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Colombatto P, Coco B, Bonino F, Brunetto MR. Management and Treatment of Patients with Chronic Hepatitis B: Towards Personalized Medicine. Viruses 2022; 14:701. [PMID: 35458431 PMCID: PMC9027850 DOI: 10.3390/v14040701] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Revised: 03/22/2022] [Accepted: 03/23/2022] [Indexed: 02/07/2023] Open
Abstract
The currently available antiviral treatments (Peg-Interferon-α and Nucleos(t)ide Analogues, NA) for chronic hepatitis B (CHB) achieve a functional cure (serum HBsAg and HDV-DNA clearance) of HBV infection in a limited number of patients. Nevertheless, the continuous pharmacological suppression of viral replication by NA halts liver disease progression lowering the risk of HCC development and improving the survival. In the near future, to fully exploit the potential of old and new drugs for HBV treatment a personalized approach to the patients will be required according to an accurate definition of their virologic, immunologic and clinical profile.
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Affiliation(s)
- Piero Colombatto
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Center of the Tuscany Region for Chronic Liver Disease and Cancer, Department of Medical Specialties, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy; (P.C.); (B.C.)
| | - Barbara Coco
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Center of the Tuscany Region for Chronic Liver Disease and Cancer, Department of Medical Specialties, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy; (P.C.); (B.C.)
| | - Ferruccio Bonino
- Institute of Biostructure and Bioimaging, National Research Council, Via De Amicis 95, 80145 Naples, Italy;
| | - Maurizia R. Brunetto
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Center of the Tuscany Region for Chronic Liver Disease and Cancer, Department of Medical Specialties, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy; (P.C.); (B.C.)
- Institute of Biostructure and Bioimaging, National Research Council, Via De Amicis 95, 80145 Naples, Italy;
- Internal Medicine, Department of Clinical and Experimental Medicine, University of Pisa, Via Savi 10, 56127 Pisa, Italy
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2
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Choi HSJ, Sonneveld MJ, Farag MS, Brouwer WP, Brakenhoff SM, Hirode G, Gehring AJ, de Man RA, Hansen BE, Janssen HLA. Effects of on-treatment ALT flares on serum HBsAg and HBV RNA in patients with chronic HBV infection. J Viral Hepat 2021; 28:1729-1737. [PMID: 34514678 DOI: 10.1111/jvh.13613] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 08/26/2021] [Accepted: 08/27/2021] [Indexed: 12/15/2022]
Abstract
As pegylated interferon alpha (PEG-IFN-α) is increasingly used in combination regimens of novel drugs, we aimed to characterize ALT flares and their relationship with serum HBsAg and HBV RNA kinetics in a large combined cohort of chronic hepatitis B (CHB) patients on PEG-IFN-α-based therapy. In this post hoc analysis of four international randomized trials, 269/130/124/128 patients on PEG-IFN-α monotherapy, PEG-IFN-α plus nucleos(t)ide analogue (NA) de novo combination, PEG-IFN-α add-on to NA or NA monotherapy were included, respectively. A flare was defined as an episode of ALT ≥5 × ULN. The association between flares and HBsAg and HBV RNA changes were examined. On-treatment flares occurred in 83/651 (13%) patients (median timing/magnitude: week 8 [IQR 4-12], 7.6 × ULN [IQR 6.2-10.5]). Flare patients were more often Caucasians with genotype A/D and had higher baseline ALT, HBV DNA, HBV RNA and HBsAg levels than the no-flare group. More flares were observed on PEG-IFN-α monotherapy (18%) and PEG-IFN+NA de novo combination (24%) vs. PEG-IFN-α add-on (2%) or NA monotherapy (1%) (p < .001). On-treatment flares were significantly and independently associated with HBsAg and HBV RNA decline ≥1 log10 at the final visit declines started shortly before the flare, progressing towards 24 weeks thereafter. On-treatment flares were seen in 16/22 (73%) patients who achieved HBsAg loss. In conclusion, ALT flares during PEG-IFN-α treatment are associated with subsequent HBsAg and HBV RNA decline and predict subsequent HBsAg loss. Flares rarely occurred during PEG-IFN-α add-on therapy and associated with low HBsAg loss rates. Combination regimens targeting the window of heightened response could be promising.
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Affiliation(s)
- Hannah S J Choi
- Toronto Centre for Liver Disease, University Health Network, Toronto, ON, Canada.,Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | - Milan J Sonneveld
- Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Mina S Farag
- Toronto Centre for Liver Disease, University Health Network, Toronto, ON, Canada
| | - Willem P Brouwer
- Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Sylvia M Brakenhoff
- Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Grishma Hirode
- Toronto Centre for Liver Disease, University Health Network, Toronto, ON, Canada
| | - Adam J Gehring
- Toronto Centre for Liver Disease, University Health Network, Toronto, ON, Canada
| | - Rob A de Man
- Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Bettina E Hansen
- Toronto Centre for Liver Disease, University Health Network, Toronto, ON, Canada.,Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada
| | - Harry L A Janssen
- Toronto Centre for Liver Disease, University Health Network, Toronto, ON, Canada
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3
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Association analysis of KIR/HLA genotype with liver cirrhosis, hepatocellular carcinoma, and NUC freedom in chronic hepatitis B patients. Sci Rep 2021; 11:21424. [PMID: 34728722 PMCID: PMC8563771 DOI: 10.1038/s41598-021-01014-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 10/21/2021] [Indexed: 11/21/2022] Open
Abstract
Natural killer cells are modulated through the binding of killer cell immunoglobulin-like receptors (KIRs) with human leukocyte antigen (HLA) class I ligands. This study investigated the association of KIR/HLA pairs with progression to liver cirrhosis, hepatocellular carcinoma (HCC) development, and nucleot(s)ide (NUC) treatment freedom in hepatitis B virus (HBV) infection. KIR, HLA-Bw, and HLA-C were genotyped in 280 Japanese HBV patients for clinical comparisons. No significant associations of KIR/HLA pairs were detected in terms of liver cirrhosis development. The KIR2DS3 positive rate was significantly higher in patients with HCC (n = 39) than in those without (n = 241) [30.8% vs. 14.9%, odds ratio (OR) 2.53, P = 0.015]. The KIR3DL1/HLA-Bw4 pair rate was significantly lower in the NUC freedom group (n = 20) than in the NUC continue group (n = 114) (25.0% vs. 52.6%, OR 0.30, P = 0.042). In conclusion, this study indicated remarkable associations of KIR/HLA with HCC development (KIR2DS3) and freedom from NUC therapy (KIR3DL1/HLA-Bw4) in HBV patients, although the number of cases was insufficient for statistical purposes. Additional multi-center analyses of larger groups are needed to clarify whether KIR/HLA pairs play a role in HBV patient status.
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Charatcharoenwitthaya P, Kaewdech A, Piratvisuth T. Controversies in Treating Chronic HBV: The Role of PEG-interferon-alfa. Clin Liver Dis 2021; 25:741-762. [PMID: 34593151 DOI: 10.1016/j.cld.2021.06.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Pegylated interferon-alpha therapy is one of the first-line chronic hepatitis B treatment. Finite treatment duration, absence of drug resistance, delayed response, and higher hepatitis B surface antigen loss than nucleos(t)ides analog therapy are the advantages of pegylated interferon-alpha treatment. Common side effects and subcutaneous injections requirement limit its use. Identifying patients likely to respond to pegylated interferon-alpha and optimizing treatment is reasonable. Motivating patients to complete the 48-week treatment is necessary. Treatment is stopped or switched to other treatment strategies in patients with stopping rule criteria. Combination therapy with nucleos(t)ides analog may improve response, but remains controversial.
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Affiliation(s)
- Phunchai Charatcharoenwitthaya
- Gastroenterology Division, Department of Internal Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Wang-Lang Road, Bangkok 10700, Thailand
| | - Apichat Kaewdech
- Gastroenterology and Hepatology Unit, Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Kanchanawanich Road, Songkhla 90110, Thailand
| | - Teerha Piratvisuth
- Gastroenterology and Hepatology Unit, Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Kanchanawanich Road, Songkhla 90110, Thailand; NKC Institute of Gastroenterology and Hepatology, Songklanagarind Hospital, Prince of Songkla University, Kanchanawanich Road, Songkhla 90110, Thailand.
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Tsuge M. Are Humanized Mouse Models Useful for Basic Research of Hepatocarcinogenesis through Chronic Hepatitis B Virus Infection? Viruses 2021; 13:v13101920. [PMID: 34696350 PMCID: PMC8541657 DOI: 10.3390/v13101920] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 09/14/2021] [Accepted: 09/20/2021] [Indexed: 12/19/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection is a global health problem that can lead to liver dysfunction, including liver cirrhosis and hepatocellular carcinoma (HCC). Current antiviral therapies can control viral replication in patients with chronic HBV infection; however, there is a risk of HCC development. HBV-related proteins may be produced in hepatocytes regardless of antiviral therapies and influence intracellular metabolism and signaling pathways, resulting in liver carcinogenesis. To understand the mechanisms of liver carcinogenesis, the effect of HBV infection in human hepatocytes should be analyzed. HBV infects human hepatocytes through transfer to the sodium taurocholate co-transporting polypeptide (NTCP). Although the NTCP is expressed on the hepatocyte surface in several animals, including mice, HBV infection is limited to human primates. Due to this species-specific liver tropism, suitable animal models for analyzing HBV replication and developing antivirals have been lacking since the discovery of the virus. Recently, a humanized mouse model carrying human hepatocytes in the liver was developed based on several immunodeficient mice; this is useful for analyzing the HBV life cycle, antiviral effects of existing/novel antivirals, and intracellular signaling pathways under HBV infection. Herein, the usefulness of human hepatocyte chimeric mouse models in the analysis of HBV-associated hepatocarcinogenesis is discussed.
