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Stinco M, Rubino C, Trapani S, Indolfi G. Treatment of hepatitis B virus infection in children and adolescents. World J Gastroenterol 2021; 27:6053-6063. [PMID: 34629819 PMCID: PMC8476329 DOI: 10.3748/wjg.v27.i36.6053] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Revised: 06/30/2021] [Accepted: 08/13/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is one of the main causes of morbidity and mortality worldwide. Most children acquire the infection perinatally or during early childhood and develop a chronic hepatitis characterized by a high viral replication and a low-inflammation phase of infection, with normal or only slightly raised aminotransferases. Although a conservative approach in children is usually recommended, different therapies exist and different therapeutic approaches are possible. The main goals of antiviral treatment for children with chronic HBV infection are to suppress viral replication and to warn the disease progression to cirrhosis and hepatocellular carcinoma, although these complications are rare in children. Both United States Food and Drug Administration (US-FDA) and European Medicines Agency (EMA) have approved interferon alfa-2b for children aged 1 year and older, pegylated interferon alfa-2a and lamivudine for children aged 3 years and older, entecavir for use in children aged 2 years and older, and adefovir for use in those 12 years of age and older. Tenofovir disoproxil fumarate is approved by EMA for children aged 2 years and older and by US-FDA for treatment in children aged 12 years and older. Finally, EMA has approved the use of tenofovir alafenamide for treatment of children aged 12 years and older or for children weighing more than 35 kg independent of age. This narrative review will provide the framework for summarizing indications to antiviral therapy in the management of chronic HBV infection in children and adolescents.
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Affiliation(s)
- Mariangela Stinco
- Department of Health Sciences, Pediatric Section, Meyer Children’s University Hospital, Florence 50139, Italy
| | - Chiara Rubino
- Department of Health Sciences, Pediatric Section, Meyer Children’s University Hospital, Florence 50139, Italy
| | - Sandra Trapani
- Department of Health Sciences, Pediatric Section, Meyer Children’s University Hospital, Florence 50139, Italy
| | - Giuseppe Indolfi
- Department Neurofarba, University of Florence and Meyer Children’s University Hospital, Florence 50139, Italy
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Cornberg M, Sandmann L, Protzer U, Niederau C, Tacke F, Berg T, Glebe D, Jilg W, Wedemeyer H, Wirth S, Höner Zu Siederdissen C, Lynen-Jansen P, van Leeuwen P, Petersen J. S3-Leitlinie der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) zur Prophylaxe, Diagnostik und Therapie der Hepatitis-B-Virusinfektion – (AWMF-Register-Nr. 021-11). ZEITSCHRIFT FUR GASTROENTEROLOGIE 2021; 59:691-776. [PMID: 34255317 DOI: 10.1055/a-1498-2512] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Markus Cornberg
- Deutsches Zentrum für Infektionsforschung (DZIF), Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover; Centre for individualised infection Medicine (CiiM), Hannover.,Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover
| | - Lisa Sandmann
- Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover
| | - Ulrike Protzer
- Institut für Virologie, Technische Universität München/Helmholtz Zentrum München, München
| | | | - Frank Tacke
- Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Charité Universitätsmedizin Berlin, Berlin
| | - Thomas Berg
- Klinik und Poliklinik für Gastroenterologie und Rheumatologie, Universitätsklinikum Leipzig, Leipzig
| | - Dieter Glebe
- Institut für Medizinische Virologie, Nationales Referenzzentrum für Hepatitis-B-Viren und Hepatitis-D-Viren, Justus-Liebig-Universität Gießen, Gießen
| | - Wolfgang Jilg
- Institut für Medizinische Mikrobiologie und Hygiene, Universität Regensberg, Regensburg
| | - Heiner Wedemeyer
- Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover
| | - Stefan Wirth
- Zentrum für Kinder- und Jugendmedizin, Helios Universitätsklinikum Wuppertal, Wuppertal
| | | | - Petra Lynen-Jansen
- Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS), Berlin
| | - Pia van Leeuwen
- Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS), Berlin
| | - Jörg Petersen
- IFI Institut für Interdisziplinäre Medizin an der Asklepios Klinik St. Georg, Hamburg
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3
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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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Abstract
Introduction: Universal infant hepatitis B virus (HBV) vaccination program has reduced HBV infection dramatically in vaccinated young generations. Management of chronically infected children is still challenging concerning high viral load with mostly mild diseases, yet with a nonnegligible proportion of advanced diseases, and long-term effect of antivirals. However, with more potent antivirals approved for pediatric patients, to start antivirals earlier in eligible patients may benefit their outcomes. This review aimed to update the current management of chronic hepatitis B in children.Areas covered: This review covered the natural history of chronic HBV infection, management of chronic hepatitis B in children from the past to the present, current consensus on the treatment of chronic hepatitis B in children, controversies in cessation of oral antivirals, and management of special populations such as pregnancy and co-infections.Expert opinions: Without contraindication, peginterferon is recommended for immune-active children ≥ 3 years old. For those intolerant, decompensating or preferring oral therapy, first-line Nucleos(t)ide analogs (NUC), Entecavir or Tenofovir, may be applied. For immune-tolerant or inactive carriers, close monitoring is crucial. When to stop NUCs and novel therapies for HBV cure await further research.
