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Lumley SF, Mokaya J, Maponga TG, Kramvis A, Dusheiko G, Irving W, Delphin M, Said Mohammed K, Downs LO, Waddilove E, Anderson M, Iwuji C, Msomi N, Ocama P, Hamid S, Adda D, Halford R, Kabagambe K, Benschop KSM, Inzaule S, Chan P, Paul MAS, Izumi K, Nisa T, De Dieu Iragena J, Girón-Callejas A, Kpossou AR, Jamiyu G, Emmanuel O, Balkissa M, Keita M, Prabdial-Sing N, Martinez A, Magongo EN, Shao Y, Sued O, Sereno LS, Shafer RW, Lesi O, Faini D, Easterbrook P, Duncombe C, Jordan MR, Matthews PC. Hepatitis B virus resistance to nucleos(t)ide analogue therapy: WHO consultation on questions, challenges, and a roadmap for the field. THE LANCET. MICROBE 2025:101076. [PMID: 40220768 DOI: 10.1016/j.lanmic.2025.101076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 12/19/2024] [Accepted: 01/14/2025] [Indexed: 04/14/2025]
Abstract
In this Review, we summarise outputs from a multidisciplinary consultation convened by WHO between July 11 and 13, 2023, to discuss hepatitis B virus (HBV) drug resistance (HBVDR). Treatment of chronic HBV infection with highly effective nucleos(t)ide analogue agents, tenofovir and entecavir, is a crucial intervention that supports the global goal of elimination of HBV infection as a public health threat. The risk of HBVDR as a threat to treatment outcomes is currently considered low from a public health perspective; however, drug resistance can influence individual outcomes, particularly among those who are treatment-experienced. We highlight the need to develop appropriate prevention, monitoring, and surveillance approaches for HBVDR, to support investment in the global scale-up of HBV diagnosis and treatment. Recommendations for the HBVDR field will ultimately be incorporated into a WHO integrated Global Action Plan for drug-resistant HIV, viral hepatitis, and priority sexually transmitted infections.
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Affiliation(s)
- Sheila F Lumley
- Nuffield Department of Medicine, University of Oxford, Oxford, UK; Department of Infectious Diseases and Microbiology, Oxford University Hospitals, Oxford, UK
| | - Jolynne Mokaya
- Parasites and Microbes, Wellcome Sanger Institute, Cambridge, UK
| | - Tongai G Maponga
- Division of Medical Virology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa; National Health Laboratory Service, Tygerberg Business Unit, Cape Town, South Africa
| | - Anna Kramvis
- Hepatitis Virus Diversity Research Unit, Department of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa
| | - Geoffrey Dusheiko
- University of the Witwatersrand, Johannesburg, South Africa; Institute of Liver Studies, King's College Hospital, London, UK
| | - William Irving
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, University of Nottingham, Nottingham, UK
| | | | | | - Louise O Downs
- Nuffield Department of Medicine, University of Oxford, Oxford, UK; Department of Infectious Diseases and Microbiology, Oxford University Hospitals, Oxford, UK; Kenya Medical Research Institute Wellcome Trust, Kilifi, Kenya
| | | | - Motswedi Anderson
- The Francis Crick Institute, London, UK; Africa Health Research Institute, Durban, South Africa; Botswana Harvard Health Partnership, Gaborone, Botswana
| | - Collins Iwuji
- Africa Health Research Institute, Durban, South Africa; Department of Global Health and Infection, Brighton and Sussex Medical School, University of Sussex, Brighton, UK
| | - Nokukhanya Msomi
- Discipline of Virology, University of KwaZulu-Natal and National Health Laboratory Service, Durban, South Africa
| | - Ponsiano Ocama
- Department of Medicine, Makerere University College of Health Sciences, Kampala, Uganda
| | - Saeed Hamid
- Department of Medicine, Aga Khan University, Karachi, Pakistan
| | - Danjuma Adda
- World Hepatitis Alliance, Geneva, Switzerland; Center for Initiative and Development and Chagro-Care Trust, Jalingo, Nigeria
| | | | - Kenneth Kabagambe
- The National Organisation for People Living with Hepatitis B, Kampala, Uganda
| | | | - Seth Inzaule
- Amsterdam Institute for Global Health and Development and Department of Global Health, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Polin Chan
- Department of Communicable Diseases, WHO South-East Asia Regional Office, New Delhi, India
| | | | - Kiyohiko Izumi
- Division of Programmes for Disease Control, WHO Western Pacific Regional Office, Manila, Philippines
| | - Tiara Nisa
- Division of Programmes for Disease Control, WHO Western Pacific Regional Office, Manila, Philippines
| | - Jean De Dieu Iragena
- Department of Global HIV, Hepatitis and Sexually Transmitted Infections, WHO, Geneva, Switzerland
| | - Amalia Girón-Callejas
- Department of Global HIV, Hepatitis and Sexually Transmitted Infections, WHO, Geneva, Switzerland
| | | | - Ganiyu Jamiyu
- National AIDS, Viral Hepatitis and STIs Control Programme, Abuja, Nigeria
| | - Omolara Emmanuel
- National AIDS, Viral Hepatitis and STIs Control Programme, Abuja, Nigeria
| | - Mahamadou Balkissa
- Programme National de Lutte contre le Sida et les Hépatites (PNLSH), Ministère de la Santé Publique, de la Population et des Affaires Sociales, Niamey, Niger
| | - Mamadou Keita
- The Sectoral Unit for the Fight against HIV, Tuberculosis and Viral Hepatitis, Ministry of Health, Bamako, Mali
| | - Nishi Prabdial-Sing
- National Institute for Communicable Diseases and National Health Laboratory Service and the Faculty of Health Sciences, Witwatersrand University, Johannesburg, South Africa; National Institute for Communicable Diseases, National Health Laboratory Service, Johannesburg, South Africa
| | - Alexander Martinez
- Gorgas Memorial Institute for Health Studies, Panama City, Panama; Department of Microbiology and Immunology, University of Panama, Panama City, Panama
| | | | - Yiming Shao
- National Centre for AIDS/STD Control and Prevention A, Chinese Center for Disease Control and Prevention, Changping Laboratory, Beijing, China
| | - Omar Sued
- HIV, STI, Viral Hepatitis and TB Unit, Department of Communicable Disease Prevention, Control, and Elimination, Pan American Health Organization, Washington, DC, USA
| | - Leandro Soares Sereno
- HIV, STI, Viral Hepatitis and TB Unit, Department of Communicable Disease Prevention, Control, and Elimination, Pan American Health Organization, Washington, DC, USA
| | - Robert W Shafer
- Department of Medicine, Division of Infectious Diseases, Stanford University, Stanford, CA, USA
| | - Olufunmilayo Lesi
- Department of Global HIV, Hepatitis and Sexually Transmitted Infections, WHO, Geneva, Switzerland; University of Lagos, Lagos, Nigeria
| | - Diana Faini
- Department of Global HIV, Hepatitis and Sexually Transmitted Infections, WHO, Geneva, Switzerland
| | - Philippa Easterbrook
- Department of Global HIV, Hepatitis and Sexually Transmitted Infections, WHO, Geneva, Switzerland
| | - Chris Duncombe
- International Association of Providers of AIDS Care, Washington DC, USA
| | - Michael R Jordan
- Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, Boston, MA, USA; Collaboratory for Emerging Infectious Diseases and Response, Tufts University, Medford, MA, USA
| | - Philippa C Matthews
- Kenya Medical Research Institute Wellcome Trust, Kilifi, Kenya; Division of Infection and Immunity, University College London, London, UK; Department of Infectious Diseases, University College London Hospital, London, UK.