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Affiliation(s)
- Masataka Tsuge
- Natural Science Center for Basic Research and Development, Department of Biomedical Science, Research and Development Division, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan; ; Tel.: +81-82-257-1510
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
- Research Center for Hepatology and Gastroenterology, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
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Chou R, Blazina I, Bougatsos C, Holmes R, Selph S, Grusing S, Jou J. Screening for Hepatitis B Virus Infection in Nonpregnant Adolescents and Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA 2020; 324:2423-2436. [PMID: 33320229 DOI: 10.1001/jama.2020.19750] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Importance A 2014 review for the US Preventive Services Task Force (USPSTF) found antiviral therapy for hepatitis B virus (HBV) infection associated with improved intermediate outcomes, although evidence on clinical outcomes was limited. Objective To update the 2014 HBV screening review in nonpregnant adolescents and adults to inform the USPSTF. Data Sources Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and Ovid MEDLINE (2014 to August 2019); with surveillance through July 24, 2020. Study Selection Randomized clinical trials (RCTs) on screening and antiviral therapy; cohort studies on screening, antiviral therapy clinical outcomes, and the association between achieving intermediate outcomes after antiviral therapy and clinical outcomes. Data Extraction and Synthesis One investigator abstracted data; a second investigator checked accuracy. Two investigators independently assessed study quality. Random-effects profile likelihood meta-analysis was performed. Results Thirty trials and 20 cohort studies, with a total of 94 168 participants, were included. No study directly evaluated the effects of screening for HBV infection vs no screening on clinical outcomes such as mortality, hepatocellular carcinoma, or cirrhosis. Screening strategies that focused on risk factors such as ever having immigrated from high-prevalence countries and demographic and behavioral risk factors would identify nearly all HBV infection cases. In 1 study (n = 21 008), only screening immigrants from high-prevalence countries would miss approximately two-thirds of infected persons. Based on 18 trials (n = 2972), antiviral therapy compared with placebo or no treatment was associated with greater likelihood of achieving intermediate outcomes, such as virologic suppression and hepatitis B e-antigen (HBeAg) or hepatitis B surface antigen loss or seroconversion; the numbers needed to treat ranged from 2.6 for virologic suppression to 17 for HBeAg seroconversion. Based on 12 trials (n = 4127), first-line antiviral therapies were at least as likely as nonpreferred therapies to achieve intermediate outcomes. Based on 16 trials (n = 4809), antiviral therapy might be associated with improved clinical outcomes, but data were sparse and imprecise. Nine cohort studies (n = 3893) indicated an association between achieving an intermediate outcome following antiviral therapy and improved clinical outcomes but were heterogeneous (hazard ratios ranged from 0.07 to 0.87). Antiviral therapy was associated with higher risk of withdrawal due to adverse events vs placebo or no antiviral therapy. Conclusions and Relevance There was no direct evidence for the clinical benefits and harms of HBV screening vs no screening. Antiviral therapy for HBV infection was associated with improved intermediate outcomes and may improve clinical outcomes.
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Affiliation(s)
- Roger Chou
- Pacific Northwest Evidence-based Practice Center, Department of Medical Informatics and Clinical Epidemiology; Oregon Health & Science University, Portland
- Division of General Internal Medicine and Geriatrics; Oregon Health & Science University, Portland
| | - Ian Blazina
- Pacific Northwest Evidence-based Practice Center, Department of Medical Informatics and Clinical Epidemiology; Oregon Health & Science University, Portland
| | - Christina Bougatsos
- Pacific Northwest Evidence-based Practice Center, Department of Medical Informatics and Clinical Epidemiology; Oregon Health & Science University, Portland
| | - Rebecca Holmes
- Pacific Northwest Evidence-based Practice Center, Department of Medical Informatics and Clinical Epidemiology; Oregon Health & Science University, Portland
| | - Shelley Selph
- Pacific Northwest Evidence-based Practice Center, Department of Medical Informatics and Clinical Epidemiology; Oregon Health & Science University, Portland
- Department of Family Medicine, Oregon Health & Science University, Portland
| | - Sara Grusing
- Pacific Northwest Evidence-based Practice Center, Department of Medical Informatics and Clinical Epidemiology; Oregon Health & Science University, Portland
| | - Janice Jou
- Pacific Northwest Evidence-based Practice Center, Department of Medical Informatics and Clinical Epidemiology; Oregon Health & Science University, Portland
- Division of Gastroenterology and Hepatology; Oregon Health & Science University, Portland
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7
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Xiao Y, Thompson AJ, Howell J. Point-of-Care Tests for Hepatitis B: An Overview. Cells 2020; 9:cells9102233. [PMID: 33023265 PMCID: PMC7650625 DOI: 10.3390/cells9102233] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 09/30/2020] [Accepted: 09/30/2020] [Indexed: 12/15/2022] Open
Abstract
Despite the heavy disease burden posed by hepatitis B, around 90% of people living with hepatitis B are not diagnosed globally. Many of the affected populations still have limited or no access to essential blood tests for hepatitis B. Compared to conventional blood tests which heavily rely on centralised laboratory facilities, point-of-care testing for hepatitis B has the potential to broaden testing access in low-resource settings and to engage hard-to-reach populations. Few hepatitis B point-of-care tests have been ratified for clinical use by international and regional regulatory bodies, and countries have been slow to adopt point-of-care testing into hepatitis B programs. This review presents currently available point-of-care tests for hepatitis B and their roles in the care cascade, reviewing evidence for testing performance, utility, acceptability, costs and cost-effectiveness when integrated into hepatitis B diagnosis and monitoring programs. We further discuss challenges and future directions in aspects of technology, implementation, and regulation when adopting point-of-care testing in hepatitis B programs.
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Affiliation(s)
- Yinzong Xiao
- Burnet Institute, 3004 Melbourne, VIC, Australia;
- Department of Gastroenterology, St Vincent’s Hospital, 3065 Fitzroy, VIC, Australia;
- Faculty of Medicine, University of Melbourne, 3010 Parkville, VIC, Australia
| | - Alexander J. Thompson
- Department of Gastroenterology, St Vincent’s Hospital, 3065 Fitzroy, VIC, Australia;
- Faculty of Medicine, University of Melbourne, 3010 Parkville, VIC, Australia
| | - Jessica Howell
- Burnet Institute, 3004 Melbourne, VIC, Australia;
- Department of Gastroenterology, St Vincent’s Hospital, 3065 Fitzroy, VIC, Australia;
- Faculty of Medicine, University of Melbourne, 3010 Parkville, VIC, Australia
- School of Public Health and Preventive Medicine, Monash University, 3004 Melbourne, VIC, Australia
- Correspondence:
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8
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Wu S, Luo W, Wu Y, Chen H, Peng J. HBsAg quantification predicts off-treatment response to interferon in chronic hepatitis B patients: a retrospective study of 250 cases. BMC Gastroenterol 2020; 20:121. [PMID: 32316928 PMCID: PMC7171920 DOI: 10.1186/s12876-020-01263-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 04/05/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND For chronic hepatitis B (CHB) patients without willingness to extend the routine duration of interferon (IFN) therapy, it is important to identify patients who will benefit from treatment cessation. Hepatitis B surface antigen (HBsAg) quantification is recommended for management of IFN therapy. At present, the understanding on end-of-treatment (EOT) HBsAg level predicting post-treatment response to IFN is still finite. METHODS A total of 2451 non-cirrhosis, HBsAg-postive patients treated with IFN-based therapy during the period from December 2010 to December 2017 at Nanfang Hospital were enrolled in this study. Serum HBsAg levels at EOT were measured to evaluate the associations between EOT HBsAg levels (Group 1, HBsAg > 0.05 and ≤ 10 IU/mL; Group 2, HBsAg > 10 and ≤ 200 IU/mL; Group 3, HBsAg > 200 IU/mL) with post-treatment HBsAg loss. Chi-squared, t-test,,Kaplan-Meier analysis, Cox regression analysis, and Multivariate Logistic regression analysis were used to analyse and evaluate differences between the there groups. RESULTS The cumulative HBsAg loss rates 5 years after treatment in Group 1-3 were 30.4% (17/56), 9.8%(4/41) and 0%(0/153) (p < 0.001). An EOT HBsAg level of > 10 IU/mL showed relatively high negative predictive value (NPV) of up to 97.9% for HBsAg loss. Low baseline HBsAg level < 25,000 IU/mL, on-treatment HBsAg decline > 1 log10IU/mL at week 24 and EOT HBsAg level ≤ 10 IU/mL were found significantly associated with HBsAg loss. A total of 6 patients have achieved HBsAg loss at EOT and 17 patients with EOT HBsAg level ≤ 10 IU/mL have achieved post-treatment HBsAg loss. Baseline characteristics, dynamic changes of on-treatment HBsAg and duration of IFN therapy were balanced across patients with EOT or post-treatment HBsAg loss. CONCLUSION EOT HBsAg level can serve as a monitoring indicator for IFN therapy. EOT HBsAg level ≤ 10 IU/mL was found to lead to high rate of post-treatment HBsAg loss. For patients without willingness to extend IFN treatment, off-treatment follow-up could be considered when HBsAg level decreased to ≤10 IU/mL.
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Affiliation(s)
- Shuai Wu
- Department of Infectious Diseases, Nanfang Hospital of Southern Medical University, Guangzhou, 510515 China
| | - Wenfan Luo
- Department of Infectious Diseases, Nanfang Hospital of Southern Medical University, Guangzhou, 510515 China
| | - Yin Wu
- Department of Infectious Diseases, Nanfang Hospital of Southern Medical University, Guangzhou, 510515 China
| | - Hongjie Chen
- Department of Infectious Diseases, Nanfang Hospital of Southern Medical University, Guangzhou, 510515 China
| | - Jie Peng
- Department of Infectious Diseases, Nanfang Hospital of Southern Medical University, Guangzhou, 510515 China
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Stournaras E, Neokosmidis G, Stogiannou D, Protopapas A, Tziomalos K. Effects of antiviral treatment on the risk of hepatocellular cancer in patients with chronic viral hepatitis. Eur J Gastroenterol Hepatol 2018; 30:1277-1282. [PMID: 30179906 DOI: 10.1097/meg.0000000000001254] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is a major complication of chronic hepatitis B (CHB) and chronic hepatitis C (CHC). Accumulating data suggest that antiviral treatment in both CHB and CHC reduces the incidence of HCC. Evidence is more consistent for interferon-based treatment in both CHB and CHC and for lamivudine in patients with CHB. However, more limited data suggest that other nucleos(t)ide analogues might also reduce the risk of HCC. In contrast, conflicting data have been reported on the effects of direct-acting antivirals on the incidence of HCC.