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Affiliation(s)
- Ming-Wei Lai
- Division of Pediatric Gastroenterology, Department of Pediatrics, Chang Gung Memorial Hospital, Linkou, Taiwan.,Liver Research Center, Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Linkou, Taiwan.,Molecular Medicine Research Center, College of Medicine, Chang Gung University, Taoyuan City, Taiwan
| | - Mei-Hwei Chang
- Department of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
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Hsu HY, Chang MH. Hepatitis B Virus Infection and the Progress toward its Elimination. J Pediatr 2019; 205:12-20. [PMID: 30244984 DOI: 10.1016/j.jpeds.2018.08.017] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 07/20/2018] [Accepted: 08/09/2018] [Indexed: 02/07/2023]
Affiliation(s)
- Hong-Yuan Hsu
- Department of Pediatrics, National Taiwan University Children's Hospital and College of Medicine, National Taiwan University, Taipei; Graduate Institute of Medical Education and Bioethics, College of Medicine, National Taiwan University, Taipei, 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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6
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Arora A, Anand AC, Kumar A, Singh SP, Aggarwal R, Dhiman RK, Aggarwal S, Alam S, Bhaumik P, Dixit VK, Goel A, Goswami B, Kumar A, Kumar M, Madan K, Murugan N, Nagral A, Puri AS, Rao PN, Saraf N, Saraswat VA, Sehgal S, Sharma P, Shenoy KT, Wadhawan M. INASL Guidelines on Management of Hepatitis B Virus Infection in Patients receiving Chemotherapy, Biologicals, Immunosupressants, or Corticosteroids. J Clin Exp Hepatol 2018; 8:403-431. [PMID: 30568345 PMCID: PMC6286881 DOI: 10.1016/j.jceh.2018.06.010] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Accepted: 06/10/2018] [Indexed: 02/09/2023] Open
Abstract
Hepatitis B Virus (HBV) reactivation in patients receiving chemotherapy, biologicals, immunosupressants, or corticosteroids is emerging to be an important cause of morbidity and mortality in patients with current or prior exposure to HBV infection. These patients suffer a dual onslaught of illness: one from the primary disease for which they are receiving the culprit drug that led to HBV reactivation, and the other from HBV reactivation itself. The HBV reactivation not only leads to a compromised liver function, which may culminate into hepatic failure; it also adversely impacts the treatment outcome of the primary illness. Hence, identification of patients at risk of reactivation before starting these drugs, and starting treatment aimed at prevention of HBV reactivation is the best strategy of managing these patients. There are no Indian guidelines on management of HBV infection in patients receiving chemotherapy, biologicals, immunosupressants, or corticosteroids for the treatment of rheumatologic conditions, malignancies, inflammatory bowel disease, dermatologic conditions, or solid-organ or bone marrow transplantation. The Indian National Association for Study of the Liver (INASL) had set up a taskforce on HBV in 2016, with a mandate to develop consensus guidelines for management of various aspects of HBV infection, relevant to India. In 2017 the taskforce had published the first INASL guidelines on management of HBV infection in India. In the present guidelines, which are in continuation with the previous guidelines, the issues on management of HBV infection in patients receiving chemotherapy, biologicals, immunosupressants, or corticosteroids are addressed.
