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Thymosin‐ɑ1 for people with chronic hepatitis B. Cochrane Database Syst Rev 2022; 2022:CD014610. [PMCID: PMC8929401 DOI: 10.1002/14651858.cd014610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the benefits and harms of thymosin‐α1 in people with chronic hepatitis B, regardless of their age, sex, and ethnicity
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Bersanelli M, Giannarelli D, Leonetti A, Buti S, Tiseo M, Nouvenne A, Ticinesi A, Meschi T, Procopio G, Danielli R. The right immune-modulation at the right time: thymosin α1 for prevention of severe COVID-19 in cancer patients. Future Oncol 2021; 17:1097-1104. [PMID: 33538178 PMCID: PMC7874885 DOI: 10.2217/fon-2020-0754] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
We presented the rationale for the use of thymosin α1 as prophylaxis of severe COVID-19 in cancer patients undergoing active treatment, constituting the background for the PROTHYMOS study, a prospective, multicenter, open-label, Phase II randomized study, currently in its start-up phase (Eudract no. 2020-006020-13). We aim to offer new hope for this incurable disease, especially to frail patient population, such as patients with cancer. The hypothesis of an effective prophylactic approach to COVID-19 would have immediate clinical relevance, especially given the lack of curative approaches. Moreover, in the ‘COVID-19 vaccine race era’ both clinical and biological results coming from the PROTHYMOS trials could even support the rationale for future combinatorial approaches, trying to rise vaccine efficacy in frail individuals. We present scientific evidence in favor of using a drug (thymosin-α1) that modulates the immune system functions to try and prevent severe COVID-19 in cancer patients who are currently receiving anticancer treatment. Thymosin-α1 is produced normally by the body in the thymus, which is present in children but not in adults. Given the better outcomes of SARS-CoV-2 infections in children, we thought that thymosin-α1 could help to protect adults from severe infections as well. In this review, we explain some scientific evidence and the background of our clinical trial, PROTHYMOS, which is investigating this preventive treatment. Our aim is to offer a new hope to these at-risk cancer patients, particularly for the elderly who are at most risk of developing severe COVID-19. Given the lack of approaches that can provide cures to COVID-19, any possibility to prevent severe infection should be explored.
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Affiliation(s)
- Melissa Bersanelli
- Medical Oncology Unit, University Hospital of Parma, Via Gramsci 14, Parma, 43126, Italy.,Medicine & Surgery Department, University of Parma, Via Gramsci 14, Parma, 43126, Italy
| | - Diana Giannarelli
- Biostatistical Unit, Regina Elena National Cancer Institute, IRCCS, Via Elio Chianesi 53, Rome, 00144, Italy
| | - Alessandro Leonetti
- Medical Oncology Unit, University Hospital of Parma, Via Gramsci 14, Parma, 43126, Italy.,Medicine & Surgery Department, University of Parma, Via Gramsci 14, Parma, 43126, Italy
| | - Sebastiano Buti
- Medical Oncology Unit, University Hospital of Parma, Via Gramsci 14, Parma, 43126, Italy.,Medicine & Surgery Department, University of Parma, Via Gramsci 14, Parma, 43126, Italy
| | - Marcello Tiseo
- Medical Oncology Unit, University Hospital of Parma, Via Gramsci 14, Parma, 43126, Italy.,Medicine & Surgery Department, University of Parma, Via Gramsci 14, Parma, 43126, Italy
| | - Antonio Nouvenne
- Geriatric Rehabilitation Medical Department, University Hospital of Parma, Via Gramsci 14, Parma, 43126, Italy
| | - Andrea Ticinesi
- Medicine & Surgery Department, University of Parma, Via Gramsci 14, Parma, 43126, Italy.,Geriatric Rehabilitation Medical Department, University Hospital of Parma, Via Gramsci 14, Parma, 43126, Italy
| | - Tiziana Meschi
- Medicine & Surgery Department, University of Parma, Via Gramsci 14, Parma, 43126, Italy.,Geriatric Rehabilitation Medical Department, University Hospital of Parma, Via Gramsci 14, Parma, 43126, Italy
| | - Giuseppe Procopio
- Genito-Urinary Oncology Unit, Fondazione IRCCS Istituto Nazionale Tumori of Milan, Via Giacomo Venezian, 1, Milano, 20133, Italy
| | - Riccardo Danielli
- Immuno-Oncology Unit, University Hospital of Siena, Viale Mario Bracci 16, Siena, 53100, Italy
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Peng D, Xing HY, Li C, Wang XF, Hou M, Li B, Chen JH. The clinical efficacy and adverse effects of Entecavir plus Thymosin alpha-1 combination therapy versus Entecavir Monotherapy in HBV-related cirrhosis: a systematic review and meta-analysis. BMC Gastroenterol 2020; 20:348. [PMID: 33076834 PMCID: PMC7574490 DOI: 10.1186/s12876-020-01477-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 09/28/2020] [Indexed: 02/06/2023] Open
Abstract
Background Previous studies have demonstrated the benefits of thymosin alpha-1 (Tα1) in anti-virus, immunological enhancement and anti-inflammation. However, it is controversial about the efficacy and safety of entecavir (ETV) plus Tα1 combination therapy versus ETV monotherapy in cirrhotic patients with hepatitis B virus (HBV) infection. Methods The systematic review and meta-analysis of randomized clinical trials (RCTs) were performed to evaluate the efficacy and safety of ETV plus Tα1 combination therapy versus ETV monotherapy in HBV-related patients with cirrhosis. We performed a systematic literature search via PubMed, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, China National Knowledge Infrastructure (CNKI), Chinese Science and Technology Journals Database (VIP), and Chinese Biological Medicine database (CBM). Relative risk (RR) and standardized mean difference (SMD) with a fixed- or random- effect model were calculated. Heterogeneity was assessed through a Cochrane Q-test and I2 values. Results Seven RCTs involving 1144 subjects were included in the systematic review and meta-analysis. Compared with ETV monotherapy, ETV plus Tα1 combination therapy led to a higher complete response (RR = 1.18; 95% CI, 1.07–1.30). In post treatment for 24 weeks, the HBV DNA undetectable rate and HBeAg loss rate were higher in ETV plus Tα1 group than in ETV alone group (RR = 1.91; 95% CI, 1.56–2.35; RR = 2.05; 95% CI, 1.62–2.60). However, after 48 and 52 weeks of treatment, there was no significant difference between the combination therapy and ETV monotherapy (RR = 1.07; 95% CI, 0.96–1.18; RR = 1.17; 95% CI, 0.89–1.55). At week 52 of treatment, the HBsAg loss rate of ETV plus Tα1 group was no significance with that of ETV alone group (RR = 1.03; 95% CI, 0.15–7.26). In comparison with ETV alone, the some biochemical parameters and liver fibrosis were obviously improved by ETV plus Tα1, and there was significant heterogeneity. In addition, the number of adverse events was significantly reduced by ETV plus Tα1, compared to ETV alone (RR = 0.48; 95% CI, 0.24–0.95). Conclusions ETV plus Tα1 might lead to a higher clinical response and a lower comprehensive adverse reaction rate in HBV-related patients with cirrhosis, compared to ETV alone. However, the whole patients included in this meta-analysis were from Chinese mainland, so that more worldwide RCTs with a larger sample size are needed to verify the current findings.
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Affiliation(s)
- Dan Peng
- Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Hai-Yan Xing
- Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Chen Li
- Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Xian-Feng Wang
- Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Min Hou
- Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Bin Li
- Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Jian-Hong Chen
- Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, 400042, China.
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Beckmann N, Salyer CE, Crisologo PA, Nomellini V, Caldwell CC. Staging and Personalized Intervention for Infection and Sepsis. Surg Infect (Larchmt) 2020; 21:732-744. [PMID: 32240042 DOI: 10.1089/sur.2019.363] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Background: Sepsis is defined as a dysregulated host response to infection, resulting in life-threatening organ dysfunction. It is now understood that this dysregulation not only constitutes excessive inflammation, but also sustained immune suppression. Immune-modulatory therapies thus have great potential for novel sepsis therapies. Here, we provide a review of biomarkers and functional assays designed to immunologically stage patients with sepsis as well as therapies designed to alter the innate and adaptive immune systems of patients with sepsis beneficially. Methods: A search of PubMed/MEDLINE and clinicaltrials.gov was performed between October 1, 2019 and December 22, 2019 using search terms such as "sepsis immunotherapy," "sepsis biomarkers," "sepsis clinical trials," and variations thereof. Results: Despite more than 30 years of research, there is still no Food and Drug Administration (FDA)-cleared biomarker that has proven to be effective in either identifying patients with sepsis who are at an increased risk of adverse outcomes or responsive to specific interventions. Similarly, past clinical trials investigating new treatment strategies have rarely stratified patients with sepsis. Overall, the results of these trials have been disappointing. Novel efforts to properly gauge an individual patient's immune response and choose an appropriate immunomodulatory agent based on the results are underway. Conclusion: Our evolving understanding of the different mechanisms perturbing immune homeostasis during sepsis strongly suggests that future successes will depend on finding the right therapy for the right patient and administering it at the right time. For such a personalized medicine approach, novel biomarkers and functional assays to properly stage the patient with sepsis will be crucial. The growing repertoire of immunomodulatory agents at our disposal, as well as re-appraisal of agents that have already been tested in unstratified cohorts of patients with sepsis, may finally translate into successful treatment strategies for sepsis.
