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Hardtke S, Yurdaydin C, Caruntu FA, Curescu MG, Yalcin K, Akarca US, Gürel S, Zeuzem S, Erhardt A, Lüth S, Papatheodoridis GV, Port K, Manns MP, Cornberg M, Kahlhöfer J, Wedemeyer H. Frequency, Severity and Impact of Pegylated Interferon Alpha-Associated Flares in Hepatitis D Infection. J Viral Hepat 2025; 32:e70022. [PMID: 40087915 PMCID: PMC11909584 DOI: 10.1111/jvh.70022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 01/13/2025] [Accepted: 02/22/2025] [Indexed: 03/17/2025]
Abstract
We analysed the frequency, severity and impact of hepatitis flares in a large Phase 2 study investigating pegylated interferon-alfa-2a (PEG-IFNa) for the treatment of hepatitis D. In the HIDIT-II study, 120 patients were treated for 96 weeks with PEG-IFNa (180 μg weekly) in combination with tenofovir disoproxil fumarate (TDF, 300 mg once daily) or placebo. Hepatitis flares were defined as ALT increases above 10 times the upper limit of normal or increases of more than 2.5-fold above baseline or nadir values. ALT flares occurred in 28 patients (23%) during treatment (< 96) and in 14 patients post-treatment until follow-up Week 24. There were no differences in the flare frequency between the two treatment arms (12 PEG-IFNa + placebo vs. 16 PEG-IFNa + TDF). The frequency of ALT increases did not differ between cirrhotic and noncirrhotic patients. None of the patients with cirrhosis experienced liver decompensation during or after a flare. Fifty-four per cent of the patients with ALT flare experienced a decrease in HDV RNA (> 1 log10 cop/ml) during subsequent study visits. Mean ALT levels early during treatment were higher in patients with HBsAg loss at follow-up Week 24. More than a third of hepatitis D patients undergoing PEG-IFNa therapy may experience ALT flares during or after treatment. ALT flares in this study posed no obvious safety risk to patients and should not lead to premature withdrawal from treatment. If ALT flares may be beneficial in single patients requires further investigation. Clinical Trial Registration: NCT00932971, EudraCT 2008-005560-13.
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Affiliation(s)
- Svenja Hardtke
- Department of Gastroenterology, Hepatology, Infectious Diseases, and EndocrinologyHannover Medical SchoolHannoverGermany
- German Center for Infectious Disease Research (DZIF)HepNet Study‐House/German Liver FoundationHannoverGermany
- University Hospital Hamburg EppendorfInstitute for Infection Research and Vaccine DevelopmentHamburgGermany
| | - Cihan Yurdaydin
- Department of GastroenterologyAnkara University Medical SchoolAnkaraTurkey
- Department of Gastroenterology & HepatologyKoc University Medical SchoolIstanbulTurkey
| | - Florin A. Caruntu
- Institutul de Boli InfectioaseBucharestRomania
- D‐SOLVE Consortium, an EU Horizon Europe Funded Project (No 101057917)HannoverGermany
| | | | | | | | | | - Stefan Zeuzem
- Department of MedicineUniversity Hospital, Goethe‐UniversityFrankfurtGermany
| | - Andreas Erhardt
- Heinrich Heine UniversityDüsseldorfGermany
- Petrus HospitalWuppertalGermany
| | - Stefan Lüth
- Department of Gastroenterology, Diabetology and HepatologyUniversity Hospital Brandenburg, Medical School (Theodor Fontane)BrandenburgGermany
- Health Sciences, Brandenburg University of Technology Cottbus—Senftenberg, the Brandenburg Medical School Theodor Fontane and the University of PotsdamPotsdamGermany
| | - George V. Papatheodoridis
- First Department of GastroenterologyMedical School, National and Kapodistrian University of Athens, General Hospital of Athens “Laiko”AthensGreece
| | - Kerstin Port
- Department of Gastroenterology, Hepatology, Infectious Diseases, and EndocrinologyHannover Medical SchoolHannoverGermany
| | - Michael P. Manns
- Department of Gastroenterology, Hepatology, Infectious Diseases, and EndocrinologyHannover Medical SchoolHannoverGermany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology, Infectious Diseases, and EndocrinologyHannover Medical SchoolHannoverGermany
- German Center for Infectious Disease Research (DZIF)HepNet Study‐House/German Liver FoundationHannoverGermany
- D‐SOLVE Consortium, an EU Horizon Europe Funded Project (No 101057917)HannoverGermany
- German Center for Infectious Disease Research (DZIF); Partnersite Hannover—BraunschweigHannoverGermany
- Cluster of Excellence RESIST (EXC 2155)Hannover Medical SchoolHannoverGermany
| | - Julia Kahlhöfer
- Department of Gastroenterology, Hepatology, Infectious Diseases, and EndocrinologyHannover Medical SchoolHannoverGermany
- German Center for Infectious Disease Research (DZIF)HepNet Study‐House/German Liver FoundationHannoverGermany
- D‐SOLVE Consortium, an EU Horizon Europe Funded Project (No 101057917)HannoverGermany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology, Infectious Diseases, and EndocrinologyHannover Medical SchoolHannoverGermany
- German Center for Infectious Disease Research (DZIF)HepNet Study‐House/German Liver FoundationHannoverGermany
- D‐SOLVE Consortium, an EU Horizon Europe Funded Project (No 101057917)HannoverGermany
- German Center for Infectious Disease Research (DZIF); Partnersite Hannover—BraunschweigHannoverGermany
- Cluster of Excellence RESIST (EXC 2155)Hannover Medical SchoolHannoverGermany
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Lei Z, Wang L, Gao H, Guo S, Kang X, Yuan J, Lv Z, Jiang Y, Yi J, Chen Z, Wang G. Mechanisms underlying the compromised clinical efficacy of interferon in clearing HBV. Virol J 2024; 21:314. [PMID: 39633459 PMCID: PMC11619119 DOI: 10.1186/s12985-024-02589-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Accepted: 11/26/2024] [Indexed: 12/07/2024] Open
Abstract
Hepatitis B virus (HBV) is a hepatotropic DNA virus that can cause acute or chronic hepatitis, representing a significant global health concern. By 2019, approximately 296 million individuals were chronically infected with HBV, with 1.5 million new cases annually and 820,000 deaths due to HBV-related cirrhosis and liver cancer. Current treatments for chronic hepatitis B include nucleotide analogs (NAs) and interferons (IFNs), particularly IFN-α. NAs, such as entecavir and tenofovir, inhibit viral reverse transcription, while IFN-α exerts antiviral effects by directly suppressing viral replication, modulating viral genome epigenetics, degrading cccDNA, and activating immune responses. Despite its potential, IFN-α shows limited clinical efficacy, partly due to HBV's interference with the IFN signaling pathway. HBV encodes proteins like HBc, Pol, HBsAg, and HBx that disrupt IFN-α function. For example, HBV Pol inhibits STAT1 phosphorylation, HBsAg suppresses STAT3 phosphorylation, and HBx interferes with IFN-α efficacy through multiple mechanisms. Additionally, HBV downregulates key genes in the IFN signaling pathway, further diminishing IFN-α's antiviral effects. Understanding these interactions is crucial for improving IFN-α-based therapies. Future research may focus on overcoming HBV resistance by targeting viral proteins or optimizing IFN-α delivery. In summary, HBV's ability to resist IFN-α limits its therapeutic effectiveness, highlighting the need for new strategies to enhance treatment outcomes.
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Affiliation(s)
- Zhuoyan Lei
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, 8 Shuren St, Gongshu District, Hangzhou, 310015, Zhejiang Province, China
| | - Luye Wang
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, 8 Shuren St, Gongshu District, Hangzhou, 310015, Zhejiang Province, China
| | - Hanlin Gao
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, 8 Shuren St, Gongshu District, Hangzhou, 310015, Zhejiang Province, China
| | - Shubian Guo
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, 8 Shuren St, Gongshu District, Hangzhou, 310015, Zhejiang Province, China
| | - Xinjian Kang
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, 8 Shuren St, Gongshu District, Hangzhou, 310015, Zhejiang Province, China
| | - Jiajun Yuan
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, 8 Shuren St, Gongshu District, Hangzhou, 310015, Zhejiang Province, China
| | - Ziying Lv
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, 8 Shuren St, Gongshu District, Hangzhou, 310015, Zhejiang Province, China
| | - Yuxin Jiang
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, 8 Shuren St, Gongshu District, Hangzhou, 310015, Zhejiang Province, China
| | - Jinping Yi
- Department of Clinical Laboratory, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Zhi Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University, Hangzhou, China
| | - Gang Wang
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, 8 Shuren St, Gongshu District, Hangzhou, 310015, Zhejiang Province, China.
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Crow MK, Olferiev M, Kirou KA. Standing on Shoulders: Interferon Research From Viral Interference to Lupus Pathogenesis and Treatment. Arthritis Rheumatol 2024; 76:1002-1012. [PMID: 38500017 DOI: 10.1002/art.42849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 01/24/2024] [Accepted: 02/29/2024] [Indexed: 03/20/2024]
Abstract
The discovery of interferon in the 1950s represents much more than the identification of the first cytokine and the key mediator of antiviral host defense. Defining the molecular nature and complexity of the type I interferon family, as well as its inducers and molecular mechanisms of action, was the work of investigators working at the highest level and producing insights of great consequence. Current knowledge of receptor-ligand interactions, cell signaling, and transcriptional regulation derives from studies of type I interferon. It is on the shoulders of the giants who produced that knowledge that others stand and have revealed critical mechanisms of the pathogenesis of systemic lupus erythematosus and other autoimmune diseases. The design of novel therapeutics is informed by the advances in investigation of type I interferon, with the potential for important impact on patient management.
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Affiliation(s)
- Mary K Crow
- Mary Kirkland Center for Lupus Research, Hospital for Special Surgery and Weill Cornell Medicine, New York City, New York
| | - Mikhail Olferiev
- Mary Kirkland Center for Lupus Research, Hospital for Special Surgery and Weill Cornell Medicine, New York City, New York
| | - Kyriakos A Kirou
- Mary Kirkland Center for Lupus Research, Hospital for Special Surgery and Weill Cornell Medicine, New York City, New York
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Jachs M, Panzer M, Hartl L, Schwarz M, Balcar L, Camp JV, Munda P, Mandorfer M, Trauner M, Aberle SW, Zoller H, Reiberger T, Ferenci P. Long-term follow-up of patients discontinuing bulevirtide treatment upon long-term HDV-RNA suppression. JHEP Rep 2023; 5:100751. [PMID: 37360907 PMCID: PMC10285645 DOI: 10.1016/j.jhepr.2023.100751] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 03/17/2023] [Indexed: 06/28/2023] Open
Abstract
BACKGROUND & AIMS Bulevirtide (BLV) is a novel antiviral drug licensed for the treatment of chronic hepatitis D. Data on the safety and efficacy of stopping BLV therapy upon long-term HDV-RNA suppression are scarce. METHODS A total of seven patients (age, 31-68 years, four with cirrhosis) included in a prospective Austrian HDV registry discontinued BLV treatment (duration, 46-141 weeks) upon long-term HDV suppression (HDV-RNA negativity, 12-69 weeks). Pegylated interferon-ɑ2a was used in combination with BLV in two patients. HDV-RNA, alanine aminotransferase, and quantitative HBsAg levels were closely monitored during treatment-free follow-up. RESULTS The seven patients were followed up for 14 to 112 weeks. Six patients completed ≥24 weeks of follow-up. HDV-RNA became detectable again in three patients within 24 weeks, whereas one additional patient showed an HDV-RNA relapse after almost 1 year. All patients who relapsed at any point had undergone BLV monotherapy. Meanwhile, HDV-RNA remained undetectable in two patients who were treated with BLV + pegylated interferon-ɑ2a. Only one patient showed significant alanine aminotransferase increases within 24 weeks of follow-up. BLV was reintroduced in three patients after 13-62 BLV-free weeks and was well tolerated, and all patients achieved virologic response again. CONCLUSIONS BLV discontinuation upon long-term HDV-RNA suppression seems safe. Retreatment with BLV was effective in case of virologic relapse. These findings are within a limited number of patients, and future studies are needed to define stopping rules and further investigate the safety of stopping BLV. IMPACT AND IMPLICATIONS Limited data exist on stopping bulevirtide (BLV) treatment in patients who achieve long-term HDV-RNA suppression. In a small cohort of seven Austrian patients discontinuing BLV therapy, HDV-RNA relapses were observed in four patients during long-term follow-up, whereas significant alanine aminotransferase increases were recorded in only one. Retreatment with BLV was effective in relapsers. The safety and efficacy of stopping BLV needs to be further studied in larger cohorts.
