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Suresh M, Menne S. Recent Drug Development in the Woodchuck Model of Chronic Hepatitis B. Viruses 2022; 14:v14081711. [PMID: 36016334 PMCID: PMC9416195 DOI: 10.3390/v14081711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 07/22/2022] [Accepted: 07/31/2022] [Indexed: 11/24/2022] Open
Abstract
Infection with hepatitis B virus (HBV) is responsible for the increasing global hepatitis burden, with an estimated 296 million people being carriers and living with the risk of developing chronic liver disease and cancer. While the current treatment options for chronic hepatitis B (CHB), including oral nucleos(t)ide analogs and systemic interferon-alpha, are deemed suboptimal, the path to finding an ultimate cure for this viral disease is rather challenging. The lack of suitable laboratory animal models that support HBV infection and associated liver disease progression is one of the major hurdles in antiviral drug development. For more than four decades, experimental infection of the Eastern woodchuck with woodchuck hepatitis virus has been applied for studying the immunopathogenesis of HBV and developing new antiviral therapeutics against CHB. There are several advantages to this animal model that are beneficial for performing both basic and translational HBV research. Previous review articles have focused on the value of this animal model in regard to HBV replication, pathogenesis, and immune response. In this article, we review studies of drug development and preclinical evaluation of direct-acting antivirals, immunomodulators, therapeutic vaccines, and inhibitors of viral entry, gene expression, and antigen release in the woodchuck model of CHB since 2014 until today and discuss their significance for clinical trials in patients.
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Jindal A, Kumar M. Sequential combination therapies for HBeAg-positive chronic hepatitis B: the search continues. Hepatol Int 2021; 15:1-3. [PMID: 33453018 DOI: 10.1007/s12072-020-10129-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 12/22/2020] [Indexed: 01/27/2023]
Affiliation(s)
- Ankur Jindal
- Department of Hepatology, Institute of Liver and Biliary Sciences, D1 Vasant Kunj, New Delhi, 110070, India
| | - Manoj Kumar
- Department of Hepatology, Institute of Liver and Biliary Sciences, D1 Vasant Kunj, New Delhi, 110070, India.
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van Campenhout MJH, Brouwer WP, Xie Q, Guo S, Chi H, Qi X, Tabak F, Streinu-Cercel A, Wang JY, Zhang NP, Idilman R, Reesink HW, Diculescu M, Simon K, Akdogan M, Mazur W, de Knegt RJ, Verhey E, Hansen BE, Janssen HLA. Long-term follow-up of patients treated with entecavir and peginterferon add-on therapy for HBeAg-positive chronic hepatitis B infection: ARES long-term follow-up. J Viral Hepat 2019; 26:109-117. [PMID: 30187612 DOI: 10.1111/jvh.12997] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 07/12/2018] [Accepted: 08/08/2018] [Indexed: 12/23/2022]
Abstract
Addition of peginterferon alpha (PEG-IFN add-on) to entecavir (ETV) treatment after a short lead-in phase results in more response than ETV monotherapy in HBeAg-positive chronic hepatitis B infection (CHB). This study is the first to assess long-term efficacy of this treatment strategy. Patients who received ETV ± 24 weeks of PEG-IFN add-on in a global trial (ARES study) and completed follow-up were eligible to participate in this observational LTFU study if they had at least one combined HBeAg and HBV DNA measurement beyond week 96 of the ARES study. The primary endpoint was combined response (HBeAg loss and HBV DNA <200 IU/mL) at LTFU. In total, 48 patients treated with PEG-IFN add-on and 48 patients treated with ETV monotherapy were included. The median follow-up duration was 226 (IQR 51) weeks, and 86/96 (90%) patients were initial non-responders. At LTFU, combined response was present in 13 (27%) vs 11 (23%) patients (P = 0.81), and 1 log10 HBsAg decline in 59% vs 28% (P = 0.02) for PEG-IFN add-on and ETV monotherapy, respectively. In 41 initial non-responders who continued ETV therapy, combined response at LTFU was present in 9 patients (PEG-IFN add-on: 5/22 [23%]; ETV monotherapy: 4/19 [21%]). Beyond week 96 of follow-up, rates of serological response became comparable between PEG-IFN add-on and ETV monotherapy. Although in this LTFU study initial non-responders were overrepresented in the add-on arm, PEG-IFN add-on possibly leads rather to accelerated HBeAg loss than to increased long-term HBeAg loss rates.
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Affiliation(s)
- Margo J H van Campenhout
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Willem Pieter Brouwer
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Qing Xie
- Infectious Diseases, Ruijin Hospital, Jiaotong University, Shanghai, China
| | - S Guo
- Infectious Diseases, Ruijin Hospital, Jiaotong University, Shanghai, China
| | - Heng Chi
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Xun Qi
- Gastroenterology and Hepatology, Shanghai Public Health Center, Fu Dan University, Shanghai, China
| | - Fehmi Tabak
- Cerrahpasa Medical Faculty, Istanbul, Turkey
| | - Adrian Streinu-Cercel
- Carol Davila University of Medicine and Pharmacy, National Institute for Infectious Diseases "Prof. Dr. Matei Balș", Bucharest, Romania
| | - Ji-Yao Wang
- Gastroenterology and Hepatology, Zhong Shan Hospital, Fu Dan University, Shanghai, China
| | - Ning-Ping Zhang
- Gastroenterology and Hepatology, Zhong Shan Hospital, Fu Dan University, Shanghai, China
| | | | - Hendrik W Reesink
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
| | - Mircea Diculescu
- Department of Gastroenterology, Fundeni Clinical Institute, Bucharest, Romania
| | - Krzysztof Simon
- Division of Infectious Diseases and Hepatology, Wroclaw Medical University, Wroclaw, Poland
| | - Meral Akdogan
- Department of Gastroenterology, Yuksek Ihtisas Hospital, Ankara, Turkey.,Department of Infectious Diseases, Silesian Medical University, Katowice, Poland
| | - Włodzimierz Mazur
- Department of Infectious Diseases, Silesian Medical University, Katowice, Poland
| | - Rob J de Knegt
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Elke Verhey
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Bettina E Hansen
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.,Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada.,Toronto Center for Liver Disease, Toronto Western and General Hospital, University Health Network, Toronto, Canada
| | - Harry L A Janssen
- Toronto Center for Liver Disease, Toronto Western and General Hospital, University Health Network, Toronto, Canada
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4
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Hsu CW, Su WW, Lee CM, Peng CY, Chuang WL, Kao JH, Chu HC, Huang YH, Chien RN, Liaw YF. Phase IV randomized clinical study: Peginterferon alfa-2a with adefovir or entecavir pre-therapy for HBeAg-positive chronic hepatitis B. J Formos Med Assoc 2018; 117:588-597. [PMID: 29456079 DOI: 10.1016/j.jfma.2017.12.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Revised: 12/01/2017] [Accepted: 12/06/2017] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Efficacy of sequential therapy with nucleos(t)ide analogues and interferons versus monotherapy in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) remains unexplored. We aimed to assess efficacy and safety of sequential therapy with adefovir (ADV) or entecavir (ETV) followed by peginterferon (PEG-IFN) alfa-2a in Taiwanese patients with HBeAg-positive. METHODS This randomized, placebo-controlled, double-blind trial was conducted at nine sites in Taiwan from April 2010 to October 2013. Patients (N = 280) were randomized 1:1:1 to receive placebo, ETV or ADV alone for four weeks, combined with PEG-IFN alfa-2a for two weeks, then PEG-IFN alfa-2a alone for 46 weeks. The primary efficacy end point was HBeAg seroconversion at 48 weeks post-treatment. RESULTS No significant differences were observed among groups for HBeAg seroconversion (PEG-IFN alfa-2a+placebo, 36.3%; PEG-IFN alfa-2a+ETV, 29.5%; and PEG-IFN alfa-2a+ADV, 27.4%), HBeAg loss (37.4%, 32.2%, and 28.6%, respectively) or change in hepatitis B surface antigen (HBsAg) levels from baseline (-0.56 IU/mL, -0.60 IU/mL, and -0.41 IU/mL, respectively). However, hepatitis B virus DNA levels were higher with PEG-IFN alfa-2a+placebo than PEG-IFN alfa+ETV at week 64 (p = 0.0412), 76 (p = 0.0311), and 88 (p = 0.0113), and alanine aminotransferase (ALT) normalization rate was higher with PEG-IFN alfa-2a+placebo than PEG-IFN alfa-2a+ADV (p = 0.0283) or PEG-IFN alfa-2a+ETV (p = 0.0369) at week 88. Sub-analysis of results revealed an association between on-treatment HBsAg and ALT levels and efficacy 48 weeks post-treatment. Safety was comparable among treatment groups. CONCLUSION Pre-therapy with ADV or ETV followed by PEG-IFN alfa-2a is not superior to PEG-IFN alfa-2a monotherapy in Taiwanese patients with HBeAg-positive CHB. CLINICAL TRIAL ID NCT: 00922207.
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Affiliation(s)
- Chao-Wei Hsu
- Liver Research Unit, Chang Gung Memorial Hospital-LinKou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Wei-Wen Su
- Changhua Christian Hospital, Department of Internal Medicine, Changhua, Taiwan
| | - Chuan-Mo Lee
- Chang Gung Memorial Hospital-Kaohsiung, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Cheng-Yuan Peng
- China Medical University Hospital, Department of Hepato-Gastroenterology, Taichung, Taiwan
| | - Wan-Long Chuang
- Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jia-Horng Kao
- National Taiwan University Hospital, Department of Hepato-Gastroenterology, Taipei, Taiwan
| | - Heng-Cheng Chu
- Tri-service General Hospital, Department of Internal Medicine, Taipei, Taiwan
| | - Yi-Hsiang Huang
- Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Rong-Nan Chien
- Liver Research Unit, Chang Gung Memorial Hospital-LinKou, Chang Gung University College of Medicine, Taoyuan, Taiwan.
| | - Yun-Fan Liaw
- Liver Research Unit, Chang Gung Memorial Hospital-LinKou, Chang Gung University College of Medicine, Taoyuan, Taiwan.
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Hsu CW, Chien RN, Liaw YF. Reply to "letter to the editor"-combination therapy for chronic hepatitis B: The future and beyond. J Formos Med Assoc 2018; 117:747-748. [PMID: 29929722 DOI: 10.1016/j.jfma.2018.05.022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2018] [Accepted: 05/30/2018] [Indexed: 01/12/2023] Open
Affiliation(s)
- Chao-Wei Hsu
- Liver Research Unit, Linkou Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Rong-Nan Chien
- Liver Research Unit, Linkou Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan.
| | - Yun-Fan Liaw
- Liver Research Unit, Linkou Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan
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6
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Su TH, Liu CJ. Combination Therapy for Chronic Hepatitis B: Current Updates and Perspectives. Gut Liver 2018; 11:590-603. [PMID: 28494575 PMCID: PMC5593320 DOI: 10.5009/gnl16215] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Revised: 06/30/2016] [Accepted: 07/02/2016] [Indexed: 12/25/2022] Open
Abstract
Nucleos(t)ide analogues (NUCs) and interferon have been used for several decades to treat chronic hepatitis B; however, the therapeutic response remains unsatisfactory. Although NUC therapy exhibits potent on-treatment viral suppression, frequent off-therapy virological relapses suggest an indefinite treatment course. Interferon modulates the innate and adaptive antiviral immune responses and thus increases the chance of viral eradication. Interferon therapy has the advantage of a finite duration, absence of drug resistance, and durable posttreatment responses. Therefore, the combination of NUCs and interferon can theoretically facilitate a synergistic therapeutic effect. This paper summarizes the current strategies of various combination therapies into three categories: the simultaneous “dual” strategy, sequential combination “add-on” strategy, and “switch” strategy. Generally, dual therapy exhibits greater on-treatment and off-therapy viral suppression and lower drug resistance compared with NUC monotherapy. Compared with interferon monotherapy, dual therapy has greater on-treatment viral suppression but shows no difference in off-therapy sustained virological responses. Specific add-on or switch strategies provide promising on-treatment efficacy in select patients. Pretreatment or on-treatment quantitative hepatitis B surface antigen and e antigen are predictive for the treatment efficacy of combination therapy. The optimal schedule of combination regimens and individualized therapy remain to be comprehensively evaluated.