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Affiliation(s)
- Nadine Beckmann
- Division of Research, Critical Care, and Acute Care Surgery, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Christen E Salyer
- Division of Research, Critical Care, and Acute Care Surgery, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Peter A Crisologo
- Division of Podiatric Medicine and Surgery, Critical Care, and Acute Care Surgery, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Vanessa Nomellini
- Division of Trauma, Critical Care, and Acute Care Surgery, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.,Division of Research, Shriner's Hospital for Children Cincinnati, Cincinnati, Ohio, USA
| | - Charles C Caldwell
- Division of Research, Critical Care, and Acute Care Surgery, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.,Division of Research, Shriner's Hospital for Children Cincinnati, Cincinnati, Ohio, USA
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Abstract
Immune therapy to ease the burden of sepsis has thus far failed to consistently improve patient outcomes. Advances in cancer immune therapy and awareness that prolonged immune-suppression in sepsis can leave patients vulnerable to secondary infection and death have driven resurgence in the field of sepsis immune-therapy investigation. As we develop and evaluate these novel therapies, we must learn from past experiences where single-mediator targeted immune therapies were blindly delivered to heterogeneous patient cohorts with complex and evolving immune responses. Advances in genomics, proteomics, metabolomics, and point-of-care technology, coupled with a better understanding of sepsis pathogenesis, have meant that personalised immune-therapy is on the horizon. Here, we review the complex immune pathogenesis in sepsis and the contemporary immune therapies that are being investigated to manipulate this response. An outline of the immune biomarkers that may be used to support this approach is also provided.
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Affiliation(s)
- Roger Davies
- Department of Anaesthetics, Pain and Intensive Care Medicine, Imperial College London, UK
- Chelsea and Westminster Hospital NHS Foundation Trust, London, UK
| | - Kieran O’Dea
- Department of Anaesthetics, Pain and Intensive Care Medicine, Imperial College London, UK
| | - Anthony Gordon
- Department of Anaesthetics, Pain and Intensive Care Medicine, Imperial College London, UK
- Imperial College Healthcare NHS Trust, London, UK
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Wu X, Shi Y, Zhou J, Sun Y, Piao H, Jiang W, Ma A, Chen Y, Xu M, Xie W, Cheng J, Xie S, Shang J, Cheng J, Xie Q, Ding H, Zhang X, Bai L, Zhang M, Wang B, Chen S, Ma H, Ou X, Jia J, You H. Combination of entecavir with thymosin alpha-1 in HBV-related compensated cirrhosis: a prospective multicenter randomized open-label study. Expert Opin Biol Ther 2018; 18:61-69. [PMID: 30063860 DOI: 10.1080/14712598.2018.1451511] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2017] [Accepted: 03/08/2018] [Indexed: 02/05/2023]
Abstract
UNLABELLED ABSTRACT Background: Thymosin alpha-1 (Ta-1) suppresses HBV viral replication, while the evidence of combination effect with nucleoide is still limited. We aimed to investigate the efficacy and safety of combination therapy of Ta-1 with entecavir (ETV) in patients with compensated liver cirrhosis. RESEARCH DESIGN AND METHODS A total of 690 patients were randomized to receive Ta-1 plus ETV (n = 351) or ETV monotherapy (n = 339) for 52 weeks after 26 weeks of ETV treatment, followed by continued entecavir therapy. The primary endpoint was defined as liver decompensation, hepatocellular carcinoma (HCC) or death. RESULTS The median followed up was 38.2 months. The cumulative incidence of liver decompensation, HCC, or death were similar between two groups. During the Ta-1 combination treatment, the HCC incidence was 1.7% in combination group and 2.1% in ETV group, without new HCC cases developed during week 39 to week 77 in combination group. The virologic response, serologic response, biochemical response was similar between two groups at week 104. Both therapies were well-tolerated. CONCLUSION There was no significant difference between two groups in endpoint events, while combination therapy with Ta-1 has a tendency to inhibit the development of HCC.
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Affiliation(s)
- Xiaoning Wu
- a Liver Research Center, Beijing Friendship Hospital , Capital Medical University, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, National Clinical Research Center of Digestive Diseases , Beijing , China
| | - Yiwen Shi
- a Liver Research Center, Beijing Friendship Hospital , Capital Medical University, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, National Clinical Research Center of Digestive Diseases , Beijing , China
| | - Jialing Zhou
- a Liver Research Center, Beijing Friendship Hospital , Capital Medical University, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, National Clinical Research Center of Digestive Diseases , Beijing , China
| | - Yameng Sun
- a Liver Research Center, Beijing Friendship Hospital , Capital Medical University, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, National Clinical Research Center of Digestive Diseases , Beijing , China
| | - Hongxin Piao
- b Infectious Department , Affiliated Hospital of Yanbian University , Yanji , China
| | - Wei Jiang
- c Department of Gastroenterology , Zhongshan Hospital, Fudan University , Shanghai , China
| | - Anlin Ma
- d Department of Infectious Diseases , China-Japan Friendship Hospital , Beijing , China
| | - Yongpeng Chen
- e Department of Infectious Diseases , Nanfang Hospital, Southern Medical University , Guangzhou , China
| | - Mingyi Xu
- f Department of Gastroenterology and Hepatology , Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , China
| | - Wen Xie
- g Center of Liver Diseases , Beijing Ditan Hospital, Capital Medical University , Beijing , China
| | - Jun Cheng
- h Institute of Infectious Diseases , Beijing Ditan Hospital, Capital Medical University , Beijing , China
| | - Shibin Xie
- i Department of Infectious Diseases , Third Affiliated Hospital, Zhongshan University , Guangzhou , China
| | - Jia Shang
- j Department of Infectious Diseases , Zhengzhou University People's Hospital , Zhengzhou , China
| | - Jilin Cheng
- k Department of Gastroenterology , Shanghai Public Health Clinical Center , Shanghai , China
| | - Qing Xie
- l Department of Infectious Diseases , Ruijin Hospital , Shanghai , China
| | - Huiguo Ding
- m Department of Gastroenterology and Hepatology , Beijing Youan Hospital, Capital Medical University , Beijing , China
| | - Xuqing Zhang
- n Department of Infectious Disease , Southwest Hospital, Third Military Medical University , Chongqing , China
| | - Lang Bai
- o Department of Infectious Disease , West China Hospital, Sichuan University , Chengdu , China
| | - Mingxiang Zhang
- p Department of Hepatology , The Sixth People's Hospital of Shenyang , Shenyang , China
| | - Bingqiong Wang
- a Liver Research Center, Beijing Friendship Hospital , Capital Medical University, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, National Clinical Research Center of Digestive Diseases , Beijing , China
| | - Shuyan Chen
- a Liver Research Center, Beijing Friendship Hospital , Capital Medical University, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, National Clinical Research Center of Digestive Diseases , Beijing , China
| | - Hong Ma
- a Liver Research Center, Beijing Friendship Hospital , Capital Medical University, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, National Clinical Research Center of Digestive Diseases , Beijing , China
| | - Xiaojuan Ou
- a Liver Research Center, Beijing Friendship Hospital , Capital Medical University, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, National Clinical Research Center of Digestive Diseases , Beijing , China
| | - Jidong Jia
- a Liver Research Center, Beijing Friendship Hospital , Capital Medical University, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, National Clinical Research Center of Digestive Diseases , Beijing , China
| | - Hong You
- a Liver Research Center, Beijing Friendship Hospital , Capital Medical University, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, National Clinical Research Center of Digestive Diseases , Beijing , China
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Naylor PH, Mutchnick MG. Immunotherapy for hepatitis B in the direct acting antiviral era: Reevaluating the thymosin α1 efficacy trials in the light of a combination therapy approach. J Viral Hepat 2018; 25:4-9. [PMID: 29052304 DOI: 10.1111/jvh.12807] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Accepted: 08/21/2017] [Indexed: 12/15/2022]
Abstract
Hepatitis B virus (HBV) causes both acute and chronic hepatitis and infects large numbers of individuals worldwide. Unfortunately, prediction of typical clinical outcome is problematic and there is considerable variability in the frequency, duration and severity of disease progression. The mainstay of HBV treatment is directed towards the suppression of HBV replication by nucleos(t)ide analogs (NUCs). The use of immunomodulators such as α-Interferon and thymosin α1 can, in select patients, results in elimination of both HBsAg and HBeAg. Given the observation that viral clearance is most effective in the presence of a strong immune response, this review summarizes data suggesting that the use of a combination of an immune modulator such as Tα1 with a highly effective NUC may result in a more successful therapeutic approach in patients with chronic hepatitis B (CHB). Results from small studies using combination Tα1 and NUCs are encouraging, and ongoing clinical trials combining entecavir with Tα1 are anticipated to provide important data assessing the use of a combination of Tα1 with a NUC to achieve resolution of CHB.
