Acute Exacerbation of Chronic Hepatitis B: Volume 2. Diagnosis and Management [1st ed.] 978-94-024-1601-5;978-94-024-1603-9

Table of contents :
Front Matter ....Pages i-xxiii
Clinical Manifestations and Laboratory Tests of AECHB and Severe Hepatitis (Liver Failure) (Liang Peng, Zhi-Liang Gao, Yu-Ming Wang, Deng-Ming He, Jing-Ming Zhao, Xue-Fan Bai et al.)....Pages 1-89
Main Complications of AECHB and Severe Hepatitis B (Liver Failure) (Jian-Xin Song, Lin Zhu, Chuan-Long Zhu, Jin-Hua Hu, Zi-Jian Sun, Xiang Xu et al.)....Pages 91-226
Early Prognostic Predictive System of AECHB and the Diagnosis of Severe Hepatitis B (Liver Failure) (Zhi Chen, Qin Ning, Guang Chen)....Pages 227-271
Treatment of AECHB and Severe Hepatitis (Liver Failure) (Yu-Ming Wang, Ke Li, Xiao-Guang Dou, Han Bai, Xi-Ping Zhao, Xiong Ma et al.)....Pages 273-370
Antiviral Therapy for AECHB and Severe Hepatitis B (Liver Failure) (Qin Ning, Ting Wu, Hai-Bin Su, Ke Ma, Jun-Ying Qi, Ming Ni et al.)....Pages 371-455
Prognosis, Prevention and Research Prospects of Progression to Severe Hepatitis B (Liver Failure) (Yu-Ming Wang, Dao-Feng Yang, Ming Wang, Nazia Selzner, Kaveh Farrokhi, Andrzej Chruscinski et al.)....Pages 457-497
Correction to: Acute Exacerbation of Chronic Hepatitis B (Qin Ning)....Pages C1-C1

Citation preview

Acute Exacerbation of Chronic Hepatitis B Volume 2. Diagnosis and Management Qin Ning Editor

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Acute Exacerbation of Chronic Hepatitis B

Qin Ning Editor

Acute Exacerbation of Chronic Hepatitis B Volume 2. Diagnosis and Management

Editor Qin Ning Department of Infectious Disease Tongji Hospital Wuhan, China

ISBN 978-94-024-1601-5    ISBN 978-94-024-1603-9 (eBook) https://doi.org/10.1007/978-94-024-1603-9 Library of Congress Control Number: 2019930050 © Springer Nature B.V. and Huazhong University of Science and Technology Press 2019 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature B.V. The registered company address is: Van Godewijckstraat 30, 3311 GX Dordrecht, The Netherlands

My dedications go to the intelligent, committed ones Wei Che and Wen Yu who served in the editorial process. A special thanks to Dr. Dong Xu, who helped to collect manuscripts in a timely fashion from all parts of the world. My dedications to all my teachers and my mentors Dr. Yongsui Dong and Dr. Gary Levy. I would like to dedicate this book to my family for their love, patience, and support. To my parents Dihua and Jinping who have stood by me through thick and thin. To my children Jianing (Jenny) and Fengning (Fred), adorable individuals who know that knowledge is no substitute for wisdom. To my husband Xiaoping for that I know you are always with me near and far, and for your constant support of my professional endeavors. To my sisters Qiao, Yuan, and Huan for your understandings and encouragements. To all my students and my secretary Ms. Jinshang Hu, you are part of my life and family.

Foreword

Acute-on-chronic liver failure (ACLF) secondary to hepatitis B virus infection is now recognized as an important worldwide life-threatening disease with a high mortality. The work described in this book by experts in the field provides important information to the reader on its pathogenesis, clinical manifestations and current and future management strategies. The work provides important new advances in the science of HBV replication and the host response. With major advances in our understanding of the virology and immunology of HBV infection, this book gives reason for cautious optimism that we will soon be able to provide exciting new therapies for this disorder. To date, with the exception of liver replacement therapy (transplantation), there are few therapeutic options for patients who develop ACLF secondary to HBV. However, advances in diagnosis as well as management strategies including introduction of antiviral agents and inhibitors of pro-inflammatory cytokines offer the hope of better short- and long-term outcomes. The advances in the basic science of ACLF and the development of small animal models outlined in this book give hope that new therapeutic approaches will lead to the control or eradication of HBV and amelioration of inflammatory disease lessening the need for liver transplantation. The work described in this book strongly supports that clinical research in ACLF should build on the findings of basic science research and be directed to carefully controlled studies with well-characterized cohorts of patients so that we can evaluate the potential of new therapeutic approaches. The use of exciting new approaches detailed here will not only provide important new therapeutics but also insights into the mechanism of disease. The findings described in this book strongly support that we are approaching an exciting new era for therapy for patients with ACLF. Toronto, ON

Gary Levy

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Preface

It is now recognized that as a consequence of chronic HBV infection, many patients with or without established cirrhosis will develop acute decompensation and multi-­ organ failure, a syndrome known as acute-on-chronic liver failure (ACLF). Once patients develop ACLF, they are at high risk of death. A number of triggers including reactivation of HBV, coinfection of hepatitis A or E virus, onset of bacterial infection, gastrointestinal bleeding and development of renal dysfunction can precipitate the development of ACLF in patients who have been previously stable. ACLF is prevalent in Asia where many patients have incubative chronic hepatitis B virus (HBV) infection. For the past decade, with an increasing understanding of the disease mechanisms and improved general internal medications, the overall mortality has significantly decreased due to HBV infection-related ACLF (HBV-ACLF) in Chinese patients. Here we have assembled a group of hepatologists and scientists from academic hospitals and universities to explore the current understanding of the clinical, genetic, virologic and immunologic factors that contribute to ACLF. In this book of 12 chapters, we have explored the current state of knowledge of HBV infection with a specific focus on the natural history and the clinical course to define important host and viral factors to the development of ACLF, sharing our profound experience and clinical procedures in early diagnosis and treatment of HBV-ACLF patients and its complications. All together about 2649 references have been cited, of which 754 were since 2012. At the beginning of the book, there is a complete table of contents, which together with the general index makes it possible for the reader to find specific topics easily. In each chapter, there is an abstract for the reader to gain a quick information of the chapter. We have also used 55 coloured figures to make the illustrations even more visual. We enlisted the helpful advice of friends, colleagues and senior experts to supplement or confirm our own interpretations. The contacts arising from these discussions have been immensely benignant to me. Here my special thanks to Prof. Gary Levy, Prof. Didier Samuel, Prof. Gyongyi Szabo, Prof. Lanjuan Li, Prof. Zhimeng Lu, Prof. Shiv Kumar Sarin, Prof. Stephen Locarnini, Prof. Xinhua Weng, Prof. Yuquan Wei and Prof. Hui Zhuang.

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Preface

Finally I should express my gratitude to the employees at HUST Press and Springer Publishing House (Mr. James Hu) for their professional help in completing this book, especially to Ms. Lian-Di Wang, senior editor, and Mr. Wei Che, projector manager, who gave their kind support at all times. Wuhan, China

Qin Ning

Acknowledgements

We would like to thank the consultants, Editorial Committee and other staff members who have contributed to the compilation of the book “Acute Exacerbation of Chronic Hepatitis B (Chinese Version)”. Consultant (In Alphabetic Order) Yu-Mei Wen Ling-Xia Zhang Editorial Board Member (In Alphabetic Order) Cheng-Wei Chen Hong-Song Chen Xin-Wen Chen Jun Cheng Zhong-Ping Duan Xue-Gong Fan Jin-Lin Hou Ji-Dong Jia Xiao-Hui Miao Ji-Fang Sheng Guang-Feng Shi De-Ming Tan De-Ying Tian Mo-Bin Wan Gui-Qiang Wang Lai Wei Qing Xie Sheng-Long Ye Xin-Xin Zhang

Fudan University Shanghai Medical College 302 Military Hospital of China 85TH Hospital of People’s Liberation Army Peking University People’s Hospital Wuhan Institute of Virology, Chinese Academy of Sciences Beijing Ditan Hospital Capital Medical University Beijing Youan Hospital Capital Medical University Xiangya Hospital Central South University Nanfang Hospital Beijing Friendship Hospital Capital Medical University Shanghai Changzheng Hospital The First Affiliated Hospital Zhejiang University Huashan Hospital XiangYa Hospital Central South University Tongji Medical College Huazhong University of Science & Technology Changhai Hospital Peking University First Hospital Peking University People’s Hospital Shanghai Jiao Tong University School of Medicine Zhongshan Hospital Shanghai Jiao Tong University School of Medicine

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Acknowledgements

xii Other Staff Member (In Alphabetic Order) Min Chen Ming-Quan Chen Hong Du Ning-Ling Ge Xiao-Meng Hu Man Xie Ling-Bo Liang Feng Liu Chun-Chen Wu Hang-Di Xu Qiao Yang Yi-Jun Zeng Heng-Hui Zhang Li Zhou Rong-Rong Zhou Peng Zhu

Yu-Ping Ding Xin-Wu Guo Jing-Lan Jin Yu Shi Xiang-Sheng Xu Lin Zhang Guang-De Zhou Yue-Ke Zhu

Jing Dong Xiao-Feng Hang Chen Li Zhan-Hui Wang Xu-Wen Xu Wei Zhang Yan Zhuang

Contents

1 Clinical Manifestations and Laboratory Tests of AECHB and Severe Hepatitis (Liver Failure)����������������������������������������������������������   1 Liang Peng, Zhi-Liang Gao, Yu-Ming Wang, Deng-Ming He, Jin-Ming Zhao, Xue-Fan Bai, and Xiao-Jing Wang 2 Main Complications of AECHB and Severe Hepatitis B (Liver Failure)��������������������������������������������������������������������������  91 Jian-Xin Song, Lin Zhu, Chuan-Long Zhu, Jin-Hua Hu, Zijian Sun, Xiang Xu, Min-You Xin, Qiong-Fang Zhang, Da-Zhi Zhang, Jia Shang, Jia-Quan Huang, and Dong Xu 3 Early Prognostic Predictive System of AECHB and the Diagnosis of Severe Hepatitis B (Liver Failure)�������������������������� 227 Zhi Chen, Qin Ning, and Guang Chen 4 Treatment of AECHB and Severe Hepatitis (Liver Failure)�������������������� 273 Yu-Ming Wang, Ke Li, Xiao-Guang Dou, Han Bai, Xi-Ping Zhao, Xiong Ma, Lan-Juan Li, Zhi-Shui Chen, and Yuan-Cheng Huang 5 Antiviral Therapy for AECHB and Severe Hepatitis B (Liver Failure)�������������������������������������������������������������������������� 371 Qin Ning, Ting Wu, Hai-Bing Su, Ke Ma, Jun-Ying Qi, Ming Ni, and Di Wu 6 Prognosis, Prevention and Research Prospects of Progression to Severe Hepatitis B (Liver Failure)�������������������������������� 457 Yu-Ming Wang, Dao-Feng Yang, Ming Wang, Nazia Selzner, Kaveh Farrokhi, Andrzej Chruscinski, and Gary Levy

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Contributors

Chief Editor Qin  Ning Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

Associate Editor Zhi Chen  The First Affiliated Hospital, Zhejiang University, Zhejiang, China Yu-Ming Wang  Southwest Hospital, Army Medical University, Chongqing, China Guan-Xin  Shen  Tongji Medical College, Huazhong University of Science and Technology, Hubei, China

Advisory Board (In Alphabetic Order) Didier Samuel  Department of Hepatology and Gastroenterology, Université ParisSud, Villejuif, France Gary  Levy  Multi Organ Transplant Program, Transplant Institute, University of Toronto, Toronto, ON, Canada Gyongyi  Szabo  University of Massachusetts Medical School, Worcester, MA, USA Hui Zhuang  Peking University Health Science Center, Beijing, China Lan-Juan Li  The First Affiliated Hospital, Zhejiang University, Zhejiang, China Shiv  Kumar  Sarin  Department of Hepatology, Institute of Liver and Biliary Sciences (ILBS), New Delhi, India Stephen  Locarnini  Victorian Infectious Diseases Melbourne Health, Melbourne, VIC, Australia

Reference

Laboratory,

Xin-Hua Weng  Huashan Hospital, Fudan University, Shanghai, China xv

xvi

Contributors

Yu-Quan  Wei  National Key Laboratory of Biotherapy, Sichuan University, Sichuan, China Zhi-Meng Lu  Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

Editorial Board Members (In Alphabetic Order) Chuan-Long  Zhu  Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China Da-Zhi Zhang  The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China Dao-Feng Yang  Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China Dong  Xu  Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China Gary  Levy  Multi Organ Transplant Program, University of Toronto Transplant Institute, Toronto, ON, Canada Guan-Xin  Shen  Tongji Medical College, Huazhong University of Science and Technology, Hubei, China Guo-Hong  Deng  Southwest Hospital, Army Medical University, Chongqing, China Hai-Bing Su  The Fifth Medical Center of PLA General Hospital, Beijing, China Hong Ren  Chongqing Medical University, Sichuan, China Hong Tang  West China Hospital, Sichuan University, Sichuan, China Yi-Ming Zhang  Huashan Hospital, Fudan University, Shanghai, China Jia  Shang  Henan Provincial People’s Hospital, Zhengzhou Shi, Henan Sheng, China Jia-Quan Huang  Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China Jian-Xin Song  Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China Jin-Hua Hu  The Fifth Medical Center of PLA General Hospital, Beijing, China Jin-Ming  Zhao  The Fifth Medical Center of PLA General Hospital, Beijing, China Jun-Qi Niu  The First Hospital of Jilin University, Jilin, China

Contributors

xvii

Jun-Ying Qi  Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China Ke Li  The Fifth Medical Center of PLA General Hospital, Beijing, China Lan-Juan Li  The First Affiliated Hospital, Zhejiang University, Zhejiang, China Mei-Fang Han  Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China Qin  Ning  Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China Tao  Chen  Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China Xi-Ping Zhao  Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China Xiao-Guang  Dou  Shengjing Hospital of China Medical University, Liaoning, China Xiao-Jing Wang  Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China Xiong  Ma  Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Xue-Fan Bai  Tangdu Hospital, Air Force Medical University, Shanxi, China Yi-Min Mao  Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Ying-Ren Zhao  The First Affiliated Hospital of Xi’an Jiaotong University, Shanxi, China Yong-Wen He  Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Hubei, China Yu-Ming Wang  Southwest Hospital, Army Medical University, Chongqing, China Yuan-Cheng  Huang  Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China Zhi Chen  The First Affiliated Hospital, Zhejiang University, Zhejiang, China Zhi-Liang Gao  The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China Zhi-Shui Chen  Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

Editors

Chief Editor Associate Editors

Qin Ning Zhi Chen

Yu-Ming Wang

Qin Ning

Zhi Chen

Yu-Ming Wang

Guan-Xin Shen

Guan-Xin Shen

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Editors

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Advisory Board (In Alphabetic Order) Didier Samuel Department of Hepatology and Gastroenterology, Université Paris-Sud, Villejuif, France Gary Levy Multi Organ Transplant Program, Transplant Institute, University of Toronto, Toronto, ON, Canada Gyongyi Szabo University of Massachusetts Medical School, Worcester, MA, USA Hui Zhuang Peking University Health Science Center, Beijing, China Lan-Juan Li The First Affiliated Hospital, Zhejiang University, Zhejiang, China Shiv Kumar Department of Hepatology. Institute of Liver and Biliary Sciences (ILBS), Sarin New Delhi, India Stephen Victorian Infectious Diseases Reference Laboratory, Melbourne Health, Locarnini Melbourne, VIC, Australia Xin-Hua Weng Huashan Hospital, Fudan University, Shanghai, China Yu-Quan Wei National Key Laboratory of Biotherapy, Sichuan University, Sichuan, China Zhi-Meng Lu Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

Didier Samuel

Gary Levy

Gyongyi Szabo

Hui Zhuang

Editors

xxi

Lan-Juan Li

Shiv Kumar Sarin

Stephen Locarnini

Xin-Hua Weng

Yu-Quan Wei

Introduction

This book assembles recent achievements in both basic research and clinical management in the field of hepatology, virology, and immunology. It provides up-to-­ date information for clinicians who can apply the relevant knowledge to their daily clinical practice and for researchers who are interested in clinically orientated studies. The updated and detailed technology and state-of-the-art treatment strategies provided in this book serve as references for clinicians and resident physicians in the daily management of ACLF. The rationality and strategies for basic research as well as patient management in this book can also be a valuable reference for other fatal and end-stage liver diseases than HBV-induced ACLF. This Volume 2 has six chapters and focuses on its diagnosis and management.

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1

Clinical Manifestations and Laboratory Tests of AECHB and Severe Hepatitis (Liver Failure) Liang Peng, Zhi-Liang Gao, Yu-Ming Wang, Deng-Ming He, Jin-Ming Zhao, Xue-Fan Bai, and Xiao-Jing Wang

Abstract

This chapter describes the clinical symptoms and signs of AECHB and HBV ACLF, classification, grading of HBV ACLF and their features, diagnostic principles and standards in liver pathology, biochemistry, and virology of HBV ACLF. 1. Liver failure is defined as serious damage to the liver cause by a variety of etiologies, leading to liver function disorder or even decompensation, and clinical syndromes with coagulopathy, jaundice, hepatic encephalopathy, and ascites. 2. Severe hepatitis B can be indicated pathologically by apparent hepatocellular necrosis, including extensive multifocal, confluent, bridging, sub-massive or massive necrosis. 3. Laboratory tests during the course of severe exacerbation of chronic hepatitis B can reflect pathological changes and liver function in a timely manner, providing objective and informative reference data for evaluation of disease severity and

L. Peng · Z.-L. Gao (*) The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China e-mail: [email protected] Y.-M. Wang · D.-M. He Southwest Hospital, The First Hospital Affiliated To AMU, Chongqing, Sichuan, China J.-M. Zhao Beijing 302 Hospital, Beijing, China X.-F. Bai Tangdu Hospital, The Fourth Military Medical University, Shanxi, China X.-J. Wang Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China © Springer Nature B.V. and Huazhong University of Science and Technology Press 2019 Q. Ning (ed.), Acute Exacerbation of Chronic Hepatitis B, https://doi.org/10.1007/978-94-024-1603-9_1

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treatment efficacy. Among the most important laboratory tests are those for ­prothrombin activity, international normalized ratio, and increases in total bilirubin concentration. 4. Severe hepatitis B is associated with interactions between the virus and host factors. Detection of HBV DNA, HBV genotype, quasispecies and HBV mutation can provide important theoretical bases for the prevention, control or mitigation of the progress of severe hepatitis B. 5. Noninvasive imaging modalities can be used to visualize the entire liver and parts of it. Measuring liver volume to evaluate liver size and liver reserve capacity is regarded as important in diagnosis, surgical approach and prognostic evaluation of patients with severe exacerbation of chronic hepatitis B and liver failure. 6. Model for End-Stage Liver Disease (MELD) is the first quantitative method developed to assess whether a patient with liver failure requires a liver transplant. The predictive value of the MELD model has been improved by the MELD-Na, iMELD, and MESO models. Several other valuable prognostic models have been developed. For example, for patients with HBV-ACLF, the established TPPM scoring system was found to be more predictive than MELD score.