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Key Words
- ACLF, Acute-on-Chronic Liver Failure
- AFP, Alphafetoprotein
- ALT, Alanine Aminotransferase
- Anti-HBc, Antibodies to Hepatitis B Core Antigen
- Anti-HBs, Antibodies to Hepatitis B Surface Antigen
- CHB, Chronic Hepatitis B
- CHOP, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone
- CKD, Chronic Kidney Disease
- DILI, Drug-Induced Liver Injury
- DNA, Deoxyribonucleic Acid
- ETV, Entecavir
- GRADE, Grading of Recommendations, Assessment, Development and Evaluation
- HAV, Hepatitis A Virus
- HBIG, Hepatitis B Immune Globulin
- HBV DNA, Hepatitis B Virus Deoxyribonucleic Acid
- HBV, Hepatitis B Virus
- HBcAg, Hepatitis B Core Antigen
- HBeAg, Hepatitis B Envelope Antigen
- HBsAg, Hepatitis B Surface Antigen
- HDV, Hepatitis D Virus
- HEV, Hepatitis E Virus
- HLA, Human Leukocyte Antigen Class I
- INASL, Indian National Association for Study of the Liver
- LAM, Lamivudine
- NAs, Nucleos(t)ide Analogs
- NHL, Non-Hodgkin’s Lymphoma
- NK, Natural Killer
- PegIFN-α, Pegylated Interferon Alpha
- RA, Rheumatoid Arthritis
- SLE, Systemic Lupus Erythematosus
- TAF, Tenofovir Alafenamide
- TDF, Tenofovir Disoproxil Fumarate
- TLC, Total Leucocyte Count
- ULN, Upper Limit of Normal
- cancer
- cccDNA, Covalently Closed Circular Deoxyribonucleic Acid
- chemotherapy
- hepatitis B
- immunosupressants
- liver failure
- rcDNA, Relaxed-Circular Deoxyribonucleic Acid
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Affiliation(s)
- Anil Arora
- Institute of Liver Gastroenterology & Pancreatico Biliary Sciences, Sir Ganga Ram Hospital, New Delhi, India
| | | | - Ashish Kumar
- Institute of Liver Gastroenterology & Pancreatico Biliary Sciences, Sir Ganga Ram Hospital, New Delhi, India
| | - Shivaram P. Singh
- Department of Gastroenterology, S.C.B. Medical College, Cuttack, India
| | - Rakesh Aggarwal
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Radha K. Dhiman
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Shyam Aggarwal
- Department of Medical Oncology, Sir Ganga Ram Hospital, New Delhi, India
| | - Seema Alam
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Pradeep Bhaumik
- Department of Medicine, Agartala Govt. Medical College (AGMC), Agartala, India
| | - Vinod K. Dixit
- Department of Gastroenterology, Institute of Medical Sciences Banaras Hindu University, Varanasi, India
| | - Ashish Goel
- Department of Hepatology, Christian Medical College, Vellore, India
| | - Bhabadev Goswami
- Department of Gastoenterology, Gauhati Medical College, Guwahati, India
| | - Ashok Kumar
- Department of Rheumatology, Fortis Flt Lt Rajan Dhall Hospital, New Delhi, India
| | - Manoj Kumar
- Department of Hepatology and Liver Transplantation, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Kaushal Madan
- Gastroenterology & Hepatology, Max Smart Super Speciality Hospital, New Delhi, India
| | | | - Aabha Nagral
- Department of Gastroenterology, Jaslok and Apollo Hospitals, Mumbai, India
| | - Amarender S. Puri
- Department of Gastroenterology, G.B. Pant Hospital, New Delhi, India
| | - Padaki N. Rao
- Hepatology, Asian Institute Of Gastroenterology, Hyderabad, India
| | - Neeraj Saraf
- Hepatology, Medanta - The Medicity, Gurugram, India
| | - Vivek A. Saraswat
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Sanjeev Sehgal
- Institute of Liver Transplantation and Regenerative Medicine, Medanta - The Medicity, Gurugram, India
| | - Praveen Sharma
- Institute of Liver Gastroenterology & Pancreatico Biliary Sciences, Sir Ganga Ram Hospital, New Delhi, India
| | | | - Manav Wadhawan
- Hepatology & Liver Transplant (Medicine), Fortis Escorts Liver & Digestive Diseases Institute (FELDI), Fortis Escorts Hospital, Delhi, India
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7
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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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8
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9
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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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10