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Affiliation(s)
- P H Naylor
- Department of Internal Medicine/Gastroenterology, Wayne State University School of Medicine, Harper University Hospital, Detroit, MI, USA
| | - M G Mutchnick
- Department of Internal Medicine/Gastroenterology, Wayne State University School of Medicine, Harper University Hospital, Detroit, MI, USA
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Abstract
INTRODUCTION Thymosin α 1 (Tα1) is a peptidic biological response modifier, which plays a significant role in activating and regulating various cells of the immune system. For the above-mentioned activities it is expected to exert a clinical benefit in the treatment of diseases where the immune system is altered. AREAS COVERED Several clinical trials have been carried out with Tα1 for treatment or prevention of many different infectious diseases such as hepatitis B and C, sepsis and Aspergillosis in bone marrow-transplanted patients. Data available on the use of Tα1 in infectious disease as well as a vaccine enhancer will be reviewed to possibly generate new working hypothesis. EXPERT OPINION Tα1 has been widely used in thousands of patients. Nevertheless, there are some issues that have not yet been properly addressed (i.e., dose, schedule, combination treatments, end-points to be evaluated in clinical trials). In the most recent clinical trials Tα1 has been used at higher doses than those commonly used in the past showing a direct proportionality between the dose and the effect. The safety profile of Tα1 is excellent and it is virtually devoid of toxicity.
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Affiliation(s)
- Roberto Camerini
- Sigma-tau SpA, R&D Department , Via Pontina km 30.400, 00040 Pomezia , Italy +390691393562 ;
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Koumbi L. Current and future antiviral drug therapies of hepatitis B chronic infection. World J Hepatol 2015; 7:1030-1040. [PMID: 26052392 PMCID: PMC4450180 DOI: 10.4254/wjh.v7.i8.1030] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 01/12/2015] [Accepted: 02/04/2015] [Indexed: 02/06/2023] Open
Abstract
Despite significant improvement in the management of chronic hepatitis B virus (HBV) it remains a public health problem, affecting more than 350 million people worldwide. The natural course of the infection is dynamic and involves a complex interplay between the virus and the host's immune system. Currently the approved therapeutic regimens include pegylated-interferon (IFN)-α and monotherapy with five nucleos(t)ide analogues (NAs). Both antiviral treatments are not capable to eliminate the virus and do not establish long-term control of infection after treatment withdrawal. IFN therapy is of finite duration and associates with low response rates, liver decompensating and numerous side effects. NAs are well-tolerated therapies but have a high risk of drug resistance development that limits their prolonged use. The imperative for the development of new approaches for the treatment of chronic HBV infection is a challenging issue that cannot be over-sided. Research efforts are focusing on the identification and evaluation of various viral replication inhibitors that target viral replication and a number of immunomodulators that aim to restore the HBV specific immune hyporesponsiveness without inducing liver damage. This review brings together our current knowledge on the available treatment and discusses potential therapeutic approaches in the battle against chronic HBV infection.
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Affiliation(s)
- Lemonica Koumbi
- Lemonica Koumbi, Hepatology and Gastroenterology Section, Department of Medicine, Imperial College London, London W2 1PG, United Kingdom
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11
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Wu X, Jia J, You H. Thymosin alpha-1 treatment in chronic hepatitis B. Expert Opin Biol Ther 2015; 15 Suppl 1:S129-32. [PMID: 25640173 DOI: 10.1517/14712598.2015.1007948] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
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Tang CM, Yau TO, Yu J. Management of chronic hepatitis B infection: current treatment guidelines, challenges, and new developments. World J Gastroenterol 2014; 20:6262-6278. [PMID: 24876747 PMCID: PMC4033464 DOI: 10.3748/wjg.v20.i20.6262] [Citation(s) in RCA: 98] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2013] [Revised: 11/24/2013] [Accepted: 01/19/2014] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B (CHB) virus infection is a global public health problem, affecting more than 400 million people worldwide. The clinical spectrum is wide, ranging from a subclinical inactive carrier state, to progressive chronic hepatitis, cirrhosis, decompensation, and hepatocellular carcinoma. However, complications of hepatitis B virus (HBV)-related chronic liver disease may be reduced by viral suppression. Current international guidelines recommend first-line treatment of CHB infection with pegylated interferon, entecavir, or tenofovir, but the optimal treatment for an individual patient is controversial. The indications for treatment are contentious, and increasing evidence suggests that HBV genotyping, as well as serial on-treatment measurements of hepatitis B surface antigen and HBV DNA kinetics should be used to predict antiviral treatment response. The likelihood of achieving a sustained virological response is also increased by extending treatment duration, and using combination therapy. Hence the paradigm for treatment of CHB is constantly evolving. This article summarizes the different indications for treatment, and systematically reviews the evidence for the efficacy of various antiviral agents. It further discusses the shortcomings of current guidelines, use of rescue therapy in drug-resistant strains of HBV, and highlights the promising clinical trials for emerging therapies in the pipeline. This concise overview presents an updated practical approach to guide the clinical management of CHB.
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Xie X, Geng S, Liu H, Li C, Yang Y, Wang B. Cimetidine synergizes with Praziquantel to enhance the immune response of HBV DNA vaccine via activating cytotoxic CD8(+) T cell. Hum Vaccin Immunother 2014; 10:1688-99. [PMID: 24643207 DOI: 10.4161/hv.28517] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Previously, we have reported that either CIM or PZQ, 2 clinical drugs, could be used to develop as adjuvants on HBV DNA vaccine to elicit both humoral and cellular immune responses. Here, we demonstrate that combinations of CIM and PZQ as adjuvants for a HBV DNA vaccine, could induce much stronger antigen specific CD4(+) and CD8(+) T cell responses compared either with CIM or PZQ alone. The synergistic effects of CIM plus PZQ to HBV DNA vaccine were observed on a higher IgG2a/IgG1 ratio, an increase of HBsAg-specific CD4(+) T cells capable of producing IFN-γ or IL-17A and a robust IFN-γ-, IL-17A-, or TNF-α-producing CD8(+) T cells to HBsAg. Most importantly, the antigen-specific CTL response was also elevated significantly, which is critical for the eradication of hepatitis B virus (HBV) infected cells. Using an HBsAg transgenic mouse model, the expression of HBsAg in the hepatic cells was also significantly reduced after immunized with pCD-S 2 in the presence of 0.5% CIM and 0.25% PZQ. Further investigations demonstrated that the synergistic effects of combination of CIM and PZQ were dependent on enhanced cytotoxic CD8(+) T cells, which was correlated with impaired activities of regulatory T cells. Therefore, combinations of CIM and PZQ have great potential to be used as effective adjuvants on DNA-based vaccinations for the treatment of chronic hepatitis B.