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Affiliation(s)
- Tung-Hung Su
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Chun-Jen Liu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.,Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
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Enomoto M, Nishiguchi S, Tamori A, Kozuka R, Fujii H, Uchida-Kobayashi S, Fukunishi S, Tsuda Y, Higuchi K, Saito M, Enomoto H, Kawada N. Sequential therapy involving an early switch from entecavir to pegylated interferon-α in Japanese patients with chronic hepatitis B. Hepatol Res 2018; 48:459-468. [PMID: 29314465 DOI: 10.1111/hepr.13050] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Revised: 11/16/2017] [Accepted: 12/29/2017] [Indexed: 01/02/2023]
Abstract
AIM The optimal combination of two currently available agents with different mechanisms of action, a nucleos(t)ide analog and pegylated interferon-α (PegIFNα), must be determined to improve treatment of chronic hepatitis B (CHB). METHODS In this study, 24 patients with CHB (14 hepatitis B envelope antigen [HBeAg]-positive patients and 10 HBeAg-negative patients) received entecavir for 36-52 weeks, followed by entecavir plus Peg-IFNα2a for 4 weeks, and finally by PegIFNα-2a alone for 44 weeks. RESULTS A sustained biochemical, virologic, and serologic response was obtained in 7/24 (29%) patients at 48 weeks post-treatment (2/14 [14%] in HBeAg-positive vs 5/10 [50%] in HBeAg-negative patients, P = 0.085). At baseline, patients with a sustained response had a significantly lower γ-glutamyl transferase level (P = 0.0023), a lower aspartate aminotransferase-to-platelet ratio index (P = 0.049), and a lower α-fetoprotein level (P = 0.042) than those without a sustained response. The decline in hepatitis B surface antigen (HBsAg) levels during the first 24 weeks of PegIFNα-2a treatment in patients with a sustained response was greater than that in patients without (P = 0.017). Additionally, HBsAg seroclearance was achieved in two patients (8.3%): one HBeAg-positive and one HBeAg-negative patient. CONCLUSION The outcomes of sequential therapy involving an early switch from entecavir to PegIFNα-2a were unsatisfactory in Japanese patients with CHB. In addition to viral factors, host metabolic characteristics and liver fibrosis/tumor markers can be used for prediction of a sustained response to therapy, but accurate prediction of the therapeutic response is difficult.
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Affiliation(s)
- Masaru Enomoto
- Department of Hepatology, Osaka City University Medical School, Osaka, Japan
| | - Shuhei Nishiguchi
- Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Akihiro Tamori
- Department of Hepatology, Osaka City University Medical School, Osaka, Japan
| | - Ritsuzo Kozuka
- Department of Hepatology, Osaka City University Medical School, Osaka, Japan
| | - Hideki Fujii
- Department of Hepatology, Osaka City University Medical School, Osaka, Japan
| | | | - Shinya Fukunishi
- Second Department of Internal Medicine, Osaka Medical College, Osaka, Japan
| | - Yasuhiro Tsuda
- Second Department of Internal Medicine, Osaka Medical College, Osaka, Japan
| | - Kazuhide Higuchi
- Second Department of Internal Medicine, Osaka Medical College, Osaka, Japan
| | - Masaki Saito
- Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Hirayuki Enomoto
- Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Norifumi Kawada
- Department of Hepatology, Osaka City University Medical School, Osaka, Japan
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Cannizzo ES, Tincati C, Binda F, Ronzi P, Cazzaniga FA, Antinori S, d'Arminio Monforte A, Marchetti G, Milazzo L. Unconventional T cells in chronic hepatitis B patients on long-term suppressive therapy with tenofovir followed by a Peg-IFN add-on strategy: A randomized study. J Viral Hepat 2018; 25:381-390. [PMID: 29091327 DOI: 10.1111/jvh.12820] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Accepted: 09/19/2017] [Indexed: 12/21/2022]
Abstract
HBV eradication in chronic hepatitis B (CHB) subjects is rarely achieved with either nucleos(t)ide analogues (NA) or pegylated interferon (Peg-IFN), which both have a limited effect in restoring immune responses. Thirty CHB subjects on long-term treatment with tenofovir (TDF) and HBV suppression were enrolled and randomized 1:2 to either receive Peg-IFN-α-2a add-on therapy or continue TDF alone. We studied γδ T and iNKT frequency and function (by flow cytometry) at baseline, at 12 weeks and 12 weeks after the end of treatment. A higher reduction in qHBsAg occurred in the add-on group compared with the NA group at W12 (P = .016) and at W24 (P = .012). A decline of qHBsAg ≥0.5 log10 at week 24 occurred in 4 of 10 patients in the add-on arm and 1 of 20 in the NA arm, respectively (P = .03). HBsAg loss was seen in 20% of subjects in the add-on group and in none of the NA group. Compared to HBV negative, CHB on TDF showed lower frequency of iNKT (P = .03) and γδ T cells (P = .03) as well as fewer γδ T cells expressing Vδ2 T-cell receptors (P = .005). No changes in unconventional T-cell frequency and function were shown in both add-on and NA patients nor were differences detected between the two treatment groups. We report persistent impairment of unconventional T cells in CHB. Despite a greater qHBsAg decline of add-on patients, our data failed to detect any effect of Peg-IFN treatment on unconventional T cells.
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Affiliation(s)
- E S Cannizzo
- Department of Health Sciences, Clinic of Infectious Diseases, ASST Santi Paolo e Carlo, University of Milan, Milan, Italy
| | - C Tincati
- Department of Health Sciences, Clinic of Infectious Diseases, ASST Santi Paolo e Carlo, University of Milan, Milan, Italy
| | - F Binda
- Department of Clinical and Biomedical Sciences Luigi Sacco, III Division of Infectious Diseases, University of Milan, Milan, Italy
| | - P Ronzi
- Department of Clinical and Biomedical Sciences Luigi Sacco, III Division of Infectious Diseases, University of Milan, Milan, Italy
| | - F A Cazzaniga
- Department of Health Sciences, Clinic of Infectious Diseases, ASST Santi Paolo e Carlo, University of Milan, Milan, Italy
| | - S Antinori
- Department of Clinical and Biomedical Sciences Luigi Sacco, III Division of Infectious Diseases, University of Milan, Milan, Italy
| | - A d'Arminio Monforte
- Department of Health Sciences, Clinic of Infectious Diseases, ASST Santi Paolo e Carlo, University of Milan, Milan, Italy
| | - G Marchetti
- Department of Health Sciences, Clinic of Infectious Diseases, ASST Santi Paolo e Carlo, University of Milan, Milan, Italy
| | - L Milazzo
- Department of Clinical and Biomedical Sciences Luigi Sacco, III Division of Infectious Diseases, University of Milan, Milan, Italy
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Ray G. Current Scenario of Hepatitis B and Its Treatment in India. J Clin Transl Hepatol 2017; 5:277-296. [PMID: 28936409 PMCID: PMC5606974 DOI: 10.14218/jcth.2017.00024] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2017] [Revised: 05/18/2017] [Accepted: 06/03/2017] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B is a significant public health problem in India, yet disease awareness is very low among the general population. The disease is mostly acquired horizontally, but the role of vertical transmission should not be underestimated. In spite of the fact that the majority of cases are e negative disease, most patients present in the advanced stage and even with hepatocellular carcinoma, the leading cause of which is hepatitis B. High-risk groups (especially tribals) also harbour significant disease burden and have a high prevalence of occult infection, supporting the potential of unknowingly spreading the disease. Findings on the relation of genotypes with disease severity or drug action have been conflicting. Though recently, oral antivirals with high genetic barrier to resistance have shown good viral suppression in the long term, e and s seroconversion is poor and relapse is universal upon therapy discontinuation. As no cure is possible with the currently available therapy, the target is long-term viral suppression by prolonged administration of oral antivirals; unfortunately, this leads to poor treatment adherence, which along with the high cost of therapy results in disease progression and spread of infection. At present, therefore, emphasis should be put on health education of the general and high-risk populations, along with health care workers to increase knowledge on such preventive measures as avoiding unsafe injection practices, high-risk sex, performing unnecessary injection and blood transfusion and providing proper screening of blood products; these efforts should be combined with intensive screening and aggressive vaccination programs, especially in high-risk groups and areas of high endemicity. Vaccination strategies are still below par and logistics should be developed for wider coverage; in addition, further research should be carried out on the efficacy and mode of usage for different types of vaccine.
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Affiliation(s)
- Gautam Ray
- Gastroenterology Unit, Department of Medicine, B.R.Singh Hospital, Kolkata, India
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Vyas AK, Jindal A, Hissar S, Ramakrishna G, Trehanpati N. Immune balance in Hepatitis B Infection: Present and Future Therapies. Scand J Immunol 2017; 86:4-14. [PMID: 28387980 DOI: 10.1111/sji.12553] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Accepted: 03/28/2017] [Indexed: 12/16/2022]
Abstract
Chronic hepatitis B virus (HBV) infection affects millions of people worldwide and about half a million people die every year. India represents the second largest pool of chronic HBV infections with an estimated 40 million chronically infected patients. Persistence or clearance of HBV infection mainly depends upon host immune responses. Chronically infected individuals remain in immune tolerant phase unless HBV flares and leads to the development of chronic active hepatitis or acute-on-chronic liver failure. Strategies based on inhibition of viral replication (nucleoside analogues) or immune modulation (interferons) as monotherapy, or in combination in sequential therapies, are currently being used globally for reducing HBV viral load and mediating HBsAg clearance. However, the immune status and current therapies for promoting sustained virological responses in HBV-infected patients remain suboptimal. Elimination of cccDNA is major challenge for future therapies, and new molecules such as NTCP, Toll-like receptor (TLR)7 agonist (GS9620) and cyclophilin have emerged as potential targets for preventing HBV entry and replication. Other than these, HBV cccDNA elimination is the major target for future therapies.