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Martin P, Nguyen MH, Dieterich DT, Lau DTY, Janssen HLA, Peters MG, Jacobson IM. Treatment Algorithm for Managing Chronic Hepatitis B Virus Infection in the United States: 2021 Update. Clin Gastroenterol Hepatol 2022; 20:1766-1775. [PMID: 34329775 DOI: 10.1016/j.cgh.2021.07.036] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 07/15/2021] [Accepted: 07/21/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Chronic hepatitis B (CHB) infection remains the most frequent etiology of hepatocellular carcinoma globally as well as a major cause of cirrhosis. Despite vaccination, substantial numbers of persons have already been infected with hepatitis B virus and remain at risk of progressive liver disease. METHODS In 2004, a CHB management algorithm was developed by a panel of North American hepatologists, which was subsequently updated in 2006, 2008, and 2015. Since the most recent version, several developments have altered the management of CHB. Tenofovir alafenamide, with a more favorable safety profile than tenofovir disoproxil fumarate, has been introduced as an initial antiviral choice as well as an alternative for long-term therapy. Quantitation of hepatitis B surface antigen is becoming more widely available in clinical practice, with implications for monitoring response to treatment. Additionally, there has been a shift in how the natural history of CHB is perceived, as newer evidence has challenged the concept that during the immunotolerant phase of infection disease progression is not a concern. Finally, recent analyses indicate that in the United States, the average age of patients with CHB has increased, implying that the presence of comorbidities, including metabolic liver disease, increasing use of biologics associated with aging will increasingly affect disease management. RESULTS This updated algorithm is intended to serve as a guide to manage CHB while new antiviral strategies are developed. CONCLUSIONS Recommendations have been based on evidence from the scientific literature, when possible, as well as clinical experience and consensus expert opinion. Points of continued debate and areas of research need are also described.
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Affiliation(s)
- Paul Martin
- Division of Digestive Health and Liver Diseases, University of Miami School of Medicine, Miami, Florida.
| | - Mindie H Nguyen
- Department of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California; Department of Epidemiology and Population Health, Stanford University Medical Center, Palo Alto, California
| | | | - Daryl T-Y Lau
- Liver Center, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Harry L A Janssen
- Toronto Centre for Liver Diseases, University Health Network, Toronto, Canada
| | - Marion G Peters
- Division of Gastroenterology, University of California, San Francisco, San Francisco, California
| | - Ira M Jacobson
- Division of Gastroenterology, NYU Langone Health, New York, New York
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Chien RN, Kao JH, Peng CY, Chen CH, Liu CJ, Huang YH, Hu TH, Yang HI, Lu SN, Ni YH, Chuang WL, Lee CM, Wu JC, Chen PJ, Liaw YF. Taiwan consensus statement on the management of chronic hepatitis B. J Formos Med Assoc 2019; 118:7-38. [PMID: 30527436 DOI: 10.1016/j.jfma.2018.11.008] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Revised: 11/06/2018] [Accepted: 11/15/2018] [Indexed: 01/10/2023] Open
Abstract
The experts of Taiwan Association for the Study of Liver (TASL) have actively participated and led the guidelines on hepatitis B virus (HBV) management by Asian Pacific Association for the Study of Liver (APASL) which is the first international association for the study of liver to publish the statement on HBV management before. However, there are more and more new data on the natural history and treatment of HBV infection in the past decade. These include new application of an old biomarker (quantitative HBsAg), clinical significance of HBV genotype and naturally occurring mutations, the role of non-invasive examination in evaluating severity of hepatic fibrosis, clinical significance of outcome calculators, new drug or new combination strategies towards more effective therapy and organ transplantation including liver and non-liver transplantation. It is time to publish the guidelines on HBV management of Taiwan. Hence, TASL have conducted an expert meeting to review, to discuss and to debate the relevant literatures, followed by draft the manuscript of HBV management guidelines and recommendations. The guidelines include general management, indications for fibrosis assessment, time to start or stop drug therapy, choice of drug to initiate therapy, when and how to monitor the patients during and after stopping drug therapy. Recommendations on the therapy of patients in special circumstances, including women in childbearing age, patients with antiviral drug resistance, concurrent viral infection, hepatic decompensation, patient receiving immune suppression or chemotherapy and patients in the setting of liver transplantation and hepatocellular carcinoma, are also included.
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Affiliation(s)
- Rong-Nan Chien
- Liver Research Unit, Linkou Chang Gung Memorial Hospital and University College of Medicine, Taoyuan, Taiwan.
| | - Jia-Horng Kao
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Cheng-Yuan Peng
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chun-Jen Liu
- Graduate Institute of Clinical Medicine, Department of Internal Medicine and Hepatitis Research Center, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Yi-Hsiang Huang
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Tsung-Hui Hu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Hwa-I Yang
- Department of Genomic Research Center, Sinica Academia, Taipei, Taiwan
| | - Sheng-Nan Lu
- Division of Hepatogastroenterology, Department of Internal Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Yen-Hsuan Ni
- Department of Pediatrics, National Taiwan University College of Medicine and Children's Hospital, Taipei, Taiwan
| | - Won-Long Chuang
- Division of Hepatobiliary and Pancreas, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Chuan-Mo Lee
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Jaw-Chin Wu
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Pei-Jer Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Yun-Fan Liaw
- Liver Research Unit, Linkou Chang Gung Memorial Hospital and University College of Medicine, Taoyuan, Taiwan
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Hou J, Wang G, Wang F, Cheng J, Ren H, Zhuang H, Sun J, Li L, Li J, Meng Q, Zhao J, Duan Z, Jia J, Tang H, Sheng J, Peng J, Lu F, Xie Q, Wei L. Guideline of Prevention and Treatment for Chronic Hepatitis B (2015 Update). J Clin Transl Hepatol 2017; 5:297-318. [PMID: 29226097 PMCID: PMC5719188 DOI: 10.14218/jcth.2016.00019] [Citation(s) in RCA: 165] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Revised: 01/14/2017] [Accepted: 01/16/2017] [Indexed: 02/05/2023] Open
Affiliation(s)
- Jinlin Hou
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
- *Correspondence to: Jinlin Hou, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, No. 1838 North Guangzhou avenue, Guangzhou 510515, China. E-mail: ; Lai Wei, Peking University People’s Hospital, Peking University Hepatology Institute, No. 11 Xizhimen South Street, Beijing 100044, China. E-mail:
| | - Guiqiang Wang
- Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Beijing, China
| | - Fusheng Wang
- The Institute of Translational Hepatology, 302 Hospital of PLA, Peking University, Beijing, China
| | - Jun Cheng
- Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Hong Ren
- Institute for Viral Hepatitis, the Key Laboratory of Molecular Biology for Infectious Diseases, the second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hui Zhuang
- Department of Microbiology of Peking University Health Science Center, Beijing, China
| | - Jian Sun
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Jie Li
- Department of Microbiology of Peking University Health Science Center, Beijing, China
| | - Qinghua Meng
- Serious Illness Medicine Inpatient Area, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Jingmin Zhao
- Department of Pathology, 302 Hospital of PLA, Peking University, Beijing, China
| | - Zhongping Duan
- Artificial Liver Center, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Jidong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
| | - Jifang Sheng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Jie Peng
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Fengmin Lu
- Department of Microbiology of Peking University Health Science Center, Beijing, China
| | - Qing Xie
- Department of Infectious Diseases, Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital, Shanghai, China
| | - Lai Wei
- Hepatology Institute, Peking University People’s Hospital, Beijing, China
- *Correspondence to: Jinlin Hou, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, No. 1838 North Guangzhou avenue, Guangzhou 510515, China. E-mail: ; Lai Wei, Peking University People’s Hospital, Peking University Hepatology Institute, No. 11 Xizhimen South Street, Beijing 100044, China. E-mail:
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Fung J, Wong T, Chok K, Chan A, Cheung TT, Dai JWC, Sin SL, Ma KW, Ng K, Ng KTP, Seto WK, Lai CL, Yuen MF, Lo CM. Long-term outcomes of entecavir monotherapy for chronic hepatitis B after liver transplantation: Results up to 8 years. Hepatology 2017; 66:1036-1044. [PMID: 28370215 DOI: 10.1002/hep.29191] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2017] [Revised: 02/28/2017] [Accepted: 03/21/2017] [Indexed: 12/17/2022]
Abstract
UNLABELLED Long-term antiviral prophylaxis is required to prevent hepatitis B recurrence for patients with chronic hepatitis B after liver transplantation. We determined the long-term outcome of 265 consecutive chronic hepatitis B liver transplant recipients treated with entecavir monotherapy without hepatitis B immune globulin. Viral serology, viral load, and liver biochemistry were performed at regular intervals during follow-up. The median duration of follow-up was 59 months. The cumulative rates of hepatitis B surface antigen (HBsAg) seroclearance were 90% and 95% at 1 and 5 years, respectively. At 1, 3, 5, and 8 years, 85%, 88%, 87.0%, and 92% were negative for HBsAg, respectively, and 95%, 99%, 100%, and 100% had undetectable hepatitis B virus (HBV) DNA, respectively. Fourteen patients remained persistently positive for HBsAg, all of whom had undetectable HBV DNA. There was no significant difference in liver stiffness for those who remained HBsAg-positive compared to those who achieved HBsAg seroclearance (5.5 versus 5.2 kPa, respectively; P = 0.52). The overall 9-year survival was 85%. There were 37 deaths during the follow-up period, of which none were due to hepatitis B recurrence. CONCLUSION Long-term entecavir monotherapy is highly effective at preventing HBV reactivation after liver transplantation for chronic hepatitis B, with a durable HBsAg seroclearance rate of 92%, an undetectable HBV DNA rate of 100% at 8 years, and excellent long-term survival of 85% at 9 years. (Hepatology 2017;66:1036-1044).
