10.1016/j.transproceed.2016.08.044] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Accepted: 08/22/2016] [Indexed: 01/16/2023]
Abstract
BACKGROUND Chronic hepatitis B virus (HBV) infection has a mild course in most children that may delay initiation of treatment even when indicated. Unfortunately, a small number of cases can progress rapidly to cirrhosis, which may require liver transplantation (LT) in early adulthood. The aim of this study was to assess the characteristics of HBV-positive young adults who received LT and to evaluate post-transplant outcomes including patient and graft survival and differences between pre- and post-implementation of Model for End-stage Liver Disease (MELD) prioritization. METHODS The United Network for Organ Sharing (UNOS) database review was conducted from 1987 to 2012, and a retrospective analysis was performed on all young adult patients (ages 18-35 years) who underwent LT in the United States with a primary diagnosis of HBV or were seropositive for HBV surface antigen at time of LT. Kaplan-Meier analysis was used to assess patient and graft survival in the pre-MELD and post-MELD eras. Factors associated with survival were identified through the use of Cox regression analysis. RESULTS A total of 522 HBV-infected subjects were included. Average age at time of transplant was 28.4 ± 5.2 years; 60.9% were male, 48.6% were white, the mean body mass index was 25 ± 5.5 kg/m2, diabetes was present in 3.9%, hepatocellular carcinoma (HCC) was present in 4.4%, and 10.4% were on dialysis prior to LT. Median follow-up after first LT was 48.2 months [12.5, 109]. During this time, 174 (33.3%) patients died with a mean age at the time of death of 31.6 ± 7.8 years, including 144 of 522 (28%) after the first LT, 26 of 74 (35%) after the second LT, and 4 of 12 (33%) after the third LT. The most common cause of death was graft failure (27.6%), followed by infection (16.6%). Overall, only 58% of patients were alive with their first LT at last follow-up. Kaplan-Meier analysis revealed worse patient and graft survival after re-transplantation in comparison to initial LT. Three hundred thirty subjects were transplanted in the pre-MELD era and 192 were transplanted in post-MELD era. Obesity, HCC, shorter ventilation use, shorter cold ischemia time, and non-white donor race were significantly more common in the post-MELD era (all with P < .05). Importantly, 5-year patient and graft survival rates were higher in the post-MELD era compared with the pre-MELD era. CONCLUSIONS LT in young adults for HBV has poor outcomes and can be associated with premature death. These findings should prompt more aggressive evaluation and treatment for HBV in young patients. Superior outcomes in the post-MELD era compared with the pre-MELD era may be attributed to pre-transplant factors, improved surgical technique, and better treatment options for HBV infection.
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Affiliation(s)
- G Rifai
- Department of Pediatric Gastroenterology, The Cleveland Clinic, Cleveland, Ohio
| | - A Anani
- Department of Digestive Disease, The Cleveland Clinic, Cleveland, Ohio
| | - I A Hanouneh
- Department of Pediatric Gastroenterology, The Cleveland Clinic, Cleveland, Ohio
| | - B Mohamad
- Department of Pediatric Gastroenterology, The Cleveland Clinic, Cleveland, Ohio
| | - A Matloob
- Department of Digestive Disease, The Cleveland Clinic, Cleveland, Ohio
| | - R Lopez
- Department of Digestive Disease, The Cleveland Clinic, Cleveland, Ohio
| | - N N Zein
- Department of Digestive Disease, The Cleveland Clinic, Cleveland, Ohio
| | - N Alkhouri
- Department of Pediatric Gastroenterology, The Cleveland Clinic, Cleveland, Ohio; Department of Digestive Disease, The Cleveland Clinic, Cleveland, Ohio.