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Affiliation(s)
- Mathias Jachs
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Rare Liver Disease (RALID) Center of the European Reference Network for Rare Hepatological Diseases (ERN RARE-LIVER), Medical University Vienna, Vienna, Austria
| | - Marlene Panzer
- Department of Medicine I and Christian Doppler Laboratory on Iron and Phosphate Biology, Medical University of Innsbruck, Innsbruck, Austria
| | - Lukas Hartl
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Rare Liver Disease (RALID) Center of the European Reference Network for Rare Hepatological Diseases (ERN RARE-LIVER), Medical University Vienna, Vienna, Austria
| | - Michael Schwarz
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Rare Liver Disease (RALID) Center of the European Reference Network for Rare Hepatological Diseases (ERN RARE-LIVER), Medical University Vienna, Vienna, Austria
| | - Lorenz Balcar
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Rare Liver Disease (RALID) Center of the European Reference Network for Rare Hepatological Diseases (ERN RARE-LIVER), Medical University Vienna, Vienna, Austria
| | - Jeremy V. Camp
- Center for Virology, Medical University of Vienna, Vienna, Austria
| | - Petra Munda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Rare Liver Disease (RALID) Center of the European Reference Network for Rare Hepatological Diseases (ERN RARE-LIVER), Medical University Vienna, Vienna, Austria
| | - Mattias Mandorfer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Rare Liver Disease (RALID) Center of the European Reference Network for Rare Hepatological Diseases (ERN RARE-LIVER), Medical University Vienna, Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Rare Liver Disease (RALID) Center of the European Reference Network for Rare Hepatological Diseases (ERN RARE-LIVER), Medical University Vienna, Vienna, Austria
| | | | - Heinz Zoller
- Department of Medicine I and Christian Doppler Laboratory on Iron and Phosphate Biology, Medical University of Innsbruck, Innsbruck, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Rare Liver Disease (RALID) Center of the European Reference Network for Rare Hepatological Diseases (ERN RARE-LIVER), Medical University Vienna, Vienna, Austria
| | - Peter Ferenci
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
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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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Lin YC, Chen YJ, Lee SW, Lee TY, Chen YH, Huang WN, Yang SS, Chen YM. Long-Term Safety in HBsAg-Negative, HBcAb-Positive Patients with Rheumatic Diseases Receiving Maintained Steroid Therapy after Pulse Therapy. J Clin Med 2021; 10:3296. [PMID: 34362079 PMCID: PMC8347429 DOI: 10.3390/jcm10153296] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 07/18/2021] [Accepted: 07/22/2021] [Indexed: 12/20/2022] Open
Abstract
UNLABELLED The risk of hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg)-negative, antibody to hepatitis B core antigen (anti-HBc)-positive patients after glucocorticoid (GC) pulse therapy remains unclear. AIMS Our study aimed to examine the safety of GC pulse therapy in HBsAg-negative, anti-HBc-positive rheumatic patients. METHODS Medical records of HBsAg-negative, anti-HBc-positive patients receiving GC pulse therapy to treat rheumatic diseases were reviewed. The primary outcome was HBV-associated hepatitis occurring within the first year after GC pulse therapy; the secondary outcome was HBsAg seroreversion occurring during the follow-up period. RESULTS We identified 5222 HBsAg-negative, anti-HBc-positive patients with rheumatic diseases who had attended Taichung Veterans General Hospital from October 2006 to December 2018. A total of 689 patients had received GC pulse therapy, with 424 patients being analyzed. Hepatitis was noted in 28 patients (6.6%) within the first year after GC pulse therapy, but none had been diagnosed as HBV-associated hepatitis. Three patients (0.7%) later developed HBsAg seroreversion, with a median interval of 97 months from the first episode of GC pulse therapy. These cases concurrently had maintained high dose oral prednisolone (≥20 mg prednisolone daily for over 4 weeks). CONCLUSIONS Amongst the HBsAg-negative, anti-HBc-positive rheumatic patients treated with GC pulse therapy, the risk of HBV-associated hepatitis within the first year was low. HBsAg seroreversion may have developed in the later stage, but only in those patients who had maintained high-dose oral steroid.
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Affiliation(s)
- Ying-Cheng Lin
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan; (Y.-C.L.); (S.-W.L.); (T.-Y.L.)
| | - Yen-Ju Chen
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan;
- Department of Medical Research, Taichung Veterans General Hospital, Taichung 40705, Taiwan
- Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan; (Y.-H.C.); (W.-N.H.)
| | - Shou-Wu Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan; (Y.-C.L.); (S.-W.L.); (T.-Y.L.)
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
| | - Teng-Yu Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan; (Y.-C.L.); (S.-W.L.); (T.-Y.L.)
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
| | - Yi-Hsing Chen
- Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan; (Y.-H.C.); (W.-N.H.)
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
| | - Wen-Nan Huang
- Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan; (Y.-H.C.); (W.-N.H.)
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
| | - Sheng-Shun Yang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan; (Y.-C.L.); (S.-W.L.); (T.-Y.L.)
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
- Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung 40227, Taiwan
- Program in Translational Medicine, National Chung Hsing University, Taichung 40227, Taiwan
- Institute of Biomedical Sciences, National Chung Hsing University, Taichung 40227, Taiwan
| | - Yi-Ming Chen
- Department of Medical Research, Taichung Veterans General Hospital, Taichung 40705, Taiwan
- Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan; (Y.-H.C.); (W.-N.H.)
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
- Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung 40227, Taiwan
- Program in Translational Medicine, National Chung Hsing University, Taichung 40227, Taiwan
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Jeong W, Choe JY, Song BC, Lee CK, Cha HS, Ghang B, Kim J. Effect of Low-Dose Corticosteroid Use on HBV Reactivation in HBsAg-positive Rheumatoid Arthritis Patients. Open Rheumatol J 2021. [DOI: 10.2174/1874312902115010039] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Background:
It is well known that the use of corticosteroids (CS) results in increased viral replication and elevated alanine aminotransferase in hepatitis B virus (HBV) patients. However, only a few studies have investigated the effect of low-dose CS on HBV reactivation. In addition, there are few studies on the effects of synthetic disease-modifying anti-rheumatic drugs on HBV reactivation.
Objective:
We investigated the reactivation of HBV in rheumatoid arthritis (RA) patients treated with long-term low-dose corticosteroids. In addition, we analyzed factors affecting HBV reactivation, including disease-modifying anti-rheumatic drugs.
Methods:
We retrospectively reviewed medical records and analyzed the incidence of HBV reactivation in RA patients who were hepatitis B surface antigen (HBsAg) positive and who were receiving ≤10 mg of prednisolone over 4 weeks. Logistic regression analysis was performed to investigate the factors that increase the risk of HBV reactivation.
Results:
A total of 141 patients were included in the study, out of which 24 (17.0%) patients had HBV reactivation. The administration of low-dose corticosteroids did not affect HBV reactivation in HBsAg-positive RA patients (odds ratio: 0.807, 95% confidence interval: 0.143–4.546, p = 0.808), nor did the duration of corticosteroid administration, average daily corticosteroid dose, and cumulative corticosteroid dose. Administration of leflunomide was found to significantly increase the risk of HBV reactivation (odds ratio: 3.851, 95% confidence interval: 1.026–14.459, p = 0.046).
Conclusion:
The administration of low-dose corticosteroids did not affect the rate of HBV reactivation, suggesting that it can be used safely. Leflunomide may increase the risk of HBV reactivation; therefore, HBV patients should be carefully monitored when receiving this drug.
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Jeyaraman M, Muthu S, Bapat A, Jain R, Sushmitha E, Gulati A, Channaiah Anudeep T, Dilip SJ, Jha NK, Kumar D, Kesari KK, Ojha S, Dholpuria S, Gupta G, Dureja H, Chellappan DK, Singh SK, Dua K, Jha SK. Bracing NK cell based therapy to relegate pulmonary inflammation in COVID-19. Heliyon 2021; 7:e07635. [PMID: 34312598 PMCID: PMC8294777 DOI: 10.1016/j.heliyon.2021.e07635] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 04/05/2021] [Accepted: 07/19/2021] [Indexed: 02/07/2023] Open
Abstract
The contagiosity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has startled mankind and has brought our lives to a standstill. The treatment focused mainly on repurposed immunomodulatory and antiviral agents along with the availability of a few vaccines for prophylaxis to vanquish COVID-19. This seemingly mandates a deeper understanding of the disease pathogenesis. This necessitates a plausible extrapolation of cell-based therapy to COVID-19 and is regarded equivalently significant. Recently, correlative pieces of clinical evidence reported a robust decline in lymphocyte count in severe COVID-19 patients that suggest dysregulated immune responses as a key element contributing to the pathophysiological alterations. The large granular lymphocytes also known as natural killer (NK) cells play a heterogeneous role in biological functioning wherein their frontline action defends the body against a wide array of infections and tumors. They prominently play a critical role in viral clearance and executing immuno-modulatory activities. Accumulated clinical evidence demonstrate a decrease in the number of NK cells in circulation with or without phenotypical exhaustion. These plausibly contribute to the progression of pulmonary inflammation in COVID-19 pneumonia and result in acute lung injury. In this review, we have outlined the present understanding of the immunological response of NK cells in COVID-19 infection. We have also discussed the possible use of these powerful biological cells as a therapeutic agent in view of preventing immunological harms of SARS-CoV-2 and the current challenges in advocating NK cell therapy for the same.