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Affiliation(s)
- James Fung
- The Liver Transplant Center, Queen Mary Hospital, Hong Kong
- Division of Gastroenterology and Hepatology, Department of Medicine, The University of Hong Kong, Hong Kong
- State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong
| | - Tiffany Wong
- The Liver Transplant Center, Queen Mary Hospital, Hong Kong
- Division of Liver Transplantation, Department of Surgery, The University of Hong Kong, Hong Kong
| | - Kenneth Chok
- The Liver Transplant Center, Queen Mary Hospital, Hong Kong
- Division of Liver Transplantation, Department of Surgery, The University of Hong Kong, Hong Kong
| | - Albert Chan
- The Liver Transplant Center, Queen Mary Hospital, Hong Kong
- Division of Liver Transplantation, Department of Surgery, The University of Hong Kong, Hong Kong
| | - Tan-To Cheung
- The Liver Transplant Center, Queen Mary Hospital, Hong Kong
- Division of Liver Transplantation, Department of Surgery, The University of Hong Kong, Hong Kong
| | - Jeff Wing-Chiu Dai
- The Liver Transplant Center, Queen Mary Hospital, Hong Kong
- Division of Liver Transplantation, Department of Surgery, The University of Hong Kong, Hong Kong
| | - Sui-Ling Sin
- The Liver Transplant Center, Queen Mary Hospital, Hong Kong
- Division of Liver Transplantation, Department of Surgery, The University of Hong Kong, Hong Kong
| | - Ka-Wing Ma
- The Liver Transplant Center, Queen Mary Hospital, Hong Kong
- Division of Liver Transplantation, Department of Surgery, The University of Hong Kong, Hong Kong
| | - Kelvin Ng
- The Liver Transplant Center, Queen Mary Hospital, Hong Kong
- Division of Liver Transplantation, Department of Surgery, The University of Hong Kong, Hong Kong
| | - Kevin Tak-Pan Ng
- Division of Liver Transplantation, Department of Surgery, The University of Hong Kong, Hong Kong
| | - Wai-Kay Seto
- Division of Gastroenterology and Hepatology, Department of Medicine, The University of Hong Kong, Hong Kong
- State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong
| | - Ching-Lung Lai
- Division of Gastroenterology and Hepatology, Department of Medicine, The University of Hong Kong, Hong Kong
- State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong
| | - Man-Fung Yuen
- Division of Gastroenterology and Hepatology, Department of Medicine, The University of Hong Kong, Hong Kong
- State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong
| | - Chung-Mau Lo
- The Liver Transplant Center, Queen Mary Hospital, Hong Kong
- State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong
- Division of Liver Transplantation, Department of Surgery, The University of Hong Kong, Hong Kong
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Choi K, Lee HM, Jun BG, Lee SH, Kim HS, Kim SG, Kim YS, Kim BS, Jeong SW, Jang JY, Kim YD, Cheon GJ. [Efficacy of tenofovir-based rescue therapy for patients with drug-resistant chronic hepatitis B]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2017; 65:35-42. [PMID: 25603852 DOI: 10.4166/kjg.2015.65.1.35] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND/AIMS Tenofovir disoproxil fumarate (TDF) plays a pivotal role in the management of drug-resistant chronic hepatitis B. However, it remains unclear whether TDF-nucleoside analogue combination therapy provides better outcomes than TDF monotherapy. This study aimed to compare the efficacy of TDF monotherapy with that of TDF-nucleoside analogue combination therapy in patients with drug-resistant chronic hepatitis B. METHODS This retrospective cohort study included 76 patients receiving TDF-based rescue therapy for more than 12 months. Suboptimal response was defined as serum HBV-DNA level of > 60 IU/mL during prior rescue therapy. Multi-drug resistance was defined as the presence of two or more drug resistance-related mutations confirmed by mutation detection assay. The relationship between baseline characteristics and virologic response (HBV DNA < 20 IU/mL) at 12 months were evaluated using logistic regression analysis. RESULTS Fifty-five patients (72.4%) were suboptimal responders to prior rescue therapy, and 26 (34.2%) had multi-drug resistance. Forty-two patients (55.3%) received combination therapy with nucleoside analogues. Virologic response at 12 months was not significantly different between the TDF monotherapy group and TDF-nucleoside analogue combination therapy group (p = 0.098). The serum HBV DNA level was reduced to -4.49 ± 1.67 log10 IU/mL in the TDF monotherapy group and to -3.97 ± 1.69 log10 IU/mL in the TDF-nucleoside analogue combination therapy group at 12 months (p = 0.18). In multivariate analysis, female sex (p = 0.032), low baseline HBV-DNA level (p = 0.013), and TDF monotherapy (p = 0.046) were predictive factors for virologic response at 12 months. CONCLUSIONS TDF monotherapy showed similar efficacy to that of TDF-nucleoside analogue combination therapy in patients with drug-resistant chronic hepatitis B.