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Affiliation(s)
- Xiaoping Xie
- State Key Laboratory for Agro-Biotechnology; College of Biological Science; China Agricultural University; Beijing, PR China
| | - Shuang Geng
- Key Laboratory of Medical Molecular Virology of MOH and MOE; Fudan University Shanghai Medical College; Shanghai, PR China
| | - Hu Liu
- State Key Laboratory for Agro-Biotechnology; College of Biological Science; China Agricultural University; Beijing, PR China
| | - Chaofan Li
- Key Laboratory of Medical Molecular Virology of MOH and MOE; Fudan University Shanghai Medical College; Shanghai, PR China
| | - Yuqin Yang
- Shanghai Public Health Clinical Center affiliated to Fudan University; Shanghai, PR China
| | - Bin Wang
- State Key Laboratory for Agro-Biotechnology; College of Biological Science; China Agricultural University; Beijing, PR China; Key Laboratory of Medical Molecular Virology of MOH and MOE; Fudan University Shanghai Medical College; Shanghai, PR China
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Li Y, Yang H, Liao H, Fan H, Liang C, Deng L, Jin S. Simultaneous determination of ten biogenic amines in a thymopolypeptides injection using ultra-performance liquid chromatography coupled with electrospray ionization tandem quadrupole mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2013; 929:33-9. [DOI: 10.1016/j.jchromb.2013.03.025] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2012] [Revised: 03/22/2013] [Accepted: 03/24/2013] [Indexed: 01/18/2023]
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Shao C, Tian G, Huang Y, Liang W, Zheng H, Wei J, Wei C, Yang C, Wang H, Zeng W. Thymosin alpha-1-transformed Bifidobacterium promotes T cell proliferation and maturation in mice by oral administration. Int Immunopharmacol 2013; 15:646-53. [DOI: 10.1016/j.intimp.2012.12.031] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2012] [Revised: 12/30/2012] [Accepted: 12/31/2012] [Indexed: 11/26/2022]
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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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17
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Abstract
BACKGROUND Infection is one of the most common complications and still remains a significant cause of morbidity and occasionally mortality in patients, especially children with nephrotic syndrome. Many different prophylactic interventions have been used or recommended for reducing the risks of infection in nephrotic syndrome in clinical practice. Whether the existing evidence is scientifically rigorous and which prophylactic intervention can be recommended for routine use based on the current evidence is still unknown. OBJECTIVES To assess the benefits and harms of any prophylactic intervention for reducing the risk of infection in children and adults with nephrotic syndrome. SEARCH METHODS We searched the Cochrane Renal Group's specialised register, the Cochrane Central Register of Controlled Trials (CENTRAL) (in The Cochrane Library), MEDLINE and Pre-MEDLINE (from 1966), EMBASE (from 1980), China Biological Medicine Database (1979 to December 2009), Chinese Science and Technique Journals Database (to December 2009), China National Infrastructure (to December 2009), WangFang database (to December 2009), reference lists of nephrology textbooks, review articles, relevant studies and abstracts from nephrology meetings without language restriction.Date of last search: 6 February 2012 SELECTION CRITERIA Randomised controlled trials (RCTs) and quasi-RCTs comparing any prophylactic interventions (pharmacological or non-pharmacological) for preventing any infection in children and adults with nephrotic syndrome. DATA COLLECTION AND ANALYSIS Two authors independently assessed and extracted information. Information was collected on methods, participants, interventions and outcomes (appearance of infection, mortality, quality of life and adverse events). Results were expressed as risk ratios (RR) for dichotomous outcomes or as mean differences (MD) for continuous data with 95% confidence intervals (CI). MAIN RESULTS Twelve studies conducted in China, including 762 children with nephrotic syndrome were identified. No studies were identified in adults. All studies compared one kind of prophylactic pharmacotherapy (intravenous immunoglobulin (IVIG), thymosin, oral transfer factor, mannan peptide tablet, Bacillus Calmette-Guerin (BCG) vaccine injection, polyvalent bacterial vaccine (Lantigen B) and two kinds of Chinese medicinal herbs: a compound of Chinese medicinal herbs (TIAOJINING) and Huangqi (astragalus) granules) plus baseline treatment with baseline treatment alone. No RCTs were identified comparing antibiotics, non-pharmacological prophylaxis, or pneumococcal vaccination. Four studies showed a significantly beneficial effect of IVIG on preventing nosocomial or unspecified infection in children with nephrotic syndrome (RR 0.47, 95% CI 0.31 to 0.73). Thymosin (RR 0.50, 95% CI 0.26 to 0.97), oral transfer factor (RR 0.51, 95% CI 0.35 to 0.73), BCG vaccine injection (RR 0.68, 95% CI 0.48 to 0.95), Huangqi granules (RR 0.62, 95% CI 0.47 to 0.83) and TIAOJINING (RR 0.59, 95% CI 0.43 to 0.81) were also effective in reducing the risk of infection in children with nephrotic syndrome. However mannan peptide tablet (RR 0.46, 95% CI 0.21 to 1.01) and polyvalent bacterial vaccine (RR 0.24, 95% CI 0.06 to1.00) were not superior to baseline treatment in reducing the risk of infection for nephrotic children. No serious adverse events were reported. AUTHORS' CONCLUSIONS IVIG, thymosin, oral transfer factor, BCG vaccine, Huangqi granules and TIAOJINING may have positive effects on the prevention of nosocomial or unspecified infection with no obvious serious adverse events in children with nephrotic syndrome. However the methodological quality of all studies was poor, the sample sizes small, and all studies were from China, and thus there is no strong evidence on the effectiveness of these interventions.
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Affiliation(s)
- Hong Mei Wu
- Department of Geriatrics, West China Hospital, Sichuan University, Chengdu,
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Abbas Z, Siddiqui AR. Management of hepatitis B in developing countries. World J Hepatol 2011; 3:292-299. [PMID: 22216369 PMCID: PMC3246547 DOI: 10.4254/wjh.v3.i12.292] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2011] [Revised: 09/26/2011] [Accepted: 10/03/2011] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B is one of the leading causes of chronic hepatitis in developing countries, with 5% to 15% of the population carrying virus. The high prevalence is due to failure to adopt appropriate measure to confine the spread of infection. Most hepatitis B patients present with advanced diseases. Although perinatal transmission is believed to be an important mode, most infections in the developing world occur in childhood and early adulthood. Factors in developing countries associated with the progression of chronic hepatitis B (CHB) include co-infections with human immunodeficiency virus, delta hepatitis virus, hepatitis C virus, alcohol intake and aflatoxin. Treatment protocols extrapolated from developed countries may need modifications according to the resources available. There is some controversy as to when to start treatment, with what medication and for how long? There is now enough evidence to support that hepatitis B patients should be considered for treatment if they show persistently elevated abnormal aminotransferase levels in the last 6 mo, checked on at least three separate occasions, and a serum hepatitis B virus DNA level of > 2000 IU/mL. Therapeutic agents that were approved by Pure Food and Drug Administration are now available in many developing countries. These include standard interferon (INF)-α, pegylated INF-α, lamivudine, adefovir, entecavir and telbivudine. Drug resistance has emerged as a major challenge in the management of patients with CHB. The role of the universal vaccination program for effective control of hepatitis B cannot be emphasized enough.
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Affiliation(s)
- Zaigham Abbas
- Zaigham Abbas, Adeel R Siddiqui, Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation, Karachi 74200, Pakistan
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19
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Lok ASF, Negro F. Hepatitis B and D. SCHIFF'S DISEASES OF THE LIVER 2011:537-581. [DOI: 10.1002/9781119950509.ch24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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20
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Tuthill C, Rios I, McBeath R. Thymosin alpha 1: past clinical experience and future promise. Ann N Y Acad Sci 2010; 1194:130-5. [PMID: 20536460 DOI: 10.1111/j.1749-6632.2010.05482.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Thymosin alpha 1, originally isolated as the compound responsible for reconstitution of immune function in thymectomized animal models, has enjoyed a wide-ranging clinical development program over the past decades, extending across multiple companies, indications, countries, and continents. This paper provides an overview of this complex picture. The extensive clinical studies began with small studies conducted with an impure mixture of peptides under the aegis of physician-sponsored INDs submitted to the US FDA, in subjects with primary immune deficiency such as DiGeorge syndrome. Subsequent studies ranged all the way to large phase-3 trials conducted with synthetically produced thymosin alpha 1 and hundreds of patients, in many countries including the United States, Italy, and China.
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Affiliation(s)
- Cynthia Tuthill
- Scientific Affairs, SciClone Pharmaceuticals, Inc., Foster City, California, USA.
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21
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Potential Role of Thymosin-alpha1 Adjuvant Therapy for Glioblastoma. JOURNAL OF ONCOLOGY 2010; 2009:302084. [PMID: 20111737 PMCID: PMC2810470 DOI: 10.1155/2009/302084] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/23/2009] [Revised: 09/28/2009] [Accepted: 10/01/2009] [Indexed: 11/18/2022]
Abstract
Glioblastomas are high-grade, malignant CNS neoplasms that are
nearly always fatal within 12 months of diagnosis. Immunotherapy
using proinflammatory cytokines such as IL-2 or IL-12 may prolong
survival with glioblastoma. Thymosin-α1 (Talpha1) is a thymic hormone and immunemodulator
that increase IL-2 production and T-cell proliferation. We
examined potential therapeutic effects of Talpha1 in experimental
in vivo glioblastoma, and characterized Talpha1's anti-tumor
effects in vitro. Rar 9L cells (104) were implanted into the right frontal lobe of adult
Long Evans rats that were subsequently treated with vehicle, BCNU,
Talpha1, or Talpha1+BCNU from postoperative day 6. Talpha1+BCNU
significantly lowered tumor burdens, and increased cure rates. In
vitro experiments demonstrated that Talpha1 had no direct effect
on viability or mitochondrial function, and instead, it increased
expression of pro-apoptosis genes, including FasL, FasR and
TNFα-R1 (65.89%, 44.08%, and 22.18%, resp.),
and increased 9L cell sensitivity to oxidative stress. Moreover,
Talpha1 enhanced 9L cell sensitivity to both Granzyme B- and
BCNU-mediated killing. The findings suggest that Talpha1 enhances
BCNUmediated eradication of glioblastoma in vivo, and that Talpha1
mediates its effects by activating pro-apoptosis mechanisms,
rendering neoplastic cells more sensitive to oxidative stress and
immune-mediated killing by Granzyme B and chemotherapeutic agents.
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22
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Holness G, Carriero DC, Dieterich DT. Hepatitis B therapies and antiviral resistance detection and management. Expert Rev Gastroenterol Hepatol 2009; 3:693-9. [PMID: 19929588 DOI: 10.1586/egh.09.64] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Hepatitis B virus (HBV) infection is an important health problem and a major cause of chronic hepatitis that can lead to cirrhosis and hepatocellular carcinoma. Durable viral suppression has been documented to lower the risk of hepatocellular carcinoma and disease progression. Treatment of chronic HBV infection remains a major clinical challenge because long-term use with approved oral antiviral agents is associated with drug resistance. Antiviral resistance can result in poor clinical outcomes; therefore first-line therapy with the most potent agent(s) is recommended to lower the risk. Early detection of resistance is paramount to possibly reduce the risk of liver-related morbidity and mortality. It is important that clinicians monitor for therapeutic efficacy and resistance, so as to optimize the management of chronic HBV.