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Sarin SK, Kumar M, Lau GK, Abbas Z, Chan HLY, Chen CJ, Chen DS, Chen HL, Chen PJ, Chien RN, Dokmeci AK, Gane E, Hou JL, Jafri W, Jia J, Kim JH, Lai CL, Lee HC, Lim SG, Liu CJ, Locarnini S, Al Mahtab M, Mohamed R, Omata M, Park J, Piratvisuth T, Sharma BC, Sollano J, Wang FS, Wei L, Yuen MF, Zheng SS, Kao JH. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int 2016; 10:1-98. [PMID: 26563120 PMCID: PMC4722087 DOI: 10.1007/s12072-015-9675-4] [Citation(s) in RCA: 1915] [Impact Index Per Article: 212.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Accepted: 09/14/2015] [Indexed: 02/06/2023]
Abstract
Worldwide, some 240 million people have chronic hepatitis B virus (HBV), with the highest rates of infection in Africa and Asia. Our understanding of the natural history of HBV infection and the potential for therapy of the resultant disease is continuously improving. New data have become available since the previous APASL guidelines for management of HBV infection were published in 2012. The objective of this manuscript is to update the recommendations for the optimal management of chronic HBV infection. The 2015 guidelines were developed by a panel of Asian experts chosen by the APASL. The clinical practice guidelines are based on evidence from existing publications or, if evidence was unavailable, on the experts' personal experience and opinion after deliberations. Manuscripts and abstracts of important meetings published through January 2015 have been evaluated. This guideline covers the full spectrum of care of patients infected with hepatitis B, including new terminology, natural history, screening, vaccination, counseling, diagnosis, assessment of the stage of liver disease, the indications, timing, choice and duration of single or combination of antiviral drugs, screening for HCC, management in special situations like childhood, pregnancy, coinfections, renal impairment and pre- and post-liver transplant, and policy guidelines. However, areas of uncertainty still exist, and clinicians, patients, and public health authorities must therefore continue to make choices on the basis of the evolving evidence. The final clinical practice guidelines and recommendations are presented here, along with the relevant background information.
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Affiliation(s)
- S K Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India.
| | - M Kumar
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - G K Lau
- Division of Gastroenterology and Hepatology, Humanity and Health Medical Centre, Hong Kong SAR, China
- The Institute of Translational Hepatology, Beijing, China
| | - Z Abbas
- Department of Hepatogastroenterlogy, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
| | - H L Y Chan
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
| | - C J Chen
- Genomics Research Center, Academia Sinica, National Taiwan University, Taipei, Taiwan
| | - D S Chen
- Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - H L Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - P J Chen
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - R N Chien
- Liver Research Unit, Chang Gung Memorial Hospital and University, Chilung, Taiwan
| | - A K Dokmeci
- Department of Gastroenterology, Ankara University School of Medicine, Ankara, Turkey
| | - Ed Gane
- New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand
| | - J L Hou
- Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Guangzhou, China
| | - W Jafri
- Department of Medicine, Aga Khan University, Karachi, Pakistan
| | - J Jia
- Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | | | - C L Lai
- Department of Medicine, University of Hong Kong, Hong Kong, China
| | - H C Lee
- Internal Medicine Asan Medical Center, Seoul, Korea
| | - S G Lim
- Division of Gastroenterology and Hepatology, National University Health System, Singapore, Singapore
| | - C J Liu
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - S Locarnini
- Research and Molecular Development, Victorian Infectious Diseases Reference Laboratory, Melbourne, Australia
| | - M Al Mahtab
- Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - R Mohamed
- Department of Medicine, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia
| | - M Omata