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MESH Headings
- Antiviral Agents/therapeutic use
- Carcinoma, Hepatocellular/diagnosis
- Carcinoma, Hepatocellular/epidemiology
- Carcinoma, Hepatocellular/prevention & control
- Carcinoma, Hepatocellular/virology
- Hepatitis B, Chronic/diagnosis
- Hepatitis B, Chronic/drug therapy
- Hepatitis B, Chronic/epidemiology
- Hepatitis B, Chronic/virology
- Hepatitis C, Chronic/diagnosis
- Hepatitis C, Chronic/drug therapy
- Hepatitis C, Chronic/epidemiology
- Hepatitis C, Chronic/virology
- Humans
- Incidence
- Liver Neoplasms/diagnosis
- Liver Neoplasms/epidemiology
- Liver Neoplasms/prevention & control
- Liver Neoplasms/virology
- Protective Factors
- Risk Factors
- Treatment Outcome
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Affiliation(s)
- Evangelos Stournaras
- First Propaedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece
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Serum miRNAs Predicting Sustained HBs Antigen Reduction 48 Weeks after Pegylated Interferon Therapy in HBe Antigen-Negative Patients. Int J Mol Sci 2018; 19:ijms19071940. [PMID: 30004437 PMCID: PMC6073286 DOI: 10.3390/ijms19071940] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Revised: 06/23/2018] [Accepted: 06/29/2018] [Indexed: 12/12/2022] Open
Abstract
The therapeutic goal for hepatitis B virus (HBV) infection is HBs antigen (HBsAg) seroclearance, which is achieved through 48-week pegylated interferon (Peg-IFN) therapy. This study aimed to identify predictive biomarkers for sustained HBsAg reduction by analyzing serum microRNAs. Twenty-two consecutive chronic HBV infection patients negative for HBe antigen (HBeAg) with HBV-DNA levels <5 log copies/mL, alanine aminotransferase (ALT) <100 U/L, and compensated liver functions, were enrolled. The patients were subcutaneously injected with Peg-IFNα-2a weekly for 48 weeks (treatment period), followed by the 48-week observation period. HBsAg 1-log drop relative to baseline levels recorded at the end of the observation period was considered effective. Sera were obtained at weeks 0 and 24 during the treatment period analyzed for microRNAs. The microRNA (miRNA) antiviral activity was evaluated in vitro using Huh7/sodium taurocholate cotransporting polypeptide (NTCP) cells. As a result, six patients achieved the HBsAg 1-log drop after the observation periods. Comparison of serum microRNA levels demonstrated that high miR-6126 levels at week 24 predicted HBsAg 1-log drop. Furthermore, miR-6126 reduced HBsAg in culture medium supernatants and intracellular HBV-DNA quantities in Huh7/NTCP cells. In conclusion, high serum miR-6126 levels during Peg-IFN therapy predicted the HBsAg 1-log drop 48 weeks after the completion of therapy. In vitro assays revealed that miR-6126 was able to suppress HBsAg production and HBV replication.
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11
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Fragilolides A-Q, norditerpenoid and briarane diterpenoids from the gorgonian coral Junceella fragilis. Tetrahedron 2017. [DOI: 10.1016/j.tet.2017.03.037] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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12
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Abstract
Chronic hepatitis B virus (HBV) infection has a significant public health impact. There are currently 7 approved therapies for chronic HBV, including standard and pegylated interferon (IFN)-α, and 5 nucleos(t)ide analogs (NUCs). IFN offers benefits over NUCs, including a finite duration of therapy and a higher rate of clearance of hepatitis Be antigen and surface antigen. These benefits need to be weighed against the potential adverse effects of IFN therapy. Some patients should not receive IFN because of advanced liver disease or comorbidities. This article reviews the mechanisms of action, efficacy, and clinical use of IFN therapy for HBV infection.
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Affiliation(s)
- Monica A Konerman
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Health System, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA
| | - Anna S Lok
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Health System, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA.
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13
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Okanoue T, Shima T, Hasebe C, Karino Y, Imazeki F, Kumada T, Minami M, Imai Y, Yoshihara H, Mita E, Morikawa T, Nishiguchi S, Kawakami Y, Nomura H, Sakisaka S, Kurosaki M, Yatsuhashi H, Oketani M, Kohno H, Masumoto A, Ikeda K, Kumada H. Long-term follow up of peginterferon-α-2a treatment of hepatitis B e-antigen (HBeAg) positive and HBeAg negative chronic hepatitis B patients in phase II and III studies. Hepatol Res 2016; 46:992-1001. [PMID: 26670363 DOI: 10.1111/hepr.12638] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2015] [Revised: 12/05/2015] [Accepted: 12/07/2015] [Indexed: 02/08/2023]
Abstract
AIM We analyzed the 5-year post-treatment response to peginterferon α-2a (PEG IFN-α-2a) in hepatitis B e-antigen (HBeAg) positive and negative chronic hepatitis B patients. METHODS One hundred and thirty-seven chronic hepatitis B (CHB) patients receiving 90 μg or 180 μg of PEG IFN-α-2a for 24 or 48 weeks in phase II or III studies were enrolled in the study, including 100 HBeAg positive patients and 37 HBeAg negative patients; 121 patients (88.4%) had genotype C. RESULTS Of the 137 patients, 94 received additional antiviral therapy because of viral reactivation and 43 did not receive any additional antiviral treatment during follow up. Five years upon PEG IFN-α-2a treatment, 32 patients (23.4%) who did not receive any additional antiviral agent after PEG IFN-α-2a therapy achieved a good response (normal serum alanine aminotransferase, low-level hepatitis B virus [HBV] DNA, and HBeAg negativity). Female sex and low HBV DNA levels by the end of treatment were independently associated with favorable 5-year post-treatment responses. Forty-eight-week administration of PEG IFN-α-2a showed a better response (26.4%) than 24-week administration (18.0%). Six patients (4.3%), four males and two females, cleared hepatitis B surface antigen (HBsAg) during the 5-year follow-up period. CONCLUSION The 48-week administration of PEG IFN-α-2a achieved better biochemical and virological responses than the 24-week administration, particularly in younger females. The 5-year post-treatment response rate was 23.4%; however, more than two-thirds of the patients received additional antiviral therapy because of viral reactivation after PEG IFN-α-2a treatment. HBsAg clearance was noted in six patients (4.3%). PEG IFN-α-2a is effective in young female patients.
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Affiliation(s)
- Takeshi Okanoue
- Center of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Suita, Japan
| | - Toshihide Shima
- Center of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Suita, Japan
| | - Chitomi Hasebe
- Department of Gastroenterology, Asahikawa Red Cross Hospital, Asahikawa, Japan
| | - Yoshiyasu Karino
- Department of Hepatology, Sapporo Kohseiren Hospital, Sapporo, Japan
| | - Fumio Imazeki
- Department of Gastroenterology and Nephrology, Chiba University, Chiba, Japan
| | - Takashi Kumada
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Masahito Minami
- Department of Gastroenterology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yasuharu Imai
- Department of Gastroenterology, Ikeda Municipal Hospital, Ikeda, Japan
| | | | - Eiji Mita
- Department of Gastroenterology, National Hospital Organization Osaka Medical Center, Osaka, Japan
| | | | - Shuhei Nishiguchi
- Division of Hepatobiliary and Pancreatic Medicine, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Yoshiiku Kawakami
- Department of Gastroenterology and Metabolism, Hiroshima University, Hiroshima, Japan
| | | | - Shotaro Sakisaka
- Department of Gastroenterolgy, Fukuoka University, Fukuoka, Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology, Musashino Red Cross Hospital, Musashino, Japan
| | - Hiroshi Yatsuhashi
- Clinical Research Center, National Hospital Organization Nagasaki Medical Center, Nagasaki, Japan
| | - Makoto Oketani
- Department of Gastroenterology and Life Style-Related Disease, Kagoshima University, Kagoshima, Japan
| | - Hiroshi Kohno
- Department of Gastroenterology, National Hospital Organization, Kure Medical Center and Chugoku Cancer Center, Kure, Japan
| | | | - Kenji Ikeda
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
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Tawada A, Kanda T, Imazeki F, Yokosuka O. Prevention of hepatitis B virus-associated liver diseases by antiviral therapy. Hepatol Int 2016; 10:574-593. [PMID: 27026375 DOI: 10.1007/s12072-016-9720-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2015] [Accepted: 02/28/2016] [Indexed: 02/06/2023]
Abstract
Hepatitis B virus (HBV) is a major cause of acute and chronic hepatitis, cirrhosis and hepatocellular carcinoma, particularly in Asia-Pacific countries. The major complications in HBV carriers are hepatocellular carcinoma (HCC), liver failure and esophageal varices following the progression to cirrhosis, while some develop HCC without cirrhosis. The progression to liver fibrosis and these other complications could be prevented by treatment with nucleos(t)ide analogues (NUCs); however, NUCs must be continuously administered for a long time. Peginterferon could lead to HBV surface antigen loss. It is difficult to use peginterferon in HBV-infected patients with decompensated cirrhosis. Acute liver failure due to HBV infection and acute exacerbation of chronic hepatitis B could be treated by NUCs. Universal vaccination programs against HBV could prevent new HBV infections globally. Here, we review the currently available treatments for HBV infection.