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Affiliation(s)
- A K Vyas
- Department of Molecular and Cellular Medicine, Institute of Liver & Biliary Sciences, New Delhi, India
| | - A Jindal
- Department of Hepatology, Institute of Liver & Biliary Sciences, New Delhi, India
| | - S Hissar
- Department of Molecular and Cellular Medicine, Institute of Liver & Biliary Sciences, New Delhi, India
| | - G Ramakrishna
- Department of Molecular and Cellular Medicine, Institute of Liver & Biliary Sciences, New Delhi, India
| | - N Trehanpati
- Department of Molecular and Cellular Medicine, Institute of Liver & Biliary Sciences, New Delhi, India
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11
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Fairman J, Liu KH, Menne S. Prevention of liver tumor formation in woodchucks with established hepatocellular carcinoma by treatment with cationic liposome-DNA complexes. BMC Cancer 2017; 17:172. [PMID: 28264666 PMCID: PMC5339946 DOI: 10.1186/s12885-017-3163-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Accepted: 03/02/2017] [Indexed: 12/15/2022] Open
Abstract
Background Approximately 250 million people worldwide are chronically infected with hepatitis B virus (HBV) and more than half of the hepatocellular carcinoma (HCC) cases are attributed to this infection. As HCC has a high mortality rate, and current treatment options are remarkably limited, the development of new therapeutic treatment strategies is warranted. Methods In this study, woodchucks infected with woodchuck hepatitis virus (WHV), and with pre-existing liver tumors, were used as a model to investigate if complexes of cationic liposomes and non-coding DNA (JVRS-100) were effective in treatment of HCC. Results It was observed that the high serum viral load that is present in a typical chronic WHV infection (i.e., approximately 100-fold higher than human viral loads) results in immune suppression and resistance to treatment with JVRS-100. Treatment of woodchucks with lower serum viral load that more closely matched with the viral load usually seen in human HBV infection appears a better model for immunotherapeutic development based on the responsiveness to JVRS-100 treatment. In the latter case, marked declines in WHV DNA and WHV surface antigen were determined over the 12-week treatment period and WHV markers stayed suppressed during most time points of the 12-week follow-up period. Even more remarkably, the formation of new liver tumors was not observed in woodchucks treated with a well-tolerated dose of JVRS-100, as compared to several new tumors that developed in vehicle-treated control animals. Conclusions Although there was little decrease in the volumes of the liver tumors existing at the time of treatment, it is generally accepted that preventing the spread and metastasis of almost always fatal cancers such as HCC and thus, reducing it to a chronic and treatable disease can also be a successful therapeutic approach. The results in woodchucks warrant the investigation of JVRS-100 as an intervention to prevent liver cancer in patients chronically infected with HBV and at high risk for HCC development.
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Affiliation(s)
- Jeffery Fairman
- Juvaris BioTherapeutics, Inc., Pleasanton, CA, 94566, USA.,Present address: SutroVax, Inc., South San Francisco, CA, 94080, USA
| | - Katherine H Liu
- Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA
| | - Stephan Menne
- Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA. .,Present address: Georgetown University Medical Center, Department of Microbiology & Immunology, Medical-Dental Building, Room C301, 3900 Reservoir Road, Washington, DC, 20057, USA.
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12
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Wang H, Wu D, Wang X, Chen G, Zhang Y, Yan W, Luo X, Han M, Ning Q. Hepatitis B virus surface protein-induced hPIAS1 transcription requires TAL1, E47, MYOG, NFI, and MAPK signal pathways. Biol Chem 2016; 397:1173-1185. [DOI: 10.1515/hsz-2015-0290] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2015] [Accepted: 06/06/2016] [Indexed: 12/30/2022]
Abstract
Abstract
The protein inhibitor of activated STAT1 (PIAS1) plays important roles in regulating virus-induced chronic hepatitis, but the interaction between hepatitis B virus (HBV) and hPIAS1 is not clear. Our aim was to verify if HBV encoding proteins enhance the transcription of hPIAS1 and which cis-elements and transcription factors were involved in the mechanism. In order to do, so a series of molecular biological methods, along with functional and histological studies, were performed. We found that the HBV surface protein (HBs) enhanced hPIAS1 transcription through the activities of TAL1, E47, myogenin (MYOG), and NFI, dependent on the activation of p38MAPK and ERK signaling pathways in vitro, which might contribute to the ineffectiveness of treatment in CHB patients. Furthermore, liver samples from patients with high HBsAg levels and HBV DNA displayed increased hPIAS1 expression and high levels of TAL1, E47, MYOG, and NFI, compared to those patients with low HBsAg levels and HBV DNA, and healthy controls. These findings suggest that the HBs protein-induced hPIAS1 transcription requires TAL1, E47, MYOG, NFI, and MAPK signal pathways. It provides new potential targets for antiviral therapeutic strategies for controlling HBV-associated diseases.
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13
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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: 1929] [Impact Index Per Article: 214.3] [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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14
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Enomoto M, Nishiguchi S, Tamori A, Kozuka R, Hayashi T, Kohmoto MT, Jomura H, Morikawa H, Murakami Y, Shiomi S, Kawada N. Long-Term Outcome of Sequential Therapy with Lamivudine Followed by Interferon-β in Nucleoside-Naive, Hepatitis B e-Antigen-Positive Patients with Chronic Hepatitis B Virus Genotype C Infection. J Interferon Cytokine Res 2015; 35:613-620. [PMID: 25884105 DOI: 10.1089/jir.2014.0234] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
It is unclear whether the combination of a nucleos(t)ide analog and interferon (IFN) is superior to monotherapy for treating chronic hepatitis B. In this study, we report the long-term outcomes of sequential therapy using lamivudine followed by IFN-β. This study included 24 hepatitis B e-antigen (HBeAg)-positive patients with chronic hepatitis B virus (HBV) genotype C infection who were treated with lamivudine alone for 16-32 weeks, then with both IFN-β and lamivudine for 4 weeks, and finally with IFN-β alone for 20 weeks. All patients were followed up for 7.1±2.8 years post-treatment. The rate of response, defined as transaminase normalization, HBeAg loss, and HBV DNA <10(4) copies/mL, was 5/24 (21%) at 24 weeks post-treatment. The patients with short-term responses were younger than those with no response (P=0.039). More short-term responders had undetectable HBV DNA at the start of IFN-β compared with the nonresponders (P=0.0059). Subsequently, 4 of the 5 short-term responders remained free of the need for further drug treatment for 4.2±3.5 years post-treatment; more short-term responders remained drug free than did nonresponders (P=0.035). In conclusion, the rate of response to sequential therapy was limited in HBeAg-positive patients with chronic HBV genotype C infection at 24 weeks post-treatment. In the majority of the short-term responders, however, the response was sustainable in the long term.
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Affiliation(s)
- Masaru Enomoto
- 1 Department of Hepatology, Osaka City University Medical School , Osaka, Japan
| | - Shuhei Nishiguchi
- 2 Department of Internal Medicine, Hyogo College of Medicine , Nishinomiya, Japan
| | - Akihiro Tamori
- 1 Department of Hepatology, Osaka City University Medical School , Osaka, Japan
| | - Ritsuzo Kozuka
- 1 Department of Hepatology, Osaka City University Medical School , Osaka, Japan
| | - Takehiro Hayashi
- 1 Department of Hepatology, Osaka City University Medical School , Osaka, Japan
| | | | - Hisato Jomura
- 3 Department of Internal Medicine, Wakakoukai Clinic , Osaka, Japan
| | - Hiroyasu Morikawa
- 1 Department of Hepatology, Osaka City University Medical School , Osaka, Japan
| | - Yoshiki Murakami
- 1 Department of Hepatology, Osaka City University Medical School , Osaka, Japan
| | - Susumu Shiomi
- 4 Department of Nuclear Medicine, Osaka City University Medical School , Osaka, Japan
| | - Norifumi Kawada
- 1 Department of Hepatology, Osaka City University Medical School , Osaka, Japan
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15
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Berraondo P, Di Scala M, Korolowicz K, Thampi LM, Otano I, Suarez L, Fioravanti J, Aranda F, Ardaiz N, Yang J, Kallakury BV, Tucker RD, Vasquez M, Menne S, Prieto J, González-Aseguinolaza G. Liver-directed gene therapy of chronic hepadnavirus infection using interferon alpha tethered to apolipoprotein A-I. J Hepatol 2015; 63:329-36. [PMID: 25772035 PMCID: PMC4508219 DOI: 10.1016/j.jhep.2015.02.048] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2014] [Revised: 02/13/2015] [Accepted: 02/23/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Current hepatitis B virus (HBV) management is challenging as treatment with nucleos(t)ide analogues needs to be maintained indefinitely and because interferon (IFN)-α therapy is associated with considerable toxicity. Previously, we showed that linking IFNα to apolipoprotein A-I generates a molecule (IA) with distinct antiviral and immunostimulatory activities which lacks the hematological toxicity of IFNα. METHODS Here, we analyse the antiviral potential of an adeno-associated vector encoding IFNα fused to apolipoprotein A-I (AAV-IA) in comparison to a vector encoding only IFNα (AAV-IFN) in two animal models of chronic hepadnavirus infection. RESULTS In HBV transgenic mice, we found that both vectors induced marked reductions in serum and liver HBV DNA and in hepatic HBV RNA but AAV-IFN caused lethal pancytopenia. Woodchucks with chronic hepatitis virus (WHV) infection that were treated by intrahepatic injection of vectors encoding the woodchuck sequences (AAV-wIFN or AAV-wIA), experienced only a slight reduction of viremia which was associated with hematological toxicity and high mortality when using AAV-wIFN, while AAV-wIA was well tolerated. However, when we tested AAV-wIA or a control vector encoding woodchuck apolipoprotein A-I (AAV-wApo) in combination with entecavir, we found that AAV-wApo-treated animals exhibited an immediate rebound of viral load upon entecavir withdrawal while, in AAV-wIA-treated woodchucks, viremia and antigenemia remained at low levels for several weeks following entecavir interruption. CONCLUSIONS Treatment with AAV-IA is safe and elicits antiviral effects in animal models with difficult to treat chronic hepadnavirus infection. AAV-IA in combination with nucleos(t)ide analogues represents a promising approach for the treatment of HBV infection in highly viremic patients.
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Affiliation(s)
- Pedro Berraondo
- Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Navarra, Spain.
| | - Marianna Di Scala
- Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Navarra, Spain
| | - Kyle Korolowicz
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, USA
| | - Linta M Thampi
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, USA
| | - Itziar Otano
- Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Navarra, Spain
| | - Lester Suarez
- Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Navarra, Spain
| | - Jessica Fioravanti
- Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Navarra, Spain
| | - Fernando Aranda
- Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Navarra, Spain
| | - Nuria Ardaiz
- Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Navarra, Spain
| | - Junming Yang
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, USA
| | - Bhaskar V Kallakury
- Department of Pathology, Georgetown University Medical Center, Washington, DC, USA
| | - Robin D Tucker
- Division of Comparative Medicine, Georgetown University Medical Center, Washington, DC, USA
| | - Marcos Vasquez
- Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Navarra, Spain
| | - Stephan Menne
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, USA
| | - Jesús Prieto
- Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Navarra, Spain
| | - Gloria González-Aseguinolaza
- Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Navarra, Spain
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16
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Huang YW, Chayama K, Kao JH, Yang SS. Detectability and clinical significance of serum hepatitis B virus ribonucleic acid. Hepatobiliary Surg Nutr 2015; 4:197-202. [PMID: 26151059 DOI: 10.3978/j.issn.2304-3881.2014.11.08] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2014] [Accepted: 10/28/2014] [Indexed: 12/18/2022]
Abstract
Serum hepatitis B virus (HBV) RNA is detected during treatment with nucleoside analogue as a consequence of interrupted reverse transcription (RT) and unaffected replicative intermediates. The presence of serum HBV RNA in chronic HBV patients is confirmed by using ribonuclease digestion. Serum HBV RNA is differentially inhibited by interferon, but not by nucleoside analogue. The inhibitory effect of interferon on HBV RNA replicative intermediates may potentiate the suppression of HBV replication. Clinical significance of serum HBV RNA includes: (I) reflect the antiviral potency of nucleoside analogue; (II) predictor of early emergence of viral mutation during lamivudine therapy; (III) independently predict initial virologic response or earlier HBV suppression during nucleoside analogue therapy; (IV) predict HBV reactivation after discontinuation of nucleoside analogue. Thus, serum HBV RNA might be useful to optimize treatment efficacy in patients with chronic HBV, including shifting of oral antivirals or conversion to immunomodulatory agent i.e., interferon. Furthermore, serum HBV RNA levels correlate better with serum quantitative HBsAg (qHBsAg) than with serum HBV DNA levels. The predictive role of serum HBV RNA in long-term treatment effects of nucleoside analogue needs further study.