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Affiliation(s)
- Giselle Holness
- Department of Medicine, Director of Outpatient Hepatology, Division of Liver Diseases, Mount Sinai School of Medicine, Annenberg 21-42, New York, NY 10029, USA
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23
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24
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Goldstein AL, Goldstein AL. From lab to bedside: emerging clinical applications of thymosin α1. Expert Opin Biol Ther 2009; 9:593-608. [DOI: 10.1517/14712590902911412] [Citation(s) in RCA: 77] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Affiliation(s)
- Allan L Goldstein
- The George Washington University School of Medicine and Health Sciences, Department of Biochemistry & Molecular Biology, 2300 I St., N.W., Room 438, Washington, DC, USA ;
| | - Adam L Goldstein
- Medical School for International Health at Ben-Gurion University of the Negev, Be'er-Sheva, Israel
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25
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Loggi E, Gramenzi A, Margotti M, Cursaro C, Galli S, Vitale G, Grandini E, Scuteri A, Vukotic R, Andreone P, Bernardi M. In vitro effect of thymosin-alpha1 and interferon-alpha on Th1 and Th2 cytokine synthesis in patients with eAg-negative chronic hepatitis B. J Viral Hepat 2008; 15:442-448. [PMID: 18221304 DOI: 10.1111/j.1365-2893.2007.00960.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
Thymosin alpha-1 (Talpha1) has been shown to be effective in chronic hepatitis B treatment. This study investigated the effect of Talpha1 and interferon-alpha (IFNalpha) on cytokine production by peripheral blood mononuclear cells (PBMCs) of 12 patients with eAg-negative chronic hepatitis B (HBV). We evaluated the effect of incubation with Talpha1, IFNalpha or both on the synthesis of T-helper 1 (Th1) cytokines [interleukin-2 (IL-2), IFNgamma] and Th2 cytokines (IL-4, IL-10) and of antiviral protein 2',5'-oligoadenylate synthetase (2',5'-OAS) in patients and in a group of 10 healthy controls. Concerning Th1 profile, controls showed lower IL-2 synthesis than HBV patients. In HBV setting, IFNalpha/Talpha1 combination was able to increase IL-2 production significantly, when compared with baseline condition. About the Th2-cytokines, controls showed statistically lower synthesis of IL-4 and higher production of IL-10, than HBV patients. In these latter, IFNalpha increased the synthesis of IL-10 compared with baseline. Interestingly, both Talpha1 alone and the IFNalpha/Talpha1 combination reversed this effect. Finally, compared with baseline, the synthesis of 2',5'-OAS was significantly higher in the presence of Talpha1 and IFNalpha alone, and in the presence of IFNalpha/Talpha1 association, while no differences were found between controls and HBV patients. In conclusion, in PBMCs from eAg-negative HBV patients, Talpha1 alone was able to increase the antiviral protein synthesis, while in association with IFNalpha, it stimulated the IL-2 synthesis and inhibited the IFN-induced IL-10 production. These results need further investigations, but reinforce the idea of an immunotherapeutic approach for chronic hepatitis B.
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Affiliation(s)
- E Loggi
- Department of Internal Medicine, Cardioangiology and Hepatology, University of Bologna, Bologna, Italy
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26
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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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27
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Liaw YF, Leung N, Kao JH, Piratvisuth T, Gane E, Han KH, Guan R, Lau GKK, Locarnini S. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update. Hepatol Int 2008; 2:263-83. [PMID: 19669255 PMCID: PMC2716890 DOI: 10.1007/s12072-008-9080-3] [Citation(s) in RCA: 743] [Impact Index Per Article: 43.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2008] [Accepted: 04/09/2008] [Indexed: 12/13/2022]
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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Affiliation(s)
- Yun-Fan Liaw
- Liver Research Unit, Chang Gung University and Memorial Hospital, 199, Tung Hwa North Road, Taipei, Taiwan,
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28
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Lee HW, Lee JI, Um SH, Ahn SH, Chang HY, Park YK, Hong SP, Moon YM, Han KH. Combination therapy of thymosin alpha-1 and lamivudine for HBeAg positive chronic hepatitis B: A prospective randomized, comparative pilot study. J Gastroenterol Hepatol 2008; 23:729-35. [PMID: 18410608 DOI: 10.1111/j.1440-1746.2008.05387.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIM Monotherapy of lamivudine, interferon-alpha (IFN-alpha), and thymosin alpha-1 (Talpha1) is unlikely to be sufficient for the eradication of a chronic hepatitis B virus (HBV) infection. The aim of our study is to elucidate whether the combination of Talpha1 and lamivudine is superior to lamivudine monotherapy in hepatitis B e antigen (HBeAg) positive naïve patients with chronic hepatitis B. METHODS Sixty-seven patients were assigned to two different groups in a randomized manner. The combination group (n = 34) received Talpha1 (1.6 mg subcutaneously, twice a week) and lamivudine (100 mg orally, daily) for 24 weeks, followed by continuous lamivudine therapy. The monotherapy group (n = 33) received lamivudine monotherapy continuously. RESULTS The incidence of HBeAg seroconversion at 24 weeks was 26.5% (9/34) in the combination group and 6.1% (2/33) in the monotherapy group (P = 0.024). However, there was no statistically significant difference between 26.5% (9/34) in the combination group and 12.1% (4/33) in the monotherapy group at 52 weeks (P = 0.138). The emergence of viral breakthrough gradually increased to 35.3% (12/34) in the combination group, and to 21.2% (7/33) in the monotherapy group at 52 weeks (P = 0.201). CONCLUSIONS The combination treatment of Talpha1 and lamivudine did not have an obvious benefit of virological and biochemical response as compared to the lamivudine monotherapy during the combination period. In addition, after the cessation of Talpha1 treatment, the combination therapy did not prevent the occurrence of viral and biochemical breakthroughs.
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Affiliation(s)
- Hyun Woong Lee
- Department of Internal Medicine, Yonsei University College of Medicine, and Yonsei Institute of Gastroenterology, Seoul, Korea
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29
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Reviews for APASL guidelines: immunomodulator therapy of chronic hepatitis B. Hepatol Int 2008; 2:140-6. [PMID: 19669298 DOI: 10.1007/s12072-008-9046-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2007] [Accepted: 01/16/2008] [Indexed: 12/20/2022]
Abstract
The primary aim of immunomodulator therapy is to help the natural human immune system to mount a defense against hepatitis B virus. IFN-alpha has been used for the treatment of HBeAg-positive and HBeAg-negative chronic hepatitis B for over two decades and has been shown to be effective in suppressing HBV replication and in inducing serological response leading to long-term clinical benefits. IFN-alpha has been used in patients with well-compensated cirrhosis with comparable or better response to that in non-cirrhotic patients. IFN-alpha therapy in patients with cirrhosis has a similar side effect profile as in those without cirrhosis. However, IFN-alpha is contraindicated in patients with overt or decompensated cirrhosis. Pegylated IFN-alpha has been shown to be effective in treatment of chronic hepatitis B with sustained response rate in about one-third of the treated patients. Peg IFN-alpha treatment in non-responders to lamivudine or adefovir dipivoxil showed similar response rate to that seen in naïve patients. Thymosin alpha(1) is effective in treatment of HBeAg-positive and HBeAg-negative chronic hepatitis B with a significantly increasing virological response over time after therapy.
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30
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Yang YF, Zhao W, Zhong YD, Yang YJ, Shen L, Zhang N, Huang P. Comparison of the efficacy of thymosin alpha-1 and interferon alpha in the treatment of chronic hepatitis B: a meta-analysis. Antiviral Res 2007; 77:136-41. [PMID: 18078676 DOI: 10.1016/j.antiviral.2007.10.014] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2007] [Revised: 10/27/2007] [Accepted: 10/30/2007] [Indexed: 11/30/2022]
Abstract
Chronic hepatitis B virus (HBV) infection is a serious problem because of its worldwide distribution and possible adverse sequelae, such as cirrhosis and hepatocellular carcinoma. Thymosin alpha-1 (Talpha1) is an immune modifier that has been shown to be effective for chronic hepatitis B (CHB) in some trials. But the trials comparing Talpha1 vs. interferon alpha (IFNalpha) treatment in CHB have been small and the results have been inconsistent. So we conducted a meta-analysis to compare the efficacy of Talpha1 and IFNalpha in the treatment of CHB. Generally, four randomized controlled trials including 199 CHB patients who received Talpha1 or IFNalpha treatment were identified through MEDLINE and EMBASE online search. Virological (for hepatitis B e antigen (HBeAg) positive patients, loss of HBV DNA and HBeAg; for HBeAg negative patients, loss of HBV DNA), biochemical (normalization of transaminases) and complete responses (fulfill criteria of biochemical and virological response simultaneously) were analyzed using the intention-to-treat method. The odds ratio (OR) was used to measure the magnitude of the efficacy. The ORs (95% confidence interval) of the virological response, biochemical response and complete response of Talpha1 over IFNalpha at the end of 6 months treatment were 0.62 (0.35, 1.10), 0.60 (0.34, 1.05) and 0.54 (0.30, 0.97), respectively. The ORs (95% confidence interval) of the virological response, biochemical response and complete response of Talpha1 over IFNalpha at the end of follow-up (6 months post-treatment) were 3.71 (2.05, 6.71), 3.12 (1.74, 5.62) and 2.69 (1.47, 4.91), respectively. These data showed that compared with IFNalpha, the benefit of Talpha1 was not immediately significant at the end of therapy, but virological, biochemical and complete response had a tendency to increase or accumulate gradually after the therapy. For three of the four trials that studied HBeAg-negative patients, the results are mostly applicable to HBeAg-negative CHB.