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Affiliation(s)
- Madhan Jeyaraman
- Department of Orthopedics, School of Medical Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh, India
| | - Sathish Muthu
- Department of Orthopedics, Government Medical College and Hospital, Dindigul, Tamil Nadu, India
| | - Asawari Bapat
- Quality and Regulatory Affairs, Infohealth FZE, United Arab Emirates
| | - Rashmi Jain
- School of Medical Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh, India
| | - E.S. Sushmitha
- Department of Dermatology, Raja Rajeswari Medical College & Hospital, Bengaluru, Karnataka
| | - Arun Gulati
- Department of Orthopedics, Kalpana Chawla Government Medical College & Hospital, Karnal, Haryana, India
| | - Talagavadi Channaiah Anudeep
- Department of Plastic Surgery, Topiwala National Medical College and BYL Nair Ch. Hospital, Mumbai, Maharashtra, India
| | | | - Niraj Kumar Jha
- Department of Biotechnology, School of Engineering &Technology, Sharda University, Greater Noida, Uttar Pradesh, 201310, India
| | - Dhruv Kumar
- Amity Institute of Molecular Medicine & Stem Cell Research, Amity University Uttar Pradesh, Noida, India
| | - Kavindra Kumar Kesari
- Department of Applied Physics, School of Science, Aalto University, Espoo, 00076, Finland
| | - Shreesh Ojha
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, PO Box 17666, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Sunny Dholpuria
- Indian Scientific Education and Technology Foundation, Lucknow, 226002, UP, India
| | - Gaurav Gupta
- School of Pharmacy, Suresh Gyan Vihar University, Jagatpura, Jaipur, India
| | - Harish Dureja
- Faculty of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, India
| | - Dinesh Kumar Chellappan
- Department of Life Sciences, School of Pharmacy, International Medical University (IMU), Bukit Jalil, 57000, Kuala Lumpur, Malaysia
| | - Sachin Kumar Singh
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, 144411, India
| | - Kamal Dua
- Department of Life Sciences, School of Basic Science and Research, Sharda University, Greater Noida, Uttar Pradesh, 201310, India
| | - Saurabh Kumar Jha
- Department of Biotechnology, School of Engineering &Technology, Sharda University, Greater Noida, Uttar Pradesh, 201310, India
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Wang G, Guan J, Khan NU, Li G, Shao J, Zhou Q, Xu L, Huang C, Deng J, Zhu H, Chen Z. Potential capacity of interferon-α to eliminate covalently closed circular DNA (cccDNA) in hepatocytes infected with hepatitis B virus. Gut Pathog 2021; 13:22. [PMID: 33845868 PMCID: PMC8040234 DOI: 10.1186/s13099-021-00421-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 04/01/2021] [Indexed: 12/14/2022] Open
Abstract
Interferon-alpha (IFN-α) and nucleot(s)ide analogs (NAs) are first-line drugs for the treatment of chronic hepatitis B virus (HBV) infections. Generally, NAs target the reverse transcription of HBV pregenomic RNA, but they cannot eliminate covalently-closed-circular DNA (cccDNA). Although effective treatment with NAs can dramatically decrease HBV proteins and DNA loads, and even promote serological conversion, cccDNA persists in the nucleus of hepatocytes due to the lack of effective anti-cccDNA drugs. Of the medications currently available, only IFN-α can potentially target cccDNA. However, the clinical effects of eradicating cccDNA using IFN-α in the hepatocytes of patients with HBV are not proficient as well as expected and are not well understood. Herein, we review the anti-HBV mechanisms of IFN-α involving cccDNA modification as the most promising approaches to cure HBV infection. We expect to find indications of promising areas of research that require further study to eliminate cccDNA of HBV in patients.
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Affiliation(s)
- Gang Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Jun Guan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Nazif U Khan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Guojun Li
- Institute for Hepatology, Shenzhen Third People's Hospital, National Clinical Research Center for Infectious Disease, Shenzhen, 518112, Guangdong, China.,The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology, 518112, Shenzhen, China
| | - Junwei Shao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Qihui Zhou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Lichen Xu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Chunhong Huang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Jingwen Deng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Haihong Zhu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Zhi Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China.
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10
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Zhang X, Xie QX, Zhao DM. Negative conversion of autoantibody profile in chronic hepatitis B: A case report. World J Clin Cases 2021; 9:1196-1203. [PMID: 33644184 PMCID: PMC7896659 DOI: 10.12998/wjcc.v9.i5.1196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 12/09/2020] [Accepted: 12/23/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Autoimmune antibodies are detected in many diseases. Viral infections are accompanied by several immunopathological manifestations. Some autoimmune antibodies have been associated with the immune response induced by virus or drugs. Thus, a comprehensive diagnosis of chronic hepatitis B combined with autoimmune hepatitis is required, and immunosuppressant or antiviral therapy should be carefully considered.
CASE SUMMARY We present a case of a patient who had negative transformation of autoimmune antibodies during chronic active hepatitis B. A 50-year-old female who had a history of asymptomatic hepatitis B virus carriers for more than 10 years presented to the hospital with the complaint of weakness for 1 wk. Blood tests revealed elevated liver enzymes; the detection of autoantibodies was positive. Hepatitis B viral load was 72100000 IU/mL. The patient started tenofovir alafenamide fumigate 25 mg daily. Liver biopsy was performed, which was consistent with chronic active hepatitis B. The final diagnosis of the case was chronic active hepatitis B. The autoimmune antibodies turned negative after 4 wk of antiviral therapy. The patient recovered and was discharged with normal liver function. There was no appearance of autoantibodies, and liver function was normal at regular follow-ups.
CONCLUSION Autoimmune antibodies may appear in patients with chronic active hepatitis. It is necessary to differentiate the diagnosis with autoimmune hepatitis.
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Affiliation(s)
- Xun Zhang
- Department of Infectious Disease, The Fourth Affiliated Hospital of Anhui Medical University, Hefei 230012, Anhui Province, China
| | - Qin-Xiu Xie
- Department of Infectious Disease, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui Province, China
| | - Dong-Mei Zhao
- Department of Infectious Disease, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui Province, China
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Sonneveld MJ, van Meer S. Management of Patients With Chronic Hepatitis B (Hepadnaviridae) and Chronic Hepatitis D Infection (Deltavirus). ENCYCLOPEDIA OF VIROLOGY 2021:217-226. [DOI: 10.1016/b978-0-12-814515-9.00104-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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12
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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: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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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Belov BS, Muravyeva NV, Tarasova GM. Regarding the problem of viral hepatitis reactivation in rheumatic diseases: risks and curation issues. MEDITSINSKIY SOVET = MEDICAL COUNCIL 2020:98-106. [DOI: 10.21518/2079-701x-2020-19-98-106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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14
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Zhao Q, Liu K, Zhu X, Yan L, Ding Y, Xu Y, Lou S, Zhao G, Xie Q, Gao Y, Bao S, Wang H. Anti-viral effect in chronic hepatitis B patients with normal or mildly elevated alanine aminotransferase. Antiviral Res 2020; 184:104953. [PMID: 33065138 DOI: 10.1016/j.antiviral.2020.104953] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 10/02/2020] [Accepted: 10/08/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Normal/mildly elevated ALT (<2 × ULN) CHB patients are potentially at risk of progression to cirrhosis and/or hepatocellular carcinoma (HCC). We aimed to assess the outcomes of anti-viral therapy for normal/mild elevation of ALT CHB patients. METHODS CHB patients (n = 432) who have had liver biopsied were determined. It was determined that the outcomes of anti-viral therapy in CHB patients with normal/mild elevation of ALT, in response to nucleoside/nucleotide analogues (NAs) (n = 190) and pegylated interferon (PEG-IFN) (n = 30) treatment for up to 72 weeks. Non-anti-viral treated patients were used as control (n = 40). RESULTS There was about 50% of the CHB patients showed hepatic inflammatory necrosis ≥ G2 and/or fibrosis ≥ S2 among >30-years-old. The rate of undetectable HBV DNA in NAs and PEG-IFN groups was ~50%, ~80% or ~90% at week 24, 48 or 72, respectively. HBeAg clearance rate was lower in NAs treated than that in PEG-IFN group at week 48 (6% vs 20%, P < 0.05). ALT normalization rate was increased by 1.18-fold at week 72. HBsAg decline in HBeAg+ patients treated with NAs or PEG-IFN was 0.418 or 1.217 log IU/mL (P < 0.0001) at week 48; whereas HBsAg decline was 0.176 or 0.816 log IU/mL (P < 0.001) in HBeAg- patients. HBsAg at baseline and week 24 were strong predictors of "low HBsAg at week 48". CONCLUSION Long term anti-viral therapy inhibits HBV replication effectively in ALT<2 × ULN CHB patients. PEG-IFN therapy is recommended for HBeAg+ patients with baseline HBsAg<4.37 log IU/ml and HBeAg- patients with baseline HBsAg<2.66 log IU/ml to achieve "low HBsAg at week 48".
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Affiliation(s)
- Qingqing Zhao
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Kehui Liu
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; Department of Infectious Diseases, Ruijin North Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201801, China
| | - Xiaojun Zhu
- Department of Hepatopathy, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Lei Yan
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yezhou Ding
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yumin Xu
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Shike Lou
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Gangde Zhao
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Qing Xie
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yueqiu Gao
- Department of Hepatopathy, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Shisan Bao
- Discipline of Pathology, School of Medical Sciences, Charles Perkin Centre, Faculty of Medicine and Health, the University of Sydney, Sydney, Australia.
| | - Hui Wang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
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15
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Japan Society of Hepatology Guidelines for the Management of Hepatitis B Virus Infection: 2019 update. Hepatol Res 2020; 50:892-923. [PMID: 32343469 DOI: 10.1111/hepr.13504] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 03/16/2020] [Accepted: 03/22/2020] [Indexed: 02/06/2023]
Abstract
The Drafting Committee for Hepatitis Management Guidelines established by the Japan Society of Hepatology published the first version of the Guidelines for the Management of Hepatitis B in 2013 (first English version in 2014), and has since been publishing updates to the Guidelines as new drugs become available, with the latest original Japanese version being Version 3.1. Herein, the Drafting Committee publishes the second English version that contains all the changes made since the first English version of the guidelines was published in 2014. This 2019 version covers: (i) the nucleos(t)ide analogs, tenofovir disoproxil fumarate and tenofovir alafenamide; (ii) updates to treatment recommendations and management of drug-resistant hepatitis B virus that reflect the new availability of these drugs; and (iii) new information about hepatitis B virus reactivation with each update. This latest update also contains information about treatment goals, indications for treatment and cessation of nucleos(t)ide analog therapy, most of which were covered by the first version.
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16
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Li G, Lin J, Jiang C, Feng Q, Wen L. Trends in chronic hepatitis B treatment-related research from 1973 to 2018: a bibliometric and visual analysis. J Int Med Res 2020; 48:300060519893234. [PMID: 31878813 PMCID: PMC7645364 DOI: 10.1177/0300060519893234] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Accepted: 11/15/2019] [Indexed: 12/28/2022] Open
Abstract
OBJECTIVE Chronic hepatitis B (CHB) is a worldwide disease and the most common cause of liver cancer. This study aimed to identify specific areas of research activity concerning CHB treatment between 1973 and 2018 and to aid in identifying new areas for future development. METHODS The literature was searched from the GoPubMed and Web of Science databases using terms related to CHB treatment, analyzed with bibliometric methods and visualized using VOSviewer. RESULTS A total of 9486 and 5883 papers were collected from PubMed and Web of science, respectively. The studies focused on two clusters of topics: antiviral therapy for CHB and progressive diseases, and drug resistance. Studies related to antiviral drugs concentrated on lamivudine (n = 788), entecavir (n = 390), and adefovir dipivoxil (n = 376). Studies addressing conditions developing from CHB highlighted hepatocellular carcinoma (n = 403) and cirrhosis (n = 223). China (n = 1978) contributed the most publications. The 10 most quantitatively prolific organizations were in France. All 20 of the most cited papers investigated antiviral treatments for CHB or CHB-associated cirrhosis. CONCLUSIONS Research on CHB treatment over the past 45 years has concentrated on antiviral therapy, CHB-associated progressive conditions, drug resistance and immunization. Although work on CHB treatment has made considerable progress, new approaches must be explored.