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Affiliation(s)
- Yi-Wen Huang
- 1 Liver Center, Cathay General Hospital Medical Center, Taipei, Taiwan ; 2 School of Medicine, Taipei Medical University, Taipei, Taiwan ; 3 Division of Gastroenterology, Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan ; 4 Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, 5 Liver Research Project Center, Hiroshima University, Hiroshima, Japan ; 6 Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan ; 7 School of Medicine, Fu-Jen Catholic University College of Medicine, Taipei, Taiwan
| | - Kazuaki Chayama
- 1 Liver Center, Cathay General Hospital Medical Center, Taipei, Taiwan ; 2 School of Medicine, Taipei Medical University, Taipei, Taiwan ; 3 Division of Gastroenterology, Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan ; 4 Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, 5 Liver Research Project Center, Hiroshima University, Hiroshima, Japan ; 6 Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan ; 7 School of Medicine, Fu-Jen Catholic University College of Medicine, Taipei, Taiwan
| | - Jia-Horng Kao
- 1 Liver Center, Cathay General Hospital Medical Center, Taipei, Taiwan ; 2 School of Medicine, Taipei Medical University, Taipei, Taiwan ; 3 Division of Gastroenterology, Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan ; 4 Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, 5 Liver Research Project Center, Hiroshima University, Hiroshima, Japan ; 6 Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan ; 7 School of Medicine, Fu-Jen Catholic University College of Medicine, Taipei, Taiwan
| | - Sien-Sing Yang
- 1 Liver Center, Cathay General Hospital Medical Center, Taipei, Taiwan ; 2 School of Medicine, Taipei Medical University, Taipei, Taiwan ; 3 Division of Gastroenterology, Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan ; 4 Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, 5 Liver Research Project Center, Hiroshima University, Hiroshima, Japan ; 6 Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan ; 7 School of Medicine, Fu-Jen Catholic University College of Medicine, Taipei, Taiwan
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Lu J, Zhang S, Liu Y, Du X, Ren S, Zhang H, Ma L, Chen Y, Chen X, Shen C. Effect of Peg-interferon α-2a combined with Adefovir in HBV postpartum women with normal levels of ALT and high levels of HBV DNA. Liver Int 2015; 35:1692-9. [PMID: 25438657 DOI: 10.1111/liv.12753] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Accepted: 11/21/2014] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Currently, routine antiviral treatment is not recommended for immune-tolerant subjects with chronic HBV infection. In this study, we assessed the treatment efficacy of combining Peg IFN α-2a with Adefovir (CPIA) in chronic HBV infected pregnant women with normal levels of ALT and high levels of HBV after delivery. METHODS Chronic hepatitis B pregnant women with normal levels of ALT and high levels of HBV DNA were treated with Telbivudine during the third trimester of their pregnancy. After childbirth, based on serological and virological parameters, the patients were either switched to CPIA treatment for 96 weeks or stopped Telbivudine treatment and followed for 48 weeks. RESULTS A total of 68 patients were enrolled in this study. Thirty (30/68) of them were switched to CPIA treatment after childbirth, 93.3% (28/30) of them achieved virological response, 56.7% (17/30) achieved HBeAg seroclearance and 26.7% (8/30) cleared HBsAg. The HBV DNA and HBeAg levels before CPIA treatment were negatively associated with HBeAg seroclearance. HBsAg and HBeAg levels in week 12 and week 24 after CPIA treatment were negatively associated with HBsAg seroclearance. Thirty-eight (38/68) patients did not receive antiviral treatment after childbirth, and none of them had HBeAg or HBsAg clearance. CONCLUSION High rates of viral response and clearance were achieved in chronic hepatitis B pregnant woman with normal levels of ALT and high levels of HBV DNA treated by CPIA after childbirth. (231 words).
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Affiliation(s)
- Junfeng Lu
- International Medical Department, Beijing Youan Hospital, Capital Medical, Beijing, China
| | - Shibin Zhang
- International Medical Department, Beijing Youan Hospital, Capital Medical, Beijing, China
| | - Yali Liu
- International Medical Department, Beijing Youan Hospital, Capital Medical, Beijing, China
| | - Xiaofei Du
- International Medical Department, Beijing Youan Hospital, Capital Medical, Beijing, China
| | - Shan Ren
- International Medical Department, Beijing Youan Hospital, Capital Medical, Beijing, China
| | - Hua Zhang
- International Medical Department, Beijing Youan Hospital, Capital Medical, Beijing, China
| | - Lina Ma
- International Medical Department, Beijing Youan Hospital, Capital Medical, Beijing, China
| | - Yue Chen
- Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, USA
| | - Xinyue Chen
- International Medical Department, Beijing Youan Hospital, Capital Medical, Beijing, China
| | - Chengli Shen
- Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, USA
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18
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Wong GLH, Wong VWS, Chan HLY. Combination therapy of interferon and nucleotide/nucleoside analogues for chronic hepatitis B. J Viral Hepat 2014; 21:825-34. [PMID: 25402543 DOI: 10.1111/jvh.12341] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2014] [Accepted: 09/09/2014] [Indexed: 12/12/2022]
Abstract
Chronic hepatitis B is one of the leading causes of cirrhosis and hepatocellular carcinoma globally. At present, seven drugs, including two interferons and five oral nucleos(t)ide analogues (NAs), have been approved for the treatment of chronic hepatitis B. Interferon works by immunomodulation, but is successful in less than a third of treated patients and is a relatively weak antiviral. NAs directly suppress the hepatitis B virus but have limited durability. Based on current data, combination of NA and interferon results in greater viral suppression but does not translate to off-treatment sustained response. Concomitant or sequential treatment also does not make a difference. Combining telbivudine and interferon also runs the risk of severe peripheral neuropathy. On the other hand, interferon switch or additional therapy in patients well controlled with NAs appears to improve the durability of off-treatment response. This article reviews current data on interferon and NA combination and discusses potential future developments.
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Affiliation(s)
- G L-H Wong
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China; Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China; State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
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19
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You CR, Lee SW, Jang JW, Yoon SK. Update on hepatitis B virus infection. World J Gastroenterol 2014; 20:13293-13305. [PMID: 25309066 PMCID: PMC4188887 DOI: 10.3748/wjg.v20.i37.13293] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2013] [Revised: 03/18/2014] [Accepted: 04/05/2014] [Indexed: 02/06/2023] Open
Abstract
Chronic infection with hepatitis B virus (HBV) leads to the development of hepatocellular carcinoma and/or chronic liver failure. Despite extensive research, the immunopathogenesis is not completely understood. Viral persistence and clinical outcomes following HBV infection depend on viral factors and host factors; including genetic factors that determine a host's immune mechanisms. The primary goal of chronic hepatitis B (CHB) treatment is to eradicate HBV or to at least maintain suppression of HBV replication. Despite recent advances in anti-viral agents for chronic HBV infection, complete eradication of the virus has been difficult to achieve. Agents for the treatment of CHB are divided mainly into two groups: immunomodulating agents and antiviral nucleos(t)ide analogues (NAs). Although NAs are safe, effective and easily administered orally, their long-term use poses the risk of drug resistance. Currently, international evidence-based guidelines have been developed to support physicians in managing CHB patients. However, treatment of patients with drug resistance is still challenging, as only a few classes of anti-HBV drugs are available and cross-resistance between drugs can occur. In addition, as the currently available genotypic test for detection of drug resistance still has limitations in identifying the different substitutions present in the same viral genome, the development of a new virologic test to overcome this limitation is necessary. Among the predictive factors associated with response to pegylated interferon (PEG-IFN) therapy, hepatitis B surface antigen quantification is considered to be a surrogate marker for monitoring response to PEG-IFN. Current practice guidelines stress the importance of profound and durable HBV viral suppression in the treatment of CHB patients. To this end, it is essential to choose a potent antiviral drug with a low risk of resistance for initial treatment of CHB to achieve sustained virological response. This review highlights recent advances in the understanding of the immunopathogenesis of HBV and currently available and developing treatment strategies against HBV infection.
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20
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Ning Q, Han M, Sun Y, Jiang J, Tan D, Hou J, Tang H, Sheng J, Zhao M. Switching from entecavir to PegIFN alfa-2a in patients with HBeAg-positive chronic hepatitis B: a randomised open-label trial (OSST trial). J Hepatol 2014; 61:777-84. [PMID: 24915612 DOI: 10.1016/j.jhep.2014.05.044] [Citation(s) in RCA: 198] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2013] [Revised: 05/16/2014] [Accepted: 05/30/2014] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Durable post-treatment response is uncommon in chronic hepatitis B (CHB) patients on nucleos(t)ide analogue therapy. Response, response predictors and safety were assessed in patients who switched from long-term entecavir (ETV) to peginterferon alfa-2a. METHODS Hepatitis B e antigen (HBeAg)-positive CHB patients who had received ETV for 9-36 months, with HBeAg <100 PEIU/ml and HBV DNA ⩽1000 copies/ml, were randomised 1:1 to receive peginterferon alfa-2a 180 μg/week or ETV 0.5mg/day for 48 weeks. The primary endpoint was HBeAg seroconversion at week 48 (ClinicalTrials.gov: NCT00940485). RESULTS 200 patients were randomised; 197 received ⩾1 study drug dose. Five patients who were anti-HBe-positive at baseline were excluded from the modified intention-to-treat population (peginterferon alfa-2a, n = 94; ETV, n = 98). Patients who switched to peginterferon alfa-2a achieved higher week 48 HBeAg seroconversion rates vs. those who continued ETV (14.9% vs. 6.1%; p = 0.0467). Only patients receiving peginterferon alfa-2a achieved HBsAg loss (8.5%). Among peginterferon alfa-2a-treated patients with HBeAg loss and HBsAg <1500 IU/ml at randomisation, 33.3% and 22.2% achieved HBeAg seroconversion and HBsAg loss, respectively. Early on-treatment HBsAg decline predicted response at week 48; highest rates were observed in patients with week 12 HBsAg <200 IU/ml (HBeAg seroconversion, 66.7%; HBsAg loss, 77.8%). Alanine aminotransferase elevations were not associated with viral rebound (n = 38). Peginterferon alfa-2a was well-tolerated. CONCLUSIONS For patients who achieve virological suppression with ETV, switching to a finite course of peginterferon alfa-2a significantly increases rates of HBeAg seroconversion and HBsAg loss. A response-guided approach may identify patients with the greatest chance of success.