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Affiliation(s)
- Kanghyug Choi
- Departments of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Han Min Lee
- Departments of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Baek Gyu Jun
- Departments of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Sae Hwan Lee
- Departments of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Hong Soo Kim
- Departments of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Sang Gyune Kim
- Departments of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
| | - Young Seok Kim
- Departments of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
| | - Boo Sung Kim
- Departments of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
| | - Soung Won Jeong
- Departments of Internal Medicine, Seoul Hospital, Seoul, Korea
| | - Jae Young Jang
- Departments of Internal Medicine, Seoul Hospital, Seoul, Korea
| | - Young Don Kim
- Department of Internal Medicine, University of Ulsan College of Medicine, Gangneung Asan Hospital, Gangneung, Korea
| | - Gab Jin Cheon
- Department of Internal Medicine, University of Ulsan College of Medicine, Gangneung Asan Hospital, Gangneung, Korea
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Kao JH, Asselah T, Dou XG, Hamed K. Telbivudine therapy for chronic hepatitis B: A journey to identify super-responders and to optimize treatment using the roadmap model. J Gastroenterol Hepatol 2017; 32:73-81. [PMID: 27515408 DOI: 10.1111/jgh.13512] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/03/2016] [Indexed: 02/06/2023]
Abstract
Hepatitis B virus (HBV) infection is one of the most serious health problems worldwide with a high risk for cirrhosis and liver cancer. Several antiviral agents have been approved for the treatment of chronic hepatitis B, leading to a rapid reduction in HBV DNA and normalization of serum alanine aminotransferase levels. Telbivudine, a potent inhibitor of HBV replication, has been shown to be well tolerated. Because of the emergence of drug resistance, optimization strategies for telbivudine therapy have been shown to improve patient responses. Optimal baseline characteristics in so-called super-responders have been used to predict the virological response. Baseline HBV DNA levels < 9 log10 copies/mL (2 × 108 IU/mL) or alanine aminotransferase levels of more than or equal to twofold the upper limit of normal in HBeAg-positive patients and HBV DNA < 7 log10 copies/mL (2 × 106 IU/mL) in HBeAg-negative patients were strong predictors for virological response. In addition, the roadmap model, based on early virological response at week 24 of therapy, is considered as a powerful tool to identify patients at risk of treatment failure (HBV DNA ≥ 300 copies/mL, i.e. 60 IU/mL) and to reduce the risk of antiviral resistance. When considering pre-treatment characteristics and on-treatment responses, telbivudine may provide physicians with a wide choice of options to effectively treat patients with chronic hepatitis B, especially those with or at risk of renal impairment, or women of childbearing age.
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Affiliation(s)
- Jia-Horng Kao
- Graduate Institute of Clinical Medicine and Hepatitis Research Center, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Tarik Asselah
- Hepatology Department, AP-HP, Beaujon Hospital, University Paris Diderot and INSERM UMR1149, Centre de Recherche sur l'inflammation, Labex INFLAMEX, Clichy, France
| | - Xiao-Guang Dou
- Department of Infectious Disease, Shengjing Hospital, China Medical University, Shenyang, China
| | - Kamal Hamed
- Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA
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Krastev Z, Petrova D, Kotzev I, Celen MK, Mendelson M, Chandra R, Pandey P, Hamed K. Telbivudine vs tenofovir in hepatitis B e antigen-negative chronic hepatitis B patients: OPTIMA roadmap study. World J Hepatol 2016; 8:1402-1413. [PMID: 27917266 PMCID: PMC5114476 DOI: 10.4254/wjh.v8.i32.1402] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Revised: 05/06/2016] [Accepted: 07/18/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To make efficacy and safety comparison of telbivudine-raodmap and tenofovir-roadmap in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) patients.
METHODS This was the first prospective, randomised, two-arm, open-label, non-inferiority study in HBeAg-negative CHB patients that compared telbivudine and tenofovir administered as per roadmap concept. Patients were treated up to 24 wk and, depending on virologic response, continued the same therapy or received add-on therapy up to 104 wk. Eligible patients received an additional 52 wk of treatment in the extension period (i.e., up to 156 wk). Patients who developed virologic breakthrough (VB) while on monotherapy also received add-on therapy. The primary efficacy endpoint was the rate of patients achieving hepatitis B virus (HBV) DNA < 300 copies/mL at week 52. Secondary efficacy endpoints included the rates of HBV DNA < 300 and < 169 copies/mL, HBV DNA change from baseline, alanine aminotransferase normalisation, hepatitis B surface antigen (HBsAg) loss, HBsAg seroconversion, VB, and emergence of resistance at various timepoints throughout the study. Safety and estimated glomerular filtration rate (eGFR) were also analysed.
RESULTS A total of 241 patients were randomised. Non-inferiority of telbivudine arm to tenofovir arm was demonstrated at week 52 (± 7 d window), with over 91% of patients in each treatment arm achieving HBV DNA level < 300 copies/mL. Both arms were similar in terms of key secondary efficacy variables at weeks 104 and 156. The percentage of patients achieving HBV DNA < 300 copies/mL remained high and was similar in the telbivudine and tenofovir arms at both weeks 104 and 156. Over 82% of patients in both arms achieved alanine aminotransferase normalisation at week 52, and this percentage remained high at weeks 104 and 156. Telbivudine treatment progressively reduced serum HBsAg levels from baseline while no change was reported in quantitative HBsAg during therapy with tenofovir. Both treaments showed acceptable safety profiles. The telbivudine arm showed eGFR improvement unlike the tenofovir arm.
CONCLUSION Efficacy was shown for both telbivudine-roadmap and tenofovir-roadmap regimens in HBeAg-negative CHB patients over 156 wk. Telbivudine arm was associated with renal improvement.
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Alternative Therapies for Chronic Hepatitis B Patients With Partial Virological Response to Standard Entecavir Monotherapy. J Clin Gastroenterol 2016; 50:338-44. [PMID: 26646801 DOI: 10.1097/mcg.0000000000000455] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Entecavir (ETV) is a first-line, oral antinucleoside agent for the treatment of chronic hepatitis B patients. Despite its high potency, some patients may still be viremic after prolonged therapy with ETV monotherapy. Long-term outcome data comparing maintained ETV monotherapy to alternative therapies in persistently viremic patients are limited. Our goal was to compare complete viral suppression (CVS) rates [hepatitis B DNA (HBV DNA)<40 to 60 IU/mL] with alternative therapies to continued ETV monotherapy in ETV partial responders. METHODS This is a retrospective cohort study consisting of 86 consecutive treatment-naive, ETV=0.5 mg partial responders (detectable HBV DNA after ≥12 mo on ETV) who maintained ETV=0.5 mg daily (n=29) or switched to either ETV=1.0 mg daily (n=32) or ETV/tenofovir (TDF)=0.5 mg/300 mg (n=25) in 3 US GI/liver clinics from January 2005 to January 2012. Patients were identified by International Classification of Diseases, Ninth Revision query and data were collected by individual chart review. For those who remained on ETV=0.5 mg, comparison at regimen "switch time" was done using values at 12 months from initial ETV therapy. Rates of CVS were evaluated using Kaplan-Meier methods. Multivariate Cox proportional hazard models were used to estimate hazard ratio (HR) relating to potential predictors to the desirable outcomes of CVS. RESULTS In all therapy groups, the majority of patients were Asian (93.1% to 100.0%), male (64.0% to 68.8%), and hepatitis B e antigen-positive (95.8% to 100.0%) and had similar baseline alanine aminotransferase (ALT) levels. However, baseline HBV DNA (7.0 vs. 7.9 vs. 7.8 log10 IU/mL, P=0.05) and HBV DNA at regimen switch point (2.9 vs. 3.7 vs. 3.6 log10 IU/mL, P=0.0014) were lower in the ETV=0.5 mg cohort compared with those switched to ETV=1.0 mg or ETV/TDF, respectively. The ETV=0.5 mg cohort also had the shortest duration of ETV=0.5 mg therapy before switch (11.8 vs. 13.5 vs. 19.2 mo, P<0.0001). After the switch point, more patients on ETV/TDF achieved CVS compared with those on ETV=0.5 mg or ETV=1.0 mg at month 6 (77.3% vs. 13.8% vs. 9.4%), month 12 (86.4% vs. 40.5% vs. 25.0%), and month 18 (100% vs. 70.2% vs. 33.3%). Compared with the ETV=0.5 mg and ETV=1.0 mg groups, the ETV/TDF group also had higher rates of ALT normalization at month 6 (73.0% vs, 46.4% vs. 63.0%), month 12 (79.7% vs. 69.5% vs. 77.9%), and month 18 (100.0% vs. 69.5% vs. 86.8%), respectively. The multivariate analyses, inclusive of baseline age and treatment duration on initial therapy with ETV=0.5 mg, indicated that the ETV/TDF combination (HR=12.19, P<0.0001) was independently and positively associated with CVS, whereas high HBV DNA levels at baseline (HR=0.77, P=0.02) and at switch point (HR=0.46, P=0.002) were negatively associated with CVS. ETV=1.0 mg dose was not a predictor for CVS compared with ETV=0.5 mg. CONCLUSIONS Following adjustments for HBV DNA levels and prior treatment duration, ETV/TDF combination therapy independently predicted superior viral suppression and ALT normalization in partial responders to ETV=0.5 mg daily compared with ETV=0.5 mg or ETV=1.0 mg monotherapy. In patients who continued to be viremic after 12 months of ETV=0.5 mg, one third were still viremic after another 18 months on the same therapy. Alternative therapies should be considered for these patients.