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Affiliation(s)
- Akinobu Tawada
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
- Safety and Health Organization, Chiba University, Chiba, 263-8522, Japan
| | - Tatsuo Kanda
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.
| | - Fumio Imazeki
- Safety and Health Organization, Chiba University, Chiba, 263-8522, Japan
| | - Osamu Yokosuka
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
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15
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Kim V, Abreu RM, Nakagawa DM, Baldassare RM, Carrilho FJ, Ono SK. Pegylated interferon alfa for chronic hepatitis B: systematic review and meta-analysis. J Viral Hepat 2016; 23:154-69. [PMID: 25967226 DOI: 10.1111/jvh.12418] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2014] [Accepted: 03/19/2015] [Indexed: 12/13/2022]
Abstract
Conventional interferon alfa and nucleos(t)ide analogues, such as lamivudine, are frequently used for chronic hepatitis B (CHB) treatment, but are associated with adverse effects and viral resistance. Here we performed a systematic review and meta-analysis evaluating all studies of pegylated interferon alfa (PEG-IFNα) treatment in hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients with CHB. We searched electronic databases--PubMed, EMBASE, Cochrane Library and LILACS--for randomized controlled trials evaluating PEG-IFNα therapy between 1999 and September 2014. Virological response was the primary outcome. We identified 14 studies involving 2829 patients. Our analysis revealed that PEG-IFNα + lamivudine combination therapy produced better virological and biochemical responses than PEG-IFNα monotherapy in HBeAg-positive and HBeAg-negative patients at the end of treatment. PEG-IFNα + adefovir dipivoxil achieved better seroconversion rate than PEG-IFNα in HBeAg-positive patients at the end of treatment. The present findings demonstrated a beneficial response rate following PEG-IFNα combination therapy with nucelos(t)ides among HBeAg-positive and HBeAg-negative patients with CHB. Further trials are needed to investigate simultaneous and sequential therapy strategies.
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Affiliation(s)
- V Kim
- Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil
| | - R M Abreu
- Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil
| | - D M Nakagawa
- Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil
| | - R M Baldassare
- Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil
| | - F J Carrilho
- Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil
| | - S K Ono
- Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil
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16
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Ozaras R, Khodor H, Yetim N, Unal UK, Demirhan YE, Gultekin G, Isal B. Monotherapy for hepatitis B infection: a review of treatment options. Expert Rev Anti Infect Ther 2015; 13:1457-68. [PMID: 26414781 DOI: 10.1586/14787210.2015.1093934] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Chronic hepatitis B (CHB) is a global health problem, causing liver failure, cirrhosis and hepatocellular carcinoma. CHB treatment aims to prevent liver-related complication. The treatment of CHB infection includes monotherapy with either interferons (IFNs) or nucleos(t)ide (NUC) analogs. IFNs have moderate antiviral effects, and their use is limited by side effects. With the availability of NUCs, IFN-intolerant and decompensated cirrhotic patients began to be treated. Lamivudine and telbivudine, nucleoside analogs, have low genetic barrier to resistance. Adefovir, a nucleotide analog, has moderate potency and potential nephrotoxicity. Entecavir and tenofovir, with their high potency, high genetic barrier to resistance and favorable safety profile are the standard of care in CHB treatment. Long-term use of NUCs with maintained viral suppression results in a decrease in liver-related complications.
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Affiliation(s)
| | - Hawa'a Khodor
- a Infectious Diseases Department, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey
| | - Nergul Yetim
- a Infectious Diseases Department, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey
| | - Umut Kaan Unal
- a Infectious Diseases Department, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey
| | - Yunus Emre Demirhan
- a Infectious Diseases Department, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey
| | - Goknil Gultekin
- a Infectious Diseases Department, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey
| | - Burak Isal
- a Infectious Diseases Department, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey
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17
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Tawada A, Kanda T, Yokosuka O. Current and future directions for treating hepatitis B virus infection. World J Hepatol 2015; 7:1541-1552. [PMID: 26085913 PMCID: PMC4462692 DOI: 10.4254/wjh.v7.i11.1541] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2015] [Revised: 03/16/2015] [Accepted: 04/28/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) persistently infects approximately 350 million people, and approximately 600000 liver-related deaths are observed per year worldwide. HBV infection is also one of the major risk factors for hepatocellular carcinoma (HCC). The persistence of serum hepatitis B e antigen (HBeAg) and high level of serum HBV DNA are thought to reflect a high HBV replication status in hepatocytes, causing cirrhosis, HCC and liver-related deaths. It has been reported that antiviral therapy, such as peginterferon and nucleos(t)ide analogues (NUCs), could suppress liver-related death by inhibiting the HBV DNA levels and inducing seroconversion from HBeAg to antibody to HBe antigen. Currently, peginterferon is widely used, but there are also several disadvantages in the use of peginterferon, such as various adverse events, the administration route and duration. It is difficult to predict the effects of treatment and interferon is contraindicated for the patients with advanced fibrosis of the liver and cirrhosis. With respect to NUCs, entecavir and tenofovir disoproxil fumarate are current the first-choice drugs. NUCs can be administered orally, and their anti-viral effects are stronger than that of peginterferon. However, because cessation of NUC administration leads to high levels of viral replication and causes severe hepatitis, they must be administered for a long time. On the other hand, the use of both interferon and NUCs cannot eliminate covalently closed circular DNA of HBV. In this review, we evaluate the natural course of chronic HBV infection and then provide an outline of these representative drugs, such as peginterferon, entecavir and tenofovir disoproxil fumarate.
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Affiliation(s)
- Akinobu Tawada
- Akinobu Tawada, Tatsuo Kanda, Osamu Yokosuka, Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba 260-8677, Japan
| | - Tatsuo Kanda
- Akinobu Tawada, Tatsuo Kanda, Osamu Yokosuka, Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba 260-8677, Japan
| | - Osamu Yokosuka
- Akinobu Tawada, Tatsuo Kanda, Osamu Yokosuka, Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba 260-8677, Japan
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18
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Russo FP, Rodríguez-Castro K, Scribano L, Gottardo G, Vanin V, Farinati F. Role of antiviral therapy in the natural history of hepatitis B virus-related chronic liver disease. World J Hepatol 2015; 7:1097-1104. [PMID: 26052398 PMCID: PMC4450186 DOI: 10.4254/wjh.v7.i8.1097] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2014] [Revised: 01/22/2015] [Accepted: 02/09/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a dynamic state of interactions among HBV, hepatocytes, and the host immune system. Natural history studies of chronic hepatitis B (CHB) infection have shown an association between active viral replication and adverse clinical outcomes such as cirrhosis and hepatocellular carcinoma. The goal of therapy for CHB is to improve quality of life and survival by preventing progression of the disease to cirrhosis, decompensation, end-stage liver disease, hepatocellular carcinoma (HCC) and death. This goal can be achieved if HBV replication is suppressed in a sustained manner. The accompanying reduction in histological activity of CHB lessens the risk of cirrhosis and of HCC, particularly in non-cirrhotic patients. However, CHB infection cannot be completely eradicated, due to the persistence of covalently closed circular DNA in the nucleus of infected hepatocytes, which may explain HBV reactivation. Moreover, the integration of the HBV genome into the host genome may favour oncogenesis, development of HCC and may also contribute to HBV reactivation.
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Affiliation(s)
- Francesco Paolo Russo
- Francesco Paolo Russo, Kryssia Rodríguez-Castro, Gastroenterology/Multiviseral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, 35128 PD Padua, Italy
| | - Kryssia Rodríguez-Castro
- Francesco Paolo Russo, Kryssia Rodríguez-Castro, Gastroenterology/Multiviseral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, 35128 PD Padua, Italy
| | - Laura Scribano
- Francesco Paolo Russo, Kryssia Rodríguez-Castro, Gastroenterology/Multiviseral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, 35128 PD Padua, Italy
| | - Giorgia Gottardo
- Francesco Paolo Russo, Kryssia Rodríguez-Castro, Gastroenterology/Multiviseral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, 35128 PD Padua, Italy
| | - Veronica Vanin
- Francesco Paolo Russo, Kryssia Rodríguez-Castro, Gastroenterology/Multiviseral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, 35128 PD Padua, Italy
| | - Fabio Farinati
- Francesco Paolo Russo, Kryssia Rodríguez-Castro, Gastroenterology/Multiviseral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, 35128 PD Padua, Italy
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19
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Goulis I, Karatapanis S, Akriviadis E, Deutsch M, Dalekos GN, Raptopoulou-Gigi M, Mimidis K, Germanidis G, Drakoulis C, Triantos C, Zintzaras E, Bakalos G, Papatheodoridis G. On-treatment prediction of sustained response to peginterferon alfa-2a for HBeAg-negative chronic hepatitis B patients. Liver Int 2015; 35:1540-8. [PMID: 25368957 DOI: 10.1111/liv.12725] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2014] [Accepted: 10/28/2014] [Indexed: 12/29/2022]
Abstract
BACKGROUND & AIMS We assessed predictors of response in HBeAg-negative chronic hepatitis B patients treated with peginterferon alfa-2a in routine clinical practice. METHODS Ninety-five HBeAg-negative patients received peginterferonalfa-2a for 48 weeks and were followed-up for 48 weeks post-treatment. Serum HBsAg and HBV DNA levels were monitored during and after therapy with valid commercial assays. Sustained response (SR) was defined as HBV DNA <2000 IU/ml at study week 96. RESULTS Twenty-two patients (23%) achieved SR and nine (9.5%) lost HBsAg. HBsAg decline was more profound in patients with SR. HBsAg decline ≥10% from baseline to week 24 was significantly associated with SR [81% (17/21) vs 37% (21/57); Odds ratio: 7.286 (2.162-24.552), P = 0.001]. The PARC rule (no decrease in HBsAg and <2 log drop in HBV DNA at week 12) was evaluated in a subset of 47 patients. Among eight patients who fulfilled the PARC rule, none achieved SR. Of the 39 patients who did not fulfil the PARC rule, 24 (62%) had HBsAg decline of ≥10% at week 24 (12 achieved SR) and 15 (38%) had HBsAg decline of <10% (1 achieved SR; negative predictive value: 93%). CONCLUSIONS In HBeAg-negative chronic hepatitis B patients treated with peginterferon alfa-2a, HBsAg decline >10% at 24 weeks is significantly associated with SR. The combination of the PARC rule and week 24 decline in HBsAg can identify almost two-thirds of patients who are unlikely to achieve SR. Clinicaltrials.gov identifier: NCT01283074.