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Affiliation(s)
- Qin Ning
- Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Meifang Han
- Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yongtao Sun
- Tangdu Hospital, The Fourth Military Medical University, Xi'an, China
| | - Jiaji Jiang
- The First Hospital, Fujian Medical University, Fuzhou, China
| | - Deming Tan
- Xiangya Hospital, Central South University, Changsha, China
| | - Jinlin Hou
- Nanfang Hospital, Nanfang Medical University, Guangzhou, China
| | - Hong Tang
- West China Hospital, Sichuan University, Chengdu, China
| | - Jifang Sheng
- The First Hospital, Zhejiang University, Hangzhou, China
| | - Mianzhi Zhao
- Shanghai Roche Pharmaceutical Co., Ltd, Shanghai, China
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A Randomized, Open-Label Clinical Study of Combined Pegylated Interferon Alfa-2a (40KD) and Entecavir Treatment for Hepatitis B "e" Antigen-Positive Chronic Hepatitis B. Clin Infect Dis 2014; 59:1714-23. [DOI: 10.1093/cid/ciu702] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
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22
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Abstract
There had been remarkable development in nucleos(t)ide analogues (NAs) and evolution in treatment strategies in last 15 years. Currently, there are five NAs available for chronic hepatitis B treatment, namely lamivudine, telbivudine and entecavir (nucleoside analogues), adefovir dipivoxil and tenofovir disoproxil fumarate (nucleotide analogues). The advantages of relatively infrequent side effects and easy administration per oral make NAs popular treatment options. The major drawback of earlier generation NAs is the risk of emergence of drug resistance. Current international guidelines recommend the use of more potent agents with high genetic barriers to resistance including entecavir and tenofovir as first line chronic hepatitis B treatment. However, there is no consensus regarding the subsequent treatment regimens in patients with suboptimal responses to NAs. De novo combination therapy of two NAs, response-guided therapy and roadmap concept in NAs with subsequent switch or add-on therapy can also potentially improve treatment efficacy and avoid resistance.
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Affiliation(s)
- Angeline Oi-Shan Lo
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
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Liu YH, Wu T, Sun N, Wang GL, Yuan JZ, Dai YR, Zhou XH. Combination therapy with pegylated interferon alpha-2b and adefovir dipivoxil in HBeAg-positive chronic hepatitis B versus interferon alone: a prospective, randomized study. JOURNAL OF HUAZHONG UNIVERSITY OF SCIENCE AND TECHNOLOGY. MEDICAL SCIENCES = HUA ZHONG KE JI DA XUE XUE BAO. YI XUE YING DE WEN BAN = HUAZHONG KEJI DAXUE XUEBAO. YIXUE YINGDEWEN BAN 2014; 34:542-547. [PMID: 25135724 DOI: 10.1007/s11596-014-1312-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/16/2014] [Revised: 06/20/2014] [Indexed: 02/05/2023]
Abstract
Currently available monotherapies of oral nucleoside/nucleotide analogs or interferon are unable to achieve a sustained and effective response in most of patients with chronic hepatitis B (CHB). The objective of the present study was to compare the efficacy and safety of pegylated interferon (Peg-IFN) alpha-2b plus adefovir dipivoxil combination therapy versus Peg-IFN alpha-2b alone. Sixty-one HBeAg-positive chronic hepatitis B patients were randomized to receive Peg-IFN alpha-2b alone (1.5 μg/kg once weekly) or Peg-IFN alpha-2b plus adefovir (10 mg daily) for up to 52 weeks. Efficacy and safety analyses were performed on all participants who received at least one dose of study medication. The rate of HBeAg seroconversion and undetectable HBV-DNA were evaluated after 52 weeks of therapy. At the end of treatment, 11 of 30 (36.7%) patients receiving combination therapy achieved HBeAg seroconversion versus 8 of 31 (25.8%) in the monotherapy group (P=0.36). In contrast, the percentage of patients with undetectable serum HBV DNA was significantly higher in the combination group than in the monotherapy group (76.7% vs. 29.0%, P<0.001). Thyroid dysfunction was more frequent in the combination group than in the monotherapy group (P<0.05). In HBeAg-positive CHB, combination of Peg-IFN alpha-2b and adefovir for 52 weeks resulted, at the end of treatment, in a higher virological response but without significant impact on the rate of HBeAg seroconversion and possibly an adverse effect on thyroid function.
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Affiliation(s)
- Yu-Hua Liu
- Department of Infectious Diseases, the First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, China
| | - Tao Wu
- Department of Infectious Diseases, the First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, China
| | - Ning Sun
- Department of Infectious Diseases, the First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, China
| | - Guang-Li Wang
- Department of Infectious Diseases, the First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, China
| | - Jian-Zhi Yuan
- Department of Infectious Diseases, the First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, China
| | - Yu-Rong Dai
- Department of Infectious Diseases, the First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, China
| | - Xiao-Hui Zhou
- Department of Infectious Diseases, the First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, China.
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Chen X, Qian Y, Yan F, Tu J, Yang X, Xing Y, Chen Z. 5'-triphosphate-siRNA activates RIG-I-dependent type I interferon production and enhances inhibition of hepatitis B virus replication in HepG2.2.15 cells. Eur J Pharmacol 2013; 721:86-95. [PMID: 24099962 DOI: 10.1016/j.ejphar.2013.09.050] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2013] [Revised: 09/06/2013] [Accepted: 09/22/2013] [Indexed: 12/25/2022]
Abstract
Hepatitis B virus (HBV) infection often results in acute or chronic viral hepatitis and other liver diseases including cirrhosis and hepatocellular carcinoma. Current therapies for HBV usually have severe side effects and can cause development of drug-resistant mutants. An alternative and safe immunotherapeutic approach for HBV infection is urgently needed for effective anti-HBV therapy. In this study, we propose a new strategy for anti-HBV therapy that activates type-I interferon (IFN) antiviral innate immunity through stimulating pattern-recognition receptors with RNA interference (RNAi) using a 5'-end triphosphate-modified small interfering RNA (3p-siRNA). We designed and generated a 3p-siRNA targeting overlapping region of S gene and P gene of the HBV genome at the 5'-end of pregenomic HBV RNA. Our results demonstrated that 3p-siRNA induced a RIG-I-dependent antiviral type-I IFN response when transfected into HepG2.2.15 cells that support HBV replication. The 3p-siRNA significantly inhibited HBsAg and HBeAg secretion from HepG2.2.15 cells in a RIG-I-dependent manner, and the antiviral effect of 3p-siRNA was superior to that of siRNA. Furthermore, 3p-siRNA had more pronounced inhibition effects on the replication of HBV DNA and the transcription of mRNA than that of siRNA. Finally, 3p-siRNA displayed antiviral activity with long-term suppression of HBV replication. In conclusion, our findings suggest that 3p-siRNA could act as a powerful bifunctional antiviral molecule with potential for developing a promising therapeutic against chronic HBV infection.
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Affiliation(s)
- Xiaojuan Chen
- Division of Infection and Immunity, Department of Electromagnetic and Laser Biology, Beijing Institute of Radiation Medicine, 27 Taiping Rd, Beijing 100850, China
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Huang R, Hao Y, Zhang J, Wu C. Interferon-alpha plus adefovir combination therapy versus interferon-alpha monotherapy for chronic hepatitis B treatment: A meta-analysis. Hepatol Res 2013; 43:1040-51. [PMID: 23356962 DOI: 10.1111/hepr.12058] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2012] [Revised: 12/18/2012] [Accepted: 12/24/2012] [Indexed: 01/28/2023]
Abstract
AIM The therapeutic effect of interferon (IFN)-α plus adefovir (ADV) combination therapy versus IFN-α monotherapy in chronic hepatitis B (CHB) treatment remains under debate. The objective of the present study was to compare the efficacy between these two regimens in CHB treatment. METHODS MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, Chinese Biomedical Literature Database, National Knowledge Infrastructure, WANFANG and VIP databases were searched until 15 April 2012. All randomized controlled trials (RCT) comparing IFN-α plus ADV combination therapy versus IFN-α monotherapy for treating CHB patients were included. Review Manager ver. 5.1.0 was used for meta-analysis. RESULTS Our results showed that the rate of undetectable serum hepatitis B virus (HBV) DNA was significantly higher in the IFN-α plus ADV combination group than in the IFN-α monotherapy group, both at 24 weeks (relative risk [RR] = 1.74, 95% confidence interval [CI] = 1.47-2.05, P < 0.00001) and 48 weeks (RR = 1.56, 95% CI = 1.35-1.80, P < 0.00001) of treatment and after treatment (RR = 1.35, 95% CI = 1.10-1.66, P = 0.004). The serum hepatitis B e-antigen (HBeAg) negativation and HBeAg seroconversion rates were also higher in the combination group. However, a greater hepatitis B surface antigen loss rate was not found in the combination group. Forty-eight weeks of combination therapy improved the alanine aminotransferase normalization rate, but did not improve the rate of undetectable HBV DNA or that of HBeAg seroconversion as compared with 24 weeks of combination therapy. CONCLUSION Based on the current studies, the efficacy of IFN-α plus ADV combination therapy is superior to IFN-α monotherapy.
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Affiliation(s)
- Rui Huang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
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Enomoto M, Tamori A, Nishiguchi S, Kawada N. Combination therapy with a nucleos(t)ide analogue and interferon for chronic hepatitis B: simultaneous or sequential. J Gastroenterol 2013; 48:999-1005. [PMID: 23338486 DOI: 10.1007/s00535-012-0742-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2012] [Accepted: 12/11/2012] [Indexed: 02/04/2023]
Abstract
Currently available antiviral treatment for chronic hepatitis B virus infection can be divided into two classes of therapeutic agents: nucleos(t)ide analogues (NAs) and interferon (IFN). The major advantages of NAs are good tolerance and potent antiviral activity associated with high rates of on-treatment response to therapy; the advantages of IFN include a finite course of treatment, absence of drug resistance, and an opportunity to obtain a post-treatment durable response to therapy. The use of these two antiviral agents with different mechanisms of action in combination is theoretically an attractive approach for treatment. Here, we have reviewed previous reports of either simultaneous or sequential combination therapy with NA and IFN for chronic hepatitis B patients. In previous studies comparing the lamivudine/IFN combination and lamivudine monotherapy in a finite course, combination therapy was associated with higher rates of sustained post-treatment response and lower rates of drug resistance than lamivudine monotherapy. However, NAs such as lamivudine are generally administered indefinitely because of high rates of post-treatment relapse. In addition, concern for drug resistance has decreased significantly with newer, high-potency NAs even when administered alone. In previous studies comparing the lamivudine/IFN combination and IFN monotherapy, the combination therapy showed greater on-treatment viral suppression, but no difference was observed in the post-treatment sustained response. Thus, whether combination therapy confers an additional benefit compared to monotherapy for treating chronic hepatitis B remains unclear. The efficacy of IFN in combination with a more potent NA, such as entecavir or tenofovir, remains to be comprehensively evaluated.