- Yamanashi Hospitals (Central and Kita) Organization, 1-1-1 Fujimi, Kofu-shi, Yamanashi, 400-8506, Japan
| | - J Park
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - T Piratvisuth
- NKC Institute of Gastroenterology and Hepatology, Prince of Songkla University, Songkhla, Thailand
| | - B C Sharma
- Department of Gastroenterology, G.B. Pant Hospital, New Delhi, India
| | - J Sollano
- Department of Medicine, University of Santo Tomas, Manila, Philippines
| | - F S Wang
- Treatment and Research Center for Infectious Diseases, Beijing 302 Hospital, Beijing, China
| | - L Wei
- Peking University Hepatology Institute, Beijing, China
| | - M F Yuen
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Hong Kong, Pofulam, Hong Kong
| | - S S Zheng
- Department of Hepatobiliary and Pancreatic Surgery, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang Province, China
| | - J H Kao
- Graduate Institute of Clinical Medicine and Hepatitis Research Center, National Taiwan University College of Medicine, National Taiwan University Hospital, Taipei, Taiwan
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11
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Gonzalez D, Paul IM, Benjamin DK, Cohen-Wolkowiez M. Advances in pediatric pharmacology, therapeutics, and toxicology. Adv Pediatr 2014; 61:7-31. [PMID: 25037123 PMCID: PMC4120955 DOI: 10.1016/j.yapd.2014.03.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
In the United States, passage of the FDASIA legislation made BPCA and PREA permanent, no longer requiring reauthorization every 5 years. This landmark legislation also stressed the importance of performing clinical trials in neonates when appropriate. In Europe the Pediatric Regulation, which went into effect in early 2007, also provides a framework for expanding pediatric clinical research. Although much work remains, as a result of greater regulatory guidance more pediatric data are reaching product labels.
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Affiliation(s)
- Daniel Gonzalez
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, 301 Pharmacy Lane, Chapel Hill, NC 27599, USA; Duke Clinical Research Institute, Duke University Medical Center, 2400 Pratt Street, Durham, NC 27705, USA
| | - Ian M Paul
- Department of Pediatrics, College of Medicine, Penn State University, 500 University Drive, HS83, Hershey, PA 17033, USA; Department of Public Health Sciences, College of Medicine, Penn State University, 500 University Drive, HS83, Hershey, PA 17033, USA
| | - Daniel K Benjamin
- Duke Clinical Research Institute, Duke University Medical Center, 2400 Pratt Street, Durham, NC 27705, USA; Department of Pediatrics, College of Medicine, Duke University, T901/Children's Health Center, Durham, NC 27705, USA
| | - Michael Cohen-Wolkowiez
- Duke Clinical Research Institute, Duke University Medical Center, 2400 Pratt Street, Durham, NC 27705, USA; Department of Pediatrics, College of Medicine, Duke University, T901/Children's Health Center, Durham, NC 27705, USA.
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12
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Chen EQ, Shi Y, Wu DB, Tang H. Liquid oral suspension adefovir dipivoxil (GS-02-526): an update on treatments for hepatitis B infection. Expert Rev Anti Infect Ther 2014; 12:919-928. [PMID: 24927815 DOI: 10.1586/14787210.2014.928588] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Though the global epidemiology of hepatitis B virus infection has declined due to effective immunization, chronic hepatitis B (CHB) remains a serious public health problem and there is still a need for more treatment options that are efficient, safe and simple for different kinds of CHB patients. Adefovir dipivoxil (ADV) liquid suspension (GS-02-526), as a new form of oral ADV, not only has competent antiviral efficacy, but is also more convenient for patients with swallowing difficulties or patients with impaired renal function requiring dosage adjustment. The clinical data evaluating the safety, tolerability and antiviral activity of liquid suspension of ADV as well as its tablet are summarized in this article. The availability of liquid oral suspension of ADV would allow more patients to receive timely and reasonable antiviral treatments.