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Defresne F, Sokal E. Chronic hepatitis B in children: Therapeutic challenges and perspectives. J Gastroenterol Hepatol 2017; 32:368-371. [PMID: 27262164 DOI: 10.1111/jgh.13459] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/15/2016] [Indexed: 02/06/2023]
Abstract
Chronic hepatitis B virus (HBV) infection and HBV-related hepatitis in children remains an unmet medical need, as current treatments are only partially effective, and only in a limited number of affected children. So-called "immunotolerant" children have not shown increased serological responses to available treatments. In cases involving more active disease, serological response has only been obtained in approximately one-third of patients when using interferon, while other cases exhibited virological response solely under continuous treatment with nucleoside analogs. Guidelines have recently been established to aid pediatricians in effectively managing this condition. With the available medications, no treatment is so far indicated for immunotolerant children, but only for cases presenting increased alanine aminotransferase levels to over 1.5-2 times the upper limit of normal for over 6 months, and without spontaneous HB envelope antigen to antibody seroconversion. The therapeutic arsenal approved by the Food and Drugs Administration and European Medicines Agency for children remains limited because of the lack of large-scale clinical trials validating treatments already approved for the adult population. Yet, the recent discovery of a specific HBV-cell surface receptor, NTCP, allows for new treatment perspectives regarding the future.
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Affiliation(s)
- Florence Defresne
- Department of Paediatrics, Saint Luc University Clinics, and Paediatric Research Unit, Institute of Experimental and Clinical Research, Catholic University of Louvain, Brussels, Belgium
| | - Etienne Sokal
- Department of Paediatrics, Saint Luc University Clinics, and Paediatric Research Unit, Institute of Experimental and Clinical Research, Catholic University of Louvain, Brussels, Belgium
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36
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Komatsu H, Inui A, Fujisawa T. Pediatric hepatitis B treatment. ANNALS OF TRANSLATIONAL MEDICINE 2017; 5:37. [PMID: 28251116 PMCID: PMC5326647 DOI: 10.21037/atm.2016.11.52] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/20/2016] [Accepted: 09/07/2016] [Indexed: 12/17/2022]
Abstract
Although the introduction of hepatitis B vaccine has been contributing to the reduction in the prevalence of hepatitis B virus (HBV) carriers worldwide, the treatment of children with chronic HBV infection is a challenge to be addressed. HBeAg seroconversion, which induces low replication of HBV, is widely accepted as the first goal of antiviral treatment in children with chronic hepatitis B. However, spontaneous HBeAg seroconversion is highly expected in children with chronic HBV infection. Therefore, the identification of children who need antiviral treatment to induce HBeAg seroconversion is essential in the management of chronic HBV infection. Guidelines and experts' opinion show how to identify children who should be treated and how to treat them. If decompensated cirrhosis is absent, interferon-alpha is the first-line antiviral treatment. Nucleos(t)ide analogues (NAs), such as lamivudine, adefovir, entecavir and tenofovir, are also available for the treatment of children, although the approval age differs among them. If decompensated cirrhosis is present, NAs are the first-line antivirals. When the emergence of drug-resistant HBV variants is taken into consideration, entecavir (approved for age 2 years or older) and tenofovir (age 12 years or older), which have high genetic barriers, will play a central role in the treatment of HBV infection. However, the optimal duration of NA treatment and adverse events of long-term NA treatment remain unclear in children. In resource-constrained countries and regions, the financial burden of visiting hospitals, receiving routine blood examination and purchasing antiviral drugs is heavy. Moreover, there is no clear evidence that the induction of HBeAg seroconversion by antiviral treatment prevents the progression of liver disease to cirrhosis and hepatocellular carcinoma in children with chronic HBV infection. It is thus imperative to clarify the clinical impact of antiviral treatment in children with HBV infection.