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Affiliation(s)
- Masaru Enomoto
- Department of Hepatology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka, 545-8585, Japan,
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Viganò M, Mangia G, Lampertico P. Results of treatment of chronic hepatitis B with pegylated interferon. Clin Liver Dis 2013; 17:425-43. [PMID: 23905814 DOI: 10.1016/j.cld.2013.05.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Persistent viral eradication or suppression through a defined course of Pegylated-interferon (PegIFN) or the administration of a long-term potent nucleot(s)ide analogues (NUCs) can impact positively the natural course of HBV infection by preventing disease progression. Despite the higher rates of off-therapy response achieved with PegIFN compared with NUC, its benefits are restricted to a subgroup of patients only. To increase the rates of patients who may benefit from PegIFN treatment, minimizing the adverse events, careful patient selections based on baseline features and on treatment HBsAg kinetics for individual treatment optimization are required.
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Affiliation(s)
- Mauro Viganò
- Hepatology Division, Ospedale San Giuseppe, Università degli Studi di Milano, Via San Vittore 12, Milano 20123, Italy
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Boglione L, D'Avolio A, Cariti G, Milia MG, Simiele M, De Nicolò A, Ghisetti V, Di Perri G. Sequential therapy with entecavir and PEG-INF in patients affected by chronic hepatitis B and high levels of HBV-DNA with non-D genotypes. J Viral Hepat 2013; 20:e11-9. [PMID: 23490378 DOI: 10.1111/jvh.12018] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2012] [Accepted: 08/01/2012] [Indexed: 12/14/2022]
Abstract
Complete eradication of hepatitis B virus (HBV) is rarely achieved. Treatment options include currently available nucleos(t)ide analogues and pegylated interferon. The aim of our exploratory study was to assess the effectiveness of sequential therapy for chronic hepatitis B (CHB) vs the current standard of care. We evaluated an association with entecavir and pegylated interferon alfa-2a (PEG-IFN) in 20 patients with hepatitis B, high HBV viremia and genotypes A, B, C and E. Patients received entecavir alone for 12 weeks, then entecavir and PEG-IFN for 12 weeks, lastly PEG-IFN alone for 36 weeks. The results were compared with 20 patients (control group) treated in the past with 48 weeks of PEG-IFN monotherapy. Our results show that complete sustained virological response (SVR) and partial SVR were, respectively, 60% and 80% in the study group and 10% and 30% in the control group; anti-HBe seroconversion rate were 76.9% vs 15%, and anti-HBs seroconversion were 20% vs 0%, respectively. We found a correlation among different genotypes and virological and serological outcomes - genotype C has a better virological response, while genotype A had a better serological response, and E genotype had a poor response. These results show that a sequential approach is a promising strategy of treatment in patients with CHB and high viremia in comparison with PEG-IFN monotherapy. The E genotype seems to have the worse rate of response and requires other treatment strategies.
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Affiliation(s)
- L Boglione
- Department of Infectious Diseases, Amedeo di Savoia Hospital, University of Turin, Turin, Italy
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Handoo FA, AlGhamdi H, Sanai FM, Altraif IH. Interferon-based Therapy for e-antigen Negative Chronic Hepatitis B Virus Infection. CURRENT HEPATITIS REPORTS 2012; 11:263-271. [DOI: 10.1007/s11901-012-0149-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Wang C, Fan R, Sun J, Hou J. Prevention and management of drug resistant hepatitis B virus infections. J Gastroenterol Hepatol 2012; 27:1432-40. [PMID: 22694205 DOI: 10.1111/j.1440-1746.2012.07198.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
In the past decade, broadened therapeutic options of oral direct antiviral agents for the treatment of chronic hepatitis B infection include: Lamivudine, Adefovir Dipivoxil, Telbivudine, Entecavir and Tenofovir Disoproxil Fumarate. These direct oral antiviral agents effectively suppress the replication of the virus and reduce the risk of potential liver-related complications. However, prolonged use of these nucleos(t)ide analogues has been associated with drug resistance that compromises the initial clinical benefits. Moreover, the oncogenic risk of mutations due to prolonged nucleos(t)ide analogue therapy needs to be further investigated by in vitro and in vivo studies. In the current era of potent nucleotide analogues, new data are emerging, we are still facing the pool of patients who have developed resistance to the prior generation of nucleos(t)ide analogues. This paper aims to focus on incidence of antiviral drug resistance and virological breakthrough, prudent selection of initial therapy, on-treatment monitoring for drug resistance and revise treatment strategies for patients with resistant virus.
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Affiliation(s)
- Cheng Wang
- Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Piccolo P, Lenci I, di Paolo D, Demelia L, Sorbello O, Nosotti L, Angelico M. A randomized controlled trial of sequential pegylated interferon-α and telbivudine or vice versa for 48 weeks in hepatitis B e antigen-negative chronic hepatitis B. Antivir Ther 2012; 18:57-64. [PMID: 22872648 DOI: 10.3851/imp2281] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/06/2012] [Indexed: 12/20/2022]
Abstract
BACKGROUND Short-term treatment for hepatitis B e antigen (HBeAg)-negative chronic hepatitis B remains unsatisfactory. The aim of our study was to compare the efficacy and safety of two sequential regimens of pegylated interferon (PEG-IFN)-α and telbivudine (LdT). METHODS Adult patients with biopsy-proven HBeAg-negative chronic hepatitis B, elevated alanine aminotransferase (ALT) and serum HBV DNA ≥ 2,000 IU/ml were randomized 1:1 at baseline to receive PEG-IFN 180 μg/week for 24 weeks followed by LdT 600 mg/day for 24 weeks (PEG-IFN first), or vice versa (LdT first), plus 24-week follow-up; individuals with HCV, HDV or HIV coinfections and lamivudine resistance were excluded. Primary end points were serum HBV DNA<2,000 IU/ml and normal ALT at week 72. RESULTS A total of 30 patients (86% male, median age 48 years) were enrolled: mean ±sd baseline serum HBV DNA was 5.56 ± 1.4 log IU/ml and ALT was 2.9 ± 2.5× upper limit of normal. At end of follow-up (week 72), HBV DNA<2,000 IU/ml was achieved in 13.3% of participants in the PEG-IFN first group versus 46.7% of those in the LdT first group (P=0.046). Mean ±sd ALT levels were significantly lower in the LdT first group (1.3 ± 0.9 versus 3.2 ± 2.7× upper limit of normal; P=0.03). PEG-IFN dose was reduced in 2 (7%) patients and 1 (7%) patient dropped out due to myalgia. CONCLUSIONS Sequential treatment with 24 weeks PEG-IFN followed or preceded by 24 weeks of LdT is safe. Virological response rate at week 72 was significantly higher in patients treated with LdT followed by PEG-IFN than vice versa. A sequential antiviral regimen of LdT followed by PEG-IFN, if confirmed in larger series, could improve response rates compared with standard PEG-IFN monotherapy.
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Affiliation(s)
- Paola Piccolo
- Hepatology Unit, Tor Vergata University, Rome, Italy.
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Abstract
Large volume of new data on the natural history and treatment of chronic hepatitis B virus (HBV) infection have become available since 2008. These include further studies in asymptomatic subjects with chronic HBV infection and community-based cohorts, the role of HBV genotype/naturally occurring HBV mutations, the application of non-invasive assessment of hepatic fibrosis and quantitation of HBV surface antigen and new drug or new strategies towards more effective therapy. To update HBV management guidelines, relevant new data were reviewed and assessed by experts from the region, and the significance of the reported findings was discussed and debated. The earlier "Asian-Pacific consensus statement on the management of chronic hepatitis B" was revised accordingly. The key terms used in the statement were also defined. The new 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, patients receiving immune suppression or chemotherapy and patients in the setting of liver transplantation and hepatocellular carcinoma, are also included.
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Abstract
INTRODUCTION Chronic hepatitis B virus (HBV) infection continues to represent a global health concern with an estimated 350 - 400 million people infected worldwide. Current treatment options are either of two IFN-based therapies or either of five oral nucleos(t)ide analogs which are used as monotherapy or in combination. Control of viral replication can be achieved basically in all patients today. However, despite the clinical efficacy of antivirals, long-term management remains a clinical challenge mainly due to the slow kinetics of HBsAg clearance. Emergence of viral resistance has been a challenge in the past with some but not all oral therapies. The development of novel therapeutic agents with different mechanisms of action might provide new opportunities to clear HBsAg and achieve HBsAg seroconversion which could be maintained off therapy. The long-term efficacy of combinations of IFN and/or nucleos(t)ide analogs might achieve antiviral synergy, preventing drug resistance and clearing viral covalently close circular DNA and infected cells. AREAS COVERED This article provides a review of recent data on the safety and efficacy of existing and emerging agents for the treatment of chronic hepatitis B infection. EXPERT OPINION Currently, entecavir and tenofovir offer a safe and effective treatment option for patients with chronic HBV with minimal to no resistance. Although entecavir and tenofovir are able to suppress replication in essentially all patients, achieving HBsAg seroconversion remains suboptimal among all antiviral therapy. There are a number of new therapies in the pipeline for the treatment of chronic HBV infection as well as revisiting IFN combined or sequential to antiviral therapy.
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Affiliation(s)
- Natravis Cox
- Duke University Medical Center, Durham, NC 27710, USA
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Moucari R, Boyer N, Ripault MP, Castelnau C, Mackiewicz V, Dauvergne A, Valla D, Vidaud M, Chanoine MHN, Marcellin P. Sequential therapy with adefovir dipivoxil and pegylated interferon alfa-2a for HBeAg-negative patients. J Viral Hepat 2011; 18:580-6. [PMID: 20487260 DOI: 10.1111/j.1365-2893.2010.01332.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
To assess the impact of sequential therapy with adefovir dipivoxil (ADV) and pegylated interferon alfa-2a (PEG-IFN) on virological (serum HBV-DNA) and serological (serum HBsAg) response in 20 consecutive HBeAg-negative patients. Patients received ADV for 20 weeks, then ADV and PEG-IFN for 4 weeks and lastly PEG-IFN for 44 weeks. Serum HBV-DNA and HBsAg were assessed at baseline, during therapy (weeks 20, 44 and 68) and follow-up (weeks 92 and 116). Sustained virological response (SVR) was defined as serum HBV-DNA <10 000 copies/mL (partial) or <70 copies/mL (complete) 24 weeks after stopping treatment. A serological response was defined as a serum HBsAg decrease ≥1 log(10) IU/mL at the end of treatment. Baseline median serum HBV-DNA and HBsAg levels were 7.6 log(10) copies/mL and 3.8 log(10) IU/mL, respectively. Ten patients (50%) achieved SVR, six of them had partial response and four complete response. Four patients (20%) achieved serological response. Complete SVRs showed a major and steep decline in HBsAg level with a median decrease of 0.5, 1.6 and 2.0 log(10) IU/mL at treatment week 20, 44 and 68, respectively. Partial SVRs showed a slight and slow decline in serum HBsAg level (0.1, 0.4, and 0.6 log IU/mL at weeks 20, 44 and 68, respectively). On-treatment serum HBsAg decrease had a high accuracy to predict SVR (AUROC = 0.88). Our results suggest that sequential therapy might be an interesting strategy for HBeAg-negative patients. Serum HBsAg kinetics seem to be an accurate tool to predict SVR. Large clinical trials are needed to explore this strategy with more potent analogues.