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Lin CC, Bair MJ, Chen CJ, Lee KH, Chen MJ, Liu CY, Chang CW, Hu KC, Liou TC, Lin SC, Wang HY, Chu CH, Shih SC, Wang TE. Off-treatment efficacy of 3-year nucleos(t)ide analogues in chronic hepatitis B patients. Kaohsiung J Med Sci 2016; 32:10-15. [PMID: 26853169 DOI: 10.1016/j.kjms.2015.11.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2015] [Revised: 11/12/2015] [Accepted: 11/23/2015] [Indexed: 12/30/2022] Open
Abstract
Lamivudine, telbivudine, and entecavir are the first-line drugs covered by the Taiwan National Health Insurance as 3-year treatments for patients with chronic hepatitis B virus (HBV), but the optimal treatment duration of each remains unclear. We aimed to detect HBV treatment-cessation durability, and compare the predictors in patients with and without clinical relapse. In this retrospective cohort study, 210 patients with chronic HBV who tested hepatitis B e-antigen positive or hepatitis B e-antigen negative were treated for 3 years with a nucleos(t)ide analogue. Of these, 102 patients continued therapy after 3 years, while 88 patients stopped treatment and were followed for 1 year due to financial difficulties. Efficacy was assessed in terms of alanine aminotransferase (ALT) level normalization, HBV DNA clearance, virus breakthrough, clinical relapse, and liver decompensation. The durability predictors were evaluated by host factors, HBV DNA, and drug differences. Eighty patients (14 on lamivudine, 19 on telbivudine, and 47 on entecavir) were recruited. There was no difference in clinical-relapse rate among lamivudine, telbivudine, and entecavir (35.7% vs. 36.8% vs. 31.9%, respectively; p = 0.916), and liver decompensated hepatitis was absent. In baseline clinical characteristics, there were no differences between the clinical-relapse and nonrelapse groups in age, sex, cirrhosis, prior treatment, HBV DNA, pretreatment ALT, or hepatitis B e-antigen (HBeAg). The mean 3(rd) year serum ALT level differed significantly between clinical-relapse and nonrelapse patients (37.5 U/L vs. 27.7 U/L, respectively; p = 0.044). The 3-year nucleos(t)ide analogue off-treatment in patients with chronic HBV delivered according to the Taiwan National Health Insurance guidelines had an overall 33.8% 1-year clinical-relapse rate without any decompensated hepatitis flare-ups.
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Affiliation(s)
- Ching-Chung Lin
- Division of Gastroenterology, Department of Internal Medicine and Liver Medical Center, Mackay Memorial Hospital, Taipei, Taiwan; Mackay Medical College, New Taipei City, Taiwan
| | - Ming-Jong Bair
- Division of Gastroenterology, Department of Internal Medicine, Mackay Memorial Hospital, Taitung Branch, Taitung, Taiwan; Department of Nursing, Meiho University, Pingtung, Taiwan
| | - Chih-Jen Chen
- Division of Gastroenterology, Department of Internal Medicine and Liver Medical Center, Mackay Memorial Hospital, Taipei, Taiwan; Mackay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan
| | | | - Ming-Jen Chen
- Division of Gastroenterology, Department of Internal Medicine and Liver Medical Center, Mackay Memorial Hospital, Taipei, Taiwan; Mackay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan
| | - Chia-Yuan Liu
- Division of Gastroenterology, Department of Internal Medicine and Liver Medical Center, Mackay Memorial Hospital, Taipei, Taiwan; Mackay Medical College, New Taipei City, Taiwan
| | - Chen-Wang Chang
- Division of Gastroenterology, Department of Internal Medicine and Liver Medical Center, Mackay Memorial Hospital, Taipei, Taiwan; Mackay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan
| | - Kuang-Chun Hu
- Division of Gastroenterology, Department of Internal Medicine and Liver Medical Center, Mackay Memorial Hospital, Taipei, Taiwan; Mackay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan
| | - Tai-Cherng Liou
- Division of Gastroenterology, Department of Internal Medicine and Liver Medical Center, Mackay Memorial Hospital, Taipei, Taiwan; Mackay Medical College, New Taipei City, Taiwan
| | - Shee-Chan Lin
- Division of Gastroenterology, Department of Internal Medicine and Liver Medical Center, Mackay Memorial Hospital, Taipei, Taiwan; Mackay Medical College, New Taipei City, Taiwan
| | - Horng-Yuan Wang
- Division of Gastroenterology, Department of Internal Medicine and Liver Medical Center, Mackay Memorial Hospital, Taipei, Taiwan; Mackay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan
| | - Cheng-Hsin Chu
- Division of Gastroenterology, Department of Internal Medicine and Liver Medical Center, Mackay Memorial Hospital, Taipei, Taiwan; Mackay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan
| | - Shou-Chuan Shih
- Division of Gastroenterology, Department of Internal Medicine and Liver Medical Center, Mackay Memorial Hospital, Taipei, Taiwan; Mackay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan
| | - Tsang-En Wang
- Division of Gastroenterology, Department of Internal Medicine and Liver Medical Center, Mackay Memorial Hospital, Taipei, Taiwan; Mackay Medical College, New Taipei City, Taiwan.
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Sarin SK, Kumar M, Lau GK, Abbas Z, Chan HLY, Chen CJ, Chen DS, Chen HL, Chen PJ, Chien RN, Dokmeci AK, Gane E, Hou JL, Jafri W, Jia J, Kim JH, Lai CL, Lee HC, Lim SG, Liu CJ, Locarnini S, Al Mahtab M, Mohamed R, Omata M, Park J, Piratvisuth T, Sharma BC, Sollano J, Wang FS, Wei L, Yuen MF, Zheng SS, Kao JH. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int 2016; 10:1-98. [PMID: 26563120 PMCID: PMC4722087 DOI: 10.1007/s12072-015-9675-4] [Citation(s) in RCA: 1920] [Impact Index Per Article: 213.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Accepted: 09/14/2015] [Indexed: 02/06/2023]
Abstract
Worldwide, some 240 million people have chronic hepatitis B virus (HBV), with the highest rates of infection in Africa and Asia. Our understanding of the natural history of HBV infection and the potential for therapy of the resultant disease is continuously improving. New data have become available since the previous APASL guidelines for management of HBV infection were published in 2012. The objective of this manuscript is to update the recommendations for the optimal management of chronic HBV infection. The 2015 guidelines were developed by a panel of Asian experts chosen by the APASL. The clinical practice guidelines are based on evidence from existing publications or, if evidence was unavailable, on the experts' personal experience and opinion after deliberations. Manuscripts and abstracts of important meetings published through January 2015 have been evaluated. This guideline covers the full spectrum of care of patients infected with hepatitis B, including new terminology, natural history, screening, vaccination, counseling, diagnosis, assessment of the stage of liver disease, the indications, timing, choice and duration of single or combination of antiviral drugs, screening for HCC, management in special situations like childhood, pregnancy, coinfections, renal impairment and pre- and post-liver transplant, and policy guidelines. However, areas of uncertainty still exist, and clinicians, patients, and public health authorities must therefore continue to make choices on the basis of the evolving evidence. The final clinical practice guidelines and recommendations are presented here, along with the relevant background information.