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Affiliation(s)
- Yong-Feng Yang
- Department of Liver Disease, the Second Hospital of Nanjing, affiliated with Medical School of South-East University, Nanjing 210003, Jiangsu Province, China.
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Garaci E, Favalli C, Pica F, Sinibaldi Vallebona P, Palamara AT, Matteucci C, Pierimarchi P, Serafino A, Mastino A, Bistoni F, Romani L, Rasi G. Thymosin Alpha 1: From Bench to Bedside. Ann N Y Acad Sci 2007; 1112:225-34. [PMID: 17600290 DOI: 10.1196/annals.1415.044] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
After the initial dramatic effects, observed in a Lewis lung carcinoma animal model, using a combination of thymosin alpha 1 (Talpha1) and interferon (IFN) after cyclophosphamide, a number of other preclinical models in mice (Friend erythroleukemia and B16 melanoma) and in rats (DHD/K12 colorectal cancer liver metastasis) have confirmed the efficacy of the combination therapy with Talpha1 and either IFN or IL-2 plus chemotherapy. These results provided the scientific foundation for the first clinical trials using Talpha1 in combination with BRMs and/or chemotherapy. Pivotal trials in advanced non-small cell lung cancer (NSCLC) and melanoma with Talpha1 and IFN-alpha low doses after cis-platinum or dacarbazine produced the first evidence of the high potentiality of this approach in the treatment of human cancer. The combination of Talpha1 and IFN-alpha was also used in patients affected by chronic B and C hepatitis including IFN-nonresponders and infected by precore mutants or genotype 1b. Further studies demonstrated additional biological activities clarifying the mechanism of action of Talpha1, partially explaining the synergism with IFN. It has been shown the capacity of activating infected dendritic cells through Toll-like receptor signaling, thus influencing the inflammation balance, and of increasing the expression of tumor, viral, and major histocompatibility complex (MHC) I antigens. Dose-response studies suggested the possibility of improving the efficacy of this molecule reducing the overall toxic. Based on these information two clinical trials are ongoing: a large phase II on advanced melanoma patients treated with Talpha1 at different doses after dacarbazine and a phase III one, on IFN-resistant hepatitis C virus (HCV) patients treated with a triple combination (IFN, ribavirin, and Talpha1).
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Affiliation(s)
- Anna S F Lok
- Division of Gastroenterology, University of Michigan Medical Center, 3912 Taubman Center, Box 0362, Ann Arbor, MI 48109-0362, USA.
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N/A, 万 谟. N/A. Shijie Huaren Xiaohua Zazhi 2006; 14:3294-3298. [DOI: 10.11569/wcjd.v14.i34.3294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Abstract
Hepatitis B virus (HBV) is one of the most prevalent viral pathogens of man with around 350 million chronically infected patients. It has been postulated that in persistently infected individuals the HBV-specific immune response is too weak to eliminate HBV from all infected hepatocytes, but sufficiently strong to continuously destroy HBV-infected hepatocytes and to induce chronic inflammatory liver disease. The primary aim in the treatment of chronic hepatitis B is to induce sustained disease remission and prevent serious complications like liver failure and/or hepatocellular carcinoma. The recent emergence of drug-resistant HBV mutants and post-treatment relapse as a consequence of nucleoside analogue monotherapy emphasizes that the principal goal should be to stimulate a successful immune response. In this paper we will focus on the immune response to HBV and we will review reported data on immunotherapeutic strategies like immunomodulatory drugs (cytokines and Thymic derivates) and vaccine therapies using currently available recombinant anti-HBV vaccines, lipopeptide-based T cell vaccine and newly developed genetic vaccines.
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Affiliation(s)
- D Sprengers
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
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36
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Liaw YF, Leung N, Guan R, Lau GKK, Merican I, McCaughan G, Gane E, Kao JH, Omata M. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2005 update. Liver Int 2005; 25:472-89. [PMID: 15910483 DOI: 10.1111/j.1478-3231.2005.01134.x] [Citation(s) in RCA: 270] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
BACKGROUND/AIMS A large amount of new data on the treatment of chronic hepatitis B has become available such that the 2003 consensus statement requires revision and update. METHODS New data were presented, discussed and debated in an expert pre-meeting to draft a revision. The revised contents were finalized after discussion in a general meeting of APASL. RESULTS Conceptual background, including the efficacy and safety profile of currently available and emerging drugs, was reviewed. Nineteen recommendations were formed and unresolved issues and areas for further study were suggested. CONCLUSION The current therapy of chronic hepatitis B is modestly effective but not satisfactory. The development of new drugs and new strategies is required to further improve the outcomes of treatment.
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Affiliation(s)
- Yun-Fan Liaw
- Liver Research Unit, Chang Gung Memorial Hospital, Taipei, Taiwan.
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Iino S, Toyota J, Kumada H, Kiyosawa K, Kakumu S, Sata M, Suzuki H, Martins EB. The efficacy and safety of thymosin alpha-1 in Japanese patients with chronic hepatitis B; results from a randomized clinical trial. J Viral Hepat 2005; 12:300-6. [PMID: 15850471 DOI: 10.1111/j.1365-2893.2005.00633.x] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Thymalfasin (thymosin alpha-1; Talpha1) is a 28-amino acid polypeptide that has shown efficacy in the treatment of chronic hepatitis B virus (HBV) infection. The objective of this study was to evaluate the long-term, dose-related efficacy and safety of Talpha1 treatment in chronic hepatitis B patients with positive HBV-DNA and abnormally high alanine aminotransferase (ALT) levels. A total of 316 patients were randomized to receive either 0.8 or 1.6 mg of Talpha1 monotherapy for 24 weeks. At the end of the 72-week observation period (12 months after cessation of therapy), 36.4% of patients in the 1.6-mg treatment group achieved normalization of ALT, 30% achieved clearance of HBV-DNA by branched DNA vs 15% by transcription-mediated amplification, and 22.8% achieved clearance of HBe-antigen. Patients in the 0.8-mg treatment group achieved similar efficacy rates, although patients with advanced fibrosis demonstrated a significantly better response rate when treated with 1.6 mg of Talpha1 monotherapy vs 0.8 mg (as determined by intragroup analysis; patients were not stratified by liver biopsy). All adverse drug reactions were mild and most involved the fluctuation of liver enzymes, which was most likely related to the positive immune effects caused by the response to Talpha1 treatment. Adverse event incidence was similar in the 1.6- and 0.8-mg treatment groups. In conclusion, Talpha1 at doses of 0.8 and 1.6 mg exhibits long-term efficacy against hepatitis B with a good safety profile.
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Affiliation(s)
- S Iino
- Department of Gastroenterology, St Marianna University, School of Medicine, Kawasaki, Kanagawa, Japan
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Abstract
Although the management of chronic hepatitis B has improved over the last decade, none of the available therapeutic agents, IFN-alpha, lamivudine and adefovir dipivoxil, can achieve sustained off-therapy responses in most cases. Therefore, several newer, mainly antiviral and immunomodulatory agents, are being evaluated. Pegylated IFN-alpha(2a) has been shown to be more effective than lamivudine or standard IFN-alpha monotherapy in achieving post-therapy biochemical and virological responses, and is expected to be licensed soon for the treatment of chronic hepatitis B. Newer antiviral agents, such as entecavir and telbivudine, appear to be quite effective initially, but their sustained off-therapy response rates remain unknown. The preliminary data of monotherapies with immunomodulatory agents, or of combination therapies, have been rather disappointing. Long-term maintenance treatment with antiviral agent(s) with good safety and tolerability profiles and low resistance rates appears to be the most realistic future therapeutic option for most chronic hepatitis B patients.
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Affiliation(s)
- Stephanos J Hadziyannis
- Henry Dunant Hospital, Department of Medicine and Hepatology, 107 Messogion Avenue, Athens 11526, Greece.