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Affiliation(s)
- Ioannis Goulis
- 4th Department of Internal Medicine, Αristotle University of Thessaloniki Medical School, Hippokration General Hospital, Thessaloniki, Greece
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20
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Abstract
Chronic hepatitis B virus (HBV) infection is a global health problem, leading to cirrhosis, hepatocellular carcinoma (HCC) and liver-related deaths. Universal hepatitis B vaccination is the most cost-effective way to eradicate HBV infection with the remarkable reduction of chronic carriage, neonatal fulminant hepatitis and childhood HCC. The introduction of highly effective antiviral agents, including lamivudine, adefovir dipivoxil, entecavir, telbivudine, tenofovir disoproxil fumarate and pegylated interferons further improve short-, medium- and long-term outcomes of chronic HBV infection, such as ALT normalization, HBV DNA suppression, HBeAg seroconversion, HBsAg seroclearance, fibrosis regression, reduction of cirrhosis, HCC, liver-related deaths and the need for liver transplantation. Above all, sustained and profound viral suppression is the key to improve the clinical outcomes of chronic hepatitis B.
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Affiliation(s)
- Tung-Hung Su
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, 1 Chang-Te Street, Taipei 10002, Taiwan
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21
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Abstract
Hepatitis B virus (HBV) infection is a major cause of cirrhosis and hepatocellular carcinoma worldwide. On the basis of virus-host interactions, the natural history of HBV carriers can be divided into four chronological phases. In the first immune tolerance phase, HBV carriers are positive for hepatitis B e antigen (HBeAg) and have high HBV replication activity, normal ALT levels as well as minimal liver disease. Ample evidence has shown that patients in the immune tolerance phase have very low viral evolution and minimal risk of fibrosis progression. However, recent immunological studies argued that HBV-specific immune responses already exist in a proportion of immune-tolerant patients and the immune activities are comparable to those in the immune clearance phase. Regarding antiviral therapy, whether these immune-tolerant patients are indicated for treatment remains debated. Previous studies showed that HBeAg-positive patients with normal or near-normal ALT levels, who are assumed to be in the immune tolerance phase, have a lower HBeAg seroconversion rate receiving either pegylated interferon or nucleos(t)ide analogue treatment. The latest clinical trial focusing on-treatment response of immune-tolerant patients with tenofovir disoproxil fumarate-based therapy also confirmed the results. The HBeAg seroconversion rates are <5% at 4 years of treatment. Considering the minimal risk of disease progression and low treatment response rates in immune-tolerant patients, current antiviral therapy should not be recommended unless the patients have advanced liver fibrosis. In addition, novel agents targeting the HBV template known as covalently closed circular DNA and aiming to reduce or eliminate it are urgently required.
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Affiliation(s)
- T-C Tseng
- Division of Gastroenterology, Department of Internal Medicine, Taipei Tzuchi Hospital, The Buddhist Tzuchi Medical Foundation, Taiwan; School of Medicine, Tzu Chi University, Hualien, Taiwan
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Thio CL, Hawkins C. Hepatitis B Virus and Hepatitis Delta Virus. MANDELL, DOUGLAS, AND BENNETT'S PRINCIPLES AND PRACTICE OF INFECTIOUS DISEASES 2015:1815-1839.e7. [DOI: 10.1016/b978-1-4557-4801-3.00148-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Liu J, Tseng TC, Yang HI, Lee MH, Batrla-Utermann R, Jen CL, Lu SN, Wang LY, You SL, Chen PJ, Chen CJ, Kao JH. Predicting Hepatitis B Virus (HBV) Surface Antigen Seroclearance in HBV e Antigen-Negative Patients With Chronic Hepatitis B: External Validation of a Scoring System. J Infect Dis 2014; 211:1566-73. [DOI: 10.1093/infdis/jiu659] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2014] [Accepted: 11/12/2014] [Indexed: 01/14/2023] Open
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Seo Y, Yano Y. Short- and long-term outcome of interferon therapy for chronic hepatitis B infection. World J Gastroenterol 2014; 20:13284-13292. [PMID: 25309065 PMCID: PMC4188886 DOI: 10.3748/wjg.v20.i37.13284] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2013] [Revised: 01/25/2014] [Accepted: 06/26/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a serious clinical problem worldwide. Conventional interferon (IFN)-α has been approved for the treatment of chronic hepatitis B (CHB). Short-term studies have demonstrated that IFN-based therapy is moderately effective in inducing the loss of hepatitis e antigen (HBeAg) or seroconversion (30%-40%) in HBeAg-positive patients and also produces sustained HBV DNA suppression (20%-30%) in HBeAg-negative patients. Many studies have reported a correlation between the HBV genotype and response to IFN treatment. The highest response rate to IFN treatment was found in patients infected with HBV genotype A, followed by HBV genotypes B, C, and D. The long-term effect of IFN-α on CHB has not yet been elucidated. The ability of IFN-α treatment to prevent new cirrhosis, complications associated with cirrhosis, and development of hepatocellular carcinoma (HCC) is controversial. The beneficial effect of IFN-α treatment in reducing the development of HCC has mainly been observed in treatment responders who already have cirrhosis. These inconsistent findings may be attributed to the inevitable limitations of comparisons across studies, including differences in the baseline characteristics of the study and the moderate suppression of HBV replication by IFN-α relative to nucleoside/nucleos(t)ide analogs.
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25
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Azmi AN, Tan SS, Mohamed R. Practical approach in hepatitis B e antigen-negative individuals to identify treatment candidates. World J Gastroenterol 2014; 20:12045-12055. [PMID: 25232242 PMCID: PMC4161793 DOI: 10.3748/wjg.v20.i34.12045] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2013] [Revised: 01/17/2014] [Accepted: 04/09/2014] [Indexed: 02/06/2023] Open
Abstract
The natural history of chronic hepatitis B is characterized by different phases of infection, and patients may evolve from one phase to another or may revert to a previous phase. The hepatitis B e antigen (HBeAg)-negative form is the predominant infection worldwide, which consists of individuals with a range of viral replication and liver disease severity. Although alanine transaminase (ALT) remains the most accessible test available to clinicians for monitoring the liver disease status, further evaluations are required for some patients to assess if treatment is warranted. Guidance from practice guidelines together with thorough investigations and classifications of patients ensure recognition of who needs which level of care. This article aims to assist physicians in the assessment of HBeAg-negative individuals using liver biopsy or non-invasive tools such as hepatitis B s antigen quantification and transient elastography in addition to ALT and hepatitis B virus DNA, to identify who will remain stable, who will reactivate or at risk of disease progression hence will benefit from timely initiation of anti-viral therapy.
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27
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The natural course of chronic hepatitis B virus infection and its management. ADVANCES IN PHARMACOLOGY 2014; 67:247-91. [PMID: 23886003 DOI: 10.1016/b978-0-12-405880-4.00007-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Chronic infection with the hepatitis B virus (HBV) runs a long natural course during which underlying changes in liver histology can progress to cirrhosis and hepatic decompensation, as well as to hepatocellular carcinoma. Therapeutic intervention is currently aiming at suppression of HBV replication by applying a number of pharmacological agents. For an optimum use of available therapies, good knowledge of the natural course of chronic infection, as well as of the role played by several viral, host, and environmental factors, is mandatory. The larger part of this chapter deals with how to treat the various subsets of patients with chronic hepatitis B (CHB), using mainly three first-line drugs: pegylated interferon-α2a, entecavir, and tenofovir, administered either in finite courses or indefinitely. The frequency of virological, serological, biochemical, and histological responses in the various subsets of patients, both during and after stopping treatment, is reviewed. It is stressed that the application of the highly potent antivirals entecavir and tenofovir, with acceptable safety records and with a high barrier to HBV resistance, represents major progress in the treatment of CHB. Despite the hitherto important developments in the treatment of viral hepatitis B, clinical cure of chronic HBV infection with HBsAg loss is achievable only in a few treated patients while eradication of HBV infection appears unrealistic. Development of new pharmacological agents acting at multiple targets of the replicative cycle of HBV may achieve higher efficacy and even cure of CHB.
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28
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Calvaruso V, Craxì A. Regression of fibrosis after HBV antiviral therapy. Is cirrhosis reversible? Liver Int 2014; 34 Suppl 1:85-90. [PMID: 24373083 DOI: 10.1111/liv.12395] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Long-lasting HBV-DNA suppression is considered to be the best surrogate end-point of antiviral therapy in patients with hepatitis B virus (HBV) related chronic hepatitis or cirrhosis, and it is a prerequisite to prevent liver-related complications and improve survival. Treatment with oral antiviral drugs in patients with HBV cirrhosis is effective in restoring liver function and improving survival even in those with decompensated cirrhosis. These agents are generally well-tolerated for long-term treatment, and several evidences have demonstrated that they are able to reverse liver fibrosis and prevent the occurrence of HCC.
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Affiliation(s)
- Vincenza Calvaruso
- Gastroenterology and Hepatology Unit, University of Palermo, Palermo, Italy
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Vlachogiannakos J, Papatheodoridis GV. HBeAg-negative chronic hepatitis B: why do I treat my patients with pegylated interferon-alfa? Liver Int 2014; 34 Suppl 1:127-32. [PMID: 24373089 DOI: 10.1111/liv.12404] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
HBeAg-negative chronic hepatitis B (CHB) is the most frequent and aggressive type of CHB. The current therapeutic options for CHB include pegylated-interferon-alfa (PEG-IFNα) and nucleos(t)ide analogues (NAs). NAs are well-tolerated and safe agents that effectively inhibit viral replication, but they should be given as long-term, probably lifelong therapy, in particular in HBeAg-negative CHB. Thus, the finite, usually 48-week, duration is the main advantage of PEG-IFNα, providing sustained virological responses (SVR) off-therapy in approximately one-fourth of patients with HBeAg-negative CHB and often leading to HBsAg loss. However, the limited efficacy is the main factor restricting the use of PEG-IFNα in CHB and therefore identifying the predictors of response is of great clinical importance. No reliable baseline predictors of response to PEG-IFNα have been identified to date, but certain studies have identified satisfactory predictors of post-PEG-IFNα response using on-treatment serological markers, mostly HBsAg levels. In particular, in HBeAg-negative CHB patients mostly with genotype D a lack of decline in HBsAg levels and a lack of decrease in HBV DNA levels ≥2 log10 copies/ml at week-12 has a nearly 100% negative predictive value for SVR off-treatment and is now recommended as a stopping rule for early discontinuation of ineffective PEG-IFNα. Prolonging PEG-IFNα therapy to 96 weeks seems to provide higher SVR rates but the application and efficacy of this approach requires further study. The combination of PEG-IFNα with NAs, mostly lamivudine, has not resulted in any therapeutic benefit so far, but newer combined approaches with PEG-IFNα and NA(s) are currently under study.