1.1

 linical Manifestations of Hepatitis B Aggravation C and Severe Hepatitis (Liver Failure)

Liang Peng, ZL Huang, YY Mei and Zhi-Liang Gao

1.1.1 D  efinitions and Clinical Classifications of Severe Hepatitis and Liver Failure Currently, both clinical and pathophysiological diagnoses are made of severe hepatitis (liver failure) in China. According to the Guideline for the Prevention and Treatment of Viral Hepatitis (2000), severe hepatitis is classified as acute severe hepatitis, subacute severe hepatitis, and chronic severe hepatitis. Acute severe hepatitis is initially diagnosed due to acute jaundice that rapidly progresses to liver failure within 2 weeks. Subacute severe hepatitis can be identified in patients with acute jaundice hepatitis that progresses to liver failure anywhere from 15  days to 24  weeks. Chronic severe hepatitis often develops with pre-existing chronic liver diseases. The clinical manifestations of chronic severe hepatitis are similar to those of subacute severe hepatitis in some patients, or, in some patients, appear similar to decompensated cirrhosis at disease onset. The diagnostic criteria for severe hepatitis in China remain to be fully developed and hence have not been introduced internationally. To meet the clinical requirements and standardize the diagnosis and therapy of liver failure, the Branch of Infectious Diseases and the Branch of Hepatology of

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the Chinese Medical Association invited experts in China to develop the first Guidelines for the Diagnosis and Therapy of Liver Failure in 2006. In those Guidelines, liver failure refers to severe liver damage caused by multiple factors. That damage to the liver results in either the severe impairment or decompensation of synthesis, detoxication, excretion, and biotransformation in the liver and subsequent clinical manifestations characterized by coagulation disorder, jaundice, hepatic encephalopathy, and ascites. On the basis of pathological features and disease progression, liver failure is classified as acute liver failure (ALF), subacute liver failure (SALF), acute-on-chronic liver failure (ACLF), and chronic liver failure (CLF). ALF is characterized by the rapid appearance of clinical manifestations. Patients with ALF usually develop a clinical syndrome of liver failure characterized by high-­ grade hepatic encephalopathy (HE, >grade 2) within 2 weeks. Patients with SALF typically present with a clinical syndrome of liver failure anywhere from 15 days to 26 weeks. Finally, ACLF refers to the acute decompensation of the liver function in the presence of pre-existing chronic liver diseases, and CLF refers to chronic decompensation of the liver function characterized by ascites or portal hypertension, coagulation disorder, and HE due to progressive liver dysfunction in the presence of hepatic cirrhosis. The published Guidelines systemically and extensively reflect the current status of the diagnosis and therapy of liver failure. In addition, the Guidelines, for the first time, focus on liver failure rather than severe hepatitis, which broadens our horizons and highlights practicability. In China, acute severe hepatitis, subacute severe hepatitis, and chronic severe hepatitis correspond closely to ALF, SLF, and ACLF, respectively, as illustrated in Table  1.1. In some patients, chronic severe hepatitis is similar to CLF in other Table 1.1  Description and comparison of liver failure and severe hepatitis Types of liver Definition failure Acute liver Abrupt onset of disease, failure development of liver failure characterized by hepatic encephalopathy of >grade 2 within 2 weeks Subacute Abrupt onset of disease and liver failure development of clinical manifestations of liver failure between 15 days and 26 weeks Acute-on-­ chronic liver failure

Acute decompensated liver function in the presence of chronic liver disease

Chronic liver failure

Chronic decompensated liver function in the presence of hepatic cirrhosis

HBV hepatitis B virus

Corresponding severe hepatitis Chronic severe hepatitis with acute onset in patients with acute severe hepatitis, HBV carriers, and chronic hepatitis B patients with mild liver lesions Subacute onset of chronic severe hepatitis in subacute severe hepatitis patients, HBV carriers, and chronic hepatitis B patients with mild liver lesions Chronic severe hepatitis in the presence of chronic liver disease (characterized by chronic hepatitis and compensated hepatic cirrhosis) Decompensated hepatic cirrhosis

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Table 1.2  Laboratory test index of AECHB Index ALT or AST TBil

Mild CHB ≤3 × ULN ≤2 × ULN

Moderate CHB >3 × ULN (2~5) × ULN

Severe CHB >3 × ULN >5 × ULN

PTA (%)

>70

70–60

60–40

ACLF >3 × ULN >10 × ULN or increase >1 mg/dL daily 17 μmol/L (>1 mg/dL). Hepatic Foetor The sulfur-containing amino acids in the intestine are degraded into mercaptans that have the odor of rotting fruit. Mercaptans cannot be metabolized in the liver and are therefore excreted from the respiratory tract. This distinctive odor is specifically noted in patients with HE. The severity of hepatic foetor may, in some cases, reflect the severity of liver injury. Coagulation Dysfunction The occurrence of coagulation dysfunction is primarily ascribed to the reduced synthesis of coagulation factors by the liver. A majority of the both coagulation and anticoagulant factors are synthesized in the liver. In addition, some coagulation-­ related factors and their inhibitors are also metabolized in the liver. The outcome of coagulation dysfunction is dependent on the severity of damage to the hepatocytes. Thus, even patients in an early stage of liver failure may present with coagulation dysfunction. Prothrombin (PT) activity is often abnormal in the early stages of liver failure and may therefore serve as a sensitive indicator for the prognosis of liver failure. Common clinical manifestations of coagulation dysfunction are mucocutaneous bleeding (i.e., spontaneous bruising, gingival bleeding, subconjunctival hemorrhage), ecchymosis at the site of injection/puncture, and purpura in more severe cases. Gastrointestinal bleeding is also common in affected individuals, whereas bleeding into/from the genitourinary tract, lung, kidney, and retroperitoneum is rare but occasionally observed in some patients. If intracranial hemorrhage develops, it is frequently life threatening. In AHF, the incidence of bleeding and severe bleeding is as high as 73 and >30%, respectively. Another cause of coagulation dysfunction is thrombocytopenia and platelet dysfunction. Of the two, thrombocytopenia is more common. Because platelets are derived from megakaryocytes in bone marrow, bone marrow fibrosis and either reduced bone marrow regeneration or invasion of lymphoma cells in the bone marrow can reduce the number of platelets. Platelets perform multiple activities, including adhesion, aggregation, release, and shrinking blood clots. Additionally, they play an important role in coagulation. Platelet dysfunction may also increase capillary permeability and fragility, which may cause either spontaneous bleeding of the skin and mucous membranes or difficult hemostasis following vascular injury. In patients with SLF, thrombocytopenia is mainly diagnosed in the latter stage of disease in which massive hepatocyte necrosis leads to posthepatic cirrhosis, portal hypertension, and hypersplenism. In CLF patients, thrombocytopenia might be present, and hepatocyte necrosis may aggravate portal hypertension and

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hypersplenism, resulting in worsening thrombocytopenia. Splenomegaly and splenic sinus hyperplasia increase the phagocytosis and destruction of platelets. Further, splenomegaly can cause enlargement of the platelet pool within the spleen. As a result, the platelets in the spleen may account for >90% of platelets in the body. The above pathological changes may finally cause a reduction in the circulating platelets. The reason for thrombocytopenia in liver disease patients without hypersplenism is still poorly understood and might be ascribed to following factors (1) the hepatitis B virus may significantly inhibit the megakaryocyte system of the bone marrow, resulting in reduced production of platelets; (2) the thrombopoietin (TPO) level is reduced. The division of megakaryocytes into platelets in the bone marrow is controlled by both megakaryocyte colony stimulating factor (Meg-CSF) and TPO.  Meg-CSF primarily regulates the proliferation of megakaryocyte progenitor cells, whereas TPO stimulates the maturation of megakaryocytes and production of platelets. TPO is almost exclusively produced by hepatocytes, and only a minority of TPO is produced in the kidney and other organs. TPO is a key factor affecting the production of platelets, and the synthesis of TPO is reduced significantly in patients with either severe hepatitis or hepatic cirrhosis, which affects the production of platelets. In patients with parenchymal liver diseases, abnormalities of platelets are present in both quality and quantity. For example, when the platelet membrane glycoprotein GPI6-IX is reduced, the aggregation of platelets following ristocetin treatment and the shrinkage of blood clots are markedly compromised; and (3) patients with liver diseases usually develop immune dysfunction and are therefore susceptible to infection. Bacterial toxins and systemic inflammatory response syndrome may also cause thrombocytopenia. One published study of ICU patients found that infection was an independent risk factor of thrombocytopenia.

1.1.2.2 Complications of Liver Failure HE HE is both a neuropsychiatric syndrome, a type of central nervous system dysfunction, and metabolic disturbance due to hepatocellular dysfunction and portosystemic shunting. HE is clinically characterized by mental and neurological abnormalities, such as abnormal personality and behaviors, irritability, sleep perversion, drowsiness, and complete loss of consciousness or coma. HE is one of the major causes of severe complications and death in patients with liver failure and is typically classified into one of the four following stages: Stage 1: the prodromal stage. This stage usually manifests with mild abnormal personality changes and behaviors, such as euphoric excitement, indifference, taciturnity, being sloppily dressed, and inappropriate defecation/urination. The affected individual can usually provide correct responses to questions but they are inarticulate and have slow speech. Flapping tremor/hepatic tremor might also be present. To test for flapping tremor, patients are asked to close their eyes with their arms stretching straight, elbows flexed, palms in dorsal extension, with separated fingers. A positive response is determined when the metacarpophalangeal joint, wrist, elbow, and shoulder show irregular movements (jitter) when held in that position within

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30 s. Physicians may also ask the patients to hold the their hand for 1 min. If the physician feels the hand tremor, the test suggests a positive diagnosis of flapping tremor. The condition is caused by afferent dysfunction of joint-reticular formation of the brainstem and a characteristic neurological manifestation. That said, flapping tremor has no specificity fro HE and can also be found in patients with either uremia or hypoxemia due to chronic respiratory disease/heart failure. The presence of flapping tremor in a patient with severe liver disease, however, is helpful for early diagnosis of HE. Patients with HE usually have a normal electroencephalogram. Stage 1 of HE lasts anywhere from several days to several weeks. Several patients with HE in the prodromal stage may have no evidence of clinical symptoms; therefore, misdiagnosis is possible. Stage 2: the precoma stage. Patients with HE in this stage usually presents with confusion, sleep and behavioral disorders, and symptoms as described in the prodromal stage further deteriorate. Patients suffer from disorientation and understanding disorders as well as conceptual confusion over time, place, and person. Patients are unable to perform simple intellectual composition (e.g., building blocks, arranging matchstick into pentagon), and have decreased computing capacity (e.g., 100–7 and continuing). Slurred speech, writing disorders, and abnormal behaviors are also common. Sleep perversion and daytime sleep and night awaking may be present. Further, hallucinations, fear, and mania are also observed, and some patients can be misdiagnosed with mental diseases. Patients with liver failure in this stage usually have evident neurological signs such as tendon hyperreflexia, increased muscle tone, ankle clonus, and presence of the Babinski sign. Flapping tremor and an abnormal electroencephalogram can also be observed. Patients may also suffer from uncontrolled muscular activities and ataxia. Stage 3: the lethargic stage. Patients with HE in the lethargic stage mainly manifest lethargy and insanity, and neurological signs continue and deteriorate. In the majority of time, patients are in a lethargic state, but can be waken up. Patients respond to questioning, but may present confusion and hallucination. Flapping tremor is also present. Muscular tension increases, and there is resistance in the passive limb movements. Pyramidal signs and abnormal waves in EEG can also be noted. Stage 4: the coma stage. Patients have complete loss of consciousness and are unable to be awakened. In a light coma, patients are responsive to painful stimuli and uncomfortable postures, have tendon hyperreflexia, and increased muscular tension. Patients in this stage are usually unable to co-operate during an examination, and a flapping tremor may not be inducible. In a deep coma, various reflexes disappear; muscular tension reduces; pupils become dilated; and there are paroxysmal convulsions, ankle clonus, hyperventilation, and abnormalities on an electroencephalogram. Stage of HE is an important indicator of severity of disease. It may reflect not only the severity of brain damage but also the severity of liver disease. It is important to recognize that there is no clear boundary between two neighboring stages and that there might be some overlap between two neighboring stages (therefore missing the middle stage of HE). When the disease condition either deteriorates or improves after therapy, the severity of HE may be reduced by one or two stages.

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As mentioned above, the initial symptoms of HE are personality changes. Patients with extrovert personalities (i.e., lively, cheerful) may become depressed, whereas patients with introverted personalities (i.e., withdrawn, reticent) may become euphoric and garrulous. The second most common symptom is a change in behaviors. Initially, patients have sloppy behaviors, such as meaningless behaviors like scattering garbage all over the place and defecating/urinating anywhere, looking at clothes, and touching the bed. Those changes are usually only identified by close observation and careful experience. There are also changes in sleep habits. Patients are often drowsy during the daytime but have difficult sleeping at night or show sleep perversion, which predicts imminent HE.  Hepatic foetor is also an important feature of HE. HE patients usually have brain edema and present with nausea, vomiting, dizziness, headache, and either irregular breathing or even apnea. As blood pressure increases there might be a paroxysmal or sustained increase in systolic blood pressure. Bradycardia may be also observed. Muscular tension can increase or the patient can develop a decerebrate posture or even opisthotonus with severe HE. The pupillary light reflex can become blunt/absent, the pupils can become mydriatic, and anisocoria can occur. Achilles and knee tendon hyperreflexia may be observed. It is important to note that some signs might not be obvious in a patient with late-stage HE. In clinical practice, clinicians may indirectly evaluate the severity of brain edema according to chemosis. Accurate evaluation of brain edema is dependent on the subdural, epidural, or cerebral parenchymal measurement of intracranial pressure. The normal intracranial pressure is 20 mmHg. The most important sign of HE is flapping tremor, which means the presence of HE in stage II. In addition, thinking and intelligence tests (such as number connection test, signature test, mapping test, and computing capability test) are abnormal in HE patients. In some HE patients (especially those with hyperammonemia due to HE), slow waves with high amplitude may be observed on electroencephalogram, and positive-evoked potential is also a characteristic change. Brain Edema, Cerebral Hernia, and Intracranial Hemorrhage Brain edema is a complication of ALF.  Typical clinical manifestations of brain edema are sustained increase in blood pressure, abnormal pupils, irregular respiration, and papilledema. More than 80% of patients with HE in stage 3 or 4 are likely to develop brain edema, and severe brain edema may result in cerebral hernia. Brain edema has the clinical presentations of increased intracranial pressure and cerebral dysfunction, which can sometimes overlap with the manifestations of HE.  It is therefore sometimes difficult to differentiate the two, potentially resulting in misdiagnosis. HE patients with brain edema may present dysphoria, irascibility, and increased muscular tension, which are more common than in patients with HE without brain edema. If there are concomitant changes in pupils and respiration together with convulsions and/or seizures, cerebral hernia is suspected. In the late stages of liver failure, patients may develop intracranial hemorrhage, causing

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respiratory and circulatory arrest and even sudden death. Thus, once cardiopulmonary arrest of unknown cause is present, intracranial hemorrhage should be considered. Gastrointestinal Bleeding Concomitant gastrointestinal bleeding in patients with severe hepatitis can be caused by multiple factors, including (1) decreased coagulation factor synthesis by hepatocytes and/or significant inactivation of active coagulation factors in the liver; (2) endotoxemia and disseminated intravascular coagulation consuming a large amount of coagulation factors; (3) hypersplenism causing abnormalities in the quality and quantity of the platelets; (4) portal hypertension causing the rupture of esophageal and gastric varices; and (5) stress response in severe hepatitis leading to diffuse gastric corrosive erosion. Of the possible complications occurring in liver failure patients, bleeding is the most common and severe. In clinical practice, gastrointestinal bleeding with severe hepatitis seems to make the primary disease worse. It may worsen liver ischemia and hypoxia and aggravate liver dysfunction and ascites. Blood in the gastrointestinal tract can be degraded into ammonia and increase the production of sulfur-like substance, resulting in HE.  In addition, bleeding may reduce immune function, which make infections difficult to control. The reduction in effective circulating blood volume may also induce hepatorenal syndrome. Taken together, bleeding may cause multiple organ dysfunction, thereby complicating treatment and reducing the success rate of therapy. The causes of upper gastrointestinal bleeding are different among patients with different types of liver failure. In ALF and SLF, bleeding is related to reduced synthesis of coagulation-related factors and stress-induced gastric mucosal lesions. In CLF, however, rupture of esophageal and gastric varices and gastric mucosal lesions secondary to portal hypertension are the main causes of gastrointestinal bleeding. In some cases, there is more than one cause of bleeding. Endotoxemia and Infection In liver failure, the ability of the monocyte-macrophage system to clear intestine-­ related endotoxins is reduced significantly, which may lead to intestine-related endotoxemia and deterioration of liver function. This clearly forms a vicious cycle and may cause multiple organ failure if it is severe enough. In addition, patients usually have compromised immune function and are susceptible to infection. Invasive manipulations and use of broad-spectrum antibiotics and immunosuppressants further increase the possibility of secondary infection. Concomitant infection in liver failure patients has the following characteristics: (1) a high incidence; (2) infection may occur at different sites either simultaneously or sequentially, and abdominal and biliary tract infection is the most common. Once pulmonary infection is present, the disease condition will likely deteriorate, directly causing death; (3) a majority of infections are nosocomial infection, and pathogens are usually resistant to common antibiotics, making therapy challenging; (4) the pathogens causing infection are diverse but mainly Gram-negative bacteria, although

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the incidence of Gram-positive and fungal infections is increasing; (5) infection is closely related to the prognosis for liver failure patients. In sum, the more severe the disease, the higher the incidence of infection is and secondary infection may worsen the condition or cause death. The early diagnosis of secondary infections is based on clinical findings such as signs of infections (i.e., fever, increase in peripheral white blood cells, deterioration of primary disease, specific symptoms of infection of a particular organ). Some patients may not present with an obvious fever and instead only show focal signs of infection. For example, in spontaneous bacterial peritonitis, examination could reveal abdominal tenderness and rebound tenderness and a slight increase in peripheral white blood cells and polymorphonuclear proportion (although they are in normal ranges). In contrast, pulmonary infections can present only with fever while the respiratory symptoms are not obvious/absent and thoracic radiographs fail to show abnormalities in affected patients. In such cases, computed tomography is required to identify the pulmonary lesions. In addition, liver failure patients are vulnerable to fungal infection, especially for those receiving long-term therapy with broad-­spectrum antibiotics. Gastrointestinal candidiasis is the most common fungal infection. Oral Candida albicans infection is characterized by thickening and a bean residue-like coating on the tongue, gastrointestinal fungal infection is characterized by increased stool frequency and stool with mucus, and pulmonary fungal infection (especially Aspergillus infection) is a severe complication of liver failure that can progress rapidly and has a high mortality rate. Once a pulmonary fungal infection is suspected, computed tomography of the thorax should be performed to confirm the diagnosis, and effective antifungal therapy should be initiated as early as possible. Hepatorenal Syndrome Hepatorenal syndrome (HRS) refers to progressive functional renal failure in the absence of primary kidney disease in patients with severe liver diseases. HRS is most often diagnosed in the late stages of severe hepatitis and hepatic cirrhosis. The main clinical manifestations of HRS include: 1 . Late stages of liver failure; 2. Renal failure after a reduction in effective circulating blood volume (e.g., water and electrolyte disorder, following paracentesis for ascites, excessive urination due to diuresis, gastrointestinal bleeding, secondary infection, vomiting, and diarrhea). However, HRS may present abruptly with no evident/discoverable causes; 3. HRS is often found in patients with moderate to severe ascites; 4. HRS has no significant relationship with jaundice and HE; and 5. Blood pressure reduces during HRS. Thus, when patients are treated with propranolol for portal hypertension, physicians should pay attention to the baseline blood pressure because reduction in blood pressure after pharmacotherapy may reduce the blood supply to the kidney and decrease glomerular filtration rate, inducing HRS;