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Affiliation(s)
- Haruki Komatsu
- Department of Pediatrics, Toho University Sakura Medical Center, Chiba, Japan
| | - Ayano Inui
- Department of Pediatric Hepatology and Gastroenterology, Eastern Yokohama Hospital, Kanagawa, Japan
| | - Tomoo Fujisawa
- Department of Pediatric Hepatology and Gastroenterology, Eastern Yokohama Hospital, Kanagawa, Japan
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37
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Clemente MG, Vajro P. An update on the strategies used for the treatment of chronic hepatitis B in children. Expert Rev Gastroenterol Hepatol 2017; 10:649-58. [PMID: 26752166 DOI: 10.1586/17474124.2016.1139450] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Chronic hepatitis B (CHB) in children shows a variety of clinical presentations, which influence its natural course and treatment options. This report provides an overview of the ongoing strategies in pediatric CHB management. Interferon-α represents the first choice of treatment in children showing HBV replication and hepatic inflammation (immune active CHB), while the recommendation is to monitor inactive/immune-tolerant children (normal transaminases and low/absent viral replication). When circumstances preclude the use of Interferon-α and in cases of compensated/decompensated cirrhosis, entecavir for children above 2 years of age or tenofovir for children above 12 years of age are the nucleos(t)ide analogues recommended by the most recent guidelines.
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Affiliation(s)
- Maria Grazia Clemente
- a Pediatric Clinic, Department of Surgical, Microsurgical and Medical Sciences , University of Sassari , Sassari , Italy
| | - Pietro Vajro
- b Pediatrics Unit, Department of Medicine and Surgery , University of Salerno , Baronissi (Salerno) , Italy
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38
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Fiorino S, Loggi E, Verucchi G, Comparcola D, Vukotic R, Pavoni M, Grandini E, Cursaro C, Maselli S, Bacchi Reggiani ML, Puggioli C, Badia L, Galli S, Viale P, Bernardi M, Andreone P. Vitamin E for the treatment of E-antigen-positive chronic hepatitis B in paediatric patients: results of a randomized phase 2 controlled study. Liver Int 2017; 37:54-61. [PMID: 27333382 DOI: 10.1111/liv.13192] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Accepted: 06/18/2016] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS The treatment of chronic hepatitis B infection (CHB) in children is still an area of great uncertainty. Vitamin E is an immunostimulating/antioxidant compound proven to be safe and effective for the treatment of adult CHB. The aim of this phase 2 controlled study was to evaluate the safety and efficacy of vitamin E for the treatment of paediatric HBeAg-positive CHB. METHODS Forty-six children were randomized in a 1:1 ratio to receive vitamin E at a dose of 15 mg/kg/day (in galenic preparation) or no treatment for 12 months and were monitored for the subsequent 12 months. Clinical, biochemical, haematological and serovirological evaluations were carried out every 3 months. RESULTS No significant side effects were associated with the vitamin E treatment. At the end of the study, anti-HBe seroconversion was obtained in 7 of 23 (30.4%) of vitamin E-treated versus 1 of 23 (4.3%) of the control patients (P = 0.05), while a virological response (≥2 log decrease in HBV-DNA from baseline) was observed in 9 of 23 (39.1%) vs. 2 of 23 (8.7%) respectively (P = 0.035). CONCLUSIONS Vitamin E administration for the treatment of paediatric CHB at the tested dosage has no significant side effects and may induce anti-HBe seroconversion. Vitamin E could represent a tool for the treatment of paediatric CHB.