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Affiliation(s)
- En-Qiang Chen
- Center of Infectious Diseases, West China Hospital of Sichuan University, No. 37 Guo Xue Xiang, Chengdu 610041, China
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13
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Della Corte C, Nobili V, Comparcola D, Cainelli F, Vento S. Management of chronic hepatitis B in children: an unresolved issue. J Gastroenterol Hepatol 2014; 29:912-919. [PMID: 24863185 DOI: 10.1111/jgh.12550] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/04/2013] [Indexed: 12/11/2022]
Abstract
Although a rather benign course of chronic hepatitis B virus (HBV) infection during childhood has been described, 3-5% and 0.01-0.03% of chronic carriers develop cirrhosis or hepatocellular carcinoma before adulthood. Considering the whole lifetime, the risk of hepatocellular carcinoma rises to 9-24% and the incidence of cirrhosis to 2-3% per year. The aim of this article is to review the current knowledge regarding the natural history and treatment of chronic hepatitis B in children and to focus on critical aspects and unresolved questions in the management of childhood HBV infection. A literature search was carried out on MEDLINE, EMBASE, and Web of Science for articles published in English in peer-reviewed journals from January 1980 to February 2013. The search terms used included "Hepatitis B virus infection," "children," "HBV," "interferon," "lamivudine," "adefovir," "entecavir," and "tenofovir." Articles resulting from these searches and relevant references cited in the articles retrieved were reviewed. The current goals of therapy are to suppress viral replication, reduce liver inflammation, and reverse liver fibrosis. Therapeutic options for children are currently limited, and the risk for viral resistance to current and future therapies is a particular concern. Based on the data available at this time, it is the consensus of the panel that it is not appropriate to treat children in the immune-tolerant phase or in the inactive carrier state. For children in the immune-active or reactivation phases, liver histology can help guide treatment decisions. Outside of clinical trials, interferon is the agent of choice in most cases; currently, available nucleoside analogs are secondary therapies.
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Affiliation(s)
- Claudia Della Corte
- HepatoMetabolic Diseases Unit, Children's Hospital Bambino Gesù, Rome, Italy
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14
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Ramsay ID, Lestner JM, O’Sullivan CP, Cruz AL, Li HK, Barker CI. Antiviral Drugs. SIDE EFFECTS OF DRUGS ANNUAL 2014:401-443. [DOI: 10.1016/b978-0-444-63407-8.00029-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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15
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Sokal EM, Paganelli M, Wirth S, Socha P, Vajro P, Lacaille F, Kelly D, Mieli-Vergani G. Management of chronic hepatitis B in childhood: ESPGHAN clinical practice guidelines: consensus of an expert panel on behalf of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition. J Hepatol 2013; 59:814-29. [PMID: 23707367 DOI: 10.1016/j.jhep.2013.05.016] [Citation(s) in RCA: 139] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2012] [Revised: 05/09/2013] [Accepted: 05/13/2013] [Indexed: 02/06/2023]
Affiliation(s)
- Etienne M Sokal
- Pediatric Gastroenterology & Hepatology, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain and Cliniques Universitaires Saint Luc, Brussels, Belgium.
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16
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Healy SA, Gupta S, Melvin AJ. HIV/HBV coinfection in children and antiviral therapy. Expert Rev Anti Infect Ther 2013; 11:251-63. [PMID: 23458766 DOI: 10.1586/eri.13.2] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Small cohort studies from countries where both HIV and HBV are endemic demonstrate prevalence rates of chronic hepatitis B in HIV-infected children of between 1 and 49%. While data on coinfected children are limited, results from studies in adults with HIV/HBV coinfection raise the concern that coinfected children may be at a higher risk of liver disease, hepatic fibrosis and cirrhosis. With the scale-up of combination antiretroviral therapy worldwide, of which lamivudine is included in most first-line regimens, coinfected children treated with lamivudine risk development of HBV resistance mutations. This article summarizes the current literature relevant to HIV/HBV coinfection in children, the options for treatment and highlights priorities for future research.