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6. The abrupt decrease in urine output suggests the presence of HRS. Diuretics usually fail to increase the urine output. Patients often have a reduction in urine sodium and concomitant hyponatremia; 7. Urinalysis shows similarities to prerenal azotemia but displays opposite features to acute tubular necrosis; 8. The symptoms of uremia may overlap with those of liver failure and cause the deterioration of original symptoms. In patients with progressive liver diseases, secondary renal dysfunction is closely related to the deterioration of their general condition, suggesting the aggravation of liver failure. In addition, the presence of uremia may contribute to metabolic complications. Coagulation dysfunction in liver disease patients may be deteriorated due to compromised aggregation of platelets during uremia. Uremia may also aggravate immune dysfunction. On the basis of clinical characteristics, HRS can be classified into two types. Type I HRS is rare, has an acute onset, and is characterized by progressive renal dysfunction. Serum creatinine may be either 2× that at baseline (i.e., >221 μmol/L or 2.5 mg/dL) within 2 weeks or creatinine clearance decreases by 50% within 24 h (i.e., creatinine clearance of 3 months. The course of disease is short, and symptoms of uremia are not obvious. In type II HRS, which is often found in CLF patients with pre-existing hepatic cirrhosis, has a chronic onset. Ascites patients with type II HRS are usually nonresponsive to diuretics. In type II HRS, renal failure shows a slow progression (lasting for several weeks to months), but the survival rate of patients is lower than that of hepatic cirrhosis patients with ascites. The main clinical consequence is refractory ascites nonresponsive to diuretics in patients with type II HRS. A follow-up study of 234 hepatic cirrhosis patients with ascites showed the accumulative incidence of HRS was 18% within 1 year and 39% within 5 years. A retrospective study showed about 17% of patients with ascites on admission had HRS and HRS patients accounted for 50% of hepatic cirrhosis patients died. However, for hepatic cirrhosis patients, the 2-year and 5-year incidence of HRS is 32% and 41% after development of ascites. A majority of patients (80–95%) die within 3 weeks after development of azotemia. Hepatopulmonary Syndrome (HPS) HPS refers to a series of pathophysiological changes and clinical manifestations (including hypoxemia) due to abnormal pulmonary vascular dilation, gas exchange disorder, and abnormal arterial oxygenation. Abnormal arterial oxygenation due to a gas exchange disorder may increase the alveolar-arterial oxygen pressure difference. Hypoxemia is an important pathophysiological basis of HPS, and HPS is a severe pulmonary complication of end-stage liver disease that is clinically characterized by dyspnea and cyanosis. HPS was first reported by Rydell Hoffbauer in 1956, but it wasn’t until 1977 that Kenned and Knudson proposed the full concept of HPS. HPS per se refers to pulmonary vascular dilation and the shunting of venous blood with low oxygenation to

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arteries in the presence of severe liver disease. HPS is mainly identified in patients with CLF (Child C hepatic cirrhosis). In addition, patients with either acute or chronic liver disease may present with a pulmonary vascular abnormality and arterial hypoxemia. HPS occurs most commonly in patients with hepatic cirrhosis secondary to chronic liver disease, including hepatitis-induced cirrhosis, cryptogenic cirrhosis, alcoholic cirrhosis, and primary biliary cirrhosis, all of which have similar pathophysiological processes as HPS. In HPS, severe ascites, portal hypertension, and arterial hypoxemia (PaO2 10 × the upper limit of normal, prothrombin activation of ≤30–40%, or pathological characteristics), but patients have no evidence of HE and no ascites. Intermediate severe hepatitis patients have grade 2 HE or obvious ascites, bleeding tendency (i.e., bleeding point, ecchymosis, and a prothrombin activation of ≤20– 30%). Advanced severe hepatitis patients develop refractory complications and HRS, gastrointestinal bleeding, severe bleeding tendency (i.e., ecchymosis at the injection site), severe infection, refractory electrolyte imbalance, HE >grade 2 brain edema, or a prothrombin activation of ≤20%.

1.1.3 N  atural History and Characteristics of Different Types of Liver Failure Currently, some investigators classify the natural history of liver failure into the following: prejaundice stage, bilirubin increase stage, bilirubin plateau stage, and bilirubin reduction stage. Those stages are based on disease progression, serum bilirubin level, and recovery of liver failure patients. In the prejaundice stage, patients have fatigue, anorexia, and an intolerance of oil. They deteriorate gradually, the urine becomes yellow, liver function detection usually shows a significant increase in aspartate aminotransferase and alanine aminotransferase (higher than several thousand), and the prothrombin activity increases. Serum bilirubin increases progressively (i.e., a daily increment of >17.1 μmol/L), and symptoms (fatigue, anorexia) deteriorate after the appearance of jaundice (which is different than manifestations of acute jaundice hepatitis). When the serum bilirubin peaks and remains relatively stable, the disease may be in the bilirubin plateau stage in some patients with no severe complications but present improved mental status and appetite. With the regeneration of hepatocytes, the disease progresses into the bilirubin reduction stage, in which the coagulation, mental status, and appetite improve. When the disease recommences its deterioration, it may progress from the so-called bilirubin increase stage directly to the end stage. In patients with ALF, the bilirubin plateau stage is not obvious, and patients might die shortly after disease onset. If patients survive ALF, the disease may be pathologically classified as a hepatocyte edema type, and liver function will improve in a short period. Not all types of liver failure (including severe hepatitis B) have clear stages based on their natural history and characteristics, and the respective features are discussed in detail as described in the following sections.

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1.1.3.1 Acute Liver Failure (Fulminant Hepatic Failure) There is still no consensus on the definition of ALF. In 2005, the US Acute Liver Failure Study Group published guidelines for the management of acute liver failure. In those guidelines, they emphasized that liver failure within 26 weeks after onset can be diagnosed with ALF in mother to child transmission of hepatitis B infection (or autoimmune hepatitis), although it has the possibility of progressing into hepatic hepatitis. In addition, some physicians propose that liver failure with an abrupt attack either secondary to chronic hepatitis B or in the presence of other hepatitis virus infection can also be classified as ALF. The pathological basis of ALF may be classified as necrosis- and degeneration-dominant (acute edema) type. In ALF of the necrosis-dominant type, hepatocytes become diffuse and massive necrosis occurs soon after disease onset. In ALF of the degeneration-dominant type, hepatocytes show diffuse and severe swelling. ALF secondary to acute hepatitis B virus (HBV) infection is rare in clinical practice. Patients with ALF secondary to acute HBV infection usually have no history of HBV infection, are relatively young, and often have predisposing factors (e.g., stress, absence of rest after disease onset, malnutrition, alcoholism, use of liver damaging drugs, pregnancy, concomitant infection). Moreover, it usually progresses rapidly, and patients may develop coagulation dysfunction before the jaundice becomes evident. Such patients present with symptoms of liver failure characterized by HE >grade 2 within 2 weeks, a prothrombin activation ≤40%, an obvious bleeding tendency (i.e., massive petechiae at an injection site), patients have no ascites, disease progresses rapidly and has a poor prognosis, and patients frequently die of complications such as brain edema or cerebral hernia within 3 weeks. Some patients may recover rapidly after appropriate therapy and are usually diagnosed with liver failure of extensive hepatocyte swelling. After recovery, the risk for hepatic cirrhosis is relatively low. Another situation is the presence of a history of HBV infection in which patients have a good liver condition and no evidence of/mild liver lesions. For HBV patients with ALF, the liver condition is good (as in ALF patients without prior HBV infection) and both ALF patients with and without prior HBV infection share pathological basis, pattern of disease onset, and clinical course. ALF usually progresses rapidly, and the four stages of ALF (i.e., prejaundice stage, bilirubin increase stage, bilirubin plateau stage, and bilirubin reduction stage) are difficult to identify. ALF may result in high mortality, and a majority of patients directly develop ALF of the bilirubin increase stage or even terminal stage. 1.1.3.2 Subacute Liver Failure (SLF, Subacute Severe Hepatitis) Pathologically, SLF not only has extensive hepatocyte necrosis but also an obvious inflammatory reaction and formation of regenerative nodules in residual hepatocytes. SLF usually has an origin of ALF. When SLF occurs in patients with or without mild liver lesions, it often shows an abrupt onset. In the early stages, SLF is similar to acute icteric hepatitis and patients progressively deteriorate. Affected individuals may also develop clinical symptoms of liver failure from 15  days to 26  weeks, including severe fatigue, loss of appetite, frequent vomiting, and

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deepening jaundice (i.e., a daily increment of >17.1 μmol/L or > 1 mg/dL and an increase in serum bilirubin of >171  μmol/L or 10  mg/dL). Patients usually have hepatic foetor, refractory abdominal distension, ascites (susceptible to concomitant peritonitis), evident bleeding tendencies, and mental and neurological symptoms. In the late stages, hepatorenal syndrome may be present and patients often develop complications (such as gastrointestinal bleeding and hepatic coma) before death. The liver either shrinks or remains normal in size. The course of SLF lasts for several weeks to several months. Patients surviving SLF following therapy usually develop postnecrotic hepatic cirrhosis. Clinically, SLF can be divided into two types. First, the ascites type results in profound jaundice (serum bilirubin of ≥171 μmol/L or > 10 × the upper limit of normal), ascites, and evident bleeding tendencies (i.e., a PTA ≤40%). HE might be absent or present in the late stages. Patients often die of HRS, upper gastrointestinal bleeding, severe secondary infection, and intracranial hemorrhage. SLF of the ascites type accounts for a majority of SLF. Second is the encephalopathy type. Such patients have HE as an initial symptom and present manifestations as in ASH except for course of disease lasting for >14 days. Patients usually die from either brain edema or cerebral hernia. SLF of the encephalopathy type is also not rare. SLF often has an abrupt onset, and the four stages (i.e., the prejaundice, bilirubin increase, bilirubin plateau, and bilirubin reduction stage) of liver failure are difficult to identify. It is usually associated with a high mortality rate.

1.1.3.3 Acute on Chronic Liver Failure (ACLF, Chronic Severe Hepatitis, CSH) The pathological basis of ACLF is similar to that of SLF; therefore, they both share clinical characteristics. A majority of patients with ACLF have ascites, spontaneous peritonitis, and biliary tract infection. In the late stages, patients may develop portal hypertension and other complications, repetitive HE and HRS, and most die of gastrointestinal bleeding and HRS. According to the Guideline for the Prevention and Therapy of Viral Hepatitis (2000), a fraction of patients with CSH meeting the diagnostic criteria can be grouped with ACLF. That is, patients have either chronic hepatitis or compensated hepatitis cirrhosis that remain stable, but some predisposing factors cause the deterioration of liver function, which, thereafter, progresses to liver failure. ACLF refers to acute decompensated liver function in the presence of chronic liver disease. The previously mentioned guidelines emphasize pre-existing chronic liver disease and liver failure due to acute liver dysfunction. It is important to note that controversy regarding the basis of chronic liver disease persists. In 2002, an English physician proposed that ACLF was diagnosed in chronic liver disease patients with compensated liver function presenting with acute aggravation of liver function within 2–4 weeks due to accidents characterized by jaundice, HE, and/or HRS. German physicians subsequently proposed that the diagnostic criteria for ACLF included (1) the liver has the histological, laboratory, or ultrasound evidence of hepatic cirrhosis; and (2) patients develop jaundice, ascites, coagulation dysfunction, and/or grade 2–4 HE, meeting the definition of

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decompensated liver function. The Guideline for the Diagnosis and Therapy of Liver Failure (2006) does not detail chronic liver diseases as a basis of liver failure. However, in general, HBV carrier status may not serve as a baseline liver disease for patients with either chronic hepatitis or hepatic cirrhosis. The term ACLF also highlights that acute or subacute deterioration of liver function occurs, which rapidly progresses to liver failure. Patients often display an abrupt onset and develop severe fatigue and evident gastrointestinal symptoms. In the early stages, there is acute liver damage; therefore, patients usually present with a significant increase in transaminase levels. Thereafter, the disease condition becomes aggravated, and patients may manifest symptoms of liver failure. ACLF can also be divided into the brain type and ascites type, of which ACLF of the brain type has a higher incidence. Further, the four stages (prejaundice, bilirubin increase, bilirubin plateau, and bilirubin reduction) of liver failure are very clear in patients with ACLF. One goal for physicians and researchers is to determine individualized therapy for ACLF patients according to the specific stage of ACLF.

1.1.3.4 Chronic Liver Failure (CLF, Chronic Severe Hepatitis) Patients with CLF usually have decompensated hepatic cirrhosis that progressively evolves into chronic liver failure, resulting in clinical manifestations of chronic decompensated liver dysfunction characterized by ascites, portal hypertension, coagulation dysfunction, and HE. The pathological basis of chronic liver failure is hepatic cirrhosis, chronic and progressive aggravation of hepatocyte injury, and reduction in hepatocytes that are unable to maintain normal liver function. Physical examination usually shows signs of chronic liver diseases (such as liver palms and spider angiomas), imaging examination shows characteristics of chronic liver diseases (such as spleen thickening), and laboratory examination also supports the diagnosis of chronic liver diseases (increased gamma-globulin and reduced/inverted albumin/globulin ratio). Of note, a majority of patients have no clear history of liver disease and may initially be misdiagnosed with ALF.  Further examinations may provide evidence of hepatic cirrhosis. When patients with hepatic cirrhosis become decompensated, the liver dysfunction usually presents with acute deterioration due to complications or gradually aggravates in a small fraction of patients. On the basis of the above findings, liver failure secondary to decompensated hepatic cirrhosis can be divided into slowly progressive liver failure and acutely deteriorating liver failure. The former shows a chronic status of liver failure and is characterized by repetitive ascites and HE. The latter shows an acute deterioration of liver function in the presence of chronic liver dysfunction, which is similar to ACLF in the disease onset and clinical course. Hepatopulmonary syndrome is often noted in acutely deteriorated liver failure, and patients usually die of heavy gastrointestinal bleeding, HRS, and severe infection. CLF is generally characterized by slow progression of liver failure, and the course of CLF is relatively long. The four stages (prejaundice, bilirubin increase, bilirubin plateau, and bilirubin reduction) of liver failure are difficult to identify. As such, finding ways to best preserve residual hepatic function reserve is one of the important therapeutic goals in affected individuals.

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 evere Hepatitis/Liver Failure: Diagnosis S and Classification

Yu-Ming Wang, Deng-Ming He Liver failure is a clinical syndrome with high mortality by severe liver damage. It is caused by a variety of causes, results in serious obstacles or decompensation of liver synthesis, detoxication, excretion and biotransformation and appears with coagulation disorders, jaundice, hepatic encephalopathy and ascites as main manifestation. Hepatic failure can be divided into acute liver failure (ALF), subacute liver failure (SALF), acute-on-chronic liver failure (ACLF), and chronic liver failure (CLF). Although the incidence of liver failure is not high in Western countries, the relevant papers, reviews, conferences and other exchanges have increased markedly in recent years. AASLD, EASL and APASL had established a thematic seminar and the definition diagnosis and classification of liver failure has been consistent. At the same time, there are different understandings. Therefore, it is necessary to discuss the main differences of liver failure diagnosis and classification, so as to develop a more rational diagnosis and classification scheme.

1.2.1 Classification of Liver Failure Mechanism The classification of liver failure involves classification of hepatic injury. A variety of factors (drugs, virus, alcohol, etc.) can cause liver cell damage. Although course and prognosis of liver cell damage are different, the most common mechanism is inflammation. Wieland et  al. found that there were two mechanisms of liver cell injury in the immune clearance of HBV; non-soluble cell damage occurring early and soluble cell damage, early mainly non-soluble cell injury, by the study of Gorillas with HBV infected. In 1994, Bonino et  al. proposed the theory of non-­ soluble liver cell damage in the study of Fibrosing Cholestatic Hepatitis (FCH) study. However, this theory was ignored because many scholars believed that it ignored the background of immunosuppression. At that time, FCH was still considered as the injury of endoplasmic reticulum and Golgi apparatus by the excess replication of HBV as well as overexpression of HBV antigen during immune inhibition. However, in 2008, Masayoshi et al. reported that most effective antibodies had been detected in children after living donor liver transplantation who received chickenpox vaccine, attenuated vaccines in children, such as measles, rubella, and mumps. According to this, immune suppression cannot stop antibody production and in FCH, non-cellular immune injury may be present. Recently, we found that there were two types of HBV reactivation in immune-suppressed; high ALT type (>10 × ULN) and low ALT type (20,000 IU/mL

ALT

Recommendations

>2 × ULN

>20,000 IU/mL

20,000 IU/mL

>1 × ULN >2 × ULN

>20,000 IU/mL

≤2 × ULN

CSLD/CSID 2015 >20,000 IU/mL >2 × ULN 1 × ULN Extra-hepatic manifestations

If there is moderate to severe biopsy proved inflammation or fibrosis, start antiviral treatment If there is moderate to severe noninvasive diagnosed fibrosis, start antiviral treatment For patients with immune tolerance, if there is no family history of liver cirrhosis or liver cancer, temporarily monitor closely Start antiviral treatment If there is no spontaneous HBeAg clearance in 3–6 months, start antiviral treatment If there is moderate to severe inflammation or significant fibrosis proven by biopsy, start antiviral treatment Start antiviral treatment Knodell HAI ≥4, or necroinflammation ≥2, or fibrosis ≥2 Age >40 years, start antiviral treatment Age 30 years, start antiviral treatment May start antiviral treatment

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Table 5.3  The recommendations for the treatment of HBeAg negative patients with CHB in guidelines HBV DNA APASL 2015 >2000 IU/mL >2000 IU/mL

EASL 2017 >2,000 IU/mL

>2,000 IU/mL AASLD 2018 >2000 IU/mL >2000 IU/mL

ALT

Recommendations

>2 × ULN 1 × ULN >2 × ULN 2000 IU/mL >2 × ULN 1 × ULN Extra-hepatic manifestations

Start antiviral treatment If there is moderate to severe inflammation or significant fibrosis proven by biopsy, start antiviral treatment Start antiviral treatment Knodell HAI ≥4, or necroinflammation ≥2, or fibrosis ≥2 Age >40 years, start antiviral treatment Age 30 years, start antiviral treatment May start antiviral treatment

5.1.3.4 The Recommendations for the Treatment of Cirrhotic Patients with CHB in Guidelines The recommendations for the treatment of cirrhotic patients with CHB in guidelines (Table 5.4) [3–6]. 5.1.3.5 The Recommendations for Liver Biopsy in Guidelines The recommendations for liver biopsy in guidelines (Table 5.5) [3–6].

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Table 5.4  The recommendations for the treatment of cirrhotic patients with CHB in guidelines HBV DNA APASL 2015 Compensation Decompensation EASL 2017 Compensation

HBV DNA

Recommendations

>2000 IU/mL Detectable

Antiviral treatment Antiviral treatment, consider liver transplantation

Detectable

Decompensation

Detectable

Antiviral treatment although with normal ALT and/or HBV DNA load lower than 2000 IU/mL Antiviral treatment immediately, consider liver transplantation

AASLD 2018 Compensation Decompensation

>2000 IU/mL 2000 IU/mL

Decompensation

Detectable

Start antiviral treatment Start antiviral treatment Antiviral treatment immediately, ready to liver transplantation Ready to liver transplantation

Start antiviral treatment for HBeAg positive patients Start antiviral treatment for HBeAg negative patients with detectable HBV DNA Start antiviral treatment to avoid liver transplantation

5.1.3.6 The Recommendations for CHB Initial Treatment Options in Guidelines The recommendations for CHB initial treatment options in guidelines (Table 5.6) [3–6, 8]. 5.1.3.7 The Recommendations for CHB Cirrhosis Initial Treatment Options in Guidelines The recommendations for CHB cirrhosis initial treatment options in guidelines (Table 5.7) [3–6]. 5.1.3.8 The Recommendations for CHB Treatment Duration in Guidelines The recommendations for CHB treatment duration in guidelines (Table  5.8) [3–6, 8]. 5.1.3.9 The Conclusion of Recommendations for CHB Treatment Duration in Guidelines 1. Antiviral treatment strategies for HBeAg positive patients (Fig. 5.2). 2. Antiviral treatment strategies for HBeAg negative patients (Fig. 5.3). 5.1.3.10 T  he Recommendations for Management of Lamivudine Drug-Resistance in Guidelines The recommendations for management of lamivudine drug-resistance in guidelines (Table 5.9) [3–6, 8].