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You J, Zhuang L, Cheng HY, Yan SM, Qiao YW, Huang JH, Tang BZ, Ma YL, Wu GB, Qu JY, Wu RX. A randomized, controlled, clinical study of thymosin alpha-1 versus interferon-alpha in [corrected] patients with chronic hepatitis B lacking HBeAg in China [corrected]. J Chin Med Assoc 2005; 68:65-72. [PMID: 15759817 DOI: 10.1016/s1726-4901(09)70137-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND This study was designed to compare the efficacy and safety of thymosin-alphal (T-alpha1) with that of interferon-alpha (IFN-alpha) in patients with chronic hepatitis B who were positive for hepatitis B virus (HBV) DNA and hepatitis B envelope antibody (anti-HBe). METHODS Fifty-six patients were randomly divided into groups A and B. Both groups were comparable (p > 0.05) at baseline regarding age, sex, and alanine aminotransferase (ALT) levels. Group A patients received T-alpha1 1.6 mg subcutaneously twice weekly, while group B patients received IFN-alpha 5 million IU daily for 15 days, then thrice weekly for 6 months. Results from the 2 groups were compared with data from a group of 30 patients never treated with IFN-alpha and who were followed-up for 12 months (historical control [HC] group); the 3 groups were comparable (p > 0.05). RESULTS After treatment, a complete response (ALT normalization and HBV DNA loss) occurred in 8 of 26 patients in group A (30.8%) and 14 of 30 in group B (46.7%; chi2 = 1.476, p = 0.224). After a follow-up period of 6 months, a complete response was observed in 11 of 26 patients in group A (42.3%) and 7 of 30 in group B (23.3%; chi2 = 2.299, p = 0.129). The rate of complete response was significantly greater in the IFN-alpha than HC group at the end of therapy (46.7% vs 3.3%; chi2 = 15.022, p = 0.0001), and in the T-alphal than HC group at the end of follow-up (42.3% vs 3.3%; chi2 = 12.566, p = 0.0001). Ten of the 12 T-alphal responders (i.e. partial responders; 83.3%) experienced sustained, non-detectable HBV DNA after 6 months' treatment; 6 of the 14 T-alphal non-responders (42.9%) showed a delayed response of non-detectable HBV DNA during the follow-up period. Corresponding values for group B patients were 50% (9/18) and 0% (0/12). The rate of delayed response was significantly higher in group A than the other 2 groups (chi2 = 6.686, p = 0.010; chi2 = 4.964, p = 0.038), whereas the rate of flare was higher in group B than in the other 2 groups (chi2 = 3.445, p = 0.063; chi2 = 7.668, p = 0.006), during the follow-up period. Unlike IFN-alpha, T-alphal was well tolerated, i.e. no adverse effects were noted in group A. CONCLUSION These results suggest that a 6-month course of T-alpha1 therapy is effective and safe in patients with anti-HBe-positive chronic hepatitis B; T-alpha1 can reduce HBV replication in such patients. Compared with IFN-alpha, T-alpha1 is better tolerated and seems to induce a gradual and more sustained normalization of ALT and loss of HBV DNA. Combination therapy with T-alpha1 and IFN-alpha or nucleoside analogs for hepatitis B warrants further study.
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Affiliation(s)
- Jing You
- Department of Infectious Diseases, The First Affiliated Hospital of Kunming Medical College, Yunnan Province, China.
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Hui CK, Lau GKK. Advances in immunomodulating therapy of HBV infection. Int J Med Sci 2005; 2:24-29. [PMID: 15968336 PMCID: PMC1142221 DOI: 10.7150/ijms.2.24] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2004] [Accepted: 01/01/2005] [Indexed: 01/06/2023] Open
Abstract
Patients with chronic hepatitis B virus (HBV) infection have a higher risk of developing liver cirrhosis and hepatocellular carcinoma. Interferon-alpha, lamivudine and adefovir dipivoxil are the three approved treatment for chronic HBV infection and offers the only means of preventing the development of these complications. However, the efficacy of these agents, in terms of loss of Hepatitis B e antigen with or without seroconversion to Hepatitis B e antibody, normalization of serum alanine transaminase levels, loss of serum HBV DNA, and improvement in liver histology can only be achieved in 20-30% of those treated. Long-term treatment with either lamivudine or adefovir dipivoxil can result in the development of drug resistant mutants leading to an increased length of treatment with additional nucleoside analogues. These limitations of the current antiviral therapies underline the need for alternative therapies. Specific and nonspecific immunotherapeutic strategies to restore effective virus-specific T cell responses in those with chronic HBV infection offers an interesting alternative approach. These immunotherapeutic therapies include the adoptive transfer of HBV immunity, pegylated interferon and therapeutic vaccine therapies.
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Affiliation(s)
- Chee-Kin Hui
- 1. MRC Cancer Cell Unit, University of Cambridge, Cambridge, UK
| | - George KK Lau
- 2. Department of Medicine, University of Hong Kong, Hong Kong
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41
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Chien RN, Liaw YF. Thymalfasin for the treatment of chronic hepatitis B. Expert Rev Anti Infect Ther 2004; 2:9-16. [PMID: 15482167 DOI: 10.1586/14787210.2.1.9] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Chronic hepatitis B virus infection is a serious problem because of its worldwide distribution and possible adverse chronic sequelae, such as cirrhosis and hepatocellular carcinoma. Chronic hepatitis B infection is a dynamic state of interactions between the virus, hepatocyte and host immune response. Interferon-alpha and direct antiviral agents, such as lamivudine (Epivir, GlaxoSmithKline), are effective in the therapy of chronic HBV infection but the efficacy is far from satisfactory. Thymalfasin (thymosin alpha1; Talpha1, Zadaxintrade mark, SciClone Pharmaceuticals, Inc.) is a 28-amino acid polypeptide produced synthetically but originally isolated from thymosin fraction 5, a bovine thymus extract containing a number of immunologically active peptides. In vitro studies have shown that Talpha1 can influence T-cell production and maturation, stimulate production of Th1 cytokines such as interferon-gamma and interleukin-2, and activate natural killer cell-mediated cytotoxicity. Seven randomized controlled studies on Talpha1 monotherapy in patients with chronic hepatitis B showed that 6 months treatment with Talpha1 (1.6 mg twice-weekly) resulted in a significantly higher sustained response rate than untreated controls. The benefits of Talpha1 therapy is usually not immediately apparent during therapy. There is a trend for complete virological response to increase or accumulate gradually after the end of thymosin therapy. The results of Talpha1 and interferon combination therapy in two open-label trials were also promising. In terms of the mechanisms of action, a combination of Talpha1 and nucleoside or nucleotide analogs is a logical approach in the control of chronic HBV infection and a randomized control study is ongoing.
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Affiliation(s)
- Rong-Nan Chien
- Liver Research Unit, Chang Gung Memorial Hospital, 199 Tung Hwa North Road, Taipei, Taiwan
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Abstract
Chronic hepatitis B virus (HBV) infection is a serious clinical problem because of its worldwide distribution and potential adverse sequelae. Globally, there are approximately 350 million people infected with chronic HBV, 75% of whom live in the Asia-Pacific region. Interferon-alfa and direct antiviral agents such as lamivudine and adefovir are effective in the therapy of chronic HBV infection but the efficacy is far from satisfactory, particularly in perinatally infected patients, patients with lower ALT levels and those with HBeAg-negative chronic hepatitis B. Thymalfasin (thymosin-alpha1) is an immunoregulatory agent able to enhance Th1 response. It has been shown to trigger maturational events in lymphocytes, to augment T-cell function, and to promote reconstitution of immune defects. Studies are underway in both monotherapy and combination therapy with thymalfasin and interferon and results are promising.
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Affiliation(s)
- Yun-Fan Liaw
- Liver Research Unit, Chang Gung University and Memorial Hospital, 199, Tung Hwa North Road, Taipei, Taiwan.
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Asselah T, Castelnau C, Boyer N, Ripault MP, Marcellin P. Traitement de l’hépatite chronique B. ACTA ACUST UNITED AC 2004; 28:1215-27. [PMID: 15671931 DOI: 10.1016/s0399-8320(04)95213-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Affiliation(s)
- Tarik Asselah
- Service d'Hépatologie, INSERM U481, Hôpital Beaujon, 92110 Clichy
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44
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Lau DTY, Membreno FE. Antiviral therapy for treatment-naïve hepatitis B virus patients. Gastroenterol Clin North Am 2004; 33:581-99, ix-x. [PMID: 15324945 DOI: 10.1016/j.gtc.2004.04.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2023]
Abstract
Hepatitis B virus infection is a major public health problem worldwide,responsible for considerable morbidity and mortality from chronic liver disease. It is estimated that there are 350 million hepatitis B virus carriers globally. The prevalence of chronic hepatitis B infection varies greatly in different regions of the world. In the United States, approximately 1.5 million people are infected and 50,000 to 100,000 new cases are reported annually despite the availability of effective vaccines. This article reviews various antiviral therapies for treatment naïve hepatitis B virus patients.
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Affiliation(s)
- Daryl T-Y Lau
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The University of Texas Medical Branch, 4.106 McCullough Building, 301 University Boulevard, Galveston, TX 77555-0764, USA.