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Affiliation(s)
- Jiannis Vlachogiannakos
- Academic Department of Gastroenterology, Athens University Medical School, Laiko General Hospital, Athens, Greece
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Degasperi E, Viganò M, Aghemo A, Lampertico P, Colombo M. PegIFN-α2a for the treatment of chronic hepatitis B and C: a 10-year history. Expert Rev Anti Infect Ther 2014; 11:459-74. [DOI: 10.1586/eri.13.37] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Abstract
Accurate prediction of the sustained virological response (SVR) to antiviral therapy against chronic hepatitis B (CHB) is still a crucial problem needing profound investigation. In recent years, quantification of hepatitis B surface antigen (HBsAg), a reliable predictor of SVR and an ideal endpoint of treatment, has attracted increasing attention. Serum HBsAg titer may reflect the level of intrahepatic hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) in most patients, and vary with natural phases of chronic HBV infection, genotypes and variants, antiviral therapy, and other related factors. Serum HBsAg <200 IU/mL or yearly reduction ≥0.5 log10IU/mL may be the optimum cut-off values for prediction of the chance of spontaneous seroclearance of HBsAg. Serum HBsAg <1,000 IU/mL with HBV DNA <2,000 IU/mL may identify most of the inactive HBV carriers from active HBeAg(-) hepatitis. Interferon-based therapy can lead to more significant HBsAg decline than therapy based on nucleoside and/or nucleotide analogues. Different patterns or kinetics of HBsAg decline during therapy are related to different probabilities of SVR. A low HBsAg level, <3,000 IU/mL at baseline, or HBsAg level, <1,500 IU/mL at week 12, or a rapid on-treatment HBsAg decline of ≥0.5 log10IU/mL at week 12, may predict higher probability of SVR. However these cut-off values must be further validated for larger cohort of patients across genotypes worldwide. Incorporation of serum HBsAg level, HBeAg status, HBV DNA load, HBV genotypes, and other related factors might help establish new concept of more practical "response-guided treatment (RGT)" rules for antiviral therapy.
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Affiliation(s)
- Yuecheng Yu
- Center of Liver Diseases, Bayi Hospital, Nanjing University of Chinese Traditional Medicine, Nanjing, 210002, Jiangsu, China.
| | - Jinlin Hou
- Hepatology Unit and Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong Province, China.
| | - Masao Omata
- Yamanashi Prefectural Hospital Organization, 1-1-1 Fujimi, Kofu, 400-8506, Yamanashi, Japan
| | - Yue Wang
- National Institute for Viral Disease Control and Prevention, Chinese Center for Diseases Control and Prevention, Beijing, China.
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
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Shah U. Infections of the Liver. DISEASES OF THE LIVER IN CHILDREN 2014. [PMCID: PMC7121352 DOI: 10.1007/978-1-4614-9005-0_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
The portal vein carries blood from the gastrointestinal tract to the liver and in so doing carries microbes as well. The liver may therefore be involved in infections with a myriad number of microbial organisms. While some of these infections most commonly occur in the immunocompromised host, others affect the immune competence. Hepatic infections may be primary in nature or secondary, as part of systemic or contagious disease. The purpose of this chapter is to provide a brief overview of the various infections of the liver in the pediatric patient.
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Abaalkhail F, Elsiesy H, AlOmair A, Alghamdi MY, Alalwan A, AlMasri N, Al-Hamoudi W. SASLT practice guidelines for the management of hepatitis B virus. Saudi J Gastroenterol 2014; 20:5-25. [PMID: 24496154 PMCID: PMC3952421 DOI: 10.4103/1319-3767.126311] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Affiliation(s)
- Faisal Abaalkhail
- Department of Liver and Small Bowel Transplantation, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Hussien Elsiesy
- Adult Transplant Hepatology, Organ Transplant Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Ahmed AlOmair
- Department of Medicine, Gastroenterology Unit, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Mohammed Y. Alghamdi
- Department of Gastroenterology, King Fahad Military Medical Complex, Dharan, Saudi Arabia
| | - Abduljaleel Alalwan
- Hepatobiliary Sciences and Liver Transplantation, King Abdulaziz Medical City, National Guard Health Affairs, Riyadh, Saudi Arabia
| | - Nasser AlMasri
- Department of Gastroenterology, Prince Sultan Medical Military City, Riyadh, Saudi Arabia
| | - Waleed Al-Hamoudi
- Adult Transplant Hepatology, Organ Transplant Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
- Gastroenterology Unit, College of Medicine, King Saud University, Riyadh, Saudi Arabia
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Abstract
Chronic hepatitis B virus (HBV) infection is a dynamic state of interactions between HBV, the hepatocytes, and the patient's immune system. HBV replication is the key driving force for the HBV-related immune clearance events that determine the outcomes. The extended immune clearance phase is associated with liver disease progression, including development of cirrhosis and hepatocellular carcinoma (HCC). Thus, the primary aim of therapy is to eliminate or permanently suppress HBV to reduce hepatitis activity and thereby reduce the risk or slow the progression of liver disease.
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Lampertico P, Viganò M, Cheroni C, Facchetti F, Invernizzi F, Valveri V, Soffredini R, Abrignani S, De Francesco R, Colombo M. IL28B polymorphisms predict interferon-related hepatitis B surface antigen seroclearance in genotype D hepatitis B e antigen-negative patients with chronic hepatitis B. Hepatology 2013; 57:890-6. [PMID: 22473858 DOI: 10.1002/hep.25749] [Citation(s) in RCA: 121] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2011] [Accepted: 03/22/2012] [Indexed: 12/12/2022]
Abstract
UNLABELLED Interleukin (IL)28B polymorphisms have been associated with interferon (IFN)-induced viral clearance in patients with chronic hepatitis C. Whether this is also true for patients with the difficult-to-cure hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) is unknown. One hundred and one HBeAg-negative patients (92% genotype D) with compensated CHB (84% males, 46 years; hepatitis B virus [HBV] DNA: 6.0 log cp/mL; alanine aminotransferase [ALT]: 136 IU/L; 42% with cirrhosis) were followed up for a median of 11 years (range, 1-17) after a median of 23 months (range, 10-48) of either standard or pegylated (Peg)-IFN-alpha therapy. A post-treatment response was defined as hepatitis B surface antigen (HBsAg) clearance with or without antibody to hepatitis B surface antigen (anti-HBs) seroconversion. The rs12979860 (C>T) genotype in the IL28B locus was assessed in serum samples by using Custom TaqMan SNP Genotyping Assays (Applied Biosystems, Carlsbad, CA). During a median of 11 years of post-treatment follow-up, 21 patients (21%) cleared serum HBsAg, including 15 who developed>10 IU/mL of anti-HBs titers. Forty-eight patients (47%) had CC genotype, 42 (42%) had CT, and 11 (11%) had TT, with the allelic frequency being 68% for C allele and 32% for T allele. The rate of serum HBsAg clearance was 29% (n=14) in CC compared to 13% (n=7) in non-CC, genotype carriers (P=0.039). Baseline HBV DNA levels<6 log cp/mL (odds ratio [OR], 11.9; 95% confidence interval [CI]: 2.8-50.6; P=0.001), ALT levels>136 IU/L (OR, 6.5; 95% CI: 1.8-22.5; P=0.003), duration of IFN (OR, 1.16; 95% CI: 1.02-1.31; P=0.021), and genotype CC (OR, 3.9; 95% CI: 1.1-13.2; P=0.025) independently predicted HBsAg clearance. CONCLUSIONS IL28B polymorphism is an additional predictor of off-therapy IFN-related HBsAg seroclearance to be used in the pretreatment stratification of HBeAg-negative patients chronically infected by genotype D of HBV.
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Affiliation(s)
- Pietro Lampertico
- Migliavacca Center for the Study of Liver Disease, First Division of Gastroenterology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milano, Italy.
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Kwon JH, Kim YS, Kim SG, Jang JW, Kim TH, Jung YK, Kwon OS. The Efficacy and Safety of Peginterferon-α-2a in Korean Patients with Chronic Hepatitis B: A Multicenter Study Conducted in a Real Clinical Setting. Gut Liver 2013; 7:197-205. [PMID: 23560156 PMCID: PMC3607774 DOI: 10.5009/gnl.2013.7.2.197] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2012] [Revised: 07/06/2012] [Accepted: 07/20/2012] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND/AIMS Genotype C is the principal type of hepatitis B virus (HBV) in Koreans and is associated with poor prognosis for peginterferon α-2a therapy. The efficacy of and compliance to peginterferon α-2a therapy were investigated in Koreans with hepatitis B in a real clinical setting. METHODS Hepatitis B patients treated with peginterferon α-2a from 2008 to 2011 at four university hospitals were consecutively enrolled. RESULTS Eighty-eight patients were enrolled; 67 were hepatitis B e antigen (HBeAg)-positive. The mean treatment period was 36.1±15.2 weeks. In 26.1% of patients, treatment was discontinued due to insufficient antiviral effects and adverse events. At 24 weeks after treatment, 10/42 (23.8%) HBeAg-positive patients achieved both HBV DNA suppression to <2,000 IU/mL and HBeAg loss/seroconversion. For HBeAg-negative patients, 10/13 (76.9%) achieved HBV DNA suppression to <2,000 IU/mL at 24 weeks after treatment. During the follow-up period, 15 (30.6%) of the 49 patients who achieved HBV DNA suppression to 2,000 IU/mL developed a breakthrough HBV DNA level of >2×10(6) IU/mL. CONCLUSIONS Peginterferon α-2a therapy in Koreans with hepatitis B in a real clinical setting resulted in a lower virologic response, as compared to Western individuals, but a favorable durability. There is a need to reduce the high rate of premature discontinuation compared to the controlled studies.