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Table 5.5  The recommendations for liver biopsy in guidelines HBV DNA HBeAg APASL 2015 Positive >20,000 IU/ mL Negative >2000 IU/mL EASL 2017 Positive >2000 IU/mL Negative

>20,000 IU/ mL AASLD 2018 Positive >20,000 IU/ mL >20,000 IU/ mL Negative >2000 IU/mL CSLD/CSID 2015 Positive >20,000 IU/ mL

Negative

>2000 IU/mL

ALT

Recommendations

1 × ULN >1 × ULN

If age >30 years and/or with history of cirrhosis or liver cancer, consider biopsy Consider biopsy

>2 × ULN ≤2 × ULN 40 years, ALT between 1–2 × ULN and with history of HCC, consider biopsy Consider biopsy

1–2 × ULN 30 years, consider biopsy Consider biopsy If age >30 years, consider biopsy

Table 5.6  The recommendations for CHB initial treatment options in guidelines Abbreviation of guidelines APASL 2015

EASL 2017 AASLD 2018

CSLD/CSID 2015 WHO 2015

Recommended drugs ALT 2–5 × ULN: based on IFN-α, or NAs (entecavir and tenofovir are preferred) ALT >5 × ULN: based on IFN-α, or NAs (entecavir and tenofovir are preferred, especially when hepatic decompensation) Entecavir and tenofovir as the first-line choice, or pegylated interferons Pegylated interferon-α, entecavir or tenofovir are preferred; Interferon-α/pegylated interferon-α, lamivudine, adefovir, entecavir, tenofovir or telbivudine can be used; Adefovir or entecavir for interferon nonresponders or patients with interferon contraindication. Pegylated interferon-α, entecavir Tenofovir and entecavir as the first-line choice IFN may be considered when HBV DNA viral load and genotyping are available, or co-infection with HDV

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Table 5.7  The recommendations for CHB cirrhosis initial treatment options in guidelines Abbreviation of guidelines APASL 2015

Compensatory situation Compensation

EASL 2017

Decompensation Compensation

AASLD 2018

Decompensation Compensation

CSLD/CSID 2015

Decompensation Compensation Decompensation

Recommended drugs Entecavir or tenofovir, therapy based on interferon-α can also be used when ALT 200 IU/ml or 20000 IU/ml

5 × ULN

HBV DNA detectable 2 × ULN

HBV DNA > 2000 IU/ml or 20000 IU/ml

1 × ULN

Follow up 0

F1

F2

F3

F4

Fibrosis Stage

Fig. 5.2  Antiviral treatment strategies for HBeAg positive patients

ALT(ULN)

NAs regimen treatment

HBV DNA > 2000 IU/ml or 20000 IU/ml 2 × ULN

HBV DNA detectable Follow up

1 × ULN

0

F1

HBV DNA > 2000 IU/ml

F2

F3

F4

Fibrosis Stage

Fig. 5.3  Antiviral treatment strategies for HBeAg negative patients

Table 5.9  The recommendations for management of lamivudine drug-resistance in guidelines Abbreviation of guidelines APASL 2015 EASL 2017 AASLD 2018 CSLD/CSID 2015 WHO 2015

Recommendations Switch to tenofovir Add adefovir Add tenofovir Add tenofovir Switch to tenofovir Switch to tenofovir Switch to adefovir

5.1.3.11 T  he Recommendations for Management of Adefovir Drug-Resistance in Guidelines The recommendations for management of adefovir drug-resistance in guidelines (Table 5.10) [3–6, 8].

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Table 5.10  The recommendations for management of adefovir drug-resistance in guidelines Abbreviation of guidelines APASL 2015 EASL 2017

AASLD 2018 CSLD/CSID 2015 WHO 2015

Recommendations Switch to entecavir Switch to tenofovir If LAM-naïve: switch to ETV or TDF If LAM-resistance: switch to TDF or TAF If HBV DNA plateaus: add ETV*** or switch to ETV Add entecavir Switch to tenofovir or entecavir Add or entecavir Switch to entecavir or tenofovir Switch to adefovir

5.1.4 Antiviral Treatment in Special Populations Consensus of Antiviral Treatment in Special Populations with chronic hepatitis B was put forward by China expert committee of antiviral treatment in special population with chronic hepatitis B in 2010.

5.1.4.1 The Choice of Antiviral Drugs for Fulminant Hepatitis B In China, HBV infection is one of the main causes of liver failure. HBV related liver failure can be further divided into acute liver failure, subacute liver failure, acute-­ on-­chronic liver failure and chronic liver failure. Nucleoside analogues can be safely used in the treatment of HBV related liver failure, and improve the prognosis of patients. Nucleoside analogues treatment can improve the survival rate and reduce the incidence of complications in HBV related acute and subacute liver failure patients. Therefore, nucleoside analogues treatment should be early applied in HBsAg positive and HBV DNA detectable patients with acute and subacute liver failure, and nucleoside analogues can quickly inhibit virus, including lamivudine, entecavir and tenofovir, are recommended for these patients. Drug resistance should be monitored in long-term nucleoside analogues treatment. Remaining HBV cannot be completely excluded even when HBsAg and HBV DNA are undetectable during the treatment, therefore the antiviral treatment should continue to HBsAg seroconversion. Antiviral treatment is unnecessary for anti-HBs positive patients at first visit [9]. 5.1.4.2 Patients with HBV Related Primary Liver Cancer For patients with HBV related primary liver cancer, liver cancer resection, radiofrequency ablation and interventional therapy all can lead to HBV reactivation and liver function damage aggravation, antiviral treatment is decided depending d on liver compensatory situation. IFN-α can exhibit both anti-virus and anti-cancer effect, delay the tumor recurrence and prolong the median survival period. IFN-α should be the preference if the patients can tolerate IFN-α. If the patients have

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contraindications to IFN-α, lamivudine, adefovir or entecavir can be chosen depending on HBV DNA loads, cirrhosis compensatory situation and kidney function. For patients undergoing hepatic arterial chemotherapy, prophylactic nucleoside analogues treatment should be given before chemotherapy. For patients with advanced liver cancer, portal vein branch thrombosis, but without contraindications to IFN-α, IFN-α treatment can extend survival period [9–15].

5.1.4.3 Patients with HBV Related Liver Transplantation Patients awaiting liver transplantation because of HBV-related end-stage liver disease or liver cancer should be given nucleoside analogues with strong HBV inhibition and low drug-resistance, or nucleotides analogues combination treatment, in order to reduce viral load and prevent graft re-infection. Lamivudine and (or) adefovir combination with HBIG can be safely and effectively prevent graft re-infection, and reduce the re-infection rate to below 10%. HBV-associated liver transplant patients require lifelong treatment of antiviral drugs for the prevention of hepatitis B recurrence. HBsAg-negative patients receiving anti-HBs positive donor liver should also receive long-term treatment of lamivudine or preventive treatment of HBIG [1, 9, 16–27]. 5.1.4.4 Elderly CHB Patients According to WHO, elderly CHB patients refers to CHB patients aged ≥60 years old. Generally speaking, according to current guidelines, ≥60 years of age is not a contraindication to antiviral therapy, so their treatment can refer to the relevant guidelines, but their desire, risks and benefits of treatment should be comprehensive evaluated. Especially for the patients using IFN-α, the expected survival and liver function compensatory situation, possible side effects, underlying hypertension, diabetes, coronary heart disease, and the improvement of liver function should be comprehensive evaluated. Additionally, the treatment response, side effects, blood sugar, kidney function and occurrence of liver cancer should be closely monitored during and after treatment [9]. 5.1.4.5 Children CHB Patients Children CHB patients are usually in the immune tolerance phase of HBV infection, hence they could not receive antiviral treatment, but should be closely followed up. FDA has approved of IFN-α (2–17 years of age), lamivudine (2–17 years of age), and adefovir (12–17 years of age) for use in children. Recommended IFN-α dose is 6  MIU/m2 of body surface area three times per week, and the maximum dose is 10 MIU/m2 total body surface area. It is showed that IFN-α effects the same in children as in adult. Recommended lamivudine dose is 3 mg/(kg day) with a maximum dose of 100 mg/day. Recommended adefovir dosage and usage are the same with adult patients [9, 28–33]. 5.1.4.6 Pregnant CHB Patients Mother to child transmission is the main route of transmission of HBV infection in China, in order to block the transmission of HBV, antiviral therapy in pregnant CHB

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patients is very important. Firstly, antiviral treatment should be completed before pregnancy as possible. It is recommended to consider pregnant 6 months later after interferon or nucleoside analogs treatment. Secondly, unwanted pregnancies should be terminated during IFN-α treatment because of its pregnancy toxicity. Pregnancy safety of nucleosides analogs has not been proved by any clinical trials, but a large number of studies have shown that lamivudine and tenofovir were safe, so the treatment with lamivudine could continue under the premise of full communication with patients. Telbivudine, adefovir or entecavir treatment may switch to lamivudine treatment. Pregnant CHB patients with slight ALT elevation, should be monitored closely or given liver protection and symptomatic treatment, and given antiviral treatment after delivery. Pregnant CHB patients with poor liver function could be given lamivudine treatment after full consultations with patients and signed informed consent forms. Serum HBV DNA load in pregnant CHB patients is the key factors of mother to child transmission, and effective antiviral treatment can significantly reduce the transmission incidence. According to the findings, lamivudine or telbivudine treatment could start in 28–34 week of pregnancy to block transmission, and the withdrawal can refer to the patients with immunosuppressive agents or chemotherapy. In addition, women with husbands receiving IFN-α antiviral treatment, should only consider pregnancy 6 months later after withdrawal. There is no evidence at present that nucleosides analogs have a negative impact on sperm and embryo, pregnancy could be taken into account under the premise of full communication with patient [9, 34–45].

5.1.4.7 HBV and HCV Co-infected Patients HBV and HCV co-infection increases the incidence of severe hepatitis, liver cirrhosis and liver cancer. When co-infection, HCV may inhibit HBV generally, and different treatment should be given depending on HBV and HCV viral load and ALT level (Table 5.11) [9, 46–53]. Table 5.11  Reference scenario of antiretroviral therapy for HBV and HCV co-infection HBV DNA Undetectable

HCV DNA Detectable

ALT –

Detectable

Detectable

2 × ULN

Detectable

Undetectable

2 × ULN

Undetectable

Undetectable

–

Recommendatory strategy Referring to the standard anti-HCV treatment regimens Referring to the standard anti-HCV treatment regimens IFN-α + ribavirin ± NUCs according to the patient’s condition ★ Referring to the carrier management, do not treat, regular follow up. Referring to the standard anti-HBV treatment regimens Do not treat, regular followed up.

★ Avoid combination of IFN-α and telbivudine

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5.1.4.8 HBV and HIV Co-infected Patients HBV and HIV co-infection increases HBV DNA load, reduces spontaneous HBeAg seroconversion rate, aggravates liver damage and increases mortality in patients with liver disease. Anti-HBV regimens should combine with highly active antiretroviral therapy (HAART). If anti-HBV and HIV treatment is needed, anti-HBV drugs such as tenofovir + lamivudine or tenofovir + Truvada could be used in HAART. If HAART only contains lamivudine as anti-HBV drugs, HBV drug resistance should be closely monitored and treatment should be adjusted in time. If HAART is unnecessary, adefovir, telbivudine and IFN-α can be used for anti-­ HBV treatment. Because lamivudine, tenofovir and entecavir monotherapy induced risk of HIV drug-resistance, lamivudine, tenofovir and entecavir treatment are not recommend to these patients [9, 54–60]. 5.1.4.9 CHB Patients Underlying Kidney Disease Anti-HBV treatment is critical for hepatitis B virus associated Glomerulonephritis (HBV-AG). Patient diagnosed with HBV-AG must start anti-viral therapy as long as HBV DNA is detectable. A number of studies show that kidney disease alleviated significantly after lamivudine treatment, along with HBV DNA decline and HBeAg clearance. Adefovir has been shown to increase serum creatinine level in some patients in clinical trials, therefore should be carefully chosen. There is not enough clinical evidence of telbivudine and entecavir treatment for HBV-AG. There is no consensus of nucleoside analogue treatment for HBV-AG currently. Safety and efficacy of IFN-α and pegylated IFN-α treatment for HBV-AG have not been proved [9, 61–67]. 5.1.4.10 P  atients Receiving Immunosuppressive Agents or Cytotoxic Therapy Elevation of HBV DNA can be observed in 20–50% of the HBsAg-positive patients receiving immunosuppressive agents or cytotoxic therapy, including corticosteroids, anti-CD20 and anti-TNF. Some patients suffer from transaminase elevation and jaundice, and severe patients develop to fulminant liver failure even death. Nucleoside analogues prophylactic treatment can decrease HBV reactivation. Regardless of the HBV DNA level, HBsAg carriers should receive nucleoside analogues antiviral treatment 2–3 weeks before immunosuppressive or cytotoxic therapy. Antiviral drugs inhibit HBV DNA rapid, such as lamivudine, telbivudine and entecavir, are preferred for prophylaxis. Most patients cannot tolerate the recurrent aggravations induced by drug-resistance. Prophylaxis decision should be made depending on baseline HBV DNA load and duration of immunosuppressive therapy or cytotoxic therapy. Antiviral drugs with low resistance are recommended if prophylaxis will last more than 12 months. Treatment duration: if baseline HBV DNA ≤105 copies/mL, treatment should be continued to 6 months after immunosuppressive therapy or cytotoxic therapy completed; if baseline HBV DNA >105 copies/ mL, treatment should be continued to the referring withdrawal standard of ordinary

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CHB patients. However, IFN-α is not recommended because of the bone marrow suppression. There is no consensus of prophylactic antiviral treatment for HBsAg-negative and anti-HBc-positive patients during the immunosuppressive or cytotoxic therapy. Serum HBV marker and HBV DNA level should be monitored [9, 68–73].

5.1.4.11 Patients with Autoimmune Thyroid Disease HBV infection itself is not correlated with thyroid dysfunction. IFN-α can aggravate underlying autoimmune thyroid disease or induce emerging thyroid disease in some patients because of its immunomodulatory activity and direct thyroid toxicity. Uncontrolled thyroid dysfunction contraindicates IFN-α antiviral therapy. Patients with previous thyroid dysfunction or high titer of thyroid autoantibody (TPO-Ab >18 IU/mL) before treatment should be monitored for thyroid function during IFN-α antiviral treatment. Patients with emerging thyroid dysfunction during treatment should terminate antiviral treatment. Majority of thyroid dysfunction emerged during treatment in patients without history of thyroid dysfunction is reversible, and can restore after IFN-α withdrawal [74–77].

5.1.5 Management of Drug-Resistance Resistance to nucleoside analogues is a serious problem in CHB treatment, which does make the long-term treatment strategies become a difficulty.

5.1.5.1 Predictors of HBV Resistance Mutations A variety of factors may be associated with resistance to nucleoside analogues, including nucleoside analogue type, HBV DNA load at initial therapy, liver fibrosis/ cirrhosis, and previous nucleoside analogues treatment. In addition, male gender, high body mass index and alcohol abuse are also the risk factors of resistance mutations in antiviral therapy. However, a growing number of studies suggest that early virological response is an important indicator to predict drug resistance [78, 79]. 5.1.5.2 Prevention of Drug-Resistance Select nucleoside analogues treatment indications reasonably. Nucleoside analogues treatment is not recommended for the HBV infected patients in immune tolerant phase or non-active phase, especially those who are younger, if they do not receive immunosuppressive therapy or chemotherapy. For the CHB patients with first flare, especially those who are younger, nucleoside analogues should be given with caution after fully analysis of inductions. Select nucleoside analogues treatment strategies reasonably. Treatment should be consulted the Guideline on prevention and treatment of chronic hepatitis B in china. For patients with antiviral therapy indications, drugs with strong antiviral activity and low resistance are recommended if nucleoside analogues are chosen. The previous antiretroviral therapy, including drugs, treatment response and resistance mutations, should be understood in order to avoid nucleoside analogues with

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cross-resistance. Furthermore, sequential monotherapy treatment should be avoided for multi-drug resistance. Improve patients’ compliance. Prescribed time and adequate medication should be repeatedly emphasized to the patients during nucleoside analogues treatment. According to the clinical trial, more than 30% of cases with virologic breakthrough are resulting from poor compliance. Gradual dose reduction will significantly increase the risk of resistance and is forbidden. Regularly detect HBV DNA load and genotypic resistance and timely adjust treatment. HBV DNA load is the most important indicators of drug resistance in nucleoside analogue antiviral therapy. HBV DNA levels should be monitored regularly during treatment. Numerous clinical trial data show that early virological response is an important predictor of drug-resistance. Therefore, AASLD and EASL guidelines both recommend adjusting treatment plan based on EVR to improve the efficacy and reduce the incidence of drug resistance [6, 78–81].

5.1.5.3 Management of Emerged Drug-Resistant Mutations Patients with normal ALT and mild inflammation or fibrosis (109 copies/mL, HBeAg-­ negative patients with HBV DNA >107 copies/mL. (4) Cirrhotic (compensated and decompensated) patients and AECHB patients. (5) Other patients with HBV reactivation after transplantation, immunosuppressive therapy, combination of other viral infections such as HCV and HIV, combination of metabolic/autoimmune diseases such as insulin resistance, hyperlipidemia and (or) non-alcoholic steatohepatitis and fiber cholestatic hepatitis. The present guidelines for the treatment of refractory CHB involve virus strains resistant mutations and virologic breakthrough, partial virological response, cirrhosis, virus reactivation after liver transplantation, receiving immunosuppressive therapy, and combination of other viral infections (HCV and HIV). Majority of the treatment recommendations are based on expert consensus, clinical experience, or clinical studies of small sample. However, for patients with serological no-response or partial response, high baseline HBV viral load, AECHB, insulin resistance and non-alcoholic steatohepatitis, and fiber cholestatic hepatitis, there is no clear guidance. Currently ongoing hepatitis B related clinical researches more concentrated in drug selection and optimization of treatment-naïve patients, and only a small portion and small-scale studies involve refractory CHB.