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Affiliation(s)
- R Moucari
- Hôpital Beaujon, Service d'Hépatologie, Clichy, France INSERM U773-CRB3, Paris, France.
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Rijckborst V, Sonneveld MJ, Janssen HLA. Review article: chronic hepatitis B - anti-viral or immunomodulatory therapy? Aliment Pharmacol Ther 2011; 33:501-13. [PMID: 21198707 DOI: 10.1111/j.1365-2036.2010.04555.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND First-line treatment options for chronic hepatitis B (CHB) consist of nucleos(t)ide analogues with a high barrier to resistance (entecavir and tenofovir) or the immunomodulatory agent peginterferon (PEG-IFN). The optimal choice for individual patients remains controversial. AIM To review treatment options for CHB, with a focus on deciding between prolonged nucleos(t)ide analogue therapy or a finite course of PEG-IFN. METHODS A comprehensive literature search was undertaken. RESULTS Long-lasting, treatment-maintained suppression of hepatitis B virus (HBV) DNA without resistance is achievable in most patients by entecavir or tenofovir. A sustained off-treatment response is, however, unlikely and long-term therapy must be anticipated. PEG-IFN offers a higher rate of sustained response in a subgroup of patients, but is frequently complicated by side effects. Pre-treatment predictors of response, including HBV genotype, alanine aminotransferase and HBV DNA levels, aid in selecting patients for PEG-IFN therapy. Furthermore, on-treatment markers such as quantitative hepatitis B surface antigen may be applied to identify nonresponders early during the PEG-IFN treatment course, thereby preventing unnecessary treatment. CONCLUSIONS Both nucleos(t)ide analogues and PEG-IFN can be prescribed as first-line treatment options for CHB. However, PEG-IFN should only be considered for patients with a high chance of response based on pre-treatment and on-treatment factors.
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Affiliation(s)
- V Rijckborst
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
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Abstract
Despite the introduction of new nucleos(t)ide analogues in recent years, peginterferon is still recommended as a potential first-line treatment option by current practice guidelines for the management of chronic hepatitis B. Peginterferon offers the advantage of higher sustained off-treatment response rates compared to nucleos(t)ide analogues because of its immunomodulatory effects. Sustained transition to the inactive hepatitis B surface antigen (HBsAg) carrier state can be achieved in about 30% of hepatitis B e antigen (HBeAg)-positive patients and 20% of HBeAg-negative patients. Recent studies have focused on identification of pretreatment and on-treatment factors that allow the selection of patients who are likely to achieve a sustained response to peginterferon therapy in order to avoid the side-effects and costs associated with unnecessary treatment. Future studies need to address whether specific virologic benchmarks can guide individualized decisions concerning therapy continuation and whether peginterferon combined with new potent nucleos(t)ide analogues improves treatment outcomes.
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Affiliation(s)
- Vincent Rijckborst
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, ’s Gravendijkwal 230, Room Ca 415, 3015 CE Rotterdam, The Netherlands
| | - Harry L. A. Janssen
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, ’s Gravendijkwal 230, Room Ha 204, 3015 CE Rotterdam, The Netherlands
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Sonneveld MJ, Janssen HLA. Pros and Cons of Peginterferon Versus Nucleos(t)ide Analogues for Treatment of Chronic Hepatitis B. CURRENT HEPATITIS REPORTS 2010; 9:91-98. [PMID: 20461129 PMCID: PMC2861769 DOI: 10.1007/s11901-010-0041-7] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The emergence of new and more potent treatment options has markedly changed the treatment landscape of chronic hepatitis B. Both peginterferon and nucleos(t)ide analogues have considerable advantages and limitations, and current treatment guidelines refrain from clearly suggesting a first-line treatment option. Peginterferon offers the advantage of higher sustained response rates in both hepatitis B early antigen (HBeAg)-positive and HBeAg-negative patients, at the price of considerable side effects and high costs. Nucleos(t)ide analogues offer easy daily oral dosing, and newly registered agents can maintain viral suppression for prolonged treatment duration. However, relapse is common after therapy discontinuation and extended therapy therefore often necessary. Prolonged treatment with nucleos(t)ide analogues may enhance chances of virologic and serologic response at the potential cost of the emergence of viral resistance and side effects. Baseline and on-treatment prediction of response may help select patients for peginterferon therapy and can aid individualized treatment decisions concerning therapy continuation or discontinuation.
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Affiliation(s)
- Milan J. Sonneveld
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, ‘s Gravendijkwal 230, Room Ca4.19 3015 CE, Rotterdam, The Netherlands
| | - Harry L. A. Janssen
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, ‘s Gravendijkwal 230, Room Ha206 3015 CE, Rotterdam, The Netherlands
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Marcellin P, Sung J, Piratvisuth T. Avoiding and managing lamivudine resistance in chronic hepatitis B: current approaches and potential strategies including pegylated interferon. Liver Int 2010; 30:657-68. [PMID: 20158610 DOI: 10.1111/j.1478-3231.2010.02207.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
Since its approval for the treatment of chronic hepatitis B in 1998, lamivudine (LAM) has been used extensively throughout the world, because of its relatively low costs and favourable tolerability. However, clinical trials and cohort studies have demonstrated that a high rate of resistance to this drug develops and, as a result, it is no longer included as a first-line therapy in most current treatment guidelines. Nevertheless, because of its low cost, this drug continues to be used in many countries and the pool of patients who have developed resistance to LAM continues to increase. Thus, there is a clear need to develop coherent management strategies to treat such patients as well as limit the emergence of resistance in the first instance. The purpose of this review is to highlight the need to aim for long-term treatment success while limiting the emergence of drug resistance and its consequences for the future. In addition to add-on/switch strategies with other nucleos(t)ide analogs, currently available data suggest that interferon-based therapies, with their potential to induce a sustained response, are worthy of consideration not only for reducing de novo resistance but as an option for the management of those patients in whom drug resistance has already developed.
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Affiliation(s)
- Patrick Marcellin
- Service d'Hépatologie, INSERM-CRB3, Hôpital Beaujon, APHP University of Paris 7, Clichy, France.
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Huang YW, Chayama K, Tsuge M, Takahashi S, Hatakeyama T, Abe H, Hu JT, Liu CJ, Lai MY, Chen DS, Yang SS, Kao JH. Differential effects of interferon and lamivudine on serum HBV RNA inhibition in patients with chronic hepatitis B. Antivir Ther 2010; 15:177-84. [PMID: 20386072 DOI: 10.3851/imp1508] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
BACKGROUND Lamivudine and interferon have been widely used for the treatment of patients with chronic HBV infection. Serum HBV RNA is detected during lamivudine therapy as a consequence of interrupted reverse transcription and because RNA replicative intermediates are unaffected by the drug. In this study, we aimed to determine the detectability of serum HBV RNA during sequential combination therapy of interferon and lamivudine. METHODS HBV DNA and RNA in serum samples were quantified by reverse transcription of HBV nucleic acid extract and real-time PCR. Samples were analysed every 2 weeks to 3 months from three groups of patients: 10 male patients treated with nucleoside analogue monotherapy for 44-48 weeks (5 with lamivudine and 5 with entecavir), 6 males on sequential interferon and lamivudine combination therapy, and 3 males on lamivudine monotherapy for 20-24 weeks. RESULTS HBV RNA was not detectable in any patients before treatment, but became detectable in 15 during antiviral treatment. Among the three groups, pre-treatment HBV DNA (8.1 +/-2.4 versus 7.7 +/-1.4 versus 5.1 +/-0.3 log(10) copies/ml; P=0.06), treatment and follow-up durations (45.5 +/-2.0 versus 49.7 +/-5.6 versus 48.7 +/-6.4 weeks; P=0.32) were comparable. HBV RNA was detectable at the end of treatment or follow-up in all patients with monotherapy, but in none of those with sequential combination therapy (100% versus 0%; P<0.001). CONCLUSIONS Compared with lamivudine therapy with detectable serum HBV RNA in patients with chronic HBV infection, interferon treatment might reduce HBV DNA replication through the inhibition of HBV RNA replicative intermediates, resulting in the loss of serum HBV RNA.
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Affiliation(s)
- Yi-Wen Huang
- Liver Unit, Cathay General Hospital Medical Center, Taipei, Taiwan
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40
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Interferon and nucleoside analog combination therapy for hepatitis B. Clin J Gastroenterol 2010; 3:69-72. [DOI: 10.1007/s12328-010-0135-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2009] [Accepted: 12/25/2009] [Indexed: 11/25/2022]
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Villa E, Lei B, Taliani G, Graziosi A, Critelli R, Luongo M, Gennari W, Bianchini M, Ferretti I. Pretreatment with pegylated interferon prevents emergence of lamivudine mutants in lamivudine-naive patients: a pilot study. Antivir Ther 2010; 14:1081-7. [PMID: 20032538 DOI: 10.3851/imp1465] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND In patients with advanced fibrosis, primary end points of long-term or possibly indefinite antiviral therapy are sustained inhibition of viral replication and avoidance of emergence of resistance. In lamivudine-treated patients, the strongest predictor of emergence of YMDD mutations is baseline hepatitis B virus (HBV) DNA viral load. We aimed to verify whether abatement of viraemia by a short course of pegylated interferon (PEG-IFN-alpha2a) treatment before lamivudine treatment could prevent the emergence of lamivudine-associated mutations during long-term therapy. METHODS A total of 14 patients with hepatitis B e antigen (HBeAg)-negative infection (3 lamivudine-experienced and 11 lamivudine-naive), with moderate/high viraemia (>10(6) copies/ml) and with Ishak stage 4-6 at liver biopsy were sequentially treated with 180 microg PEG-IFN-alpha2a for a period long enough to reach HBV DNA levels < or =10(3) copies/ml or have a decrease of 3 log(10) copies/ml from baseline. Lamivudine was then added to PEG-IFN-alpha2a treatment for 1 month and finally continued as monotherapy for 2 years or until viral breakthrough. RESULTS Baseline HBV DNA (mean +/-se 2.3 x 10(7) +/-7.2 x 10(7) copies/ml) decreased with PEG-IFN-alpha2a treatment to target value in mean +/-se 3.7 +/-1.3 months. None of the 11 lamivudine-naive patients developed genotypic resistance and were still HBV-DNA-negative after a mean +/-se observation period of 23 +/-2 months, whereas the three lamivudine-experienced patients developed YMDD mutations after 6, 9 and 12 months of lamivudine monotherapy (P=0.003, Fisher's exact test). CONCLUSIONS In lamivudine-naive patients, abatement of HBV DNA<10(3) copies/ml by pretreatment with PEG-IFN-alpha2a completely prevents the emergence of YMDD mutants after 24 months of lamivudine monotherapy. This sequential schedule can optimize the use of a well tolerated, effective and inexpensive drug, such as lamivudine, in highly viraemic HBV patients.
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Affiliation(s)
- Erica Villa
- Gastroenterology Unit, Azienda Ospedaliero-Universitaria, University of Modena and Reggio Emilia, Modena, Italy.