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45
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Lebray P, Vallet-Pichard A, Michel ML, Fontaine H, Sobesky R, Bréchot C, Pol S. Immunomodulatory drugs and therapeutic vaccine in chronic hepatitis B infection. J Hepatol 2004; 39 Suppl 1:S151-9. [PMID: 14708695 DOI: 10.1016/s0168-8278(03)00336-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Affiliation(s)
- Pascal Lebray
- Service d'Hépatologie, Hôpital Necker Enfants Malades, 75730 Paris Cédex 15, France
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46
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Andreone P, Gramenzi A, Cursaro C, Felline F, Loggi E, D'Errico A, Spinosa M, Lorenzini S, Biselli M, Bernardi M. Thymosin-alpha 1 plus interferon-alpha for naive patients with chronic hepatitis C: results of a randomized controlled pilot trial. J Viral Hepat 2004; 11:69-73. [PMID: 14738560 DOI: 10.1046/j.1365-2893.2003.00470.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
In this pilot study, we evaluated the efficacy of interferon-alpha (IFN) plus Thymosin-alpha 1 (TA1) to that of IFN alone in naive patients with chronic hepatitis C. Twenty-two patients were randomized to receive interferon-alpha 2b (3 million units three times a week) plus thymosin-alpha l (900 microg/m2 body surface area) and 19 received interferon-alpha 2b alone at the same dose. Patients were treated for 6 months and followed up for another 6 months. Biochemical (alanine aminotransferase values) and virological (hepatitis C virus-RNA) responses to treatment were determined. Combination treatment showed significantly higher efficacy than monotherapy in achieving virological end-of-treatment response (P = 0.03). At 6-month follow up, the sustained biochemical and virological response was not different between the two groups. Our results indicate that the immune modulator TA1 may enhance the end-of-treatment response in naive patients with chronic hepatitis C. Higher doses and/ore more prolonged courses as well as the association with new interferon formulation such as pegylated interferons could improve the sustained response rates to this treatment.
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Affiliation(s)
- P Andreone
- Semeiotica Medica, Dipartimento di Medicina Interna, Cardioangiologia ed Epatologia, Università di Bologna Istituto Oncologico, Italy.
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Abstract
BACKGROUND Infection is one of the most common complications and still remains a significant cause of morbidity and occasionally mortality in patients, especially children with nephrotic syndrome. Many different prophylactic interventions have been used or recommended for reducing the risks of infection in nephrotic syndrome in clinical practice. Whether the existing evidence is scientifically rigorous and which prophylactic intervention can be recommended for routine use based on the current evidence is still unknown. OBJECTIVES To assess the benefits and harms of any prophylactic interventions for reducing the risk of infection in children and adults with nephrotic syndrome. SEARCH STRATEGY We searched the Cochrane Renal Group Specialised Register (January 2003), The Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library Issue 1, 2003), MEDLINE and Pre-MEDLINE (1966 - February 2003), EMBASE (1980 - February 2003), China Biological Medicine Database (CBMdisc, 1979 - December 2002), reference lists of nephrology textbooks, review articles, relevant trials and abstracts from nephrology scientific meetings without language restriction. SELECTION CRITERIA Randomised controlled trials (RCTs) and quasi-RCTs comparing any prophylactic interventions (pharmacological or non-pharmacological) for preventing any infection in children and adults with nephrotic syndrome. DATA COLLECTION AND ANALYSIS Two reviewers independently assessed and extracted information. Information was collected on method, participants, interventions and outcomes ( appearance of infection, mortality, quality of life and adverse events). MAIN RESULTS Five RCTs conducted in China, including 308 children with nephrotic syndrome were identified. No trials were identified in adults. All trials compared one kind of prophylactic pharmacotherapy (IVIG, thymosin or a compound of Chinese medicinal herbs - TIAOJINING) in addition to baseline treatment with baseline treatment alone. No RCTs were identified comparing antibiotic or non-pharmacological prophylaxis, or pneumococcal vaccination. Three trials showed a significantly better effect of IVIG on preventing nosocomial or unspecified infection in children with nephrotic syndrome (RR 0.39, 95% CI 0.18 to 0.82). Thymosin and TIAOJINING were also effective for reducing the risks of infection in children with nephrotic syndrome with RR 0.50 (95%CI 0.26 to 0.97) and 0.59 (95%CI 0.43 to 0.81) respectively. No serious adverse events were reported. REVIEWERS' CONCLUSIONS IVIG, thymosin and TIAOJINING may have positive effects on prevention of nosocomial or unspecified infection with no obvious serious adverse events in children with nephrotic syndrome. However the methodological quality of all trials was poor, the sample sizes small and all studies were from China, and thus there is no strong evidence on the effectiveness of these interventions.
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Affiliation(s)
- H M Wu
- Chinese Cochrane Center, Department of Gerontology, West China Hospital, Si Chuan University, Chengdu, Si Chuan, China, 610041
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Affiliation(s)
- Hari S Conjeevaram
- Division of Gastroenterology, University of Michigan Medical Center, 3912 Taubman Center, Ann Arbor, MI 48109-0362, USA
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Yu AS, Keeffe EB. Nucleoside analogues and other antivirals for treatment of hepatitis B in the peritransplant period. Clin Liver Dis 2003; 7:551-72. [PMID: 14509526 DOI: 10.1016/s1089-3261(03)00044-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Chronic HBV infection is a common cause of advanced liver disease that is associated with substantial mortality. Furthermore, chronic hepatitis B was historically a controversial indication for liver transplantation because of a low post-transplant survival, with graft infection being the major contributor to adverse outcomes. The initial use of hepatitis B immune globulin as prophylaxis, followed later by combined therapy with lamivudine, markedly reduced viral recurrence and improved the survival of patients transplanted for acute or chronic hepatitis B with liver failure. Lamivudine alone can also be used for long-term prophylaxis against de novo HBV infection that can be transmitted by organs from donors positive for anti-HBc or anti-HBs. When used in patients with decompensated chronic hepatitis B with cirrhosis, lamivudine has been shown to improve clinical manifestations, prolong pretransplant survival, and defer, or even obviate, the need for transplantation. Despite prophylaxis, viral mutations with breakthrough reinfection may occur and lead to liver failure. The recently approved adefovir dipivoxil, which is active against lamivudine-resistant mutation, and other nucleoside analogs that are in various phases of development, offer hope as rescue therapy for viral recurrence. Other therapeutic alternatives in the future may include gene therapy and immune interventions.
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Affiliation(s)
- Andy S Yu
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA
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50
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Saruc M, Ozden N, Turkel N, Ayhan S, Hock LM, Tuzcuoglu I, Yuceyar H. Long-term outcomes of thymosin-alpha 1 and interferon alpha-2b combination therapy in patients with hepatitis B e antigen (HBeAg) negative chronic hepatitis B. J Pharm Sci 2003; 92:1386-95. [PMID: 12820143 DOI: 10.1002/jps.10401] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Hepatitis B e antibody (HbeAb) and hepatitis B virus (HBV) DNA positive chronic hepatitis is a clinical entity, distinct from classical hepatitis B e antigen (HbeAg) positive chronic hepatitis B. Our aim was to evaluate the long-term therapeutic efficacy of the combination of interferon alpha-2b and thymosin-alpha1 compared with lamivudine plus interferon alpha-2b and interferon alpha-2b alone. Fifty-two patients with HbeAg-negative chronic hepatitis B were assigned to three different groups in a nonrandomized manner. Group 1 (n = 27) received thymosin-alpha1 [1.6 mg subcutaneously (sc), twice a week] and interferon alpha-2b (10 MIU sc, three times per week) for 26 weeks, subsequently followed by interferon alpha-2b monotherapy at the same dosage for an additional 26 weeks. Group 2 (n = 10) received interferon alpha-2b (10 MIU sc, three times per week) for 52 weeks. Group 3 (n = 15) received interferon alpha-2b (10 MIU sc, three times per week) and lamivudine [100 mg orally (po), q.d.] for 52 weeks, followed by continuous lamivudine (100 mg po, q.d.) therapy. By the end of 78 weeks, a sustained response (SR-6 mo) was seen in 74% (20/27) of the patients within Group 1. On the contrary, Groups 2 and 3 had sustained response rates of 40 (4/10) and 53.3% (8/15), respectively (p = 0.13). At the end of 12 months post-treatment in Group 1, a virological and biochemical response rate was seen in 70.3% of patients (19/27); in contrast, Groups 2 and 3 had response rates of 20 (2/10) and 26.6% (4/15), respectively (p = 0036). At the end of the 18-month post-treatment follow-up period, 71.4% (19/27) of patients in Group 1, 10% of patients in Group 2 (1/10), and 20% of patients in Group 3(3/15) preserved their sustained response (p = 0.0003). Interferon alpha-2b and thymosin-alpha1 combination therapy results in significant virological and biochemical response rates compared with standard therapeutic regimens and is well tolerated.
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Affiliation(s)
- Murat Saruc
- University of Nebraska Medical Center, Eppley Cancer Research Institute, Omaha, NE, USA.
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