5.1.7 Antiviral Therapy for AECHB Anti-HBV treatment was not taken into account in AECDHB in the past. It is thought that immune pathological damage is the key in the development of AECHB, and HBV is just a promoter. The role of hepatitis virus in development of AECHB has not been paid enough attention. With the study of AECHB mechanism deep going, more and more scholars have realized that constant HBV replication induced hyperactive immune response is a major factor in exacerbation. When HBV induces hypersensitivity, a large amount of immune complexes generate and activate the immune network, leading to serious hepatocyte damage through the following mechanisms: (1) Th1 cells activate, release interleukin-2 (IL-2), and mediate cytotoxicity of cytotoxic T cell (CTL), macrophages and natural killer (NK) cells; (2) macrophages activated by HBV and endotoxin release cytokines (including tumor necrosis factor TNF-α and fgl2), inducing direct hepatocyte damage or secondary damage by microcirculation disturbance; (3) Fas ligands (Fas-L) express increasingly on the surface of infected hepatocytes, conjunct to Fas expressed by CTL, and induced apoptosis. Antiviral therapy can quickly suppress HBV replication, reduce intercellular viral spread, and inhibit the membrane target antigen expression, so as to inhibit CTL attack and relieve hepatocyte injury and necrosis. Antiviral treatment at early stage in disease is the pivot to terminate intense cellular and humoral immunity. Therefore, it is advocated to start antiviral treatment for severe hepatitis patients with HBV replication. Some scholars believe that viral load is an important indicator for AECHB, although it does not directly related to liver damage. HBeAg and HBV DNA

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seroclearance is important for remission and positive for improving cure rate of severe hepatitis. Therefore, early effective anti-viral therapy can reduce the viral load, suppress virus generation by infected hepatocytes, decrease infection of newborn hepatocytes, alleviate liver inflammation and is beneficial to liver recovery. Antiviral therapy has become an effective treatment for AECHB [82]. Whether antiviral therapy increase or alleviate immune response in the advanced stage of severe hepatitis had been controversial. However, recent studies reach a consensus that antiviral treatment can slow disease progression and improve recent survival rate. In most early studies, lamivudine failed to improve liver function and survival in AECHB compared to placebo [83–87]. However, a study from Taiwan showed that lamivudine could improve survival in patients with baseline total bilirubin less than 342  mmol/L (20  mg/dL) [88]. Wong and Chan reported that antiviral therapy in AECHB cannot improve resent survival, but could prevent further deterioration [89]. In early stage, there is intense immune response, high viral load, severe inflammation, and ongoing immune liver damage. Viral load can affect the progression and prognosis. Patients with HBV DNA positive have a relative poor prognosis because of more virus antigen on hepatocyte surface activating immune injury. In middle-advanced stage, the impact of HBV DNA on progression and prognosis would weaken because immune response has alleviated after self-regulation. Therefore, HBV DNA level in early severe CHB is a significant indicator for prognosis, and antiviral therapy is essential. In middle-advanced stage, HBV DNA level has little influence on the prognosis, and antiviral therapy is meaningful to prevent recurrence. In addition, lamivudine can obtain sustained virologic response, but long-term treatment may induce viral resistance and virologic breakthrough, which reduce the efficacy of antiviral therapy [90]. Most recent studies suggest that antiviral therapy for HBV DNA positive patients in early severe hepatitis can postpone disease progression and improve recent survival rate [91]. Ma et  al. analyzed 248 cases of HBV-ACLF retrospectively. 124 patients added entecavir on the basis of standard medical treatment, another 124 patients only received standard medical treatment without nucleoside analogues. The 1-month and 3-month survival rate of entecavir-treated patients were 72.58% (90/124) and 61.59% (76/124) respectively, and significantly higher than those of control with 53.23% (66/124) and 61.29% (57/124). Entecavir-treated patients get a significant improved MELD scores compared to control post treatment, suggesting that entecavir can postpone progression of HBV-ACLF and improve recent survival [92]. Lin et  al. investigated 120 HBV-ACLF cases with entecavir treatment, and concluded that entecavir can significantly increase the survival rate [93]. Hu et al. investigated the efficacy of lamivudine and entecavir on HBV-ACLF. After 1-month treatment, survival rates are similar, but clinical improvement rate in lamivudine and entecavir group were significantly higher than basic treatment group. After 6-month treatment, the cumulative survival rates of lamivudine and entecavir group were 65.8%, 60.1% respectively and significantly higher than the basic treatment group (42%). In patients with baseline HBV DNA >107 IU/mL, cumulative survival rate in antiviral treatment group were higher than basic treatment group. Patients

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with pretreatment MELD scores >30 had a lower cumulative survival rate than patients with MELD scores ≤2, but obtained better response to antiviral therapy. It also showed that there was no significant difference in efficacy using entecavir and lamivudine treatment for HBV-ACLF [94]. Tillmann et al. summarized 14 cases of AECHB with lamivudine treatment. It suggested that patients with lamivudine treatment had an overall survival rate without transplant of 78.2%, but patients without lamivudine only 45.7% [95]. Garg et al. found that tenofovir can significantly reduce HBV DNA levels in HBV-ACLF, improve CTP and MELD score, and decrease mortality. HBV DNA decrease of more than 2lg copies/mL after 2-week treatment is a predictor of good prognosis.

5.2

Antiviral Therapy for Severe Hepatitis B (Liver Failure)

Hai-Bin Su Liver failure is a common syndrome, and its incidence is increasing with the use of alcohol and growing epidemic of obesity and diabetes. Liver failure is defined as inability of the liver to perform its normal, metabolic, excretory and biotransformation functions by Chinese Medical Association [96]. Its manifestation includes coagulopathy, jaundice, hepatic encephalopathy (HE) and ascites. Liver failure can be divided into four classes: acute liver failure (ALF), sub-acute liver failure (SALF), acute on chronic liver failure (ACLF), and chronic liver failure (CLF) according to histopathological characteristics and the progression of disease. ALF is a syndrome with liver function deterioration rapidly accompanied with a grade II or higher HE within 2 weeks illness duration. SALF onset is slowly than ALF that symptoms occur within 2–26 weeks. Liver failure occurred with known or unknown chronic liver disease refer to ACLF. CLF is defined as Progressive deterioration and decompensation of liver function in patients with liver cirrhosis, mainly manifested with complications of portal hypertension. Based on the severity of clinical manifestations, sub-acute and acute-on-chronic liver failure can be divided into early, middle, and end stages. Early stage has severe fatigue and gastrointestinal symptoms, total bilirubin level is more than 171 μmol/L or daily increase of total bilirubin is more than 17 μmol/L and prothrombin activity (PTA) is less than 40%. Middle stage has stage II HE and/or ascites and PTA ≤30%. End stage has refractory complications such as stage III or higher HE, hepatorenal syndrome, massive hemorrhage of the upper alimentary tract, severe infection and refractory fluid and electrolyte imbalance, PTA ≤20%. Otherwise, Asian Pacific Association for the Study of the Liver (APASL) define ACLF as a severe liver injury, leading to coagulation abnormality usually with an INR ≥1.5, and any degree of mental alteration (HE) in a patient with pre-existing liver disease and with an illness duration less than 4 weeks [97]. Etiology, epidemic and precipitating factors of liver failure are different between western countries and China. Non-infection factors such as alcohol and drug induced liver failure are predominant in western countries [98]. However, hepatitis B virus (HBV) infection is the main reason to induce liver failure [99]. We

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retrospective analysis the etiology of 1977 cases of liver failure came from 13 provinces in China northern area from 2002 to 2006 and found HBV infection induced liver failure was about 82.8% [99]. So far, liver transplantation is the most effective way to treat HBV induced liver failure. But due to the cost and shortage of organ donor, liver transplantation can’t be used widely. Comprehensive treatment including supportive therapy, antiviral therapy and immunoregulation therapy is the main way to treat HBV related liver failure in China. But mortality of liver failure is high and total curative rate is only about 35.56% because of the complicate pathophysiology in liver failure [100]. The precise mechanism underlying the liver injury caused by HBV-ACLF and the factors contributing to the progression of liver failure remain unknown. Generally, virus factors, host factors, and their interaction determine the outcome of ACLF. HBV DNA replication is one of the key factors causing the progression from liver damage to liver failure. The HBV DNA level is closely associated with the risk of hepatocellular carcinoma development, and HBV DNA suppression significantly improves the prognosis of cirrhosis. Current clinical guidelines advocate oral antiviral treatment in decompensated cirrhosis and sustained HBV DNA suppression to reduce sequelae [4, 96, 97, 101].

5.2.1 T  heory Basis of Antiviral Therapy for Severe Hepatitis B (Liver Failure) 5.2.1.1 The Association Between HBV Genotype and Severe Hepatitis B (Liver Failure) Eight different HBV genotypes (A–H) have been described based on their genomic heterogeneity. Many studies showed that the severity of HBV infection correlated with HBV genetype. In the Asia-Pacific countries, genotype B and C HBV are predominant with genotype C HBV associated with delayed HBeAg seroconversion and more aggressive disease activity as compared to other HBV genotypes [102]. Patients infected with HBV genetype C have high HBV DNA level and high HBeAg positive rate than people infected with other HBV genetypes. These patients have low response to anti-viral therapy and progress to liver failure, particular in patients infected with genetype C2. Zhang et  al. analyses 2922 hepatitis B patients and found that the most common HBV genetype was B and C in chronic hepatitis B patients [103]. Patients infected with genetype C was more predisposed to chronic and cirrhosis and hepatic carcinoma. Genetype B and C had no influence on illness progression in acute and mild patients, but HBeAg positive rate and HBV DNA level were high in patients infected with genetype C. Further studies showed that HBV BCP/pre C mutation was associated with HBV genetype. A1846T and C1913 mutation probably associated with ACLF.  C1913 was an independent prognostic factor in ACLF patients [104]. 5.2.1.2 The Effect of Gene Mutation HBV DNA polymerase lack proof function which can lead to viral mutation during replication. In addition, HBV exist in many quasispecies. Under select press,

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quasispecies variance can cause the change of HBV replication, pathogenicity, antigen epitope which lead to influence immune response and viral resistance. Over immune response can result in severe liver injures. HBV pro core/core, pre S, P gene and multi gene mutation were found to be associated with liver failure [105]. One of the functions of HBeAg is to induce immune tolerance. In the absence of HBeAg, patients harboring pre-core mutant HBV may have a more rigorous immunological response. Chronic infection with pre-core mutants has been often associated with multiple flares with interspersed asymptomatic periods. Mutations at the basal core promoter (BCP) regions lead to decreased HBeAg synthesis, active liver histology, and increased viral replication. These exacerbations are seen to lead to fulminant hepatic failure [89, 106, 107]. We investigated HBV BCP A1762T/G1764A double mutation in liver failure patients [104]. Longitudinal study showed that nucleotide mutation sites were occurred more in HBV-ACLF than cirrhosis patients among which nt53, nt1846, nt1896 and nt1913 were associated with HBV-ACLF. T1846 mutation was found exist more in genetype B than genetype C (57.1% vs 30.4%), A/G1913 mutation is found frequently in HBeAg negative patient than positive patients (28% vs 13.2%). These indicated that pre core/BCP mutation associated with the occurrence of liver failure and influence patients outcome. HBx is a multifunction regulatory protein which can influence gene transcription, activate signal transduction, enhance viral replication, accelerate protein degradation and regulate cell apoptosis. HBx can participate in the process of HBV pre S and BCP/pre core mutation

5.2.1.3 Immune Characteristics in Liver Failure Liver failure caused by chronic HBV infection (i.e., chronic severe hepatitis B) is a common life-threatening disease in China. The pathogenesis of chronic severe hepatitis B is complex and is currently not completely understood. However, one widely accepted mechanism is the induction of cellular immune responses mediated primarily by cytotoxic T lymphocytes (CTLs) and delayed-type hypersensitivity T cells. These immune responses are induced by viral protein antigens expressed in the target cell surface due to the active replication of HBV and eventually result in large areas of liver cell necrosis [108]. The specific mechanisms may involve several factors [109]. Using a hybridization assay for HBV DNA and a conventional enzyme immunoassay to measure the HBeAg level, an earlier study showed significant parallel increases in serum HBeAg and HBV DNA levels and accumulation of intracellular viral proteins several weeks before the hepatitis flare. In addition, there was a subsequent increase in anti-HBe production and HBeAg/anti-HBe immune complex formation, implicating the important role of the immune response to HBV in initiating the hepatitis flare [110]. Immunohistologic studies during the hepatitis flares have shown CD8+ T cells in the mononuclear cell infiltrates, strong membranous expression of human leukocyte antigen class I (HLA-I), and cytoplasmic or membranous/submembranous hepatitis B core antigen (HBcAg) expression [111, 112]. Some findings suggest that hepatitis B flares are the results of dynamic changes of the innate and adaptive immune responses with HLA-I restricted, CTL

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mediated immune cytolysis of HBV antigen(s) expressing hepatocytes and its downstream apoptotic mechanisms [113, 114]. The activated Th1 cells release interleukin-2 and excite cytotoxic effects of CTLs, macrophages, Natural Killer cells, and lymphokines [102]. Macrophages, activated by HBV and endotoxins, release various cytokines mainly with tumor necrosis factor (TNF)-a, which directly damage liver cells and also result in secondary injury of liver cells through disturbances in microcirculation. Fas ligands (Fas L) are highly expressed in the surface of HBV-infected liver cells and combine with Fas expressed by CTLs, together inducing hepatocellular apoptosis. Therefore, antiviral therapy early in chronic severe hepatitis B is beneficial for suppressing intense cellular immune responses induced by HBV replication. If HBV replication is suppressed rapidly, the immune pathological responses of chronic severe hepatitis B may be reduced, thus effectively blocking the disease progression.

5.2.2 C  linical Research of Antiviral Therapy for Severe Hepatitis B (Liver Failure) The administration of anti-HBV therapy in chronic severe hepatitis B (acute- or subacute-on-chronic liver failure) is still undergoing research, and limited data are presently available. So far, anti HBV treatment drugs include interferon and oral antiviral drugs. Interferon application is contraindicated in the treatment of liver failure due to its limited anti-viral efficacy, significant adverse drug effects, and induction of immune enhancement, which can further result in aggravation of liver damage. Oral anti HBV drugs including Adefovir dipivoxil (ADV), Lamivudine (LAM), Telbivudine (TBV), Entecavir (ETV) and Tenofovir (TDF) have few adverse effects. Antiviral therapy may have the advantage of shortening the replication and thereby reduce disease duration without the side effects of interferon. Therefore, many studies have been carried out to find the efficacy of oral antiviral drugs on patients with liver failure.

5.2.2.1 Antiviral Therapy in HBV Related Acute Liver Failure The effect of antiviral therapy in HBV related acute liver failure is controversial. Some studies reported that antiviral therapy can’t improve outcome because HBVDNA can be eradicated spontaneously due to enhanced immune response in liver failure patients. But HBV infection is the initial factor to induce over immune response that can lead to liver damage. Early treatment with antiviral therapy can inhibit HBV DNA replication and attenuate immune reaction which can reduce liver damage, hepatocyte apoptosis and necrosis. Tillmann et al. [115] reported that 17 acute HBV related liver failure patients were treated with LAM and 20 patients were treated with placebo. Encephalopathy occurred in 3 (17.6%) and 11 (68.6%) patients, respectively (p = 0.005). It demonstrated that early use of antiviral drugs can reduce the rate of encephalopathy and mortality. In addition, a prospective study about ETV on 6 acute liver failure patients demonstrated that ETV can reduce HBV DNA load significantly and 5 patients achieved anti HBsAg conversion [116].

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Therefore, monitor closely and early use antiviral drugs to reduce hepatocyte apoptosis and necrosis on patients with HBV related acute liver failure are very important.

5.2.2.2 Antiviral Therapy in HBV Related Acute on Chronic Liver Failure (HBV-ACLF) The objective of antiviral treatment for HBV-ACLF is to reduce viral load at an appreciably high rate, thereby promoting reduction in hepatocyte cell death and improved survival outcomes by prevention of decompensation related multiorgan complications in this group of severely ill patients. Several studies have delineated the fact that low pretreatment HBV DNA load and a rapid decrement in viral load improves outcomes in HBV-ACLF [117], whereas a study from India reported that a 2 log decrease in HBV DNA at week 2 improved survival benefit in patients with HBV-ACLF [118]. Antiviral therapy also promotes chances of stabilization to liver transplant time and improves transplant outcomes. Studies have debated on the issue of antiviral therapy related improvement in the long term [119]. LAM decreased viral load significantly, but did not result in significant biochemical or clinical improvement compared with those patients given placebo. Mortality of patients receiving nucleoside analog therapy was significantly lower than the placebo group, which indicated that antiviral therapy improved prognosis of patients with HBV-ACLF if implemented as soon as possible [117]. Even in the age of effective antiviral therapy, early transfer to a transplantation facility should be considered before managing conservatively by medical means. The APASL consensus guidelines on ACLF describe the value of early and prompt institution of antiviral therapy in HBV-ACLF. HBV DNA levels are now not an indication for commencement of antivirals in HBV-ACLF reactivation, as earlier starting of such therapy, even prophylactic, has been found to have great survival benefit in the long run. From 2006 to 2009, early and middle stage HBV-ACLF patients in our hospital were recruited in a prospective study to evaluate the efficacy and safety of LAM and ETV [120]. No antiviral therapy was used in control group. This study showed that LAM or ETV can reduce 3 and 6 months mortality, improve survival rate on patients with ACLF-HBV. Three and 6 months cumulative survival rate of LAM and ETV therapy were 69.2% and 65.8%, 67% and 60.1%, respectively, which was higher than control group (42% and 42%, p = 0.045 and 0.04). No significant different on survival rate between LAM and ETV (p  =  0.723). This study also showed that MELD score was an effective prognostic predict factor on patients with ACLF-­ HBV. Patients with MELD score less than 30 had a good outcome. Another study also demonstrated that For HBeAg-negative patients with HBV-ACLF, when entecavir was added to comprehensive therapy, a MELD score ≥30 predicted very poor prognosis due to fatal liver failure [121]. Hu et al. made a survival analysis on 190 HBV-ACLF patients and results indicated that nucleoside analog application in early and middle stage HBV-ACLF can improve survival rate and prolong patients’ life. Median survival time was 5.7 and 1.79 months in patients treated with and without antiviral therapy. Another study indicated that patients with MELD score 30–40 and HBV DNA load decrease 2 log

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had a better outcome than patients with HBV DNA load decrease less than 2 log within 4 weeks treatment [122]. In addition, mortality had no relationship with HBV DNA load if MELD score >40. Xiao et al. also demonstrated that nucleoside analog treatment is an independent prognosis predict factor in 219 HBV induced liver failure. LAM and ETV had no difference. Although antiviral therapy can improve patients survival rate, treatment with and without nucleoside analog had no difference in late stage liver failure patients.