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Affiliation(s)
- Jung Hyun Kwon
- Department of Internal Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea College of Medicine, Incheon, Korea
| | - Young Seok Kim
- Department of Internal Medicine, Soonchunhyang University Bucheon Hospital and Digestive Disease Center and Research Institute, Soonchunhyang University College of Medicine, Bucheon, Korea
| | - Sang Gyune Kim
- Department of Internal Medicine, Soonchunhyang University Bucheon Hospital and Digestive Disease Center and Research Institute, Soonchunhyang University College of Medicine, Bucheon, Korea
| | - Jeong Won Jang
- Department of Internal Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea College of Medicine, Incheon, Korea
| | - Tae Hun Kim
- Department of Internal Medicine, Ewha Medical Research Institute, Ewha Womans University School of Medicine, Seoul, Korea
| | - Young Kul Jung
- Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University of Medicine and Science, Incheon, Korea
| | - Oh Sang Kwon
- Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University of Medicine and Science, Incheon, Korea
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Lampertico P, Viganò M, Colombo M. Why do I treat HBeAg-negative chronic hepatitis B patients with pegylated interferon? Liver Int 2013; 33 Suppl 1:157-63. [PMID: 23286860 DOI: 10.1111/liv.12064] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
Chronic hepatitis B (CHB) in serum HBeAg negative patients is a difficult to cure, progressive disease leading to end-stage liver disease and hepatocellular carcinoma. Currently, there are two different treatment strategies for such patients: a finite course of Pegylated interferon (PEG-IFN) or long-term administration of the more potent and less resistance-prone nucleot(s)ide analogues (NUC), i.e. entecavir and tenofovir. Although NUC may ensure persistent viral suppression by preventing disease progression in most patients, they require lifelong administration with the hypothetical disadvantages of cost, lack of long-term safety data and, most important, the null rates of HBsAg seroclearance. On the other hand, 1 year of PEG-IFN has the advantage of providing an immune-mediated control of hepatitis B virus (HBV) infection, with the possibility of achieving a sustained off-treatment response in 20% of the patients, ultimately leading to HBsAg loss in approximately 50% of these. However, these sustained response rates can be significantly increased by carefully selecting candidates for PEG-IFN therapy based upon baseline ALT and HBV DNA levels, viral genotype and IL28B polymorphisms, by extending PEG-IFN therapy beyond 48 weeks and, most importantly, by applying early on-treatment stopping rules based upon HBsAg kinetics. Overall, PEG-IFN is an ideal treatment strategy in selected patients with HBeAg-negative CHB, because of its well-recognized and predictable safety profile and a unique mechanism of antiviral activity leading to long-lasting immune control. Because of these features, new therapeutic trials based upon a combination of PEG-IFN and third generation NUC such as entecavir and tenofovir, in both naïve and NUC-exposed patients, are ongoing to further increase the rates of HBsAg seroclearance, which remains the 'ideal end-point' in all HBeAg-negative CHB subjects.
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Affiliation(s)
- Pietro Lampertico
- A.M. e A. Migliavacca Center for Study of Liver Disease, 1st Division of Gastroenterology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milano, Italy.
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Abstract
Chronic hepatitis B virus (HBV) infection is a dynamic state in which HBV replication is the key driving force of disease progression, resulting in the development of hepatic decompensation, cirrhosis and hepatocellular carcinoma (HCC). The primary aim of therapy is to eliminate or suppress HBV to reduce the activity of hepatitis thus reducing the risk of or slowing the progression of liver disease. Treatment with nucleos(t)ide analogues (Nuc) may result in rapid suppression of HBV replication with normalization of serum transaminases and restore liver function thus increasing survival in patients with hepatic decompensation. The long-term benefits of a finite course of interferon α (IFN) therapy include a sustained and cumulative response, as well as a reduction in the progression of fibrosis and in the development of cirrhosis and/or HCC. Long-term Nuc therapy may also result in histological improvement or reversal of advanced fibrosis and reduction in disease progression including the development of HCC. Hepatitis B surface antigen (HBsAg) seroclearance, a status close to a "cure", may also occur in patients with a sustained or maintained viral response, especially in those with IFN-based therapy. Pegylated IFN (PEG-IFN) and newer Nucs may have even better long-term outcomes because of improved efficacy and/or a low risk of drug resistance. However, treatment outcomes are still far from satisfactory. The development of more effective and safe but affordable anti-HBV agents/strategies is needed to further improve outcomes.
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Affiliation(s)
- Yun-Fan Liaw
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan.
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Asahina Y, Izumi N, Oketani M, Kumada H, Kurosaki M, Koike K, Suzuki F, Takikawa H, Tanaka A, Tanaka E, Tanaka Y, Tsubouchi H, Hayashi N, Hiramatsu N, Yotsuyanagi H. Guidelines for the management of hepatitis B virus infection. KANZO 2013; 54:402-472. [DOI: 10.2957/kanzo.54.402] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Lee D, Chung YH, Lee SH, Kim SE, Lee YS, Kim KM, Lim YS, Lee HC, Lee YS, Yu E. Effect of response to interferon-α therapy on the occurrence of hepatocellular carcinoma in patients with chronic hepatitis B. Dig Dis 2012; 30:568-73. [PMID: 23258096 DOI: 10.1159/000343068] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
OBJECTIVES The aim of this study was to examine whether interferon-α (IFN-α) therapy may reduce the occurrence of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) and to determine its effect based on responsiveness to IFN-α therapy. METHODS A total of 641 biopsy-proven CHB patients were treated with IFN-α2b. They were followed by biochemistry and/or imaging studies at 3- to 6-month intervals for a median period of 113 months (range 6-222). RESULTS HCC was detected in 22 patients and 5- and 10-year cumulative occurrence rates were 0.4 and 3.2%, respectively. In univariate analysis, age (p < 0.001), serum AFP levels (p < 0.001), and serum HBV-DNA levels (p = 0.002) at baseline were associated with HCC development. HCC occurred less frequently in biochemical responders at the end of treatment than in non-responders (p = 0.001). However, virologic response was not associated with HCC development. Multivariate analysis showed that poor biochemical response (p = 0.007) as well as older age (p = 0.018) and a higher serum AFP level (p < 0.001) remained independent predisposing factors of HCC development in CHB patients treated with IFN-α. CONCLUSION The results suggest that the biochemical but not virologic response to IFN-α therapy reduces independently the occurrence of HCC in patients with CHB.
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Affiliation(s)
- Danbi Lee
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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Karabay O, Tuna N, Esen S. Comparative efficacy of pegylated interferons α-2a and 2b in the treatment of HBeAg-negative chronic hepatitis B infection. Eur J Gastroenterol Hepatol 2012; 24:1296-1301. [PMID: 22825647 DOI: 10.1097/meg.0b013e328356eac2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
INTRODUCTION Interferons, pegylated interferons (PegIFN), and oral antivirals are used in the treatment of chronic hepatitis B (CHB) virus infection. The number of studies comparing the efficacy of PegIFNs in the treatment of HBe antigen-negative CHB is rather limited. In this trial, the efficacy of two PegIFN products used in the treatment of CHB is compared. METHODS Study data were obtained from 16 tertiary healthcare service centers located in various areas of Turkey. Data of patients who were consecutively treated with PegIFN α-2a or α-2b for CHB were recorded retrospectively. Hepatitis B virus DNA and liver enzymes were analyzed at the beginning of the treatment and during weeks 12, 24, 48, and 72. A P-value less than 0.05 was considered to be significant. RESULTS A total of 155 patients were enrolled in this trial. Two cases were excluded because of insufficient data. Among the remaining 153 patients, 81 (53%) patients were in the PegIFN α-2a group and 72 (47%) patients were in the α-2b group. Treatment success was found to be 17.2% for the PegIFN α-2a group and 18.0% for the PegIFN α-2b group (P>0.05). In terms of efficacy (weeks 24, 48, and 72), there were no significant differences between the groups (P>0.05). CONCLUSION According to our results, for HBe antigen-negative CHB cases, the response rate during the sixth month after the treatment with PegIFN was determined to be ∼17%. No difference was found between the efficacy rates of the two PegIFN products used in the treatment of HBe antigen-negative CHB.
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Affiliation(s)
- Oguz Karabay
- Department of Infectious Diseases and Clinical Microbiology, School of Medicine, University of Sakarya, Korucuk, Sakarya Campus, Turkey
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Rijckborst V, Ferenci P, Akdogan M, Pinarbasi B, ter Borg MJ, Simon K, Flisiak R, Akarca US, Raptopoulou-Gigi M, Verhey E, van Vuuren AJ, Boucher CA, Hansen BE, Janssen HLA. Long-term follow-up of hepatitis B e antigen-negative patients treated with peginterferon α-2a: progressive decrease in hepatitis B surface antigen in responders. Eur J Gastroenterol Hepatol 2012; 24:1012-1019. [PMID: 22668876 DOI: 10.1097/meg.0b013e3283557e23] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
OBJECTIVE Peginterferon (PEG-IFN) is considered as a first-line treatment option for hepatitis B e antigen (HBeAg)-negative chronic hepatitis B. We aimed to evaluate the long-term response to PEG-IFN in HBeAg-negative patients. METHODS All patients enrolled in the PARC study who completed the treatment phase were eligible for this long-term follow-up (LTFU) study. Patients received PEG-IFN α-2a (180 μg weekly) ± ribavirin (1000-1200 mg daily) for 48 weeks and had at least one additional LTFU visit after the initial follow-up period of 24 weeks (mean duration 2.1 ± 0.2 years). Retreated patients were considered nonresponders. RESULTS Of 117 patients who completed the treatment phase, 79 (68%) were included in this LTFU study. Among 19 patients with a combined response at 24 weeks after treatment [initial responders; hepatitis B virus DNA<10 000 copies/ml (<1714 IU/ml) and normal alanine aminotransferase], 12 (63%) sustained this response through LTFU. Three additional patients showed such a response at LTFU, resulting in a total of 15 (19%) combined responders at LTFU. A marked decrease in the serum hepatitis B surface antigen (HBsAg) levels was observed in initial responders, resulting in HBsAg clearance in 26% of the patients (6% of all LTFU participants). CONCLUSION About one-third of HBeAg-negative patients with a response to PEG-IFN at 24 weeks after treatment subsequently had a relapse during 2 years of follow-up. Despite the limited overall efficacy of PEG-IFN, patients responding to PEG-IFN treatment showed a marked decrease in serum HBsAg, resulting in a high rate of HBsAg clearance, which indicates the need for predictors of response to PEG-IFN in HBeAg-negative disease.