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Affiliation(s)
- Sirio Fiorino
- Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy
- Unità Operativa di Medicina Interna, Ospedale Maggiore, AUSL Bologna, Bologna, Italy
| | - Elisabetta Loggi
- Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy
| | - Gabriella Verucchi
- Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy
| | - Donatella Comparcola
- Unità Operativa Malattie Epatometaboliche, Ospedale Pediatrico del Bambin Gesù, Rome, Italy
| | - Ranka Vukotic
- Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy
| | - Michele Pavoni
- Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy
| | - Elena Grandini
- Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy
| | - Carmela Cursaro
- Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy
| | - Silvia Maselli
- Unità Operativa di Farmacia Clinica, Azienda Ospedaliero Universitaria di Bologna, Policlinico Sant'Orsola-Malpighi, Bologna, Italy
| | | | - Cristina Puggioli
- Unità Operativa di Farmacia Clinica, Azienda Ospedaliero Universitaria di Bologna, Policlinico Sant'Orsola-Malpighi, Bologna, Italy
| | - Lorenzo Badia
- Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy
| | - Silvia Galli
- Unità Operativa di Microbiologia e Virologia, Azienda Ospedaliero Universitaria di Bologna, Policlinico Sant'Orsola-Malpighi, Bologna, Italy
| | - Pierluigi Viale
- Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy
| | - Mauro Bernardi
- Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy
| | - Pietro Andreone
- Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy
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Abstract
Chronic hepatitis B virus (HBV) infection has a significant public health impact. There are currently 7 approved therapies for chronic HBV, including standard and pegylated interferon (IFN)-α, and 5 nucleos(t)ide analogs (NUCs). IFN offers benefits over NUCs, including a finite duration of therapy and a higher rate of clearance of hepatitis Be antigen and surface antigen. These benefits need to be weighed against the potential adverse effects of IFN therapy. Some patients should not receive IFN because of advanced liver disease or comorbidities. This article reviews the mechanisms of action, efficacy, and clinical use of IFN therapy for HBV infection.
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Affiliation(s)
- Monica A Konerman
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Health System, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA
| | - Anna S Lok
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Health System, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA.
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40
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Abstract
The diagnosis and treatment of infection with hepatitis B and C has undergone a paradigm shift in the past decade. Although children with these infections are usually asymptomatic with normal liver function, their evaluation and management can often involve complex issues and require specialized expertise. Here the authors review the common clinical scenarios which might be encountered by a general pediatrician, explain the various tests available for diagnosis, and provide practical guidelines for managing these children.
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Affiliation(s)
- Rohan Malik
- Department of Pediatric Gastroenterology, Hepatology and Clinical Nutrition, Royal Children's Hospital, 50 Flemington Road, Parkville, 3052, Victoria, Melbourne, Australia
| | - Winita Hardikar
- Department of Pediatric Gastroenterology, Hepatology and Clinical Nutrition, Royal Children's Hospital, 50 Flemington Road, Parkville, 3052, Victoria, Melbourne, Australia.
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41
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Chang KC, Wu JF, Hsu HY, Chen HL, Ni YH, Chang MH. Entecavir Treatment in Children and Adolescents with Chronic Hepatitis B Virus Infection. Pediatr Neonatol 2016; 57:390-395. [PMID: 26806847 DOI: 10.1016/j.pedneo.2015.09.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2015] [Revised: 08/21/2015] [Accepted: 09/04/2015] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND The aim of this study was to investigate the treatment response of entecavir (ETV) in children and adolescents with chronic hepatitis B (CHB) who acquired infection perinatally or during early childhood. METHODS A total of nine treatment-naïve patients [median aged 12.2 years (range: 2.6-18.0); five girls and four boys], with hepatitis B e antigen (HBeAg) seropositive > 6 months, alanine aminotransferase (ALT) > 2 times of upper limit of normal value (30 IU/L), were enrolled for ETV therapy. They received ETV therapy with a dose of 0.015 mg/kg/d, with a maximal dose of 0.5 mg daily for at least 52 weeks. Another 27 untreated CHB patients matched for age, sex, ALT levels, and HBeAg status were recruited as the control group. A complete response at 48-52 weeks was defined as follows: (1) normalization of ALT; (2) undetectable hepatitis B virus DNA; and (3) HBeAg/anti-HBe seroconversion. All 36 patients were retrospectively reviewed for their biochemical, serological, and virologic responses. RESULTS ETV-treated patients achieved rapid ALT normalization (all before 8 months of treatment) compared with the control group (p < 0.001) and they had a greater chance of achieving undetectable HBV DNA levels at Week 52 after treatment (55.6% vs. 11.1%, p = 0.013). The cumulative incidence rates of HBeAg seroconversion were similarly high in both groups (ETV group 44% at 1 year 78% at 2 years; control group 37% at 1 year 63% at 2 years, respectively). The ETV group also had a trend of better complete response than the control group (22.2% vs. 0%, p = 0.057). None of the ETV-treated patients reported significant adverse effects. CONCLUSION Entecavir for pediatric CHB treatment is safe and shows clinical benefits in short-term biochemical and virologic responses. Further studies to determine long-term remission and drug resistance are required.