5.2.2.3 Antiviral Therapy in Chronic Liver Failure Currently, liver transplantation is the ultimate therapeutic option for decompensated cirrhosis patients. However, liver transplantation can’t be used in all patients because of the shortage of donor organs. Therefore, the aim to treat decompensated cirrhosis is to decrease the occurrence of disease associated complications and the liver associated mortality rate [123]. The natural history of decompensated HBV-related cirrhosis is affected by high HBV replication which may exist in some decompensated HBV-related cirrhosis patients [123]. Hepatic necroinflammation and fibrosis progression are improved after sustained viral suppression is achieved which can prevent decompensation in cirrhosis [124]. Oral NAs treatment are strongly recommended in most clinical guidelines for decompensated HBV-related cirrhosis patients no matter what HBV DNA replication level is [109, 110]. Yao et al. [125] found that CTP scores was reduced more than three points in 69% LAM treated patients with severely decompensated cirrhosis. Furthermore, CTP scores was decreased to less than seven point in 38% of these patients, and their statuses on the United Network of Organ Sharing waiting list changed to inactive. A randomized controlled trial in Asia demonstrated less liver-related morbidity in the LAM-treated patients with HBV associated advanced compensated cirrhosis compared to the untreated controls because of the reduced incidence of hepatic decompensation and lower risk of HCC. Increased CTP scores were noted in 3.4% of the patients in the LAM group compared to 8.8% of the patients in the placebo group (p = 0.02) [126]. Fontana et al. showed most deaths caused by liver related complications occurred within the first 6 months in patients with decompensated HBV-related cirrhosis treated with LAM. Pretreatment high HBV DNA replication level, serum bilirubin and creatinine were associated with 6-months mortality rates significantly [127]. This finding indicates early antiviral therapy might be important. 5.2.2.4 Antiviral Drugs in HBV Related Liver Failure Lamivudine LAM is a nucleoside analogue that inhibits HBV DNA synthesis which was the first oral drug to treat chronic HBV infection in 1998. Its mechanism is to compete with nature cytidine to inhibit HBV polymerase, then terminate HBV replication. Chan et al. [128] studied the effect of lamivudine in treatment of severe hepatitis-B-related acute exacerbations leading to ACLF in 28 patients as against 18 controls. It was concluded that lamivudine had no survival benefit compared with conventional treatment in severe aggravations of chronic hepatitis B and that liver transplantation

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should be considered in these patients with thrombocytopenia and high bilirubin. However, another meta study [129] analysis 242 studies to evaluate the short-term effect of lamivudine (LMV) treatment for severe chronic hepatitis B. They found that the survival rates and PTA of the test group were distinctively higher than those of the control group at weeks 4, 8, and 12 of the treatment course. The HBV-DNA negative change rate was distinctively higher throughout the 12 weeks of LMV treatment. For patients who started LMV treatment in the middle stage, the mortality rate of the test group was lower. They concluded that LMV decreased HBV-­DNA levels in the serum, improved liver function in patients, and enhanced survival rate during the early and medium stages of severe chronic hepatitis B. Tsubota et al. [130] studied 25 patients with spontaneous severe acute exacerbation treated with lamivudine, and found that lamivudine monotherapy did not prevent hepatic failure deterioration significantly, but it resulted in long-term benefits. Baseline serum bilirubin, pre-existing cirrhosis and baseline PT were independent determinants of prognosis. Adefovir ADV is an acyclic nucleotide analogue of adenosine monophosphate. Use of adefovir for HBV-ACLF has been rare. In two case reports, adefovir dipivoxil failed to salvage cases of lamivudine resistance after jaundice and liver failure developed. A lower antiviral potency and the potential risk of nephrotoxicity of ADV remain a problem for routine use as a first-line treatment. It is hence not advisable to use adefovir as a first-line drug in the treatment of acute severe exacerbation. But considered to the high viral resistant to LAM, ADV plus LAM can reduce the incidence of LAM resistance. The combination of ADV and LAM can be used in liver failure patients. 128 patients with decompensated cirrhosis caused by LAM-resistant HBV were treated with ADV and HBV DNA level become undetectable occurred in 81% of patients and CTP scores were improved [131]. But another study focused on long time outcome found that resistance to ADV was 20% and renal toxicity was confirmed in 3% of patients [132]. Entecavir ETV is a cyclopentyl guanosine analogue that can inhibit HBV polymerase’s function. Compared with LAM and ADV, ETV has a more potent activity against wild type HBV [133, 134]. ETV has been studied in in cirrhotic patients. One Korea study showed CTP and MELD scores were improved in 55 patients treated with ETV for 12 month. The 2-year cumulative incidence of HCC was 6.9%, and the cumulative death rate was 17% [90]. Many studies have been carried out to compared the efficacy of ETV and LAM to treat HBV related ACLF. The short-term efficacy of entecavir vs lamivudine was similar and the degree of pretreatment liver failure significantly affected the outcome of treatment [135, 136]. In summary, the pros and cons of LAM vs ETV in decompensated or severe acute exacerbation of chronic hepatitis B were ETV being more effective in promoting faster viral load decrement. Also the available clinical evidence suggests that clinicians treating chronic hepatitis B patients with acute HBV exacerbation or decompensated liver disease should use the most potent nucleoside analogs available [137].

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Telbivudine TBV is a synthetic thymidine nucleoside analogue that has potent antiviral activity against HBV. One study investigated the short-term efficacy and safety of TBV therapy in liver failure patients caused by chronic hepatitis B virus (HBV) infection [138]. In this study, 20 patients were treated with TBV, and the other 18 patients were treated with LAM. HBV DNA levels in the TBV group fell to the lower limit of detection after the fifth week, which was more rapid than in the LAM group. In addition, the total bilirubin and prothrombin time activity of the patients with TBV treatment showed a more significant improvement as compared to the patients treated with LAM from the start of the fifth week. They concluded that TBV treatment is superior to LAM treatment in improving the condition of patients with liver failure as a result of chronic HBV infection in the short term. But viral resistance is also a major concern. A study in decompensated cirrhosis patients with HBV infection showed genotypic resistance was developed in 27% of the TBV patients during the 2-year period [139]. Therefore, TBV used as a first-line treatment has limitations in patients with HBV-related decompensated cirrhosis. Tenofovir TDF is an acyclic nucleotide analogue with potent inhibition of HBV polymerase/ reverse transcriptase. In a seminal study by Garg et al. [90], consecutive patients with ACLF due to spontaneous reactivation of chronic hepatitis B were randomized to receive either TDF or placebo. The primary endpoint was survival at 3 month. More than 2 log reduction in HBV DNA levels at 2 weeks was associated with survival rate. The authors concluded that TDF had potent activity to reduce HBV-DNA levels, improve CTP and MELD scores, and reduce mortality in patients with severe spontaneous reactivation of chronic hepatitis B presenting as ACLF, and that reduction in HBV-DNA levels at 2 week should be considered a desirable goal and a good predictor of survival. Until now, no studies have reported viral resistance to TDF. Therefore, TDF and ETV can be considered to be the first-line therapy because their potent activity against HBV replication and high resistance barrier. In addition, the data about TDF to treat HBV-ACLF is limited. Thus, larger prospective and multicenter studies are encouraged to evaluate further the effect of TDF on short-­ term mortality of patients with HBV associated ACLF.

5.2.3 P  rospects on Antiviral Therapy for Severe Hepatitis B (Liver Failure) There still lack multicenter, larger samples, prospective and randomized clinical trial to test the efficacy of antiviral therapy. But it is likely that antiviral therapy with nucleos(t)ide can improve patients survival rate in patients with HBV-related liver failure [140]. Therefore, antiviral therapy is reasonable to try in patients with high HBV DNA replication. In recent year, LAM and other nucleoside analogue have been used in severe hepatitis B wildly. The efficacy of antiviral therapy is correlated with the time to start. Many clinical trials demonstrated that early antiviral treatment is important for patients with liver

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failure [141]. Antiviral therapy used in early and middle stage liver failure can improve patients survival rate. In patients with late stage, such as serum total bilirubin is more than 342 μmol/L, it’s rare that patients can get benefit from antiviral therapy. Therefore, early use antiviral therapy can reduce viral load, inhibit viral replication, reduce new hepatocyte be infected by HBV again and alleviate liver inflammation and all of that are benefit to hepatocyte regeneration. The criteria for antiviral therapy dependent on HBV DNA level in serum. Some people suggested antiviral therapy should be used in patients with HBeAg positive and HBV DNA >104 copies/mL or HBeAg negative and HBV DNA >103 copies/ mL. However, take into account over immune response in liver failure patients that associated with viral eradication, even patients with HBsAg positive and HBV DNA undetectable should be considered for antiviral therapy. In our opinion, antiviral therapy should be used in all liver failure patients with HBV replication immediately. The feature of oral antiviral drugs should be considered when used in liver failure patients. Side effects of nucleos(t)ide, including elevate CK, myopathies and lactate acidosis, can occurred during treatment. We observed the change and effect of elevated CK during the treatment of ETV and LAM in liver failure patients. We found that no different of CK elevation in both drugs. CK elevation was consistence with infection and hepatic renal syndrome. But long term safety of NAs has not been confirmed in liver failure patients. Antiviral therapy should be used for life because the NAs treatment can’t eradicate cccDNA in the hepatocyte. Some cirrhotic patients developed viral resistance to LAM during long-term LAM therapy which cause virologic response loss [142, 143]. In antiviral treatment naïve patient, The LAM resistance rate is up to 70% after 5 years of continuous therapy and the annual resistance rate is up to 20% [6], compared with that ETV resistance rate is less than 0.5% in patients treated with ETV at 4 years [144]. Therefore, LAM should be used with careful monitoring for the development of resistance. And ETV or TDF rather than LAM is recommended to be used as the first-line therapy in patients with HBV infection because of its high genetic barrier and potent activity against HBV replication [145]. Multiorgan failure occurred rapidly frequently in liver failure patients. Although some patients can recover treated by comprehensive and antiviral therapy, all patients should be evaluated for liver transplantation. It’s challenge to study the effect of NA, how and when to use NA and how to treat viral resistance to NA in liver failure patients. Further studies are needed to evaluate patient outcomes after antiviral therapy with NA in liver failure patients.

5.3

 ntiviral Treatment for Hepatitis B Virus Related Liver A Cirrhosis

Ke Ma and Qin Ning For patients with chronic hepatitis B (CHB), HBV continue replication caused progression of liver disease, eventually lead to cirrhosis or hepatocellular carcinoma.

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The principle of treatment for HBV-related cirrhosis is a comprehensive treatment, including antiviral, anti-inflammatory, hepatoprotective treatment and anti-fibrosis, which antiviral treatment is the key point. Since 1999, listed lamivudine, there were many new ideas and concepts on treatment for HBV-related cirrhosis, liver failure. A large number of evidence-based medicine evidence suggests that sustained suppression of HBV by anti-viral treatment can reduce liver inflammation and fibrosis, reduce or delay disease progression, and ultimately improve survival rates and quality of life. Internationally there are many CHB antiviral therapy management guidelines, but antiviral therapy for HBV-related cirrhosis was still a hot and difficult issue in clinic. This article reviews some of the new progress and new perspectives of antiviral therapy liver cirrhosis based on the recent research.

5.3.1 G  oals and Endpoints of Antiviral Treatment for HBV-­ Related Cirrhosis Management is guided by recommendations from the American Association for the Society of Liver Disease (AASLD) [6], European Association for the Study of Liver (EASL) [4], Asian Pacific Association for the Study of Liver (APASL) [146], and Society of Hepatology and Infectious Diseases of Chinese Medical Association (CMA) have formed a consensus [3]. Guideline 2015 edition issued by the Chinese Medical Association clearly stated that the overall goal of treatment is to CHB was to suppress HBV as long as possible, relieve inflammation or necrosis of liver cells and liver fibrosis, prevent the progression of cirrhosis, reduce and prevent the occurrence of hepatic decompensation, HCC and its complications, thereby improving the quality of life and survival rate. For patients with cirrhosis, whether compensated or non-compensated, antiviral treatment can delay or reduce hepatic decompensation and HCC occurs, does not change the final outcome of end-stage liver cirrhosis. In the guideline 2010 edition issued by the Chinese Medical Association, the goal of antiviral therapy in HBV compensated cirrhotic patients is to prevent progression of the disease to decompensated cirrhosis, end-stage liver disease, hepatocellular carcinoma. The goal of antiviral therapy in HBV-related decompensated cirrhosis is to improve the hepatic disease severity, improve the clinical symptoms and quality of life, and prolong patient’s survival. For the endpoint of the antiviral treatment, the definition of each guide is slightly different. Guideline 2018 edition issued by AASLD explicitly mentioned these patients with compensated cirrhosis should receive long-term treatment. However, treatment maybe stopped in HBeAg positive patients if they have confirmed HBeAg seroconversion and have completed at least 6 months of consolidation therapy and in HBeAg negative patients if they have confirmed HBsAg clearance. For these patients with decompensated cirrhosis life-long treatment is recommended. Guidelines 2008 issued by American Society of Digestive Disease [147] recommend long-term treatment until negative HBV DNA and HBsAg disappears. In the

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guideline 2017 edition issued by EASL, Endpoint of antiviral treatment has even been further subdivided into “ideal endpoint”, “satisfactory endpoint” and “basic endpoint”, where “ideal endpoint” means to achieve HBsAg clearance with/without HBsAg seroconversion.

5.3.1.1 Antiviral Therapeutic Indications Patients with liver cirrhosis generally have characteristics of longer course of disease, most of mother to child transmission, the large proportion of treated patients, high complexity of quasispecies and higher risk of resistance. The clinical treatment decisions in these patients need to consider a variety of factors, including long-term treatment, delay disease progression, improve histology, low resistance rates, good safety and patient tolerance, etc. There are differences in current guidelines of countries in antiviral therapy indications for liver cirrhosis, mainly cutoff viral load. For compensated cirrhosis, 2012 APASL guideline pointed HBV DNA >2000 IU/mL, 2009 AASLD guideline that the HBV DNA >2000 IU/mL or HBV DNA 500 IU/L in HBV DNA positive patients for 3–6 months post-LT. Compared to the monotherapy of HBIG or lamivudine, these combined treatments are highly effective [261, 277]. However, the long-term use of HBIG has many disadvantages, such as high cost, the need for injection, headache, flushing, and chest pain [270, 278]. Moreover, the long-term use of lamivudine induces viral resistance, which leads to a high rate of recurrence post-LT [162]. A number of studies have shown that IM HBIG has similar kinetics and produces roughly equivalent trough concentrations of anti-HBs compared to IV equivalent doses of HBIG but less expensive [279]. The largest reported data of prophylaxis with using of IM HBIG comes from investigators in Australia and New Zealand [280]. IM 400 or 800 IU HBIG daily for 1 week from transplantation and monthly thereafter. Lamivudine, 100 mg/day, was administered to candidates waiting for transplantation with hepatitis B surface antigen (HBsAg)-positive and continued posttransplantation. Thirty-seven patients with positive HBsAg (34 patients had hepatitis B, 2 patients had hepatitis B and C, and 1 patient had hepatitis B, C, and D) underwent liver transplantation using this protocol. Thirty-six patients were HBV DNA positive. The therapy had no significant adverse events and was well tolerated. All patients were HBV DNA negative and 31 patients were HBsAg negative at latest follow-up. This investigation suggested that low-dose HBIG combined with Lamivudine prevented recurrence of hepatitis B posttransplantation is more cost-effective. Long-term results of this protocol showed that the actual rate of HBV recurrence at 5 years was 4% in 147 HBsAg-positive patients underwent liver transplantation [281]. Recently, entecavir and tenofovir have been approved as the first-line regimen for the treatment of chronic hepatitis B. These new NAs have replaced lamivudine as the prophylaxis of HBV recurrence post LT. According to EASL Clinical Practice Guidelines, to achieve the lowest level of HBV DNA pre-LT, NAs with high barrier to resistance is recommended as pre-transplant antiviral therapy for all HBsAg positive patients undergoing liver transplantation [4]. Hu et al [282] reported a lower hepatitis B recurrence rate in patients received entecavir than those received lamivudine. A total of 145 patients were administered entecavir combined with low-­ dose HBIG, and 171 patients received lamivudine plus low-dose HBIG in the control group. Two patients in the entecavir group developed HBV recurrence with no evidence of viral resistance in the median 36 months follow-up time. Eleven patients in the lamivudine group developed HBV recurrence, three of whom were proved HBV resistance in the median 77 months follow-up period. Further analysis demonstrated that HCC at the time of liver transplantation and low anti-HBs titer post-liver transplantation were independent risk factors for HBV recurrence. Perrillo

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et al. [20] investigated the efficacy of entecavir combined with various HBIG regimens after liver transplantation. Sixty-one patients with HBV-related liver disease took 1.0 mg/day of entecavir plus various HBIG regimens. In the median 72 weeks follow-up period, only 2 patients showed positivity HBsAg but HBV DNA remained undetected. Na et al. [283] showed that 4 of 262 recipients who received entecavir plus HBIG experienced HBV recurrence after liver transplantation in the median 49 months follow-up time. Among these 4 patients, 3 had received lamivudine followed by entecavir. Studies concerning the efficacy of tenofovir in the prophylaxis of HBV reinfection post-LT are limited. Jiménez-Pérez et  al. [284] reported that four patients received tenofovir plus HBIG with or without entecavir for the prophylaxis of hepatitis B recurrence. No hepatitis B recurrence was observed in these four patients at 12 months. Several researchers have investigated if it was possible to stop HBIG after an initial successful prophylaxis with combined HBIG/lamivudine. In one largest prospective study, 29 patients who were HBVDNA negative before liver transplantation received prophylaxis with HBIG/lamivudine for 1 month after transplantation, then they were randomized to continue combination prophylaxis or lamivudine monotherapy [285]. The early results showed that there was no recurrence case in either group by 18 months. However, 15–20% of the patients who were converted to lamivudine monotherapy had viral breakthrough because of lamivudine resistance in longer follow-up [286]. An alternative choice was to change from HBIG/lamivudine to a combination of antiviral drugs had a higher barrier of resistance than lamivudine. Several studies indicated that this method may be more effective [287, 288]. In a prospective study, 16 of 34 patients receiving prophylaxis with low-­dose IM HBIG/ lamivudine 12  months post-LT were changed to adefovir/lamivudine combination therapy, whereas the other patients continued previous prophylaxis [288]. At a median of 21 months post-switch, patients in both group had no recurrence. One A low titer of HBsAg in serum was detected in 1 patient in the adefovir/lamivudine group but HBV DNA was negative. This change in therapy improved the life quality of patients and significantly saved the cost. More recently, a multicenter, prospective study demonstrated the results of HBIG-sparing regimen combined with lamivudine plus adefovir dipivoxil initiated at the time of waiting for liver transplantation and continued post-transplantation [289]. Twenty-six patients were recruited into this study at the time of listing for transplantation. Twelve patients had LAM exposure before the study, but none had lamivudine resistance. To the 20 patients who underwent transplantation, 800 IU/day of intramuscular HBIG was given immediately after transplantation for 7 days. All transplanted patients remained alive without HBV recurrence at a median of 57 months after transplantation. After the completion of this prospective study, the regimen was modified that no perioperative HBIG was administered if the pretransplant HBV DNA level 10 IU/L following cessation of HBIG and immunization with 1–3 courses of recombinant IM HBV vaccine [290, 291]. However, other investigations using the same protocol have failed to replicate these results [292, 293]. Moreover, the low response (16–62%) was reported in cirrhotic patients awaiting for LT [294]. More recently, Di Paolo et al investigated the efficacy of 1 year, monthly vaccination together with HBIG plus lamivudine in LT patients. One year after vaccination, 44.4% patients maintained anti-HBs titers more than 100 IU/L [295]. These results suggested that HBIG can be considered as an additional strategy in the prophylaxis against HBV recurrence post LT: (1) vaccine administration should be long-lasting (e.g. 1 year); (2) passive prophylaxis with HBIG should preferably be maintained during the initial phase of vaccination and NAs should be maintained during the entire vaccination period.