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Affiliation(s)
- S K Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India.
| | - M Kumar
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - G K Lau
- Division of Gastroenterology and Hepatology, Humanity and Health Medical Centre, Hong Kong SAR, China
- The Institute of Translational Hepatology, Beijing, China
| | - Z Abbas
- Department of Hepatogastroenterlogy, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
| | - H L Y Chan
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
| | - C J Chen
- Genomics Research Center, Academia Sinica, National Taiwan University, Taipei, Taiwan
| | - D S Chen
- Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - H L Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - P J Chen
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - R N Chien
- Liver Research Unit, Chang Gung Memorial Hospital and University, Chilung, Taiwan
| | - A K Dokmeci
- Department of Gastroenterology, Ankara University School of Medicine, Ankara, Turkey
| | - Ed Gane
- New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand
| | - J L Hou
- Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Guangzhou, China
| | - W Jafri
- Department of Medicine, Aga Khan University, Karachi, Pakistan
| | - J Jia
- Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | | | - C L Lai
- Department of Medicine, University of Hong Kong, Hong Kong, China
| | - H C Lee
- Internal Medicine Asan Medical Center, Seoul, Korea
| | - S G Lim
- Division of Gastroenterology and Hepatology, National University Health System, Singapore, Singapore
| | - C J Liu
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - S Locarnini
- Research and Molecular Development, Victorian Infectious Diseases Reference Laboratory, Melbourne, Australia
| | - M Al Mahtab
- Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - R Mohamed
- Department of Medicine, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia
| | - M Omata
- Yamanashi Hospitals (Central and Kita) Organization, 1-1-1 Fujimi, Kofu-shi, Yamanashi, 400-8506, Japan
| | - J Park
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - T Piratvisuth
- NKC Institute of Gastroenterology and Hepatology, Prince of Songkla University, Songkhla, Thailand
| | - B C Sharma
- Department of Gastroenterology, G.B. Pant Hospital, New Delhi, India
| | - J Sollano
- Department of Medicine, University of Santo Tomas, Manila, Philippines
| | - F S Wang
- Treatment and Research Center for Infectious Diseases, Beijing 302 Hospital, Beijing, China
| | - L Wei
- Peking University Hepatology Institute, Beijing, China
| | - M F Yuen
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Hong Kong, Pofulam, Hong Kong
| | - S S Zheng
- Department of Hepatobiliary and Pancreatic Surgery, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang Province, China
| | - J H Kao
- Graduate Institute of Clinical Medicine and Hepatitis Research Center, National Taiwan University College of Medicine, National Taiwan University Hospital, Taipei, Taiwan
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Zhang XX, Li MR, Cao Y, Zhang RW, Zhang Y, Li F, Xi HL, Xu XY. Dynamics of Genotypic Mutations of the Hepatitis B Virus Associated With Long-Term Entecavir Treatment Determined With Ultradeep Pyrosequencing: A Retrospective Observational Study. Medicine (Baltimore) 2016; 95:e2614. [PMID: 26825915 PMCID: PMC5291585 DOI: 10.1097/md.0000000000002614] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Revised: 12/22/2015] [Accepted: 01/05/2016] [Indexed: 12/20/2022] Open
Abstract
The aim of the study is to explore the evolution of genotypic mutations within the reverse transcriptase region in partial virological responders (PVRs) receiving long-term entecavir (ETV) treatment. A total of 32 patients were classified as completely virological responders (CVRs) (n = 12) or PVRs (n = 20). Five partial responders were hepatitis B virus (HBV)-DNA positive after long-term therapy, which lasted for >3 years. A total of 71 serum samples from these 32 patients were assayed by ultra-deep pyrosequencing (UDPS): 32 samples were from all patients at baseline, and 39 were from PVRs with sequential inter-treatment. Approximately 84,708 sequences were generated per sample. At baseline, the quasispecies heterogeneity did not significantly differ between the 2 groups. The frequencies of substitutions indicating pre-existence of nucleos(t)ide analog resistant (NAr) mutants ranged from 0.10% to 6.70%, which did not statistically differ between groups either. However, the substitutions associated with the NAr mutants were significantly different from those associated with the non-NAr mutants in 13 patients; 6 of these patients were PVRs and the others were CVRs. Five patients were HBV DNA positive after regular ETV monotherapy for >3 years, and 4 of these patients underwent mild NAr substitution fluctuations (<20%). One patient developed virological breakthrough while bearing single, double, and triple (rtL180 M, rtM204 V, rtS202G) substitutions. In addition to the common substitutions, unknown amino acid substitutions, such as rtL145 M/S, rtF151Y/L, rtR153Q, rtI224 V, rtN248H, rtS223A, rtS256C, need to be further verified. NAr substitutions are observed at frequencies of 0.10% to 6.7% before therapy. Long-term ETV therapy generally results in virological responses, as long as the proportion of resistance mutations remains at a relatively low level. Genotypic resistance to ETV is detected in all PVRs receiving long-term ETV therapy.
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Affiliation(s)
- Xia-Xia Zhang
- From the Department of Infectious Disease, Peking University First Hospital, No.8 Xishiku Street, Xicheng District, Beijing, China
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Li N, Xu JH, Yu M, Wang S, Si CW, Yu YY. Relationship between virological response and FIB-4 index in chronic hepatitis B patients with entecavir therapy. World J Gastroenterol 2015; 21:12421-12429. [PMID: 26604649 PMCID: PMC4649125 DOI: 10.3748/wjg.v21.i43.12421] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Revised: 06/17/2015] [Accepted: 09/02/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate whether long-term low-level hepatitis B virus (HBV) DNA influences dynamic changes of the FIB-4 index in chronic hepatitis B (CHB) patients receiving entecavir (ETV) therapy with partial virological responses.
METHODS: We retrospectively analyzed 231 nucleos(t)ide (NA) naïve CHB patients from our previous study (NCT01926288) who received continuous ETV or ETV maleate therapy for three years. The patients were divided into partial virological response (PVR) and complete virological response (CVR) groups according to serum HBV DNA levels at week 48. Seventy-six patients underwent biopsies at baseline and at 48 wk. The performance of the FIB-4 index and area under the receiver operating characteristic (AUROC) curve for predicting fibrosis were determined for the patients undergoing biopsy. The primary objective of the study was to compare the cumulative probabilities of virological responses between the two groups during the treatment period. The secondary outcome was to observe dynamic changes of the FIB-4 index between CVR patients and PVR patients.