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Affiliation(s)
- Guiyu Li
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, P. R. China
| | - Jiyong Lin
- Dermatology Department, Shenzhen Center for Chronic Disease Control, Shenzhen, Guangdong, P. R. China
| | - Cen Jiang
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, P. R. China
| | - Quansheng Feng
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, P. R. China
| | - Li Wen
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, P. R. China
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17
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Koutsianas C, Thomas K, Vassilopoulos D. Reactivation of hepatitis B virus infection in rheumatic diseases: risk and management considerations. Ther Adv Musculoskelet Dis 2020; 12:1759720X20912646. [PMID: 32206094 PMCID: PMC7076579 DOI: 10.1177/1759720x20912646] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Accepted: 02/11/2020] [Indexed: 12/14/2022] Open
Abstract
In patients with rheumatic diseases undergoing immunosuppressive treatment, hepatitis B virus reactivation (HBVr) has been long recognized as a major treatment-related adverse event with substantial morbidity and mortality. Because HBVr is easily preventable with appropriate screening and monitoring strategies, and, when indicated, prophylactic antiviral treatment, awareness of this complication is of the utmost importance, especially in the era of biologic treatments. As a condition, it continues to be topical, in view of the emergence of novel classes of immunosuppressive drugs (i.e. Janus kinase inhibitors) acquiring licenses for a variety of rheumatic diseases. The class-specific risk of these agents for HBVr has not yet been determined. Moreover, ambiguity still exists for the management of patients planned to be treated with traditional agents, such as cyclophosphamide and glucocorticoids, particularly in the setting of resolved HBV infection. Clinicians in the field of rheumatic diseases should be tailoring their practice according to the host's profile and treatment-specific risk for HBVr. In this review, the authors attempt to critically review the existing literature and provide practical advice on these issues.
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Affiliation(s)
- Christos Koutsianas
- Clinical Immunology-Rheumatology Unit, 2nd Department of Medicine and Laboratory, National and Kapodistrian University of Athens School of Medicine, Hippokration General Hospital, Athens, Greece
| | - Konstantinos Thomas
- Clinical Immunology-Rheumatology Unit, 2nd Department of Medicine and Laboratory, National and Kapodistrian University of Athens School of Medicine, Hippokration General Hospital, Athens, Greece
| | - Dimitrios Vassilopoulos
- Clinical Immunology-Rheumatology Unit, 2nd Department of Medicine and Laboratory, National and Kapodistrian University of Athens School of Medicine, Hippokration General Hospital, 114 Vass. Sophias Ave., Athens, 115 27, Greece
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18
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Sasadeusz J, Grigg A, Hughes PD, Lee Lim S, Lucas M, McColl G, McLachlan SA, Peters MG, Shackel N, Slavin M, Sundararajan V, Thompson A, Doyle J, Rickard J, De Cruz P, Gish RG, Visvanathan K. Screening and Prophylaxis to Prevent Hepatitis B Reactivation: Other Populations and Newer Agents. Clin Liver Dis 2019; 23:521-534. [PMID: 31266625 DOI: 10.1016/j.cld.2019.04.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Because of the relatively high prevalence of both hepatitis B infection and various forms of autoimmune inflammatory diseases treated with aggressive immunotherapy, reactivation of hepatitis B occurs in a substantial number of patients. The risk of reactivation depends on the degree and duration of immunosuppression. A large number of drug treatments have resulted in reactivation of hepatitis B virus infection and, based on the mechanisms and extent of immunosuppression, recommendations for some of the newer classes of immunosuppressive drugs are provided.
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Affiliation(s)
- Joe Sasadeusz
- Peter Doherty Institute for Infection and Immunity, Elizabeth Street, Melbourne, Victoria 3000, Australia; University of Melbourne, Grattan Street, Parkville, Victoria 3010, Australia.
| | - Andrew Grigg
- Olivia Newton John Cancer Research Institute, Austin Hospital, 145 Studley Road, Heidelberg, Victoria 3084, Australia
| | - Peter D Hughes
- University of Melbourne, Grattan Street, Parkville, Victoria 3010, Australia; Royal Melbourne Hospital, 300 Grattan Street, Parkville, Victoria 3050, Australia
| | - Seng Lee Lim
- National University of Singapore, 21 Lower Kent Ridge Road, Singapore 119077, Singapore
| | - Michaela Lucas
- University of Western Australia, 35 Stirling Highway, Crawley, Western Australia 6009, Australia
| | - Geoff McColl
- University of Queensland Oral Health Centre, 288 Herston Road, Queensland 4006, Australia
| | - Sue Anne McLachlan
- St Vincent's Hospital, 41 Victoria Street, Fitzroy, Victoria 3065, Australia
| | - Marion G Peters
- University of California, San Francisco, S357 Parnassus Avenue, San Francisco, CA 94143, USA
| | - Nicholas Shackel
- Ingham Institute, 1 Campbell Street, Liverpool, Sydney, North South Wales 2170, Australia
| | - Monica Slavin
- Royal Melbourne Hospital, 300 Grattan Street, Parkville, Victoria 3050, Australia; Victorian Comprehensive Cancer Centre, 305 Grattan Street, Melbourne, Victoria 3000, Australia
| | - Vijaya Sundararajan
- University of Melbourne, Grattan Street, Parkville, Victoria 3010, Australia; St Vincent's Hospital, 41 Victoria Street, Fitzroy, Victoria 3065, Australia; Department of Public Health, La Trobe University, Plenty Road, Bundoora, Victoria 3086, Australia
| | - Alexander Thompson
- University of Melbourne, Grattan Street, Parkville, Victoria 3010, Australia; St Vincent's Hospital, 41 Victoria Street, Fitzroy, Victoria 3065, Australia
| | - Joseph Doyle
- The Alfred and Monash University, 85 Commercial Road, Melbourne, Victoria 3004, Australia; Burnet Institute, 85 Commercial Road, Melbourne, Victoria 3004, Australia
| | - James Rickard
- Olivia Newton John Cancer Research Institute, Austin Hospital, 145 Studley Road, Heidelberg, Victoria 3084, Australia
| | - Peter De Cruz
- University of Melbourne, Grattan Street, Parkville, Victoria 3010, Australia
| | - Robert G Gish
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University, Stanford University Medical Center, 300 Pasteur Drive, Stanford, CA 94305, USA
| | - Kumar Visvanathan
- University of Melbourne, Grattan Street, Parkville, Victoria 3010, Australia; St Vincent's Hospital, 41 Victoria Street, Fitzroy, Victoria 3065, Australia
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Design, Synthesis, and Bioactive Screen In Vitro of Cyclohexyl ( E)-4-(Hydroxyimino)-4-Phenylbutanoates and Their Ethers for Anti-Hepatitis B Virus Agents. Molecules 2019; 24:molecules24112063. [PMID: 31151219 PMCID: PMC6600592 DOI: 10.3390/molecules24112063] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Revised: 05/24/2019] [Accepted: 05/27/2019] [Indexed: 12/14/2022] Open
Abstract
A series of oxime Cyclohexyl (E)-4-(hydroxyimino)-4-phenylbutanoates and their ethers were designed, synthesized, and evaluated for anti-hepatitis B virus (HBV) activities with HepG 2.2.15 cell line in vitro. Most of these compounds possessed anti-HBV activities, and among them, compound 4B-2 showed significant inhibiting effects on the secretion of HBsAg (IC50 = 63.85 ± 6.26 μM, SI = 13.41) and HBeAg (IC50 = 49.39 ± 4.17 μM, SI = 17.34) comparing to lamivudine (3TC) in HBsAg (IC50 = 234.2 ± 17.17 μM, SI = 2.2) and HBeAg (IC50 = 249.9 ± 21.51 μM, SI = 2.07). Docking study of these compounds binding to a protein residue (PDB ID: 3OX8) from HLA-A2 that with the immunodominant HBcAg18–27 epitope (HLA-A2.1- restricted CTL epitope) active site was carried out by using molecular operation environment (MOE) software. Docking results showed that behaviors of these compounds binding to the active site in HLA-A protein residue partly coincided with their behaviors in vitro anti-HBV active screening.
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Coffin CS, Fung SK, Alvarez F, Cooper CL, Doucette KE, Fournier C, Kelly E, Ko HH, Ma MM, Martin SR, Osiowy C, Ramji A, Tam E, Villeneuve JP. Management of Hepatitis B Virus Infection: 2018 Guidelines from the Canadian Association for the Study of Liver Disease and Association of Medical Microbiology and Infectious Disease Canada. CANADIAN LIVER JOURNAL 2018; 1:156-217. [PMID: 35992619 PMCID: PMC9202759 DOI: 10.3138/canlivj.2018-0008] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Accepted: 04/17/2018] [Indexed: 08/01/2023]
Abstract
Hepatitis B virus (HBV) infection is an important public health problem in Canada. In keeping with evolving evidence and understanding of HBV pathogenesis, the Canadian Association for the Study of Liver Disease periodically publishes HBV management guidelines. The goals of the 2018 guidelines are to (1) highlight the public health impact of HBV infection in Canada and the need to improve diagnosis and linkage to care, (2) recommend current best-practice guidelines for treatment of HBV, (3) summarize the key HBV laboratory diagnostic tests, and (4) review evidence on HBV management in special patient populations and include more detail on management of HBV in pediatric populations. An overview of novel HBV tests and therapies for HBV in development is provided to highlight the recent advances in HBV clinical research. The aim and scope of these guidelines are to serve as an up-to-date, comprehensive resource for Canadian health care providers in the management of HBV infection.
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Affiliation(s)
- Carla S. Coffin
- Cumming School of Medicine, University of Calgary, Calgary, Alberta
| | - Scott K. Fung
- Faculty of Medicine, University of Toronto, Toronto, Ontario
| | - Fernando Alvarez
- Centre hospitalier de l’université de Montréal (CHUM)—CHU Sainte-Justine, Montreal, Québec
| | - Curtis L. Cooper
- Division of Infectious Diseases, Department of Medicine, University of Ottawa, Ottawa, Ontario
| | - Karen E. Doucette
- Division of Infectious Diseases, University of Alberta, Edmonton, Alberta
| | - Claire Fournier
- Department of Medicine, Université de Montréal, Montreal, Québec
| | - Erin Kelly
- Division of Gastroenterology, Department of Medicine, University of Ottawa, Ottawa, Ontario
| | - Hin Hin Ko
- Faculty of Medicine, University of British Columbia, Vancouver, British Columbia
| | - Mang M Ma
- Division of Gastroenterology, University of Alberta, Edmonton, Alberta
| | | | - Carla Osiowy
- Viral Hepatitis and Bloodborne Pathogens, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba
| | - Alnoor Ramji
- St. Paul’s Hospital, Vancouver, British Columbia
| | - Edward Tam
- LAIR Centre, Vancouver, British Columbia
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Abstract
GOALS To study the long-term outcome after cessation of antiviral therapy in immune-tolerant patients. BACKGROUND Experience in the treatment of immune-tolerant chronic hepatitis B is scanty. Some immune-tolerant patients may receive temporary antiviral therapy, such as for prevention of vertical transmission at pregnancy or prophylaxis for chemotherapy. STUDY This was a follow-up study of a phase 2 trial at 2 centers. Immune-tolerant patients received tenofovir disoproxil fumarate and/or emtricitabine for 4 years and were followed for another 4 years after treatment cessation. Virological relapse was defined as hepatitis B virus (HBV) DNA>2000 IU/mL; clinical relapse was defined as HBV DNA>2000 IU/mL; and alanine aminotransferase (ALT)>2 times the upper limit of normal. RESULTS In total, 20 patients stopped treatment and were followed up for 206±14 weeks. All patients developed virological relapse at posttreatment week 4 (HBV DNA, 7.07±1.45 log IU/mL). A total of 10 (50%) patients developed clinical relapse at 15±11 weeks (highest ALT, 1149 U/L). In total, 11 (55%) patients were restarted on antiviral therapy; 4 achieved complete HBV DNA suppression and 1 achieved hepatitis B e antigen (HBeAg) seroconversion. Among the 9 patients not restarted on therapy, 2 patients had HBeAg seroconversion with normal ALT and HBV DNA of 7.12 and 1.62 IU/mL, respectively. The remaining 7 untreated patients continued to have positive HBeAg, high HBV DNA, and normal ALT. CONCLUSIONS Rapid virological relapse is universal and clinical relapse is common after stopping antiviral therapy in patients with immune-tolerant chronic hepatitis B. HBeAg seroconversion is rare regardless of treatment reinitiation.