5.5.3 M  anagement for Hepatitis B Recurrence and Drug Resistance After Liver Transplant Lamivudine is the most widely used NA to prevent hepatitis B recurrence. However, lamivudine resistance can result in hepatic decompensation and increases the rate of post-transplant recurrence. Newer NAs with lower resistance rates should therefore replace lamivudine in hepatitis B prophylaxis. Schiff et  al [296] investigated the effect of adefovir dipivoxil as the rescue therapy in listing or post-LT patients with chronic hepatitis B and lamivudine-resistance. Among listing patients, the percentage of HBV DNA levels undetectable at weeks 48 and 96 was 59% and 65%, respectively. After 48 weeks, liver function normalized in 77% and 76% of these patients respectively. And coagulation function normalized in 60% and 84% of these patients respectively. Among post-transplantation patients, the percentage of serum HBV DNA levels undetectable at weeks 48 and 96 was 40% and 65%, respectively. After 48 weeks, liver function and coagulation function normalized in 51%, 81%, 76%, and 56% of these patients, respectively. Among listing patients who underwent liver transplantation, prevention of graft reinfection over a median of 35 weeks was similar among patients who did or did not receive HBIG. HBsAg was detected on the first test only in 6% and 9% of patients who did or did not receive HBIG, respectively. Serum HBV DNA was detected on follow-up in 6% and 0% of patients who did or did not receive HBIG, respectively. Adefovir dipivoxil-­ related adverse events occurred in 4% of patients and led to drug withdrawal. Cumulative resistance rate were 0%, 2%, and 2% at 48, 96, and 144 weeks, respectively. In conclusion, adefovir dipivoxil is safe and effective in prevention of graft reinfection with or without HBIG for listing or post-transplant CHB patients with lamivudine-resistance. More recently, one study indicated that late HBIG replaced by adefovir dipivoxil (at least 12 months post-transplant) can prevent late HBV recurrence at less cost [288]. In a prospective open-labeled study, lamivudine plus adefovir dipivoxil given from the time of listing was well tolerated, prevented

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lamivudine resistance pre-transplantation and post-transplantation, regardless of the baseline HBV-DNA level [289]. The rescue therapy for patients with lamivudine or telbivudine resistance is to add adefovir or tenofovir, or change to tenofovir + emtricitabine. For patients with adefovir resistance, the approach is to add lamivudine or entecavir, or switch to tenofovir + emtricitabine. For patients with entecavir resistance, the approach is to add adefovir or tenofovir. Combination therapy is still effective for some patients with multi-antiviral drugs-resistance according to evidence based medicine and clinical practice [297]. Regular monitoring and follow-up for patients post LT is also very important. Items include liver function, hepatitis B markers, HBV DNA quantitative, mutant, blood concentration of immunosuppressive drug and ultrasound examination. For hepatitis B recurrence patients, therapy include: support treatment, hepatocyte protection, anti HBV therapy, immunosuppressant regimen adjustment (withdrawal, reduction or change immunosuppressive agents) and liver retransplant.

5.5.4 P  rospects of Antiviral Therapy for Liver Transplant Patients Hepatitis B is a major cause of liver failure in Asia, although the use of HBIG plus lamivudine can effectively prevent HBV reinfection in liver transplantation, but the cost is high. Active immunization approach is still controversial. Combined HBIG/ nucleos(t)ide prophylaxis should be considered to switch to oral prophylaxis at 1 or 2 years post-LT, particularly in patients with low HBV DNA loads before antiviral therapy or HBV DNA negative at LT, and in patients with liver failure due to HBV or HDV coinfection, since these patients are at lower risk of recurrence once HBIG is ceased. Recently, the seminal discovery of sodium taurocholate co-transporting polypeptide (NTCP) as the cellular receptor for HBV entry has opened up many channels of investigation, making HBV entry amenable to therapeutic intervention. Several FDA approved drugs with NTCP inhibiting activity were tested for their ability to inhibit HBV infection of the cell line [298–300]. These investigations indicate the possibility of using NTCP inhibitor in the prophylaxis of hepatitis B recurrence post LT.

5.6

Novel Antiviral Therapies for Hepatitis B

Di Wu and Qin Ning

5.6.1 Definition of “Cure” for HBV Infection Both host and viral factors are associated with the chronicity of HBV infection. HBV has a capability of escaping the host immune responses. More importantly,

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The HBV genome forms a stable minichromosome, namely covalently closed circular DNA (cccDNA), in the nuclei of infected hepatocytes, enabling HBV to persist its infection [301]. The goal of anti-HBV therapy is to prevent the progression of HBV-related liver disease, which may be achieved initially through sustained immunologic control over HBV, and ultimately, by completely eliminating the virus [4, 302, 303]. However, due to the fact that HBV cccDNA persists stably at a very low level even after the loss of HBsAg in chronic infected patients, elimination of HBV (complete cure) is rarely achieved. It is suggested that serum HBsAg could represent a surrogate marker of intrahepatic cccDNA and a marker of host immune control of HBV infection. Seroclearance of HBsAg is found to be associated with functional remission and improved long-term clinical outcomes in patients with chronic hepatitis B, under this circumstance, even though HBV genome cannot be cleared, the host immune system is in general sufficient to control the few persisting infected hepatocytes [304–306]. Therefore, HBsAg seroclearance with or without the appearance of HBsAb (functional cure) is considered the ideal endpoint for anti-­ HBV therapy, representing durable immunologic control over the virus and complete suppression of HBV replication, which is the critical step towards complete cure for hepatitis B [4, 302, 303]. NUC and IFN or its PEGylated form, Peg-IFN, are the only two types of approved antiviral therapeutics. As the ideal endpoint for anti-HBV treatment, HBsAg loss is achieved in very few patients after long-term NUC or 48-week courses of Peg-IFN therapy [307–309]. These current standard antiviral therapies can only suppress the HBV replication and viral protein production, but cannot eliminate HBV cccDNA and cure chronic HBV infection. Therefore, new treatment approaches such as optimal combination therapy with the approved antivirals or emerging novel therapeutics are needed to improve rates of HBsAg loss and, ideally, HBsAg seroconversion.

5.6.2 Interferon-Based Combination Therapy Different characteristics, mechanisms of action and antiviral activities of NUC and IFN provide the possibility of combining these two types of agents for improving chances of sustained post-treatment response, thereby allowing the discontinuation of NUC without virus relapse, through harnessing both immunomodulatory and direct antiviral mechanisms [310, 311]. According to the updated Chinese Guidelines, Asian-Pacific guidelines, as well as European guidelines for the treatment of chronic hepatitis B, sequential therapy with additional Peg-IFN or switching to Peg-IFN can be considered in CHB patients who have achieved virological remission by long-term NUC treatment [312], though clinical trials evaluating either simultaneous or sequential combination therapy with NUC and IFN for CHB patients drew different conclusions. Several previous studies exploring the efficacy of simultaneous combination with Peg-IFN and LAM or ADV have demonstrated that the therapeutic strategy led to higher rates of virological response during treatment, but did not improve durable

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post-treatment responses [308, 309, 313, 314]. An exploratory study showed that combination treatment with Peg-IFN plus ADV for 48 weeks led to remarkable decline in serum HBV DNA level and intrahepatic cccDNA, which was significantly correlated with reduced serum HBsAg [315]. A recent study evaluating the efficacy of combination therapy with LdT and Peg-IFN in HBeAg-positive CHB patients have demonstrated that the combination therapy led to greater reductions in HBV DNA and HBsAg levels, however, it may contribute to an increased risk of unexpected severe peripheral neuropathy, combination therapy with LdT and Peg-­ IFN should not be used [316]. In a prospective, active-controlled randomized trial evaluated loss of HBsAg in patients receiving the combination of TDF and Peg-IFN for a finite duration, CHB patients were randomly assigned to receive combination therapy for 48 weeks, combination therapy for 16 weeks followed by TDF for 32 weeks, TDF for 120 weeks, or Peg-IFN for 48 weeks. The study demonstrated that, 9.1% of patients receiving 48-week course of combination therapy with TDF and Peg-IFN had HBsAg loss, which was significantly higher than those receiving TDF or Peg-IFN given alone [317]. However, it is worth noting that a prolonged follow­up of these subgroups of patients is required to determine the durability of treatment response and long-term benefits. Although simultaneous combination of Peg-IFN and NUC other than TDF may not improve sustained response rate, the optimal approach for combination treatment remains to be determine and should take into consideration the time schedule of drug administration. Late breaking clinical trials have demonstrated that sequential combination therapy with NUC and IFN, either “switch” or “add-on”, showed more promising results, with higher probabilities of HBeAg seroconversion and HBsAg loss than NUC monotherapy. An observation study has shown that the add-on of Peg-IFN to a stable NUC therapy in CHB patients with suppression of HBV DNA, induced HBsAg seroconversion in 2 out of 12 patients [318]. A prospective study demonstrated that additional of Peg-IFN to a long-term NUC treatment in HBeAg-negative patients with undetectable HBV DNA, led to a durable HBsAg loss in 6 out of 10 patients [319]. A global multicentered, randomized controlled trial (ARES study) assessed the effectiveness of add-on Peg-IFN to ETV therapy in HBeAg positive patients, compared to ETV monotherapy, 24 weeks of Peg-IFN add-on therapy did not improve response rates (defined as HBeAg loss with HBV DNA 1.5 and the presence of hepatic encephalopathy (HE). In China, where acute on chronic disease is more prevalent the presence of HE is known to be associated with a poor outcome. However, although HE is important both for or diagnosis and prognosis of CSH, HE is not a common finding in CSH in China and subclinical HE is difficult to diagnose. In North America and Europe, HE is easily diagnosed in patients with acute liver injury, whereas while in China jaundice, not HE, was common in patients with CSH. Newer models that have been adapted to assess severity of liver disease including the Mayo Model for end stage liver disease (MELD) have not proven to be of value in patients with CSH. In addition to etiology, a number of other factors influence outcome of CSH, including age, co-morbidities, total bilirubin level, prothrombin time (INR), and serum creatinine. Other additional factors that may be of value include the measurement of levels of α fetal protein (AFP) which may be indicative of hepatic regeneration and complications including the development of HE and hepato-renal syndrome.

6.1.1.1 Age Patients over 40 years of age who develop ALF and CSH have a higher mortality. Although the exact reason for this is not clear it is known that elderly patients have poor immunity and often succumb to severe infections. Additionally, hepatocyte regeneration is reduced in the elderly. 6.1.1.2 Host Factors There have been few studies on genetic susceptibility to severe hepatitis B. However, data is emerging largely derived from studies conducted in the Asian population that variability in both innate and adaptive immune response genes including tumor necrosis factor (TNF-α and TNF-β), interleukin-10 (IL-10), interferon-γ inducible protein 10 (IP-10, CXCL-10), vitamin D receptor (VDR), and human leukocyte antigen (HLA) as well as the ability to mount an appropriate cell mediated antiviral response are associated with outcome.

6.1.2 Prognostic Indicators of Severe Hepatitis B 6.1.2.1 Total Bilirubin Bilirubin is taken up and metabolized in the liver, so that levels of serum bilirubin are an excellent measure of liver excretory function. High bilirubin levels are indicative of deterioration of liver function. In CSH there is massive hepatocyte necrosis,

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which results in decreased absorption, transportation, binding and excretion of bilirubin. Thus, measurement of serum total bilirubin level is positively correlate with degree of hepatocyte necrosis. Furthermore in CSH, it is known that patients with high bilirubin level have a poor prognosis.

6.1.2.2 Serum Cholesterol The liver also plays a key role in the absorption, synthesis and transportation of cholesterol. Liver supplies 60–80% total body cholesterol. When hepatocytes are severely damaged, the synthesis of cholesterol decreases and cholesterol levels correlate with degree of liver injury and mortality. Thus, levels of cholesterol are indicator of poor liver synthetic function. 6.1.2.3 Serum Albumin Albumin is known to be synthesized in the rough endoplasmic reticulum (RER) of hepatocytes. When hepatocytes are severely damaged, synthesis of albumin decreases and serum albumin levels fall. However as the half life of albumin is 20 days, measurements of albumin do not reflect acute injury and therefore do not correlate with prognosis especially in patients with acute liver necrosis. Furthermore, the use of albumin infusions also limits the usefulness of measurement of serum albumin as a predictor of outcome. Prealbumin is also synthesized by hepatocytes and has a shorter half-life. It is relatively easy and inexpensive to measure prealbumin and thus measurement of serum prealbumin levels potentially could be a more sensitive and specific measure of liver function. 6.1.2.4 Hepatic Encephalopathy (HE) HE is neurological and psychiatric disorder that is seen during all phases of liver failure. But especially in patients with CSH and cirrhosis. Precipitating causes of HE include upper gastrointestinal tract hemorrhage, ingestion of a high protein diet, infection and large volume drainage of ascites. It has been reported by the King’s College Group that the presence of HE and a high INR are associated with poor outcome in ALF (ref). It is also known that patients with CSH who develop HE also have a poor prognosis and high mortality. Thus it is important to prevent and early treat HE to improve patient outcomes. 6.1.2.5 Acute Kidney Injury (AKI) and HRS Disturbances in hemodynamic parameters including systemic vasodilation is a common complication of cirrhosis. The result of changes in blood flow in the splanchnic system leads to reduced blood flow to abdominal organs including the liver and kidneys. This leads to water sodium retention (ascites formation), increased total intravascular volume and increased cardiac output. The development of liver cirrhosis, leads to systemic vasoconstriction and reduced renal blood flow. The compensatory increase in cardiac output is usually insufficient to sustain perfusion pressure (high output heart failure), leading to a further reduction in renal blood flow and kidney failure. Ultimately this may lead to the development of hepatorenal syndrome (HRS), which is one of the most serious complications of end-stage liver disease.

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As a consequence of complications of cirrhosis including GI hemorrhage, ascites, serious infections, patients often develop acute renal injury manifested by oliguria or anuria, azotemia and electrolyte imbalance. Although the pathogenesis of HRS is not totally known, most scholars believe that it is secondary to a functional rather than structural renal change. Once HRS develops survival rates decrease markedly and patients survival may only be 1–3 months. Differences between AKI and HRS were as following: (1) HRS occurs in patients with liver cirrhosis who have ascites and a serum creatinine (Cr) >133 μmol/L; (2) acute kidney injury (AKI) is characterized by a precipitous rise in serum creatinine Cr to >26.4 mmol/L, or a 50% increase above baseline. To firmly make the diagnosis of HRS it is important to rule out extra hepatic causes of renal failure. In contrast the diagnosis of AKI is relatively straightforward but treatment must be individualized and directed to precipitating causes.

6.1.2.6 AFP Serum alfa fetoprotein (AFP) is a glycoprotein which is mainly synthetized in human embryonic liver. Levels of AFP decrease with age but increases can be seen in patients with acute or chronic viral hepatitis reflecting both liver damage and liver cell regeneration. Levels of AFP in patients with fulminant hepatitis, is regarded as an index of liver cell regeneration, AFP decreases in patients with severe hepatitis indicating stem cell necrosis and poor regeneration. In a prospective study, AFP levels in ALF had a dynamic change; a higher level of AFP was not found to be associated with a good prognosis, however, patients with high levels of AFP levels within 3  days after hospitalization had a better prognosis, probably reflecting hepatocyte regeneration. In patients with CSH, levels of AFP remained above baseline probably reflecting ongoing liver damage. Sustained elevations of AFP are often associated with the development of hepatocellular carcinoma (HCC). 6.1.2.7 Gc Protein Gc protein, also referred to Vitamin D-binding protein (DBP), is an α globulin and a member of the multi-gene superfamily which includes albumin, prealbumin and alpha fetal protein (AFP). Most of these proteins have approximately a 55 kU in molecular mass and are secreted by the hepatic parenchymal cells. Gc protein is highly abundant in serum and binds to vitamin D and has many physiological functions, including the removal of actin, enhancement of chemotactic activity and macrophage activation of C5 on neutrophils, regulation of the activity of osteoclasts and transport of fatty acid and endotoxin. As Gc protein is produced by liver cells, changes in levels of Gc protein can reflect changes in liver function including the amount of hepatic necrosis and degree of liver reserve. Thus measurements of levels of Gc may be if use in estimating the prognosis of patients with fulminant hepatic necrosis. It has been suggested that reduced levels of Gc protein may lead to actin deposition in the blood vessels leading to multiple organ failure. Therefore, Gc protein can also be a useful indicator for measuring ALF multiple organ failure.

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6.1.2.8 Serum Sodium Level Hyponatremia is seen often in patients with CSH. Serum sodium concentration in patients is related with presence of liver cirrhosis, refractory ascites, spontaneous bacterial peritonitis, hepatic encephalopathy and hepatorenal syndrome [2]. Some believe that hyponatremia should be added into the new model for end-stage liver disease (Na MELD) to improve its predictability (ref). A number of studies have suggested that hyponatremia is an important index for evaluating the prognosis of liver cirrhosis. Studies have shown that relative risk (RR) of levels of serum sodium was 0.023, which suggest that serum sodium may be a protective factor affecting the prognosis. So, maintaining normal serum sodium could reduce the risk of death in patients with severe hepatitis. Hyponatremia might result in increase of osmotic pressure difference between intracellular and extracellular pressure and induce or aggravate brain edema and increase the incidence of hepatic encephalopathy and central pons demyelinating lesions. Central pons demyelinating lesions with hyponatremia might be precipitated by rapidly replacing sodium. It was worth noting that although hyponatremia, refractory ascites and AKI can all exist independently, but in most patients they are interconnected (Fig.  6.1). Hyponatremia is seen in nearly half of patients with decompensated cirrhosis who have sodium and water retention. Hyponatremia is known to be associated with intractable ascites and AKI.  Once refractory ascites develops, worsening hyponatremia and sodium and water retention results in AKI. Finally, AKI, as a final complication, in turn, leads to hyponatremia (including water sodium retention) and refractory ascites. Given the extremely high case fatality rate for AKI, dealing with hyponatremia as soon as it develops is key to prevent refractory ascites and AKI.  Therefore, the prevention of hyponatremia might improve the survival rate in patients with CSH. Hyponatremia and water-sodium retention can become important reasons of refractory ascites and AKI, meanwhile, refractory ascites can also lead to further development of hyponatremia and water-sodium retention, and result in the incidence of the complication of AKI eventually; Following the incidence of AKI, it will in turn cause the occurrence of hyponatremia (including water-sodium retention) and refractory ascites.

Fig. 6.1  The relationship among the hyponatremia, refractory ascites and AKI

Hyponatremia and water-sodium retention

Refractory ascites

AKI

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6.1.2.9 Virus Factors In Asia, serious hepatitis B occurs mostly on the basis of CHB, CHB is divided into two categories: HBeAg positive and HBeAg negative, the pre-C area or core area promoter mutation of hepatitis B virus (HBV) is the main mechanism of severe HBeAg-negative CHB development. At present, reports from China as well as the rest of the world show that the proportion of HBeAg negative CHB patients is increasing. As an example data emerging from Taiwan and Hong Kong shows that the proportion of HBeAg negative CHB is about 90% of total CHB [3]. The effect of HBeAg on the prognosis of severe hepatitis has now been studied extensively, and it was found that the prognosis of HBeAg negative severe hepatitis B patients was worse than that of HBeAg positive patients. A possible reason for this finding is that chronically infected patients are HBeAg negative for a long time, their average age is greater and these patients have liver cirrhosis. The presence of liver cirrhosis is an important prognostic factor in patients with CSH.  It is known that, patients with cirrhosis are more susceptible to hepatic decompensation, the development of hepatic encephalopathy and hepatorenal syndrome. 6.1.2.10 Genotype Studies in China and throughout the world have shown that HBV genotype may also be related to disease progression, clinical manifestations, prognosis and response to antiviral therapy. Although a number of studies have examined the effect of genotype on anti-HBV response and drug resistance, there has been to date no systematic and comprehensive study examining this and the published results differ significantly. A number of studies have examined the effect of interferon therapy on HBeAg positive CHB patients. Hou et al. showed, that the treatment response of patients who were infected with HBV genotype A was better than that of patients who were infected with non-genotype A [4]. Kao et al. from Taiwan reported in their study that the response rate was 41% and 15% in 58 cases of patients with CHB and chronic hepatitis C (CHC), respectively [5]. There is still considerable debate regarding the inconsistent research results in China investigating the effect of lamivudine on anti-HBV responses. Studies have shown that the treatment response and resistance rate of genotype B were better than those of genotype C, the HBV YMDD mutant (YIDD/YVDD) occurred frequently in genotype C and genotype D. Long-term efficacy of lamivudine on antiHBV responses conducted by Kobayashi et  al. showed that genotype A was more susceptible to develop the YMDD mutation than genotype B and genotype C. HBV DNA levels have been found to affect the prognosis of patients with chronic severe hepatitis B. A previous study reported that the HBV DNA level in patients who died was higher than that in patients who responded to medical therapy (ref). In the group of patients with chronic severe hepatitis B who died, HBV DNA high replication accounted for 61.26% of the total cohort. Although the virus load was not directly related to liver damage in patients with chronic severe hepatitis, HBV DNA negative conversion was an important factor that disease could be controlled. Hache et al. also has reported that serum HBV DNA levels were independent predictors of disease progression of hepatitis B [6]. In that study, the rates of

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improvement and median survival time of 3 months in patients with early and late treatment with antiviral therapy, suggesting that use of early antiviral therapy can reduce hepatic necrosis and promote tissue repair and regeneration through reduction of HBV replication.