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Carey I, Harrison PM. Monotherapy versus combination therapy for the treatment of chronic hepatitis B. Expert Opin Investig Drugs 2010; 18:1655-66. [PMID: 19852566 DOI: 10.1517/13543780903241599] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Nucleos(t)ide analogues, active against hepatitis B polymerase, suppress viral replication and improve clinical outcome. However, the emergence of drug-resistant mutants can result in treatment failure. OBJECTIVES We describe how the choice of first-line therapy is critical to long-term treatment success. METHODS A review of current drug therapies is provided. RESULTS/CONCLUSIONS Monotherapy with early-generation drugs (lamivudine or adefovir) was associated with a high rate of viral drug resistance and combination therapy with these agents was shown to reduce the incidence of resistance. The latest-generation drugs (entecavir and tenofovir) are potent inhibitors of viral replication and, in treatment-naive subjects, viral resistance to entecavir is uncommon and is not yet reported to tenofovir. Therefore, monotherapy with either entecavir or tenofovir is the current preferred option in treatment-naive patients. Combination therapy is appropriate in those with drug-resistant HBV infection, where drug choice is guided by the viral drug-resistance genotype/phenotype. Although combination therapy has been advocated in other patient groups (e.g., those with decompensated cirrhosis and following liver transplantation), there are, as yet, no data to mandate the use of combination therapy in such patients and any perceived benefit must be weighed against increased cost and risk for toxicity.
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Affiliation(s)
- Ivana Carey
- Division of Gene and Cell-based Therapy, Department of Liver Studies and Transplantation, King's College London, Denmark Hill Campus, Bessemer Road, London SE5 9PJ, UK
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Kishida Y, Haruna Y, Naitoh M, Katayama K, Kashiwagi T. Multiple Cytokine Profiling of the Therapeutic Responses to Ribavirin and Pegylated Interferon-α2b Using an “Induction” Approach With Natural Interferon-β in Difficult-to-Treat Chronic Hepatitis C. J Interferon Cytokine Res 2009; 29:353-68. [PMID: 19441887 DOI: 10.1089/jir.2008.0110] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Affiliation(s)
- Yutaka Kishida
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Osaka Kaisei Hospital, Osaka, Japan
| | - Yoshimichi Haruna
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Osaka Prefectural General Medical Center, Osaka, Japan
| | - Masahumi Naitoh
- Department of Internal Medicine, Osaka Kouseinenkin Hospital, Osaka, Japan
| | - Kazuhiro Katayama
- Department of Internal Medicine, Osaka Kouseinenkin Hospital, Osaka, Japan
| | - Toru Kashiwagi
- Department of Nuclear Medicine and PET Center, Hyogo College of Medicine, Hyogo, Japan
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Abstract
In 2007, the world celebrated the 50th anniversary of the discovery of interferon (IFN) by Isaacs and Lindenmann. Subsequently, the IFN-alpha gene was cloned, fully sequenced and IFN-alpha was produced in recombinant form. Recombinant IFN-alpha is now used as the basis for treatment of chronic hepatitis C virus infection and can also be used to treat certain forms of chronic hepatitis B virus infections. IFNs have also been used in other viral infections, although with less success. The antiviral mechanisms of IFNs are reviewed in this chapter as well as the utility of IFNs in the treatment of persistent viral infections.
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Affiliation(s)
- Hans-Georg Kräusslich
- Hygiene Institute Department of Virology, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 324, Heidelberg, 69120 Germany
| | - Ralf Bartenschlager
- Hygiene Institute Department of Virology, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 324, Heidelberg, 69120 Germany
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45
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Hofmann WP, Soriano V, Zeuzem S. Antiviral combination therapy for treatment of chronic hepatitis B, hepatitis C, and human immunodeficiency virus infection. Handb Exp Pharmacol 2008:321-46. [PMID: 19048206 DOI: 10.1007/978-3-540-79086-0_12] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
This chapter reviews the main chemotherapeutic strategies used against human infections caused by agents responsible for the most important chronic viral illnesses, namely hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV). There is no doubt that most current knowledge about combination antiviral therapy has been developed in the battle against HIV. The availability of more than 20 antiretroviral drugs has permitted to explore their efficacy when given in combination, an opportunity that unfortunately has only been possible since recent years for chronic hepatitis C and still is in the early stages for chronic hepatitis B. However, new antiviral compounds targeting each of these viruses are developed rapidly and will provide further opportunities to explore the efficacy of combination antiviral therapy. While sufficient suppression of HIV RNA and HBV DNA can only be achieved by long-term administration of potent antiviral drugs, HCV RNA may be completely eradicated from the infected individual after a limited duration of treatment.
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Abstract
The main goals of chronic hepatitis B treatment should be the long-term suppression of viral replication to minimize disease progression and the risk for the development of hepatocellular carcinoma. Treatment end-points, depending on surrogate markers alone, in particular hepatitis B e-antigen seroconversion, may not be ideal for patients who acquire the disease early in life. Currently-available drugs include interferons and oral nucleoside/nucleotide analogs. Although interferon therapy provides a finite treatment period, a significant proportion of patients may not respond, and long-term outcome is inconclusive. Long-term efficacy has been demonstrated for both lamivudine and adefovir. However, prolonged nucleoside/nucleotide analog therapy is associated with the emergence of drug-resistant mutations. Therefore, nucleoside/nucleotide analogs with a high genetic barrier and potent antiviral activity, such as entecavir, should be used to reduce the chance of developing drug-resistant mutations. Drugs with a low genetic barrier, including lamivudine and telbivudine, should be used in conjunction with early testing for antiviral response. This can predict favorable outcomes in the long term. The early detection of drug-resistant mutations should prompt clinicians to either add or switch to another agent with a different drug-resistance profile. There are currently no treatment models in the use of combination or sequential therapy in treatment-naïve patients. To date, long-term treatment appears to be the most effective option. Despite recent advances made with better understanding on the natural history of chronic hepatitis B infection and with newer antiviral drugs available, challenges remain with respect to treatment criteria, treatment end-points, and duration of treatment.
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Affiliation(s)
- James Fung
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong
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Abstract
This article summarizes the current state of antiviral therapy of hepatitis B with special attention given to areas that remain controversial or poorly defined. Strict adherence to liver association practice guidelines may result in missed opportunities to treat patients with significant underlying liver disease. In particular, recommended ALT thresholds may not appropriately reflect disease activity or degree of fibrosis. There is growing evidence that an alternative treatment paradigm for preventing late-stage disease complications may be indicated in highly viremic patients with early life exposure to hepatitis B. Pegylated interferon therapy is often a better choice for young to middle-aged patients with genotype A and B because of the higher rate of HBeAg seroconversion and a greater chance for HBsAg seroconversion in both HBeAg-positive and -negative patients as compared to nucleoside analogs. Nucleoside analog monotherapy is the current standard of care for many patients. However, long-term monotherapy results in resistance to a variable degree and sequential monotherapy may result in multi-drug resistant virus. Which patients would specifically benefit from early combination therapy also remains poorly defined. The rapidity and robustness of the suppression of HBV DNA while on a nucleoside analog should be monitored relatively early during treatment because it affects treatment outcome and the rate of resistance. While great progress has been made in treating hepatitis B, many important issues require further study.
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Leung N. Recent data on treatment of chronic hepatitis B with nucleos(t)ide analogues. Hepatol Int 2008; 2:163-78. [PMID: 19669301 PMCID: PMC2716844 DOI: 10.1007/s12072-008-9061-6] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2007] [Accepted: 01/25/2008] [Indexed: 12/13/2022]
Abstract
Forty years ago in 1967, Professor Blumberg discovered the Australian Antigen, later known as the hepatitis B surface antigen, and was awarded the Nobel Prize. This discovery enables the diagnosis of hepatitis B virus (HBV) infection and defines its epidemiology. Viral hepatitis B infection affects global health situation, and chronic hepatitis B (CHB) is particularly serious in the Asia-Pacific region. HBV vaccines created the first breakthrough in HBV prevention. Through universal HBV vaccination program for the newborns, promoted since the mid-1980s, the main route that perpetuates chronic infection from mother to child is curbed. Most children and young adults now have immunity against HBV infection. The next breakthrough comes with therapy for CHB. This prevents progression to cirrhosis and hepatocellular carcinoma. Standard interferon therapy with modest efficacy has been largely replaced by therapy with nuclos(t)ide analogues or pegylated interferons alfa-2a and -2b. Lamivudine was approved by the FDA USA in 1998, followed by adefovir dipivoxil in 2002, entecavir in 2005, and telbivudine in 2006. Clevudine, tenofovir, and many promising candidates are in different stages of development and clinical trial. This paper critically reviews recent data published or presented since the APASL Consensus and Guideline Update of 2005. Clinical efficacy mostly in patients with raised serum alanine aminotransferase will be analyzed.
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Affiliation(s)
- Nancy Leung
- Department of Medicine, Alice Ho Miu Ling Nethersole Hospital, Room 65, J6, 11 Chuen On Road, Taipo, NT, Hong Kong,
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Kumar M, Sarin SK. Systematic review: combination therapies for treatment-naïve chronic hepatitis B. Aliment Pharmacol Ther 2008; 27:1187-209. [PMID: 18373730 DOI: 10.1111/j.1365-2036.2008.03695.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND There is a renewed interest in use of combination therapies in treatment-naïve chronic hepatitis B (CHB) because of limitations of monotherapies. AIM To discuss the current status of combination therapies in treatment-naïve CHB. METHODS PubMed search was done using 'combination', 'sequential' and 'chronic hepatitis B' as the search terms. RESULTS The two most popular combination therapies include 'combination of nucleos(t)ide analogues' and 'combination of interferons and nucleos(t)ide analogues'. Combination therapies using two nucleos(t)ide analogues do not lead to higher long-term efficacy. However, addition of a nucleos(t)ide analogue with a good resistance profile to a nucleos(t)ide analogue with a lower genetic barrier to resistance decreases the risk of emergent resistance to the latter. Greater sustained virological, biochemical and seroconversion rates are observed with addition of lamivudine to conventional interferon, but pegylated-interferon monotherapy is equally effective as combination with lamivudine. Again, resistance to lamivudine is lower with its combination with interferons. CONCLUSIONS The answer to the question whether hepatitis B can be treated better with combination or monotherapy remains largely unknown. Additional trials are warranted of combination therapies of peginterferon and potent nucleos(t)ide analogues or therapies with the combined use of nucleos(t)ide analogues or immunomodulators.
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Affiliation(s)
- M Kumar
- Department of Gastroenterology, G.B. Pant Hospital, Affiliated to the University of Delhi, New Delhi, India
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50
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Abstract
Large amounts of new data on the natural history and treatment of chronic hepatitis B virus (HBV) infection have become available since 2005. These include long-term follow-up studies in large community-based cohorts or asymptomatic subjects with chronic HBV infection, further studies on the role of HBV genotype/naturally occurring HBV mutations, treatment of drug resistance and new therapies. In addition, Pegylated interferon alpha2a, entecavir and telbivudine have been approved globally. To update HBV management guidelines, relevant new data were reviewed and assessed by experts from the region, and the significance of the reported findings were discussed and debated. The earlier "Asian-Pacific consensus statement on the management of chronic hepatitis B" was revised accordingly. The key terms used in the statement were also defined. The new guidelines include general management, special indications for liver biopsy in patients with persistently normal alanine aminotransferase, 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, patients receiving immune-suppressive medications or chemotherapy and patients in the setting of liver transplantation, are also included.
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