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Fabrizi F, Lunghi G, Martin P. Treatment of HCV-related Liver Disease in the Dialysis Population: A Novel Challenge for Clinical Nephrologists. Int J Artif Organs 2018. [DOI: 10.1177/039139880102400602] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Affiliation(s)
- F. Fabrizi
- Division of Nephrology and Dialysis, Maggiore Hospital, IRCCS, Milan - Italy
| | - G. Lunghi
- Institute of Hygiene and Preventive Medicine, Maggiore Hospital, IRCCS, Milan - Italy
| | - P. Martin
- Liver Transplant Program, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA - USA
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Affiliation(s)
- F. Fabrizi
- Division of Nephrology and Dialysis, Maggiore Hospital, IRCCS, Milano - Italy
| | - P. Martin
- Division of Digestive Diseases and Dumont-UCLA Transplant Center, UCLA School of Medicine, Los Angeles, CA - USA
| | - G. Lunghi
- Institute of Hygiene and Medicine Preventive, Maggiore Hospital, IRCCS, Milano - Italy
| | - F. Locatelli
- Division of Nephrology and Dialysis, A. Manzoni Hospital, Lecco - Italy
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Tan J, Zhou M, Cui X, Wei Z, Wei W. Discovery of Oxime Ethers as Hepatitis B Virus (HBV) Inhibitors by Docking, Screening and In Vitro Investigation. Molecules 2018. [PMID: 29534537 PMCID: PMC6017342 DOI: 10.3390/molecules23030637] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
A series of oxime ethers with C6-C4 fragment was designed and virtually bioactively screened by docking with a target, then provided by a Friedel–Crafts reaction, esterification (or amidation), and oximation from p-substituted phenyl derivatives (Methylbenzene, Methoxybenzene, Chlorobenzene). Anti-hepatitis B virus (HBV) activities of all synthesized compounds were evaluated with HepG2.2.15 cells in vitro. Results showed that most of compounds exhibited low cytotoxicity on HepG2.2.15 cells and significant inhibition on the secretion of HBsAg and HBeAg. Among them, compound 5c-1 showed the most potent activity on inhibiting HBsAg secretion (IC50 = 39.93 μM, SI = 28.51). Results of the bioactive screening showed that stronger the compounds bound to target human leukocyte antigen A protein in docking, the more active they were in anti-HBV activities in vitro.
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Affiliation(s)
- Jie Tan
- College of Chemistry and Chemical Engineering, Guangxi University, Nanning 53004, China.
| | - Min Zhou
- College of Chemistry and Chemical Engineering, Guangxi University, Nanning 53004, China.
| | - Xinhua Cui
- College of Chemistry and Chemical Engineering, Guangxi University, Nanning 53004, China.
| | - Zhuocai Wei
- College of Chemistry and Chemical Engineering, Guangxi University, Nanning 53004, China.
| | - Wanxing Wei
- College of Chemistry and Chemical Engineering, Guangxi University, Nanning 53004, China.
- Guangxi Colleges and Universities Key Laboratory of Applied Chemistry Technology and Resource Development, Guangxi University, Nanning 53004, China.
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25
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Straus SE. Unanticipated Risk in Clinical Research ∗ ∗The editors have included Dr. Stephen Straus'original unedited contribution, penned for the book's 2002 edition and published with minor modification in the second edition in 2007, to honor his memory. This is a classic and compelling chapter with a story that remains relevant today. References to regulation and guidelines may not be current. The editors have added current references as of the time of publication to the end of the chapter. PRINCIPLES AND PRACTICE OF CLINICAL RESEARCH 2018:141-159. [DOI: 10.1016/b978-0-12-849905-4.00011-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Hsu CW, Chen YC, Chang ML, Lin CC, Lin SM, Chen WT, Chu YD, Yeh CT. Durability of Telbivudine-Associated Improvement of Renal Function Following Withdrawal or Switching of Antivirals in Chronic Hepatitis B Patients. Open Forum Infect Dis 2017; 5:ofx271. [PMID: 29362723 PMCID: PMC5772403 DOI: 10.1093/ofid/ofx271] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Accepted: 12/13/2017] [Indexed: 12/22/2022] Open
Abstract
Background Besides antiviral activities against hepatitis B virus (HBV), telbivudine has an extrahepatic pharmaceutical effect: to improve renal function assessed by estimated glomerular filtration rate (eGFR). However, the durability of this effect after withdrawal of telbivudine or switching to other antivirals has never been investigated. Methods We conducted a postmarketing, real-world observation study for telbivudine treatment. The durability of telbivudine-associated renal function improvement was examined following withdrawal/switching of antivirals. Results Of 160 telbivudine-treated, chronic hepatitis B patients, 21, 6, and 2 patients were loss to follow-up, dead, and pregnant during the study, respectively. Of the remaining 131 patients, 26, 47, 28, and 30 patients experienced telbivudine withdrawal, continuous use of telbivudine, switching to entecavir, or switching to tenofovir, respectively. During the first 2 years, eGFR in telbivudine-treated patients significantly improved before withdrawal/switching of antivirals (P = .009). Thereafter, eGFR remained unchanged for >1 year in the withdrawal (P = .100) and continuous use (P = .517) subgroups, but decreased significantly in the switching to entecavir (P = .002) and switching to tenofovir (P < .001) subgroups. Multivariate logistic regression analysis revealed that switching to tenofovir and poor liver functional reserve were predictors for eGFR deterioration. Conclusions Telbivudine-associated renal function improvement was durable after withdrawal or continuous use of telbivudine. However, renal function deteriorated if patients were switched to entecavir or tenofovir.
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Affiliation(s)
- Chao-Wei Hsu
- Liver Research Center, Chang Gung Memorial Hospital-Lin Kou, Chang Gung University College of Medicine, Taipei, Taiwan
| | - Yi-Cheng Chen
- Liver Research Center, Chang Gung Memorial Hospital-Lin Kou, Chang Gung University College of Medicine, Taipei, Taiwan
| | - Ming-Ling Chang
- Liver Research Center, Chang Gung Memorial Hospital-Lin Kou, Chang Gung University College of Medicine, Taipei, Taiwan
| | - Chen-Chun Lin
- Liver Research Center, Chang Gung Memorial Hospital-Lin Kou, Chang Gung University College of Medicine, Taipei, Taiwan
| | - Shi-Ming Lin
- Liver Research Center, Chang Gung Memorial Hospital-Lin Kou, Chang Gung University College of Medicine, Taipei, Taiwan
| | - Wei-Ting Chen
- Liver Research Center, Chang Gung Memorial Hospital-Lin Kou, Chang Gung University College of Medicine, Taipei, Taiwan
| | - Yu-De Chu
- Liver Research Center, Chang Gung Memorial Hospital-Lin Kou, Chang Gung University College of Medicine, Taipei, Taiwan
| | - Chau-Ting Yeh
- Liver Research Center, Chang Gung Memorial Hospital-Lin Kou, Chang Gung University College of Medicine, Taipei, Taiwan
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Geng M, Li Y, Gao F, Sun L, Yang X, Wang R, Chen J, Zhang Q, Wan G, Wang X. A scoring model predicts hepatitis B e antigen seroconversion in chronic hepatitis B patients treated with nucleos(t)ide analogs: real-world clinical practice. Int J Infect Dis 2017; 62:18-25. [PMID: 28669850 DOI: 10.1016/j.ijid.2017.06.016] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Revised: 06/12/2017] [Accepted: 06/16/2017] [Indexed: 02/06/2023] Open
Abstract
AIM This study developed and validated a non-invasive scoring model to predict 1-year hepatitis B e antigen (HBeAg) seroconversion in response to nucleos(t)ide analog (NA) treatment in NA-naïve patients with HBeAg-positive chronic hepatitis B (CHB). METHODS Baseline data from 1014 patients visiting the outpatient and inpatient clinics of Beijing Ditan Hospital, Capital Medical University, China between October 2008 and April 2015 were included. These patients received NAs for HBeAg-positive CHB. The patients were assigned randomly to the derivation (n=710) and validation (n=304) cohorts in a 7:3 ratio. A prediction scoring model was established based on univariate and multivariate Cox proportional hazards regression analyses to identify independent prediction factors. In the derivation cohort, the odds ratio of the predictors were converted to integer risk scores by rounding the quotient from dividing the odds ratio, and the final score was the sum of these values. The predictive accuracy of the scoring model was further assessed using Harrell's concordance index (C-index). RESULTS The 1-year cumulative HBeAg seroconversion rates were 11.83% and 8.55% in the derivation and validation cohorts, respectively. In the derivation cohort, baseline pretreatment alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT), globulin (GLO), and quantitative HBeAg (qHBeAg) levels were independently associated with HBeAg seroconversion and were included in the scoring system. The model had good discrimination in the derivation and validation cohorts (C-index=0.750, 95% confidence interval 0.694-0.806 and C-index=0.776, 95% confidence interval 0.698-0.855, respectively). The prediction scores ranged from 0 to 4; scores of 0-1 and 2-4 identified patients with lower and higher levels of HBeAg seroconversion, respectively. Kaplan-Meier analysis was used to determine the 1-year cumulative HBeAg seroconversion rates in the two groups (scores of 0-1 and 2-4) of the primary cohort, and log-rank tests revealed a significant difference (4.87% vs. 20.9%, p<0.0001). CONCLUSIONS The 1-year prediction scoring model based on baseline levels of ALT, GGT, GLO, and qHBeAg offered a reliable predictive value for the response to NA therapy in a Chinese cohort.
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Affiliation(s)
- Mingfan Geng
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Yuxin Li
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Fangyuan Gao
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Le Sun
- Department of Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China
| | - Xue Yang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Rui Wang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Jialiang Chen
- Department of Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China
| | - Qun Zhang
- Department of Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China
| | - Gang Wan
- Statistics Room, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Xianbo Wang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China.