6.1.2.11 Fasting Blood Glucose (FBG) The liver is known to be important for maintaining blood sugar balance through glycogen synthesis and gluconeogenesis. Patients with severe hepatitis have a decreased ability to inactivate insulin, leading to increased blood insulin levels and low blood sugar levels. Fasting blood glucose levels were closely related to the severity of hepatitis and in patients with severe hepatic necrosis the incidence of hypoglycemia has been reported to be higher. Fasting blood glucose levels are negatively correlated with serum total Bilirubin and positively correlated with PTA value. At the same time, fasting blood glucose levels were closely related to prognosis. The presence of hypoglycemia is the setting of CSH is associated with a lower clinical recovery rate and worse prognosis. These results fully showed that detection of fasting blood glucose is important to understand the degree of liver cell necrosis, and its monitoring may be useful in predicting the survival rates in patients with CSH.

6.1.3 Indicators for Evaluating Prognosis of Severe Hepatitis B A Diagnostic model of prevention and control standards for patients with CSH was created at the 2000 national conference on the 10th of viral hepatitis in Xi’an. In 2006, experts from China came together to establish guidelines for the diagnosis, prognosis and treatment of patients with liver failure. Meta analysis of patients with CSH (2429 cases) found that total bilirubin, prothrombin activity (PTA), hepatic encephalopathy, levels of serum creatinine and AFP were different between patients who survived and died (Table 6.1). Table 6.1  Analysis of the comparison results of TBil, PTA, AFP, hepatic encephalopathy and creatinine level between the survival group and the death group

Variable T.BiL

Number of Heterogeneity research literature Q P 14 155.91 0.00

Effect sizes and parameters I2% 89.5

WMD 132.10

95% CI 96.40–177.90

Z 5.66

P 0.00

−10.20 to − 5.20 −129.29 to − 24.50 0.27–0.51 1.27–1.49

6.03

0.00

2.88

0.01

6.61 8.02

0.00 0.00

PTA

9

93.62

0.00

54.3

−7.75

AFP

6

75.20

0.00

92.0

−76.90

Creatinine HE

5 7

6.17 14.96

0.29 0.04

35.1 62.1

0.39 1.38

Redraw from Lin Ju-Sheng, et al. Meta analysis on prognostic factors of patients with severe hepatitis B. Chinese Journal of Experimental and Clinical Infectious Diseases (Electronic Edition): 2011. 5(1): 14–19. https://doi.org/10.3877/cma.j.issn.1674-1358.2011.01.003 [Article in Chinese] [7]

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In recent years, studies have shown that some clinical signs of liver failure patients, serum biochemical/radiographic parameters and application of antiviral therapy were closely related to the prognosis of CSH suggesting that these data could be used for assessing the prognosis of liver failure.

6.1.3.1 Clinical Signs It is known that a number of clinical parameters are associated with outcome to HBV infection including male gender, older age, poor nutritional status, development of jaundice and signs of clinical deterioration including presence of ascites or poor coagulation (bruising). Although not specific, they are associated with poor outcomes. 6.1.3.2 Biochemical Parameters Besides routine laboratory tests including serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), AST/ALT ratio, α fetal protein (AFP), total bilirubin (TBil), prothrombin activity (PTA), total cholesterol (TC), cholinesterase (CHE) and albumin, in recent years a number of factors related to the prognosis have been found. These include arterial blood ketone body ratio, imaging examination, levels of the Gc protein, osteopontin, fibronectin, cortisol concentration, serum free fatty acids, prealbumin, fasting glucose, tumor necrosis factor alpha (TNFα), c-reactive protein (CRP), peripheral blood vitamin D binding protein, serum sodium, arterial blood lactic acid salt and blood ammonia [8–10]. 6.1.3.3 Prognostic Indicators Still in the Research Some additional markers might be associated with the prognosis of CSH, including hepatocellular apoptosis or necrosis related markers (coagulation protein sol, M65/ antigen, cytochrome C, etc.), liver cell proliferation, regeneration markers such as follicle inhibition/activin A (follistatin/activin A, F/A) ratio, aging marker protein 30 (senescence marker protein 30, SMP30), stem cell factor (stem cell factor, SCF), and factors that promote the platelets (TPO thrombopoietin). It is well known that the immune system contributes both to liver injury and repair. For example, HBV infected hepatocytes are surrounded by a large number of mononuclear—macrophage cells (Kupffer cells), which contribute to liver cell apoptosis through secretion and release of a number of inflammatory cytokines including TNF alpha, interleukins and interferons. Some indicators reflect mono-macrophage function including expression of CD163, CD154, human leukocyte antigen (human leukocyte antigen, HLA) and other biomarkers such as micro RNAs (miRNAs), called S100b, troponin I and other markers, which also showed potential prognostic value of CSH. 6.1.3.4 Coagulation Factors The liver is pivotal to coagulation and the vast majority of clotting factors such as I, II, VII, X, XI are synthesized in the liver. Patients with CSH, who have marked liver parenchyma necrosis have reduced hepatic synthesis of clotting factors, increased consumption leading to prolongation of prothrombin time and PTA decline.

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Table 6.2 Biological half-lives of liver-synthesized clotting factors

Clotting factors Factor I (Fibrinogen) Factor II (Prothrombin) Factor V Factor VII Factor IX Factor X a

Half-life 1.5–6.3 days 2.8–4.4 daysa 12–36 h 2–5 ha 20–52 ha 32–48 ha

Vitamin K-dependent posttranslational carboxylation

Fulminant hepatitis is associated with marked disturbances in coagulation including a decrease a number of clotting factors, especially factor VII and V (Table  6.2). Measurement of prothrombin time (PT) and activated partial-thromboplastin time (APTT) is used to evaluate the risk of bleeding in ALF patients. Used international standardization ratio (INR) to measure PT, when INR 1.5 or higher, is an important diagnostic and prognostic indicator of ALF.  When the INR  ≥6.5 prognosis was generally poor. Researchers have shown that through comprehensive Logistic regression analysis older age (>40  years), plasma prothrombin activity decrease (≤10%) and the presence of systemic inflammatory response syndrome (SIRS) are indicators of poor prognosis of CSH. Coagulation dysfunction is an important diagnostic and prognostic indicator for liver failure (including CSH), so monitoring of coagulation factors has proven to be a useful indicator of poor prognosis Platelet was one of important participators in coagulation. Numbers and function of blood platelets change during liver dysfunction. Because thrombopoietin (TPO) is synthesized primarily in the liver, when CSH occurred, TPO synthesis decreases, resulting in decreased numbers of platelets. Chan et al. has reported that only platelet count (≤143*E+09/L) and serum bilirubin (>172  μmol/L) are independent prognostic factors for mortality of CSH in patients without HE. Mortality of CSH with high blood bilirubin and a low platelet count was 69%; with a low platelet count alone was 11; with a high blood bilirubin was 13% and without both there was no mortality. Others have confirmed these results (Table 6.3).

6.1.4 P  rognosis Assessment Analysis of Severe Hepatitis B (Comparison of Different Analysis System) CSH accompanied by marked liver cell necrosis caused by excessive immune response is associated with a very high mortality. According to the severity of disease it is critical to evaluate the early prognosis to guide the best clinical treatment, including comprehensive medical treatment, artificial liver support and liver transplantation. Different countries have now adopted MELD and the King’s College scoring system to evaluate CSH.  The MELD score was mainly used initially to determine candidacy for TIPS and later adapted to determine priority of liver transplantation [11]. Factors affecting prognosis of CSH have always been hot spots of

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Table 6.3  The independent prognostic factors of acute-on-chronic severe hepatitis B

Age Sex Albumin Bilirubin Prothrombin time ALT PLT HBeAg HBV DNA Serum creatinine AFP Liver fibrosis Ascites Child–Pugh grade

Chan et al. N = 46 – – – Increase (>172) – – Reduce (≤143 × 109/L) – No study – No study No study No study No study

Yuen et al. N = 47 – – Reduce Increase Extend – Reduce

Chien et al. N = 91 – – – Increase Extend – –

Tsubota et al. N = 50 – – – Increase Extend – –

– – – – Emergence – High

– – – – – Emergence High

– – No study – Emergence – No study

HBeAg Hepatitis b virus e antigen, – no difference

research. Global regional different etiology of CSH causes different prognostic factors, and ALF internationally is mainly caused by the overuse of acetaminophen, but by HBV infection in China.

6.1.4.1 MELD Scoring System The model for end-stage liver diseases (MELD) mainly used bilirubin, INR and Creatinine and etiology to evaluate end-stage liver disease. In 2000 Malinchoc et al. first used MELD to predict mortality of end-stage liver disease patients received transjugular intrahepatic portosystemic shunt (TIPS) and confirmed that MELD was useful to predict end-stage liver disease mortality and postoperative survival time [12]. The MELD formula was, R  =  3.8 ln[total bilirubin (mg/ dL)] + 11.2 × ln(INR) + 9.6 ln/creatinine (mg/dL) + 6.4 × (etiology: cholestasis and alcoholic liver cirrhosis is 0, other reasons for 1). Kamath et al. modified formula for convenient for calculating as follows: R = 3.8 ln[total bilirubin (mg/dL)] + 11.2 ln(INR) + 9.6 ln/creatinine (mg/dL) + 6.4 (etiology: bile or alcoholic 0, other 1). Value of R positively correlated with mortality and negatively correlated with survival rate [13]. The MELD score for patients with liver failure provided an effective evaluation index. In MELD classification, however, serum creatinine, bilirubin and INR, were easily influenced by other diseases, which could directly affect liver disease. Therefore, in order to avoid extrahepatic factors fluctuations affecting accuracy of the MELD classification of serum creatinine, MELD classification should be used in the patient’s hemodynamic stability and on the basis of full rehydration. At the same time, MELD score had yet to incorporate other factors which affect outcome including, ascites, hemorrhage, hepatic encephalopathy, because complications of liver cirrhosis including the presence of portal hypertension might directly threaten

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patients’ life. The MELD scoring system has proven to be a highly effective model for assessing end-stage liver disease, and had important clinical value in evaluating liver disease severity and prognosis.

6.1.4.2 MELD-Na Scoring System Hyponatremia in liver failure patients is mainly caused by peripheral arterial expansion, effective blood volume reduction, peripheral blood circulation deficiency stimulating pressure sensor and volume receptor activating three kinds of vasoconstrictor systems, including the vasopressin system, the aldosterone renin-­ vasoconstriction system and the sympathetic nervous system, all of which act on kidneys, causing water sodium retention and diluted hyponatremia. These neurohumoral systems and the degree of kidney damage are associated with the severity of portal hypertension. Thus, serum sodium could be used to reflect the severity of portal hypertension. Portal hypertension is an important factor in patients with liver failure leading to a number of complications and is a leading cause of death in CSH. Some reports have shown that hyponatremia is an independent predictor of hepatorenal syndrome, and it has become apparent that serum sodium is an important prognosticator of liver cirrhosis. Recognition of this has led to adding serum sodium into MELD to define new scoring formula. The MELD-Na calculation formula is: the MELD score-Na = MELD + 1.59 × [135 − serum sodium (mmol/L)]. When serum sodium is greater than 135  mmol/L, serum sodium is equal to 135 mmol/L in calculation. When serum sodium is less than 120 mmol/L, serum sodium is equal to 120  mmol/L in calculation. Studies have now confirmed that MELD-Na could predict prognosis of patients with end-stage more precisely than MELD, but there was no significant statistical difference. It has been suggested that larger studies will confirm the value of adding Na to MELD in assessing patient mortality. The MELD-Na score can effectively predict the 3  month mortality rates of patients with CSH, and also can be used as a therapeutic evaluation index. Some researches using MELD score combined with CPT have shown that MELD ≥18 and TC ≤2.8 nmol/L could be used to predict the long-term prognosis of decompensated cirrhosis, but its predictive value still has not been studied in liver failure (including CSH). Li et al. investigated 213 patients (213 cases of CSH) and found that rates of cirrhosis, infection, hepatic encephalopathy (HE) level, total bilirubin, total cholesterol (CHO), cholinesterase (CHE), blood urea nitrogen (BUN), serum creatinine (Cr), serum sodium, white blood cell count (WBC), α fetus protein (AFP), international standardization ratio (INR) and PT were different between patients who died and those who survived, However there was no difference in ALT, AST, albumin and hemoglobin (HGB) between the two groups. The study finally developed a regression model using multivariate analysis, as follows: Logit (P) = 1.573 * Age +  1.338 * HE − 0.011 * CHO + 0.011 * 1.608 Cr − 0.109 * Na + 1.298 * INR + 11.057. Data showed that this model had a higher predictive value (e.g., introduction of age) than MELD, but its application in clinical practice needs further investigation for validation.

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6.1.4.3 iMELD Scoring System Integrated Model for End-stage Liver Disease (iMELD) Score was established by Luca et al. It adds age and serum sodium to MELD and the formula is as follow: iMELD = MELD + 0.3 × (age) − (0.7 × serum sodium) + 100. Studies have shown that adding age and serum sodium into the original MELD formula could strengthen its survival prediction. The MELD, MELD-Na and iMELD scoring systems do not include any complications in their formulation. In a large number of cases, however, it has been shown that complications of liver disease lead to deterioration and shorten survival time. Additionally, in China the majority of patients with liver failure are secondary to HBV infection, and studies have demonstrated that antiviral treatment is an independent predictor for prognosis of liver failure. Therefore, in clinical practice the use of a multi-factor MELD prognostic index regression model should be adopted to predict prognosis of liver failure first, and then the use of MELD-Na and iMELD in combination with relevant clinical issues including complications, and the use of antiviral treatment may improve the predictability of MELD to make more accurate judgment to prognosis. 6.1.4.4 King’s College Criteria The King’s College Criteria has been widely adopted worldwide to assess patients with acute liver failure (ref). Although its specificity is high, its sensitivity is not high. And it has not proven to be as useful for patients with subacute liver failure and CSH. 6.1.4.5 Child-Turcotte-Pugh (CTP) Scoring The CTP scoring has been used to quantify the liver reserve function of patients with established cirrhosis. CT scoring was first put forward by Child and Turcotte, then Pugh replaced general condition with hepatic encephalopathy and the scoring system was renamed CTP. In CTP, the score ranges from 5 to 15. Liver reserve is divided into A, B, C level 3 (Table 6.4). The CTP scoring system is mainly used for patients with liver cirrhosis. As CSH is most commonly seen in patients with cirrhosis, the use of the CTP scoring system may be useful for clinical diagnosis, treatment and prognosis. However, CTP also has its shortcomings, (1) the main target population was people with cirrhosis; (2) it includes subjective parameters, i.e. degrees of ascites and hepatic encephalopathy, so it is difficult to standardize these Table 6.4  CTP scoring criteria Indicator HE (grade) Ascites TBil (μmol/L) Albumin (g/L) Prothrombin time extended (s)

1 point No No 35 51 6

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parameters; (3) CTP could not differentiate anomalies and significance of abnormal laboratory parameters, known as the upper limit effect (ceiling effect); (4) objective indicators such as albumin and PTA was not standardized across laboratories; (5) the scores were too concentrated. There are only 8 points between maximum and minimum, and thus many patients had same score. Despite these limitations, the sensitivity of CTP scoring predicting mortality was about 78%, and specificity was 83% [14]. However the CTP scoring system has not proven to be as useful to assess patients with CSH. However, in China as the main cause of CSH is on the basis of chronic HBV infection and most of the patients had cirrhosis, the CTP scoring system has proven to be more useful for evaluating liver function reserve and furthermore it has proven easy to use. In the clinic, using a combination of MELD and CTP to assess liver function and prognosis has proven to be useful.

6.1.5 Lethal Factors of Severe Hepatitis B CSH caused by HBV produces a syndrome similar to acute liver failure which is characterized by severe clinical symptoms and high mortality. As the liver is central to maintaining normal human physiology, damage to the liver affects multiple systems including the lung, heart, kidney and coagulation systems often leading to death. Therefore, in an attempt to improve the survival rate and prognosis of patients, research is now focused on the multi system alterations that occur in patients with CSH.

6.1.5.1 Bacterial Infections and Systemic Inflammatory Response Syndrome Bacterial infection is a common complication of liver failure, especially chronic liver failure with decompensated cirrhosis. An acute infection in patients with established cirrhosis often leads to further patient deterioration. Patients with cirrhosis are prone to bacterial infection because of an increase in bacterial translocation and reduced mononuclear/macrophage function [15, 16]. The presence of ascites in CSH is known to be associated with an increased risk of spontaneous bacterial peritonitis (SBP). As a consequence of SBP, there is a release of pro-inflammatory mediators including TNF, IFN gamma and nitric oxide synthase (NOs) which lead to activation of the coagulation system (thrombosis), reduced systemic vascular resistance leading to hypotension. Ultimately the patient may present in a shock like state with high levels of serum lactate reflecting tissue hypoperfusion. It is now known that bacterial infection is one of the most important factors leading to death in CSH. 6.1.5.2 Upper Gastrointestinal Hemorrhage and Hepatic Encephalopathy Upper gastrointestinal hemorrhage is a common complication of cirrhosis reflecting the presence of portal hypertension. In China CSH is seen in patients who have chronic hepatitis and cirrhosis. Upper gastrointestinal hemorrhage was not only secondary to

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More protein Factors related HE: Blood ammonia Benzodiazepines Hyponatremia Inflammatory cytokines

Injury

Infection

HE

Bleeding

Acidosis

Sedative

Diuretics Hyponatremia

Radial glial cells swelling oxidative stress

The radial glial cells swelling caused by various factors

Fig. 6.2  The inducing factors of HE. Redraw from Häussinger D, Schliess F. Pathogenetic mechanisms of hepatic encephalopathy. Gut, 2008, 57(8):1156–1165 [17]

the presence of esophageal and gastric varices, but also by disorders in blood coagulation as a consequence of poor hepatic synthesis of clotting factors and infection. GI hemorrhage is a medical emergency which can lead not only to hypovolemic shock but also can precipitate hepatic encephalopathy (Fig. 6.2). HE can be seen in acute and chronic liver disease and in the setting of CSH is often a lethal event.

6.1.5.3 Acute Kidney Injury AKI refers to a rapid deterioration in renal function as reflected by an increased serum creatinine to 26.4 mmol/L, or a rise of 50% from baseline (increased to 1.5 times). It is associated with a decrease in urine output (oliguria) to