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Affiliation(s)
- Kai-Chi Chang
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan; Department of Emergency, National Taiwan University Hospital, Taipei, Taiwan
| | - Jia-Feng Wu
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Hong-Yuan Hsu
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Huey-Ling Chen
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Yen-Hsuan Ni
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Mei-Hwei Chang
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.
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Pawłowska M, Domagalski K, Smok B, Rajewski P, Wietlicka-Piszcz M, Halota W, Tretyn A. Continuous up to 4 Years Entecavir Treatment of HBV-Infected Adolescents - A Longitudinal Study in Real Life. PLoS One 2016; 11:e0163691. [PMID: 27685782 PMCID: PMC5042476 DOI: 10.1371/journal.pone.0163691] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Accepted: 09/13/2016] [Indexed: 12/27/2022] Open
Abstract
This study evaluated the long-term (up to 4 years) efficacy and safety of entecavir ETV treatment and analysed the significance of baseline and on-treatment factors in long-term ETV outcomes in adolescents with chronic hepatitis B (CHB). We determined the cumulative virological and serological outcomes of 44 adolescents with CHB receiving ETV for up to 4 years. To investigate the dynamics of HBV DNA, ALT activity and hepatitis B e antigen (HBeAg) seroconversion over time and their associations with the considered factors, generalized estimating equation (GEE) models were used. The cumulative rates of undetectable HBV DNA (<20 IU/ml) and HBeAg seroconversion after 4 years were 89.7% and 55.4%, respectively. In the study group, we showed that having undetectable HBV DNA at the 6th or 12th month of therapy predicted the achievement of a sustained response rate (SRR, defined as the loss of HBV DNA, loss of HBeAg and ALT normalization) at year 3 of ETV therapy (P = 0.048, OR = 5.83; P = 0.012; OR = 14.57, respectively). The GEE analysis indicated that of the different factors, the duration of ETV therapy had a strong impact on the achievement of virological suppression, HBeAg seroconversion and SRR in adolescents. Each month after the initiation of therapy, the odds of loss of HBV DNA increased by approximately 5% (OR = 1.05, P<0.0001), on average. Additionally, the GEE analysis revealed that adolescents with an age at infection of ≥10 years had 3 times higher odds of achieving undetectable HBV DNA than patients with a younger infection age (OR = 3.67, P = 0.028). None of the ETV-treated patients reported significant adverse effects. ETV is an effective and safe treatment option for adolescents with CHB. Undetectable HBV DNA in the 6th and/or 12th month of ETV treatment and older age at infection could predict maintained virological suppression.