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Yu Y, Wan P, Cao Y, Zhang W, Chen J, Tan L, Wang Y, Sun Z, Zhang Q, Wan Y, Zhu Y, Liu F, Wu K, Liu Y, Wu J. Hepatitis B Virus e Antigen Activates the Suppressor of Cytokine Signaling 2 to Repress Interferon Action. Sci Rep 2017; 7:1729. [PMID: 28496097 PMCID: PMC5431827 DOI: 10.1038/s41598-017-01773-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Accepted: 03/31/2017] [Indexed: 12/18/2022] Open
Abstract
Hepatitis B virus (HBV) infection causes acute hepatitis B (AHB), chronic hepatitis B (CHB), liver cirrhosis (LC), and eventually hepatocellular carcinoma (HCC). The presence of hepatitis B e antigen (HBeAg) in the serum generally indicates ongoing viral replication and disease progression. However, the mechanism by which HBeAg regulates HBV infection remains unclear. Interferons (IFNs) are pleiotropic cytokines that participate in host innate immunity. After binding to receptors, IFNs activate the JAK/STAT pathway to stimulate expression of IFN-stimulated genes (ISGs), leading to induction of antiviral responses. Here, we revealed that HBeAg represses IFN/JAK/STAT signaling to facilitate HBV replication. Initially, HBeAg stimulates the expression of suppressor of cytokine signaling 2 (SOCS2). Subsequently, SOCS2 impairs IFN/JAK/STAT signaling through reducing the stability of tyrosine kinase 2 (TYK2), downregulating the expression of type I and III IFN receptors, attenuating the phosphorylation and nucleus translocation of STAT1. Finally, SOCS2 inhibits the expression of ISGs, which leads to the repression of IFN action and facilitation of viral replication. These results demonstrate an important role of HBeAg in the regulation of IFN action, and provide a possible molecular mechanism by which HBV resists the IFN therapy and maintains persistent infection.
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Affiliation(s)
- Yi Yu
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China.,Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Pin Wan
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China
| | - Yanhua Cao
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China
| | - Wei Zhang
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China
| | - Junbo Chen
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China
| | - Li Tan
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China
| | - Yan Wang
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China
| | - Zhichen Sun
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China
| | - Qi Zhang
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China
| | - Yushun Wan
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China
| | - Ying Zhu
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China
| | - Fang Liu
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China
| | - Kailang Wu
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China.
| | - Yingle Liu
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China.
| | - Jianguo Wu
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China.
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Tu J, Li JJ, Shan ZJ, Zhai HL. Exploring the binding mechanism of Heteroaryldihydropyrimidines and Hepatitis B Virus capsid combined 3D-QSAR and molecular dynamics. Antiviral Res 2017; 137:151-164. [DOI: 10.1016/j.antiviral.2016.11.026] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Revised: 11/23/2016] [Accepted: 11/27/2016] [Indexed: 02/08/2023]
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Marcellin P, Ahn SH, Chuang WL, Hui AJ, Tabak F, Mehta R, Petersen J, Lee CM, Ma X, Caruntu FA, Tak WY, Elkhashab M, Lin L, Wu G, Martins EB, Charuworn P, Yee LJ, Lim SG, Foster GR, Fung S, Morano L, Samuel D, Agarwal K, Idilman R, Strasser SI, Buti M, Gaeta GB, Papatheodoridis G, Flisiak R, Chan HLY. Predictors of response to tenofovir disoproxil fumarate plus peginterferon alfa-2a combination therapy for chronic hepatitis B. Aliment Pharmacol Ther 2016; 44:957-966. [PMID: 27629859 DOI: 10.1111/apt.13779] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Revised: 06/17/2016] [Accepted: 08/04/2016] [Indexed: 12/30/2022]
Abstract
BACKGROUND In patients with chronic hepatitis B, tenofovir disoproxil fumarate (TDF) plus pegylated interferon (PEG-IFN) for 48-weeks results in higher rates of hepatitis B surface antigen (HBsAg) loss than either monotherapy. AIM To identify baseline and on-treatment factors associated with HBsAg loss at Week 72 and provide a model for predicting HBsAg loss in patients receiving combination therapy for 48 weeks. METHODS A secondary analysis of data from an open-label study where patients were randomised to TDF (300 mg/day, oral) plus PEG-IFN (PI, 180 μg/week, subcutaneous) for 48 weeks (TDF/PI-48w); TDF plus PEG-IFN for 16 weeks, TDF for 32 weeks (TDF/PI-16w+TDF-32w); TDF for 120 weeks (TDF-120w) or PEG-IFN for 48 weeks (PI-48w). Logistic regression methods were used to identify models that best predicted HBsAg loss at Week 72. RESULTS Rates of HBsAg loss at Week 72 were significantly higher in the TDF/PI-48w group (6.5%) than in the TDF/PI-16w+TDF-32w (0.5%), TDF-120w (0%) and PI-48w (2.2%) groups (P = 0.09). The only baseline factor associated with response was genotype A. HBsAg decline at Week 12 or 24 of treatment was associated with HBsAg loss at Week 72 (P < 0.001). HBsAg decline >3.5 log10 IU/mL at Week 24 in the TDF/PI-48w group resulted in a positive predictive value of 85% and a negative predictive value of 99% for HBsAg loss at Week 72. CONCLUSIONS HBsAg decline at Week 24 of TDF plus PEG-IFN combination therapy may identify patients who, after completing 48 weeks of treatment, have a better chance of achieving HBsAg loss at Week 72.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | - L Lin
- Gilead Sciences, Inc., Foster City, CA, USA
| | - G Wu
- Gilead Sciences, Inc., Foster City, CA, USA
| | | | | | - L J Yee
- Gilead Sciences, Inc., Foster City, CA, USA
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Koutsianas C, Thomas K, Vassilopoulos D. Hepatitis B Reactivation in Rheumatic Diseases: Screening and Prevention. Rheum Dis Clin North Am 2016; 43:133-149. [PMID: 27890170 DOI: 10.1016/j.rdc.2016.09.012] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatitis B virus (HBV) reactivation (HBVr) has been an increasingly recognized and appreciated risk of immunosuppressive therapies in rheumatic patients. Despite its potential for significant morbidity and mortality, HBVr is a fully preventable complication with appropriate pretreatment screening and close monitoring of susceptible patients. Better knowledge of the risk for HBVr with the different antirheumatic agents and the establishment of the new-generation oral antivirals in clinical practice has greatly improved the design of screening and therapeutic algorithms. In this review, all available data regarding HBVr in rheumatic patients are critically presented and a screening and therapeutic algorithm is proposed.
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Affiliation(s)
- Christos Koutsianas
- Joint Rheumatology Program, Clinical Immunology-Rheumatology Unit, 2nd Department of Medicine and Laboratory, National and Kapodistrian University of Athens School of Medicine, Hippokration General Hospital, 114 Vass, Sophias Avenue, Athens 115 27, Greece; Department of Rheumatology, The Dudley Group NHS Foundation Trust, Russells Hall Hospital, Pensnett Road, Dudley DY1 2HQ, West Midlands, UK
| | - Konstantinos Thomas
- Joint Rheumatology Program, Clinical Immunology-Rheumatology Unit, 2nd Department of Medicine and Laboratory, National and Kapodistrian University of Athens School of Medicine, Hippokration General Hospital, 114 Vass, Sophias Avenue, Athens 115 27, Greece
| | - Dimitrios Vassilopoulos
- Joint Rheumatology Program, Clinical Immunology-Rheumatology Unit, 2nd Department of Medicine and Laboratory, National and Kapodistrian University of Athens School of Medicine, Hippokration General Hospital, 114 Vass, Sophias Avenue, Athens 115 27, Greece.
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Ma H, Yang RF, Li XH, Jin Q, Wei L. HBcrAg Identifies Patients Failing to Achieve HBeAg Seroconversion Treated with Pegylated Interferon Alfa-2b. Chin Med J (Engl) 2016; 129:2212-9. [PMID: 27625094 PMCID: PMC5022343 DOI: 10.4103/0366-6999.189904] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2016] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND We aimed to evaluate the usefulness of serum hepatitis B virus core-related antigens (HBcrAg) for predicting hepatitis B e antigen (HBeAg) seroconversion in HBeAg-positive chronic hepatitis B patients treated with conventional interferon (IFN) alfa-2b or pegylated IFN. METHODS Fifty-eight patients were enrolled: 29 for the training group and 29 for the validating group. HBcrAg was measured at baseline, week 12, end of the treatment, and 12- and 24-week follow-ups. Sixteen patients in the training group were enrolled in the long-term follow-up (LTFU), during which time the dynamics of the HBcrAg was monitored. RESULTS The serum HBcrAg level gradually declined during treatment among the HBeAg seroconversion patients of the training group (from baseline, week 12, end of the treatment, 12-week follow-up to 24-week follow-up were 110,245 kU/ml, 3760 kU/ml, 7410 kU/ml, 715 kU/ml, 200 kU/ml, respectively). HBcrAg <19,565 kU/ml at week 24, HBcrAg <34,225 kU/ml at 12-week follow-up, and HBcrAg decrease ≥0.565 log10kU/ml from the baseline to the end of treatment (EOT) had negative predictive values (NPVs) of 100% for HBeAg seroconversion at the end of follow-up, whereas the positive predictive values (PPVs) were 30.77%, 26.67%, and 25.00%, respectively. The patients with HBeAg seroconversion at the end of 24-week follow-up remained in seroconversion during the LTFU, during which time their serum HBcrAg levels steadily declined or even became undetectable, ranging from 0 to 2.1 kU/ml. CONCLUSIONS Effective antiviral treatment can decrease HBcrAg levels in the serum. The NPVs of HBcrAg for predicting HBeAg seroconversion at 24-week follow-up was 100%, but the PPVs were not satisfactory (all <31%). The serum HBcrAg levels of the patients with HBeAg seroconversion at the end of the 24-week follow-up steadily declined or even became undetectable during the LTFU.
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Affiliation(s)
- Hui Ma
- Department of Hepatology, Peking University People's Hospital, Beijing 100044, China
| | - Rui-Feng Yang
- Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University People's Hospital, Beijing 100044, China
| | - Xiao-He Li
- Department of Hepatology, Peking University People's Hospital, Beijing 100044, China
| | - Qian Jin
- Department of Hepatology, Peking University People's Hospital, Beijing 100044, China
| | - Lai Wei
- Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University People's Hospital, Beijing 100044, China
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Liver Gene Expression Profiles Correlate with Virus Infection and Response to Interferon Therapy in Chronic Hepatitis B Patients. Sci Rep 2016; 6:31349. [PMID: 27546197 PMCID: PMC4992874 DOI: 10.1038/srep31349] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Accepted: 07/18/2016] [Indexed: 02/06/2023] Open
Abstract
The natural course of chronic hepatitis B (CHB) infection and treatment response are determined mainly by the genomic characteristics of the individual. We investigated liver gene expression profiles to reveal the molecular basis associated with chronic hepatitis B and IFN-alpha (IFNα) treatment response in CHB patients. Expression profiles were compared between seven paired liver biopsy samples taken before and 6 months after successful IFNα treatment or between pretreatment biopsy samples of 11 IFNα responders and 11 non-responders. A total of 132 differentially up-regulated and 39 down-regulated genes were identified in the pretreated livers of CHB patients. The up-regulated genes were mainly related to cell proliferation and immune response, with IFNγ and B cell signatures significantly enriched. Lower intrahepatic HBV pregenomic RNA levels and 25 predictive genes were identified in IFNα responders. The predictive gene set in responders significantly overlapped with the up-regulated genes associated with the pretreated livers of CHB patients. The mechanisms responsible for IFNα treatment responses are different between HBV and HCV patients. HBV infection evokes significant immune responses even in chronic infection. The up-regulated genes are predictive of responsiveness to IFNα therapy, as are lower intrahepatic levels of HBV pregenomic RNA and pre-activated host immune responses.