RESULTS: For hepatitis B e antigen (HBeAg)-positive patients (n = 178), the cumulative probability of achieving undetectable levels at week 144 was 95% and 69% for CVR and PVR patients, respectively (P < 0.001). In the Cox proportional hazards model, a lower pretreatment serum HBV DNA level was an independent factor predicting maintained viral suppression. The cumulative probability of achieving undetectable levels of HBV DNA for HBeAg-negative patients (n = 53) did not differ between the two groups. The FIB-4 index efficiently identified fibrosis, with an AUROC of 0.80 (95%CI: 0.69-0.89). For HBeAg-positive patients, the FIB-4 index was higher in CVR patients than in PVR patients at baseline (1.89 ± 1.43 vs 1.18 ± 0.69, P < 0.001). There was no significant difference in the reduction of the FIB-4 index between the CVR and PVR groups from weeks 48 to 144 (-0.11 ± 0.47 vs -0.13 ± 0.49, P = 0.71). At week 144, the FIB-4 index levels were similar between the two groups (1.24 ± 0.87 vs 1.02 ± 0.73, P = 0.06). After multivariate logistic regression analysis, a lower baseline serum HBV DNA level was associated with improvement of liver fibrosis. In HBeAg-negative patients, the FIB-4 index did not differ between the two groups.
CONCLUSION: The cumulative probabilities of HBV DNA responses showed significant differences between CVR and PVR HBeAg-positive CHB patients undergoing entecavir treatment for 144 wk. However, long-term low-level HBV DNA did not deteriorate the FIB-4 index, which was used to evaluate liver fibrosis, at the end of three years.
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Martin P, Lau DTY, Nguyen MH, Janssen HLA, Dieterich DT, Peters MG, Jacobson IM. A Treatment Algorithm for the Management of Chronic Hepatitis B Virus Infection in the United States: 2015 Update. Clin Gastroenterol Hepatol 2015; 13:2071-87.e16. [PMID: 26188135 DOI: 10.1016/j.cgh.2015.07.007] [Citation(s) in RCA: 83] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Revised: 07/01/2015] [Accepted: 07/09/2015] [Indexed: 02/07/2023]
Abstract
Chronic hepatitis B (CHB) continues to be an important public health problem worldwide, including in the United States. An algorithm for managing CHB was developed by a panel of United States hepatologists in 2004 and subsequently updated in 2006 and 2008. Since 2008, additional data on long-term safety and efficacy of licensed therapies have become available and have better defined therapeutic options for CHB. The evidence indicates that potent antiviral therapy can lead to regression of extensive fibrosis or even cirrhosis, thus potentially altering the natural history of CHB. In addition, appropriate choice of antiviral agent can minimize the risk of resistance. This updated algorithm for managing CHB is based primarily on evidence from the scientific literature. Where data were lacking, the panel relied on clinical experience and consensus expert opinion. The primary aim of antiviral therapy for CHB is durable suppression of serum hepatitis B virus (HBV) DNA to low or undetectable levels. CHB patients who have HBV DNA >2000 IU/mL, elevated alanine aminotransferase level, and any degree of fibrosis should receive antiviral therapy regardless of their hepatitis B e antigen status. CHB patients with HBV DNA >2000 IU/mL and elevated alanine aminotransferase level but no evidence of fibrosis may also be considered for antiviral therapy. Approved antiviral therapies for CHB are interferon alfa-2b, peginterferon alfa-2a, lamivudine, adefovir, entecavir, telbivudine, and tenofovir, although the preferred first-line treatment choices are peginterferon alfa-2a, entecavir, and tenofovir. In determining choice of therapy, considerations include efficacy, safety, rate of resistance, method of administration, duration, and cost.
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Affiliation(s)
- Paul Martin
- Division of Hepatology, University of Miami School of Medicine, Miami, Florida.
| | - Daryl T-Y Lau
- Liver Center, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Mindie H Nguyen
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford, California
| | - Harry L A Janssen
- Toronto Centre for Liver Diseases, University Health Network, Toronto, Canada
| | | | - Marion G Peters
- Division of Gastroenterology, University of California, San Francisco, San Francisco, California
| | - Ira M Jacobson
- Department of Medicine, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York, New York
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Lu L, Yip B, Trinh H, Pan CQ, Han SHB, Wong CC, Li J, Chan S, Krishnan G, Wong CC, Nguyen MH. Tenofovir-based alternate therapies for chronic hepatitis B patients with partial virological response to entecavir. J Viral Hepat 2015; 22:675-81. [PMID: 25417914 PMCID: PMC4442074 DOI: 10.1111/jvh.12368] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Accepted: 10/18/2014] [Indexed: 12/22/2022]
Abstract
Entecavir (ETV) is a first-line antiviral therapy for treating chronic hepatitis B (CHB); however, some patients have suboptimal response to ETV. Currently, there are limited data on how to approach these patients. Therefore, our aim was to compare the effectiveness of two alternate therapies--tenofovir (TDF) monotherapy and combination therapy of ETV+TDF--in CHB patients with ETV partial virological response. We conducted a retrospective study of 68 patients who had partial virological response to ETV, defined as having detectable HBV DNA following at least 12 months of ETV, and were switched to TDF monotherapy (n = 25) or ETV+TDF (n = 43). Patients were seen in seven US liver/community-based clinics and started on ETV between 2005 and 2009. The majority of patients were male; the vast majority were Asian and had positive hepatitis B e antigen (HBeAg). Patients in both groups had similar pretreatment characteristics. Complete viral suppression (CVS) rates with TDF monotherapy and ETV+TDF were similar after 6 months (71% vs 83%, P = 0.23) and 12 months (86% vs 84%, P = 0.85), and there was no statistically significant difference in CVS rates even when only patients with higher HBV DNA levels at switch (>1000 IU/mL) were evaluated. Multivariate analysis indicated that ETV+TDF was not an independent predictor of CVS compared to TDF monotherapy (OR = 1.19, P = 0.63). In conclusion, TDF monotherapy and ETV+TDF are comparable in achieving CVS in CHB patients with partial virological response to ETV. Long-term alternate therapy with one pill (TDF monotherapy) vs two pills (ETV+TDF) could lead to lower nonadherence rates and better treatment outcomes.
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Affiliation(s)
- Louis Lu
- Medical School, University of Michigan Medical School, Ann Arbor, MI, USA
,Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA
| | - Benjamin Yip
- Medical School, Eastern Virginia Medical School, Norfolk, VA, USA
| | - Huy Trinh
- San Jose Gastroenterology, San Jose, CA, USA
| | - Calvin Q. Pan
- Division of Gastroenterology and Hepatology, NYU Langone Medical Center, NYU School of Medicine, New York, NY, USA
| | - Steven-Huy B. Han
- Pfleger Liver Institute, Ronald Reagan UCLA Medical Center, Los Angeles, CA, USA
| | | | - Jiayi Li
- Palo Alto Medical Foundation, Mountain View, CA, USA
| | | | - Gomathi Krishnan
- Stanford Center for Clinical Informatics, Stanford University School of Medicine, Stanford, CA, USA
| | | | - Mindie H. Nguyen
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA
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Prolonged entecavir therapy is not effective for HBeAg seroconversion in treatment-naive chronic hepatitis B patients with a partial virological response. Antimicrob Agents Chemother 2015; 59:5348-56. [PMID: 26100697 DOI: 10.1128/aac.01017-15] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Accepted: 06/10/2015] [Indexed: 02/07/2023] Open
Abstract
The aims of this study were to investigate the efficacy of prolonged entecavir (ETV) therapy in treatment-naive chronic hepatitis B (CHB) patients and to determine whether continuous ETV therapy is feasible to achieve HBeAg seroconversion, particularly in patients with partial virological response (PVR). A total of 142 treatment-naive patients with CHB were enrolled. The mean duration of treatment was 65 (range, 26 to 90) months, and 86 patients (60.6%) were HBeAg positive. PVR was defined as detectable hepatitis B virus (HBV) DNA (>116 copies/ml) at year 1. The cumulative incidence of virological response (VR) increased from 54.9% at year 1 to 98.2% at year 7. HBeAg positivity (odds ratio [OR], 4.146; P = 0.001) and initial alanine aminotransferase (ALT) (OR, 0.997; P = 0.004) were independent risk factors for PVR. Among the 64 patients with PVR, 47 patients (73.4%) achieved VR within 4 years after prolonged ETV therapy without treatment adaptation. Three patients (2.1%) experienced virological breakthrough and HBV variants with genotypic resistance. The cumulative rate of HBeAg seroconversion was significantly higher in the patients with VR than in the patients with PVR (P = 0.018). None of the PVR patients with HBV DNA at ≥5,000 copies/ml at year 1 ever experienced HBeAg seroconversion. Multivariate analysis identified VR at year 1 as the only determinant of HBeAg seroconversion (hazard ratio [HR], 3.009; P = 0.010). In conclusion, although there were patients with PVR, prolonged ETV therapy showed excellent VR, with only 2.1% emergence of viral resistance during a 7-year follow-up. However, to achieve HBeAg seroconversion, drug modification is needed for HBeAg-positive patients with PVR (especially those with HBV DNA at ≥5,000 copies/ml at year 1).