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Affiliation(s)
- Małgorzata Pawłowska
- Department of Paediatric Infectious Diseases and Hepatology, Faculty of Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Krzysztof Domagalski
- Centre for Modern Interdisciplinary Technologies, Nicolaus Copernicus University, Toruń, Poland
- * E-mail:
| | - Beata Smok
- Department of Paediatric Infectious Diseases and Hepatology, Faculty of Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Paweł Rajewski
- Provincial Infectious Diseases Hospital, Bydgoszcz, Poland
| | - Magdalena Wietlicka-Piszcz
- Department of Theoretical Foundations of Biomedical Sciences and Medical Information Technology, Faculty of Pharmacy, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Waldemar Halota
- Department of Infectious Diseases and Hepatology, Faculty of Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Andrzej Tretyn
- Department of Plant Physiology and Biotechnology, Nicolaus Copernicus University, Toruń, Poland
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Man Cho S, Choe BH. Treatment strategies according to genotype for chronic hepatitis B in children. ANNALS OF TRANSLATIONAL MEDICINE 2016; 4:336. [PMID: 27761440 PMCID: PMC5066031 DOI: 10.21037/atm.2016.09.06] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Accepted: 08/19/2016] [Indexed: 01/05/2023]
Abstract
This review article was requested by editor-in-chief of this journal as 'pediatric CHB treatment' for the upcoming special issue. The main objective of chronic hepatitis B (CHB) treatment is diminishing the risk of complications related to chronic liver disease. In Asia, there are already some reports about hepatocellular carcinoma (HCC) in hepatitis B virus (HBV) infected children. The key points of treatment in children with CHB infections are selection of which patients to treat and conformation of the optimal therapy time that would reduce viral resistance. The choice of therapy is determined by the district (Western/Eastern), HBV genotype, medical accessibility, and economic state of the country. Newly developed nucleos(t)ide analogues (NAs) are potent in children with CHB. However, to improve therapeutic efficacy, physicians are recommended to follow treatment guidelines and determine the specific genotype in the CHB patient. In this article, the treatment of pediatric CHB is reviewed according to differences in genotype.
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Affiliation(s)
- Seung Man Cho
- Department of Pediatrics, Dongguk University School of Medicine, Gyeongju, Korea
| | - Byung-Ho Choe
- Department of Pediatrics, Kyungpook National University School of Medicine, Daegu, Korea
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44
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Pietrzak-Nguyen A, Piradashvili K, Fichter M, Pretsch L, Zepp F, Wurm FR, Landfester K, Gehring S. MPLA-coated hepatitis B virus surface antigen (HBsAg) nanocapsules induce vigorous T cell responses in cord blood derived human T cells. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2016; 12:2383-2394. [PMID: 27516081 DOI: 10.1016/j.nano.2016.07.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Revised: 07/18/2016] [Accepted: 07/23/2016] [Indexed: 02/06/2023]
Abstract
Chronic hepatitis B virus (HBV) infection is the most prevalent serious liver infection in the world. A frequent route of infection represents mother-to-child transmission. Efficient control of HBV replication depends on antigen-specific cellular immune response mediated by dendritic cells (DCs). Aim of the present study was to evaluate optimized adjuvant combinations, efficiently maturing monocyte-derived neonatal and adult dendritic cells (moDCs). In addition, the potential of polymeric HBsAg-nanocapsules (HBsAg-NCs) was investigated regarding up-take by moDCs and the subsequent induction of specific T cell responses in a human co-culture model. Simultaneous stimulation of moDCs with MPLA and IFNγ induced up-regulation of CD80 and HLA-DR along with vigorous secretion of IL-12p70. MPLA-coating of HBsAg-NCs promoted NCs-uptake by moDCs. Finally, MPLA-HBsAg-NCs-pulsed moDCs with IFNγ increased T cell proliferation and induced antigen-specific IFNγ release by T cells. The herein presented vaccine approach provides a rational for neonatal and therapeutic immunization strategies against HBV.
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Affiliation(s)
- Anette Pietrzak-Nguyen
- Children's Hospital, University Medical Center, Johannes-Gutenberg University, Mainz, Germany
| | | | - Michael Fichter
- Children's Hospital, University Medical Center, Johannes-Gutenberg University, Mainz, Germany
| | - Leah Pretsch
- Children's Hospital, University Medical Center, Johannes-Gutenberg University, Mainz, Germany
| | - Fred Zepp
- Children's Hospital, University Medical Center, Johannes-Gutenberg University, Mainz, Germany
| | | | | | - Stephan Gehring
- Children's Hospital, University Medical Center, Johannes-Gutenberg University, Mainz, Germany.