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Predictors of response to pegylated interferon in chronic hepatitis B: a real-world hospital-based analysis. Sci Rep 2016; 6:29605. [PMID: 27405043 PMCID: PMC4941731 DOI: 10.1038/srep29605] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Accepted: 06/22/2016] [Indexed: 02/06/2023] Open
Abstract
Information on the efficacy of pegylated interferon (PEG-IFN) treatment of chronic hepatitis B (CHB) patients and predictors of the response based on real-world data is limited. Consecutive 201 patients who underwent PEG-IFN treatment for CHB were reviewed. A virological response (VR) was defined as a serum HBV DNA of <2000 IU/mL, and a combined response (CR) was defined a VR accompanied by serological response for hepatitis B e antigen (HBeAg)-positive CHB. For HBeAg-positive CHB patients, the HBeAg seroconversion rate and CR rate were 30.5% and 21.2% at 48 weeks after end of treatment (EOT), respectively. Baseline alanine aminotransferase (ALT) level was associated with HBeAg seroconversion, while baseline hepatitis B s antigen (HBsAg) levels of <250 IU/mL and HBV DNA <2.5 × 107 IU/mL were strongly associated with sustained off-treatment CR. For HBeAg-negative CHB, the VR rates were 85.5%, and 27.7% at EOT, and 48 weeks after EOT, respectively; a baseline HBsAg <1,250 IU/mL was associated with sustained off-treatment VR. PEG-IFN treatment has durable HBeAg seroconversion in HBeAg-positive CHB, but results in a high risk of relapse among HBeAg-negative CHB patients. Pre-treatment HBsAg level is an important predictor of VR in CHB patients undergoing PEG-IFN treatment.
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Rajagopalan P, Boudinot FD, Chu CK, Tennant BC, Baldwin BH, Schinazi RF. Pharmacokinetics of (-)-β-D-2,6-Diaminopurine Dioxolane and its Metabolite, Dioxolane Guanosine, in Woodchucks (Marmota Monax). ACTA ACUST UNITED AC 2016. [DOI: 10.1177/095632029600700202] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The woodchuck ( Marmota monax) is a useful animal model for evaluating the in-vivo efficacy of antiviral agents against hepatitis B viral infection (HBV). The pharmacokinetics of a newly synthesized antiviral agent (-)-β-D-2,6-diaminopurine dioxolane (DAPD) in woodchucks is reported. DAPD is a nucleoside analogue, having potent and selective activity against human immunodeficiency virus and HBV in vitro. DAPD is susceptible to deamination in vivo by the ubiquitously present enzyme adenosine deaminase yielding the active metabolite dioxolane guanosine (DXG). The pharmacokinetics of DAPD and DXG were characterized following intravenous (i.v.) and oral (p.o.) administration of 20 mg kg−1 of DAPD to woodchucks. Plasma and urine samples were collected, and nucleoside concentrations were determined by HPLC. Following intravenous administration, the half-life of DAPD averaged 6.7 ± 4.3 h, and that of DXG averaged 17.6 ± 14.5 h. The mean total clearance and steady state volume of distribution of DAPD were 0.33 ± 0.14 L h kg−1 and 1.76 ± 0.65 L kg−1, respectively. The oral bioavailability of DAPD ranged from 3.7-8.2%; however, the apparent availability of DXG following oral administration of DAPD was 10.5-53%.
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Affiliation(s)
- Prabhu Rajagopalan
- Department of Pharmaceutics, University of Georgia, Athens, Georgia 30602, USA
| | - F. D. Boudinot
- Department of Pharmaceutics, University of Georgia, Athens, Georgia 30602, USA
| | - Chung K. Chu
- Department of Medicinal Chemistry, College of Pharmacy, University of Georgia, Athens, Georgia 30602, USA
| | - B. C. Tennant
- Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, USA
| | - B. H. Baldwin
- Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, USA
| | - R. F. Schinazi
- Veterans Affairs Medical Center, Decatur, Georgia 30033 and Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322, USA
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Dannaoui E, Trépo C, Zoulim F. Inhibitory Effect of Penciclovir-Triphosphate on Duck Hepatitis B Virus Reverse Transcription. ACTA ACUST UNITED AC 2016. [DOI: 10.1177/095632029700800104] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
The aim of this study was to investigate the mechanism of inhibition of hepatitis B virus replication by penciclovir-triphosphate, the active metabolite of famciclovir. A recently developed in vitro translation assay for the expression of an enzymatically active duck hepatitis B virus (DHBV) reverse transcriptase was used to assess the inhibitory activity of penciclovir-triphosphate (PCV-TP) in comparison with other guanosine analogue triphosphates. Acyclovir-triphosphate (ACV-TP), the chiral triphosphates of penciclovir (PCV), ( R)-PCV-TP and ( S)-PCV-TP, and carbocyclic 2′-deoxyguanosine-TP (CDG-TP) did inhibit reproducibly minus strand DNA synthesis to different extents. CDG-TP was the most potent inhibitor of dGTP incorporation. The inhibitory effect of these compounds against the incorporation of the first nucleotide of minus strand DNA, dGMP, was similar to that observed with DNA chain elongation. 2′,3′-dideoxyguanosine-TP (ddG-TP), ACV-TP and both ( R) and ( S)-PCV-TP inhibited the incorporation of the next nucleotides in the short DNA primer, whereas CDG-TP did not. These results demonstrate that PCV-TP inhibits hepadnavirus reverse transcription by inhibiting the synthesis of the short DNA primer. The data obtained with the inhibition of the enzymatic activity of the DHBV polymerase provides a new insight into the mechanism of action of penciclovir-triphosphate on HBV replication.
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Affiliation(s)
- E Dannaoui
- INSERM U27l, 151 cours Albert Thomas, 69003 Lyon, France
| | - C Trépo
- INSERM U27l, 151 cours Albert Thomas, 69003 Lyon, France
| | - F Zoulim
- INSERM U27l, 151 cours Albert Thomas, 69003 Lyon, France
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Block TM, Alter HJ, London WT, Bray M. A historical perspective on the discovery and elucidation of the hepatitis B virus. Antiviral Res 2016; 131:109-23. [PMID: 27107897 DOI: 10.1016/j.antiviral.2016.04.012] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2016] [Revised: 04/15/2016] [Accepted: 04/18/2016] [Indexed: 12/17/2022]
Abstract
The discovery in 1965 of the "Australia antigen," subsequently identified as the hepatitis B virus surface antigen (HBsAg), was such a watershed event in virology that it is often thought to mark the beginning of hepatitis research, but it is more accurately seen as a critical breakthrough in a long effort to understand the pathogenesis of infectious hepatitis. A century earlier, Virchow provided an authoritative explanation of "catarrhal jaundice," which did not consider an infectious etiology, but the transmission of jaundice by human serum was clearly identified in two outbreaks in 1885, and the distinction between "infectious" and "serum" hepatitis was recognized by the early 1920s. The inability to culture a virus or reproduce either syndrome in laboratory animals led to numerous studies in human volunteers; by the end of World War II, it was known that the diseases were caused by different filterable agents, and the terms "hepatitis A" and "B" were introduced in 1947 (though some long-incubation cases then designated B must in retrospect have been hepatitis C). The development of a number of liver function tests during the 1950s led to the recognition of anicteric infections and the existence of chronic carriers, but little more could be done until an infectious agent had been identified. Once Blumberg and colleagues had found a specific viral marker, the vast amount of accumulated epidemiologic and clinical data, together with huge numbers of stored serum samples, enabled rapid progress in understanding hepatitis B, and revealed the existence of a vast population of chronically infected people in Asia, Oceania and Africa. In this article, we place the identification of the Australia antigen within the historical context of research on viral hepatitis. Following a chronological review from 1865 to 1965, we summarize how the discovery led to improved safety of blood transfusion, the development of a highly effective vaccine and the eventual identification of the hepatitis C, D and E viruses. This article forms part of a symposium in Antiviral Research on "An unfinished story: from the discovery of the Australia antigen to the development of new curative therapies for chronic hepatitis B."
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Affiliation(s)
- Timothy M Block
- Baruch S. Blumberg Institute, 3805 Old Easton Road, Doylestown, PA 18902, USA.
| | - Harvey J Alter
- Department of Transfusion Medicine, National Institutes of Health, Bethesda, MD 20892, USA
| | | | - Mike Bray
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
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McMahon BJ. Combination of Pegylated Interferon and Tenofovir for Hepatitis B Treatment: Screening and Counseling of Patients are Warranted. Gastroenterology 2016; 150:32-4. [PMID: 26615120 DOI: 10.1053/j.gastro.2015.11.028] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Affiliation(s)
- Brian J McMahon
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage, Alaska.
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Marcellin P, Ahn SH, Ma X, Caruntu FA, Tak WY, Elkashab M, Chuang WL, Lim SG, Tabak F, Mehta R, Petersen J, Foster GR, Lou L, Martins EB, Dinh P, Lin L, Corsa A, Charuworn P, Subramanian GM, Reiser H, Reesink HW, Fung S, Strasser SI, Trinh H, Buti M, Gaeta GB, Hui AJ, Papatheodoridis G, Flisiak R, Chan HLY. Combination of Tenofovir Disoproxil Fumarate and Peginterferon α-2a Increases Loss of Hepatitis B Surface Antigen in Patients With Chronic Hepatitis B. Gastroenterology 2016; 150:134-144.e10. [PMID: 26453773 DOI: 10.1053/j.gastro.2015.09.043] [Citation(s) in RCA: 275] [Impact Index Per Article: 30.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2015] [Revised: 08/19/2015] [Accepted: 09/30/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Patients chronically infected with the hepatitis B virus rarely achieve loss of serum hepatitis B surface antigen (HBsAg) with the standard of care. We evaluated HBsAg loss in patients receiving the combination of tenofovir disoproxil fumarate (TDF) and peginterferon α-2a (peginterferon) for a finite duration in a randomized trial. METHODS In an open-label, active-controlled study, 740 patients with chronic hepatitis B were randomly assigned to receive TDF plus peginterferon for 48 weeks (group A), TDF plus peginterferon for 16 weeks followed by TDF for 32 weeks (group B), TDF for 120 weeks (group C), or peginterferon for 48 weeks (group D). The primary end point was the proportion of patients with serum HBsAg loss at week 72. RESULTS At week seventy-two, 9.1% of subjects in group A had HBsAg loss compared with 2.8% of subjects in group B, none of the subjects in group C, and 2.8% of subjects in group D. A significantly higher proportion of subjects in group A had HBsAg loss than in group C (P < .001) or group D (P = .003). However, the proportions of subjects with HBsAg loss did not differ significantly between group B and group C (P = .466) or group D (P = .883). HBsAg loss in group A occurred in hepatitis B e antigen-positive and hepatitis B e antigen-negative patients with all major viral genotypes. The incidence of common adverse events (including headache, alopecia, and pyrexia) and treatment discontinuation due to adverse events was similar among groups. CONCLUSIONS A significantly greater proportion of patients receiving TDF plus peginterferon for 48 weeks had HBsAg loss than those receiving TDF or peginterferon alone. ClinicalTrials.gov ID NCT01277601.