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Affiliation(s)
- Sara A Healy
- Seattle Biomedical Research Institute, Seattle, WA, USA
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17
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Abstract
Hepatitis B virus (HBV) infection is a worldwide health problem, which can cause acute liver failure, acute hepatitis, chronic hepatitis, liver cirrhosis, and liver cancer. It is most prevalent in Asia, Africa, Southern Europe, and Latin America. Approximately 2 billion people in the world have been infected by HBV, with more than 350 million as chronic carriers. Implementation of the HBV vaccine led to a significant reduction in viral transmission in many areas of the world; however, it remains highly endemic in many developing countries. The main source of infection in childhood is via perinatal transmission or horizontal transmission during preschool years. The majority of children with chronic hepatitis B (CHB) infection are asymptomatic; however, they may develop progressive disease and are at increased risk of advanced liver disease or liver cancer before their third decade. All children with chronic HBV infection should be regularly monitored for disease progression. The goal of therapy for children with CHB is to arrest disease progression and reduce the risk of developing cirrhosis and cancer. The available medications have a low success rate because of immunotolerance in the child and the development of viral resistance to standard therapy. Therefore, case selection and determination of the best time to commence treatment are essential to increase treatment efficacy and reduce the risk of viral resistance.
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Affiliation(s)
- Mona Abdel-Hady
- Liver Unit, Birmingham Children's Hospital, Steelhouse Lane, Birmingham, B4 6NH, UK.
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18
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Xi ZF, Xia Q, Zhang JJ, Chen XS, Han LZ, Zhu JJ, Wang SY, Qiu DK. De novo hepatitis B virus infection from anti-HBc-positive donors in pediatric living donor liver transplantation. J Dig Dis 2013; 14:439-45. [PMID: 23638710 DOI: 10.1111/1751-2980.12066] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
OBJECTIVE The aim of this study was to analyze the incidence and risk factors of de novo hepatitis B virus (HBV) infection from hepatitis B core antibody (anti-HBc)-positive donors in pediatric living donor liver transplantation (LDLT). METHODS We retrospectively analyzed 46 recipients without pre-liver transplantation (LT) HBV infection evidence who underwent LDLT from October 2006 to May 2011 in our center. HBV markers, including hepatitis B surface antigen (HBsAg) and antibody (anti-HBs), anti-HBc, hepatitis B e antigen (HBeAg) and antibody (anti-HBe) were determined in both donors and recipients before LT and in recipients after LT. HBV DNA titer was measured if the recipients were strongly suspected of de novo HBV infection. RESULTS Without prophylaxis, de novo HBV infection occurred in 11 of 46 recipients (23.9%) 6-36 months after LT. All 11 patients received grafts from anti-HBc-positive donors. The donors' baseline status and the characteristics of recipients at the time of transplantation were not associated with the acquisition of de novo hepatitis B infection. The overall 2-year survival rate of patients from anti-HBc-positive donors was 84.2%. Two de novo HBV-infected patients who had YMDD mutation were given adefovir combined with lamivudine, and their liver function gradually improved during the follow-up period. CONCLUSIONS Anti-HBc-positive donors can significantly increase the incidence of de novo HBV infection in HBsAg-negative recipients. Administration with adefovir in patients who are resistant to lamivudine seems to be an effective and safe way for de novo HBV infection.
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Affiliation(s)
- Zhi Feng Xi
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
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19
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Abstract
HBV and HCV are the predominant causes of chronic viral hepatitis in children and adults. The main purposes of the present review are to provide the reader with a comprehensive overview of the currently available therapies for chronic hepatitis B and C in children and to critically review the current guidelines and indications for treatment provided by the major international societies and by the consensus of expert panels. Overall, a conservative approach is generally warranted in children with chronic hepatitis B. For HCV, the high effectiveness of pegylated interferon and ribavirin in children with genotype 2 or 3 chronic infection supports the decision to treat. For genotype 1 infection the encouraging results of the use of direct antiviral agents in adults suggest a more conservative approach.
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Affiliation(s)
- Giuseppe Indolfi
- Pediatric & Liver Unit, Meyer Children’s University Hospital of Florence, Viale Pieraccini 34, Firenze, Italy, I-50134
| | - Alessandro Nesi
- Pediatric & Liver Unit, Meyer Children’s University Hospital of Florence, Viale Pieraccini 34, Firenze, Italy, I-50134
| | - Massimo Resti
- Pediatric & Liver Unit, Meyer Children’s University Hospital of Florence, Viale Pieraccini 34, Firenze, Italy, I-50134
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