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45
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Iregbu KC, Nwajiobi-Princewill PI. Viral Load Pattern Among Hepatitis B Surface Antigen-positive Patients: Laboratory Perspective and Implications for Therapy. Ann Med Health Sci Res 2016; 6:95-9. [PMID: 27213092 PMCID: PMC4866374 DOI: 10.4103/2141-9248.181835] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Hepatitis B viral infection is an old medical problem with worldwide distribution. It is usually diagnosed using serologic methods. However, the decision as to which patient to treat or not remains challenging due to the poor sensitivity of serologic markers as prognostic or severity markers. Viral load (VL) determination using polymerase chain reaction techniques is a useful tool in decision-making. AIM To determine the proportion of hepatitis B-positive patients who fall into different care groups based on the Society for Gastroenterology and Hepatology in Nigeria (SOGHIN) and National Institute for Health and Care Excellence guidelines, respectively, using result of hepatitis B virus (HBV) DNA determination. MATERIALS AND METHODS This is a retrospective and descriptive study. Data from all patients sent to the medical microbiology laboratory, National Hospital Abuja over a period of 28 months (November 2012 to February 2015) for hepatitis B DNA VL determinations were analyzed using Microsoft Excel 2010 (Microsoft Corporation, Redmond, WA, USA) and IBM SPSS version 20.0 (IBM SPSS, Inc., Chicago, IL, USA). RESULTS A total 666 patients, with mean age of 33.2 years, were tested. For those whose ages were known 36.2% (100/276) were below 30 years and 63.8% (176/276) 30 years and above. Exactly 66.7% (444/666) were males and the remaining 33.3% (222/666) were females. The VL of the patients varied from 20 to 1.7 × 10(8) IU/ml, with an average of 3.5 × 10(6) IU/ml. Around 76.1% (507/666) had measurable assay levels (20 - 1.7 × 10(8) IU/ml); 10.8% (76/666) had below 20 IU/ml and 3.8% (25/666) above 1.7 × 10(8) IU/ml. About 9.3% (62/666) had no detectable HBV DNA in their samples. About 46.8% (312/666) of the patients had levels between 20 and 2 × 10(3) IU/ml; 16.4% (109/666) had between 2001 and 2 × 10(4) IU/ml while 16.7% (111/666) had VL of between 20,001 and 1.7 × 10(8) IU/ml. Males tended to have detectable and higher VLs than females (P = 0.04). CONCLUSION HBV DNA assay used in accordance with existing treatment guidelines will improve quality of care. To avoid unnecessary liver biopsy, there is a need to further fine-tune the SOGHIN guidelines.
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Affiliation(s)
- KC Iregbu
- Department of Medical Microbiology, National Hospital, Garki, Abuja, Nigeria
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46
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The Korean Association for the Study of the Liver (KASL). KASL clinical practice guidelines: management of chronic hepatitis B. Clin Mol Hepatol 2016; 22:18-75. [PMID: 27044762 PMCID: PMC4825166 DOI: 10.3350/cmh.2016.22.1.18] [Citation(s) in RCA: 150] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Accepted: 02/22/2016] [Indexed: 01/10/2023] Open
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47
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Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH. AASLD guidelines for treatment of chronic hepatitis B. Hepatology 2016; 63:261-83. [PMID: 26566064 PMCID: PMC5987259 DOI: 10.1002/hep.28156] [Citation(s) in RCA: 1568] [Impact Index Per Article: 174.2] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Accepted: 08/25/2015] [Indexed: 12/11/2022]
Affiliation(s)
| | | | - Kyong-Mi Chang
- Corporal Michael J. Crescenz VA Medical Center & University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
| | - Jessica P Hwang
- The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Maureen M Jonas
- Boston Children's Hospital, Harvard Medical School, Boston, MA
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48
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Komatsu H, Inui A. Chronic hepatitis B in children in the United States and Canada: international origins place the disease burden on children even in the era of universal vaccination. Transl Pediatr 2016; 5:1-4. [PMID: 26835398 PMCID: PMC4729037 DOI: 10.3978/j.issn.2224-4336.2015.12.08] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2015] [Accepted: 12/30/2015] [Indexed: 01/05/2023] Open