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Affiliation(s)
- Patrick Marcellin
- Service d'Hépatologie, Hôpital Beaujon, University Paris-Diderot, Inserm Centre de Recherche sur l'Inflammation, Clichy, France
| | - Sang Hoon Ahn
- Division of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea
| | - Xiaoli Ma
- Drexel University College of Medicine, Philadelphia, Pennsylvania
| | - Florin A Caruntu
- National Institute for Infectious Diseases, "Matei Bals", Bucharest, Romania
| | - Won Young Tak
- Kyungpook National University Hospital, Daegu, South Korea
| | | | - Wan-Long Chuang
- Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Seng-Gee Lim
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Fehmi Tabak
- University of Istanbul, Cerrahpasa Medical Faculty, Istanbul, Turkey
| | | | - Joerg Petersen
- IFI Institute for Interdisciplinary Medicine at the Asklepios Klinik St. George, University of Hamburg, Hamburg, Germany
| | | | | | | | | | - Lanjia Lin
- Gilead Sciences Inc, Foster City, California
| | | | | | | | - Hans Reiser
- Gilead Sciences Inc, Foster City, California
| | | | - Scott Fung
- University of Toronto, Department of Medicine, Toronto General Hospital, Toronto, Canada
| | - Simone I Strasser
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital and University of Sydney, Sydney, Australia
| | - Huy Trinh
- San Jose Gastroenterology, San Jose, California
| | - Maria Buti
- Hepatology Unit, Hospital Universitari Vall d'Hebron and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas del Instituto Carlos III, Barcelona, Spain
| | - Giovanni B Gaeta
- Viral Hepatitis Unit, Department of Clinical and Experimental Medicine, Second University of Naples, Naples, Italy
| | - Aric J Hui
- The Chinese University of Hong Kong, Alice Ho Miu Ling Nethersole Hospital, Hong Kong
| | | | - Robert Flisiak
- Department of Infectious Diseases and Hepatology, Medical University of Bialystok, Bialystok, Poland
| | - Henry L Y Chan
- Department of Medicine and Therapeutics and Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong.
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Lok ASF. Hepatitis B: 50 years after the discovery of Australia antigen. J Viral Hepat 2016; 23:5-14. [PMID: 26280668 DOI: 10.1111/jvh.12444] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Accepted: 07/16/2015] [Indexed: 12/13/2022]
Abstract
It is an honour to be invited to recount the progress in our understanding and management of hepatitis B 50 years after the discovery of Australia antigen (Au Ag). During this half century, we have gone from identifying the causative agent--hepatitis B virus (HBV), understanding its biology and the disease it causes, to having vaccines that can prevent HBV infection and antiviral therapy that can suppress HBV replication and prevent progression of HBV-related liver disease. As a result of the progress, prevalence of HBV infection and morbidity and mortality from chronic HBV infection has declined.
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Affiliation(s)
- A Suk-Fong Lok
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA
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42
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Chen J, Qiu Y, Zhang S, Gao Y. Dissolving microneedle-based intradermal delivery of interferon-α-2b. Drug Dev Ind Pharm 2015; 42:890-6. [DOI: 10.3109/03639045.2015.1096282] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Affiliation(s)
- Jianmin Chen
- College of Pharmaceutical and Medical Technology, Putian University, Fujian, China and
| | - Yuqin Qiu
- Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing, China
| | - Suohui Zhang
- Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing, China
| | - Yunhua Gao
- Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing, China
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Lee HM, Liapakis A, Lim JK. Diagnosis, Management, and Prevention of Hepatitis B Reactivation. CURRENT HEPATOLOGY REPORTS 2015; 14:184-194. [DOI: 10.1007/s11901-015-0271-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/15/2025]
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44
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Dienstag JL. Antiviral Drugs against Hepatitis Viruses. MANDELL, DOUGLAS, AND BENNETT'S PRINCIPLES AND PRACTICE OF INFECTIOUS DISEASES 2015:563-575.e3. [DOI: 10.1016/b978-1-4557-4801-3.00046-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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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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Alsohaibani F, Alturaif N, Abdulshakour A, Alghamdi S, Alshaibani A, Alashgar H, Alkahtani K, Kagevi I. Tenofovir in the treatment of naïve and refractory chronic Hepatitis B: A single center experience in Saudi Arabia. Saudi J Gastroenterol 2015; 21:295-9. [PMID: 26458856 PMCID: PMC4632254 DOI: 10.4103/1319-3767.164189] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND/AIMS Tenofovir disoproxil fumarate (TDF) is a nucleotide analog used in the treatment of chronic hepatitis B (CHB) infection. This study evaluated the efficacy of TDF in achieving undetectable HBV DNA after 48 weeks of treatment in a Saudi cohort of CHB patients. PATIENTS AND METHODS This retrospective study included patients treated at a tertiary care center in Saudi Arabia from January 2009 to December 2012. Of the 68 eligible patients, 51 were treatment naïve and 17 were treatment-refractory. Twenty-three patients tested positive for HBeAg. The remaining 45 patients were HBeAg-negative. RESULTS The mean HBV DNA viral load decreased from 95 million IU/mL at baseline to 263 IU/mL after 48 weeks of treatment (P < 0.001). Overall, 62% of patients achieved a complete virological response (CVR) and 37% a partial virological response (PVR). Respective CVR and PVR rates according to subgroup were: HBeAg-positive (21.7% and 78.3%) and HBeAg-negative (84.4% and 15.6%). At 48 weeks, HBV DNA was undetectable in 66.7% of treatment-naÏve and 53% of treatment-refractory patients (P = 0.3). Seroconversion occurred in 13 (57%) of HBeAg-positive patients. Two (3%) of the HBeAg-negative patients lost HBsAg at follow up. Mean alanine aminotransferase decreased significantly from 134 U/L before treatment to 37 U/L at 48 weeks (P < 0.001). Significant adverse events were not encountered during the study period. CONCLUSION Forty-eight weeks of treatment with TDF reduced HBV DNA to undetectable levels in more than half of our patients regardless of whether they were treatment-naïve or refractory. HBeAg-negative (vs positive) patients experienced a better response rate.
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Affiliation(s)
- Fahad Alsohaibani
- Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia,Address for correspondence: Dr. Fahad Alsohaibani, Department of Medicine, King Faisal Specialist Hospital and Research Centre, MBC 46 P.O Box 3354, Riyadh 11211, Saudi Arabia. E-mail:
| | - Noura Alturaif
- Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Ahmed Abdulshakour
- Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Saad Alghamdi
- Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Alfadel Alshaibani
- Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Hamad Alashgar
- Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Khalid Alkahtani
- Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Ingvar Kagevi
- Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
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Perrillo RP, Gish R, Falck-Ytter YT. American Gastroenterological Association Institute technical review on prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. Gastroenterology 2015; 148:221-244.e3. [PMID: 25447852 DOI: 10.1053/j.gastro.2014.10.038] [Citation(s) in RCA: 389] [Impact Index Per Article: 38.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Robert P Perrillo
- Hepatology Division, Baylor University Medical Center, Department of Medicine, University of Texas Southwestern, Dallas, Texas
| | - Robert Gish
- Division of Gastroenterology and Hepatology, Department of Medicine,Stanford University, Palo Alto, California; Hepatitis B Foundation, Doylestown, Pennsylvania
| | - Yngve T Falck-Ytter
- Division of Gastroenterology and Hepatology, Department of Medicine, Case and VA Medical Center, Case Western Reserve University, Cleveland, Ohio
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Dienstag JL, Delemos AS. Viral Hepatitis. MANDELL, DOUGLAS, AND BENNETT'S PRINCIPLES AND PRACTICE OF INFECTIOUS DISEASES 2015:1439-1468.e7. [DOI: 10.1016/b978-1-4557-4801-3.00119-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Arends P, Rijckborst V, Zondervan PE, Buster E, Cakaloglu Y, Ferenci P, Tabak F, Akarca US, Simon K, Sonneveld MJ, Hansen BE, Janssen HLA. Loss of intrahepatic HBsAg expression predicts sustained response to peginterferon and is reflected by pronounced serum HBsAg decline. J Viral Hepat 2014; 21:897-904. [PMID: 24444353 DOI: 10.1111/jvh.12218] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2013] [Accepted: 10/09/2013] [Indexed: 12/18/2022]
Abstract
There is a lack of knowledge regarding the effect of peginterferon (PEG-IFN) on the expression of intrahepatic hepatitis B core and surface antigen (HBcAg and HBsAg) in chronic hepatitis B (CHB) and its relation with response to therapy. Fifty-two HBeAg-positive and 67 HBeAg-negative CHB patients with paired liver biopsies taken at baseline and after 1 year of PEG-IFN therapy were studied. After PEG-IFN therapy, HBeAg-negative patients showed a significant reduction in both intrahepatic HBcAg (P = 0.04) and HBsAg expression (P < 0.001). In contrast, a reduction in intrahepatic HBcAg expression was not observed in HBeAg-positive patients, while a trend in reduction of intrahepatic HBsAg staining was found (P = 0.09). Post-treatment, 7 (13%) HBeAg-positive and 9 (14%) HBeAg-negative patients had no expression of intrahepatic HBsAg. Patients without any intrahepatic HBsAg expression post-treatment were more likely to achieve a combined response (HBeAg loss with hepatitis B virus (HBV) DNA <2000 IU/mL for HBeAg -positive and HBV DNA <2000 IU/mL and normal alanine aminotransferase for HBeAg-negative CHB): 71% vs 5% for HBeAg-positive (P < 0.001) and 60% vs 16% for HBeAg-negative patients (P = 0.004), respectively. Moreover, a more profound decline of serum HBsAg was observed in patients with absence of intrahepatic HBsAg staining (3.1 vs 0.4 log IU/mL, P < 0.001 and 1.7 vs 0.4 log IU/mL, P = 0.005 for HBeAg-positive and HBeAg-negative CHB, respectively). In conclusion, PEG-IFN reduces expression of intrahepatic HBsAg. Loss of HBsAg as assessed by immunohistochemistry from the liver predicts a sustained response and is reflected in a pronounced serum HBsAg decline.
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Affiliation(s)
- P Arends
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
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Cai Q, Chen F, Shao X, Zhang X, Zhao Z, Gao Z. Treatment of pegylated interferon-α2a in chronic hepatitis B patients demonstrating a spontaneous decline in HBV DNA after acute exacerbation. Antivir Ther 2014; 20:217-24. [PMID: 25138110 DOI: 10.3851/imp2832] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/17/2014] [Indexed: 10/24/2022]
Abstract
BACKGROUND Acute exacerbation (AE) in chronic hepatitis B (CHB) is usually followed by a spontaneous decline in HBV DNA levels. The subsequent treatment is controversial. In this study, we evaluated the efficacy and safety of pegylated interferon-α2a (PEG-IFN-α2a) for such CHB patients. METHODS A total of 74 hepatitis B e antigen (HBeAg)-positive patients with a spontaneous HBV DNA decline (by >2 log10 IU•ml(-1), compared with baseline levels before antiviral treatment) after AE (alanine aminotransferase [ALT]: 10-30-fold the upper limit of normal [ULN], total bilirubin [TBIL]: 2-20 mg•dl(-1), prothrombin time activity >60%) were included. In total, 22 patients (group A) received PEG-IFN-α2a treatment (180 µg•kg(-1)•week(-1), when ALT was <10 ULN and TBIL<2 mg•dl(-1)) for 48 weeks, with 48 weeks of treatment-free follow-up. Twenty-one patients (group B) selected continual entecavir therapy. Thirty-one patients (group C, control group) received routine liver-protective drugs. RESULTS At week 96, virological response rates were 90.5%, 100% and 48%, and ALT normalization rates were 81%, 95% and 40% for groups A, B and C, respectively. HBeAg seroconversion rates were 71.4%, 45% and 32% in groups A, B and C, respectively. A high hepatitis B surface antigen (HBsAg) loss rate was observed in PEG-IFN-α2a-treated patients, while no entecavir-treated patients achieved HBsAg loss. Group A patients suffered from typical PEG-IFN therapy-related adverse events. No severe adverse event was observed in any groups. CONCLUSIONS PEG-IFN-α2a is effective and safe for treating CHB patients demonstrating a spontaneous decline in HBV DNA after AE, and yields an increased likelihood of HBsAg loss.
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Affiliation(s)
- Qingxian Cai
- The Department of Infectious Disease, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, PR China
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