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Choi HN, Song JE, Lee HC, Jo HH, Lee CH, Kim BS. Efficacy of prolonged entecavir monotherapy in treatment-naïve chronic hepatitis B patients exhibiting a partial virologic response to entecavir. Clin Mol Hepatol 2015; 21:24-31. [PMID: 25834799 PMCID: PMC4379194 DOI: 10.3350/cmh.2015.21.1.24] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2014] [Revised: 02/24/2015] [Accepted: 02/25/2015] [Indexed: 12/13/2022] Open
Abstract
Background/Aims The optimal management of patients exhibiting a partial virologic response (PVR) to entecavir (ETV) has not been determined. The aim of this study was to determine the long-term efficacy of prolonged ETV monotherapy in treatment-naïve chronic hepatitis B (CHB) patients exhibiting a PVR to ETV therapy. Methods This study included 364 treatment-naïve CHB patients treated with ETV for ≥48 weeks and who received continuous ETV monotherapy for ≥96 weeks. PVR was defined as a decrease in serum hepatitis B virus (HBV) DNA of more than 2 log10 IU/mL from baseline but with detectable HBV DNA by real-time PCR assay at week 48. Results Fifty-two of the 364 patients (14.3%) showed a PVR. Among them, 41 patients received continuous ETV monotherapy for ≥96 weeks (median duration 144 weeks, range 96-312 weeks), and 40 of these patients (95%) achieved a virologic response (VR, HBV DNA <20 IU/mL) during prolonged ETV monotherapy (median duration 78 weeks, range 60-288 weeks). The cumulative probabilities of a VR at weeks 96, 144, and 192 from treatment initiation were 78.0%, 92.7%, and 95.1%, respectively. The VR rate was 97.2% (35/36) in HBeAg-positive patients and 100% (5/5) in HBeAg-negative patients. In multivariate analysis, HBeAg positivity (odds ratio [OR], 9.231; 95% confidence interval [CI], 1.03-82.91; P=0.047) and a high baseline HBV DNA level (OR, 0.170; 95% CI, 0.08-0.37; P=0.000) were independently associated with a delayed virologic response. No patient developed genotypic resistance to ETV during follow-up. Conclusions Long-term ETV monotherapy is effective for achieving a VR in treatment-naïve CHB patients exhibiting a PVR to ETV. HBeAg positivity and high baseline HBV DNA level were independently associated with a delayed virologic response.
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Affiliation(s)
- Han Na Choi
- Department of Internal Medicine, Catholic University of Daegu School of Medicine, Daegu, Korea
| | - Jeong Eun Song
- Department of Internal Medicine, Catholic University of Daegu School of Medicine, Daegu, Korea
| | - Hyeon Chul Lee
- Department of Internal Medicine, Catholic University of Daegu School of Medicine, Daegu, Korea
| | - Hyeong Ho Jo
- Department of Internal Medicine, Catholic University of Daegu School of Medicine, Daegu, Korea
| | - Chang Hyeong Lee
- Department of Internal Medicine, Catholic University of Daegu School of Medicine, Daegu, Korea
| | - Byung Seok Kim
- Department of Internal Medicine, Catholic University of Daegu School of Medicine, Daegu, Korea
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Vlachogiannakos J, Papatheodoridis GV. Optimal therapy of chronic hepatitis B: how do I treat HBeAg-positive patients? Liver Int 2015; 35 Suppl 1:100-6. [PMID: 25529094 DOI: 10.1111/liv.12719] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
Current agents for the treatment of chronic hepatitis B (CHB) can be classified into interferon-α (standard or pegylated) (IFN) and nucleos(t)ide analogues (NAs). IFN therapy has the advantage of a finite duration (48 weeks) with a chance for durable sustained off-treatment response in HBeAg positive CHB patients. However, these benefits are limited to approximately 30% of HBeAg positive patients, while parenteral administration and potential side effects are common patient concerns. Thus, patients who can benefit from IFN therapy must be carefully selected and monitored. Recently, stopping rules for IFN non-responders were developed based on 12-week HBsAg levels. NAs are currently used in most CHB patients. They are administered in one tablet daily and can be used in all patients with excellent tolerability and a good safety profile. The current first-line options, entecavir (ETV) and tenofovir (TDF), are highly potent with a minimal risk of resistance during long-term monotherapy. Prolongation of entecavir or tenofovir maintains the initially high virological remission rates in adherent HBeAg positive patients and modifies the long-term outcomes. The need for a long-term, perhaps indefinite, treatment duration is the main limitation of ETV or TDF, which may sometimes be safely discontinued in HBeAg positive patients who achieve stable HBeAg seroconversion. Since there will always be safety concerns and family planning issues with long-term therapy, NAs should be used carefully particularly in young HBeAg positive patients with minimal-mild liver disease.
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Affiliation(s)
- Jiannis Vlachogiannakos
- Academic Department of Gastroenterology, Athens University Medical School, Laiko General Hospital, Athens, 11527, Greece
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Therapeutic strategies for a functional cure of chronic hepatitis B virus infection. Acta Pharm Sin B 2014; 4:248-57. [PMID: 26579392 PMCID: PMC4629125 DOI: 10.1016/j.apsb.2014.05.002] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2014] [Revised: 05/20/2014] [Accepted: 05/23/2014] [Indexed: 02/07/2023] Open
Abstract
Treatment of chronic hepatitis B virus (HBV) infection with the viral DNA polymerase inhibitors or pegylated alpha-interferon has led to a significant retardation in HBV-related disease progression and reduction in mortality related to chronic hepatitis B associated liver decompensation and hepatocellular carcinoma. However, chronic HBV infection remains not cured. The reasons for the failure to eradicate HBV infection by long-term antiviral therapy are not completely understood. However, clinical studies suggest that the intrinsic stability of the nuclear form of viral genome, the covalently closed circular (ccc) DNA, sustained low level viral replication under antiviral therapy and homeostatic proliferation of hepatocytes are the critical virological and pathophysiological factors that affect the persistence and therapeutic outcomes of HBV infection. More importantly, despite potent suppression of HBV replication in livers of the treated patients, the dysfunction of HBV-specific antiviral immunity persists. The inability of the immune system to recognize cells harboring HBV infection and to cure or eliminate cells actively producing virus is the biggest challenge to finding a cure. Unraveling the complex virus–host interactions that lead to persistent infection should facilitate the rational design of antivirals and immunotherapeutics to cure chronic HBV infection.
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Gerlich WH. Reduction of Infectivity in Chronic Hepatitis B Virus Carriers among Healthcare Providers and Pregnant Women by Antiviral Therapy. Intervirology 2014; 57:202-11. [DOI: 10.1159/000360949] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
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