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Affiliation(s)
- Vincent Rijckborst
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
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Abstract
Hepatocellular carcinoma (HCC) is a challenging malignancy of global importance. It is associated with a high rate of mortality and its prevalence in the United States and in Western Europe is increasing. Cirrhosis is the strongest and the most common known risk factor for HCC, usually due to hepatitis C virus (HCV) and hepatitis B virus (HBV) infections. However, different lines of evidence identify in non-alcoholic fatty liver disease (NAFLD) a possible relevant risk factor for occurrence of HCC. Given the continuing increase in the prevalence of obesity and diabetes, the incidence of non-alcoholic steatohepatitis-related HCC may also be expected to increase, and a potential role of behavior treatment and/or insulin-sensitizing drugs can be envisaged. Vaccination against HBV is the most efficient primary prevention measure currently available to reduce the HCC incidence and mortality in high-incidence areas, while data on the role of interferon (IFN) and nucleos(t)ide analogues (NUC) are still controversial. The pooling of data from the literature suggests a slight preventive effect of antiviral therapy on HCC development in patients with HCV-related cirrhosis, but the preventive effect is limited to sustained virological responders.
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Affiliation(s)
- Giuseppe Cabibbo
- Sezione di Gastroenterologia, DIBIMIS, University of Palermo, Palermo, Italy
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Buti M, García-Samaniego J, Prieto M, Rodríguez M, Sánchez-Tapias JM, Suárez E, Esteban R. Documento de consenso de la AEEH sobre el tratamiento de la infección por el virus de la hepatitis B (2012). GASTROENTEROLOGIA Y HEPATOLOGIA 2012; 35:512-28. [PMID: 22749508 DOI: 10.1016/j.gastrohep.2012.04.006] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/22/2012] [Accepted: 04/23/2012] [Indexed: 12/13/2022]
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Long-term efficacy of interferon therapy in patients with chronic hepatitis B virus infection in Japan. J Gastroenterol 2012; 47:814-22. [PMID: 22361865 DOI: 10.1007/s00535-012-0548-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2011] [Accepted: 01/05/2012] [Indexed: 02/04/2023]
Abstract
BACKGROUND Few studies have investigated the long-term effects of interferon (IFN) therapy for chronic hepatitis B (CHB). In this retrospective study, we investigated the efficacy of and predictors of response to IFN therapy in CHB patients. METHODS We analyzed data for 615 Japanese CHB patients (hepatitis B e antigen [HBeAg]-positive 414, HBeAg-negative 201) treated with IFN, and conducted follow up for a median duration of 8.1 years (range 0.5-23.2). Responders were defined as patients who showed continuously normalized alanine transaminase (ALT) levels, HBeAg clearance, and low hepatitis B virus (HBV) DNA levels at 6 months post-treatment or for a span of more than 6 months until each test point at 1, 3, 5, and 10 years. RESULTS The IFN response rates of all patients were 21, 18, 21, 23, and 25% at 6 months and 1, 3, 5, and 10 years, respectively. On multivariate analysis, significant determinants of the outcome of IFN therapy were as follows: at 6 months and 1 year, young age, low HBV DNA levels, and long duration of treatment; at 3 years, long duration of treatment, young age, and high level of albumin; at 5 years, high level of albumin, female, and pretreated with IFN; and at 10 years, HBeAg-negative. Sixty-nine of the 615 patients (11%) achieved seroclearance of hepatitis B surface antigen (HBsAg). On multivariate analysis, age ≥30 years, HBV genotype A, and male were all independent factors predicting the achievement of HBsAg seroclearance. CONCLUSION HBeAg, HBV DNA level, age, sex, albumin, duration of treatment, pretreatment with IFN, and HBV genotype were important factors in determining long-term response to IFN therapy.
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Parusu T, Ponneri V. RP-HPLC method for simultaneous determination of atenolol and indapamide in pharmaceutical dosage forms, human blood and milk. ACTA ACUST UNITED AC 2012. [DOI: 10.5155/eurjchem.3.2.138-142.537] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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Abstract
UNLABELLED The guideline on the management of chronic hepatitis B (CHB) was first developed in 2004 and revised in 2007 by the Korean Association for the Study of the Liver (KASL). Since then there have been many developments, including the introduction of new antiviral agents and the publications of many novel research results from both Korea and other countries. In particular, a large amount of knowledge on antiviral resistance--which is a serious issue in Korea--has accumulated, which has led to new strategies being suggested. This prompted the new guideline discussed herein to be developed based on recent evidence and expert opinion. TARGET POPULATION The main targets of this guideline comprise patients who are newly diagnosed with CHB and those who are followed or treated for known CHB. This guideline is also intended to provide guidance for the management of patients under the following special circumstances: malignancy, transplantation, dialysis, coinfection with other viruses, pregnancy, and children.
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MESH Headings
- Acute Disease
- Adolescent
- Adult
- Aged
- Alanine Transaminase/blood
- Antiviral Agents/therapeutic use
- Asian People
- Aspartate Aminotransferases/blood
- Carcinoma, Hepatocellular/diagnosis
- Carcinoma, Hepatocellular/etiology
- Child
- Child, Preschool
- Coinfection/drug therapy
- DNA, Viral/blood
- Drug Resistance, Viral
- Drug Therapy, Combination
- Female
- Hepatitis B Surface Antigens/blood
- Hepatitis B e Antigens/blood
- Hepatitis B virus/genetics
- Hepatitis B, Chronic/complications
- Hepatitis B, Chronic/diagnosis
- Hepatitis B, Chronic/drug therapy
- Humans
- Immunosuppression Therapy
- Infectious Disease Transmission, Vertical/prevention & control
- Liver/pathology
- Liver/physiology
- Liver Cirrhosis/physiopathology
- Liver Neoplasms/diagnosis
- Liver Neoplasms/etiology
- Liver Transplantation
- Male
- Middle Aged
- Pregnancy
- Renal Dialysis
- Republic of Korea
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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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50
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Fan HB, Guo YB, Zhu YF, Chen AS, Zhou MX, Li Z, Xu LT, Ma XJ, Yan FM. Hepatitis B Virus Genotype B and High Expression of Interferon Alpha Receptor β Subunit are Associated With Better Response to Pegylated Interferon Alpha 2a in Chinese Patients With Chronic Hepatitis B Infection. HEPATITIS MONTHLY 2012; 12:333-8. [PMID: 22783345 PMCID: PMC3389359 DOI: 10.5812/hepatmon.6173] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/22/2012] [Revised: 04/14/2012] [Accepted: 04/24/2012] [Indexed: 12/11/2022]
Abstract
BACKGROUND Hepatitis B virus (HBV) is one of leading causes of various hepatic diseases including acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Hundreds of million people worldwide are infected by HBV, chronically. OBJECTIVES This study in conducted to investigate the influence of Hepatitis B virus (HBV) genotypes and type I IFN-αreceptor β subunit (IFNAR2) expression in liver on response to treatment with pegylated IFN-α-2a (Peg-IFN-α-2a) for chronic hepatitis B infection. PATIENTS AND METHODS In this study, 65 eligible patients with chronic hepatitis B disease were enrolled. HBV genotypes of these patients were analyzed by using PCR-RFLP of the surface gene of HBV. The expression of IFNAR2 in the liver was immune histochemically investigated using anti-IFNAR2 antibody. All immune histochemical slides were read semi-quantitatively by image analysis. Chronic hepatitis B patients were treated with Peg-IFN-α2a therapy for a 48-week period and followed up for 24 weeks. Baseline characteristics and sustained viral response (SVR) to Peg-IFN-α-2a therapy were evaluated. RESULTS 55 % of patients exhibited HBV genotype B and 31.7 % patients exhibited HBV genotypes C infections. After treatment with Peg-IFN-α-2a, SVR was achieved in 66.7 % of patients with HBV genotype B and in 26.3 % of patients with HBV genotype C (P = 0.009). Semiquantitative and the image analysis indicated by gray level values revealed a higher IFNAR2 expression in the group with severe inflammation (P < 0.001). Patients' high IFNAR2 protein expression had a significant impact on SVR to Peg-IFN-α-2a therapy (P = 0.028). CONCLUSIONS HBV genotype B and high expression of IFNAR2 in the liver of chronic hepatitis B patients are closely associated with better response to Peg-IFN-α-2a therapy in chronic hepatitis B disease.
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Affiliation(s)
- He Bin Fan
- Department of Infectious Disease, The People’s Liberation Army 161 Hospital, Wuhan, China
- Corresponding author: He-Bin Fan, Department of Infectious Disease, The People’s Liberation Army 161 Hospital, Wuhan, 430010, Hubei, China. Tel.: +86-2750169074, Fax: +86-2750169007, E-mail:
| | - Ya Bin Guo
- Department of Infectious Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - You Fu Zhu
- Department of Infectious Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - An Shen Chen
- Department of Infectious Disease, The People’s Liberation Army 161 Hospital, Wuhan, China
| | - Mu Xiu Zhou
- Department of Pathology, The People’s Liberation Army 161 Hospital, Wuhan, China
| | - Zhi Li
- Department of Infectious Disease, The People’s Liberation Army 161 Hospital, Wuhan, China
| | - Li Tong Xu
- Department of Infectious Disease, The People’s Liberation Army 161 Hospital, Wuhan, China
| | - Xiao Ju Ma
- Department of Infectious Disease, The People’s Liberation Army 161 Hospital, Wuhan, China
| | - Fu Ming Yan
- Department of Infectious Disease, The People’s Liberation Army 161 Hospital, Wuhan, China
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