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49
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Jonas MM, Lok ASF, McMahon BJ, Brown RS, Wong JB, Ahmed AT, Farah W, Mouchli MA, Singh S, Prokop LJ, Murad MH, Mohammed K. Antiviral therapy in management of chronic hepatitis B viral infection in children: A systematic review and meta-analysis. Hepatology 2016; 63:307-18. [PMID: 26566163 DOI: 10.1002/hep.28278] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2015] [Accepted: 10/04/2015] [Indexed: 12/13/2022]
Abstract
UNLABELLED Most individuals with chronic hepatitis B viral (HBV) infection acquired the infection around the time of birth or during early childhood. We aimed to synthesize evidence regarding the effectiveness of antiviral therapy in the management of chronic HBV infection in children. We conducted a comprehensive search of multiple databases from 1988 to December 2, 2014, for studies that enrolled children (<18 years) with chronic HBV infection treated with antiviral therapy. We included observational studies and randomized controlled trials (RCTs). Two independent reviewers selected studies and extracted data. In the 14 included studies, two cohort studies showed no significant reduction in the already low risk of hepatocellular carcinoma or cirrhosis and 12 RCTs reported intermediate outcomes. In RCTs with posttreatment follow-up <12 months, antiviral therapy compared to placebo improved alanine aminotransferase normalization (risk ratio [RR] = 2.3, 95% confidence interval [CI] 1.7-3.2), hepatitis B e antigen (HBeAg) clearance/loss (RR = 2.1, 95% CI 1.5-3.1), HBV DNA suppression (RR = 2.9, 95% CI 1.8-4.6), HBeAg seroconversion (RR = 2.1, 95% CI 1.4-3.3), and hepatitis B surface antigen clearance (RR = 5.8, 95% CI 1.1-31.5). In RCTs with posttreatment follow-up ≥12 months, antiviral therapy improved cumulative HBeAg clearance/loss (RR = 1.9, 95% CI 1.7-3.1), HBeAg seroconversion (RR = 2.1, 95% CI 1.3-3.5), alanine aminotransferase normalization (RR = 1.4, 95% CI 1.1-1.7), and HBV DNA suppression (RR = 1.4, 95% CI 1.1-1.8) but not hepatitis B surface antigen clearance or seroconversion. CONCLUSION In children with chronic HBV infection, antivirals compared to no antiviral therapy improve HBV DNA suppression and frequency of alanine aminotransferase normalization and HBeAg seroconversion.
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Affiliation(s)
- Maureen M Jonas
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA
| | - Anna S F Lok
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI
| | - Brian J McMahon
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage, AK
| | - Robert S Brown
- Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY
| | - John B Wong
- Department of Medicine, Tufts Medical Center, Boston, MA
| | - Ahmed T Ahmed
- Evidence-Based Practice Research Program, Mayo Clinic, Rochester, MN.,Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN
| | - Wigdan Farah
- Evidence-Based Practice Research Program, Mayo Clinic, Rochester, MN.,Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN
| | | | - Siddharth Singh
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | | | - Mohammad Hassan Murad
- Evidence-Based Practice Research Program, Mayo Clinic, Rochester, MN.,Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN.,Division of Preventive, Occupational and Aerospace Medicine, Mayo Clinic, Rochester, MN
| | - Khaled Mohammed
- Evidence-Based Practice Research Program, Mayo Clinic, Rochester, MN.,Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN.,Division of Preventive, Occupational and Aerospace Medicine, Mayo Clinic, Rochester, MN
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50
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McMahon BJ. Two Key Components to Address Chronic Hepatitis B in Children: Detection and Prevention. J Pediatr 2015; 167:1186-7. [PMID: 26409308 DOI: 10.1016/j.jpeds.2015.09.015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2015] [Accepted: 09/03/2015] [Indexed: 01/11/2023]
Affiliation(s)
- Brian J McMahon
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage, Alaska.
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