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Sandmann L, Berg T, Deterding K, Fischer N, Hinrichsen H, Petersen J, Tacke F, Cornberg M. Addendum „Antivirale Therapie der chronischen Hepatitis-D-Virusinfektion“ zur S3-Leitlinie „Prophylaxe, Diagnostik und Therapie der Hepatitis-B-Virusinfektion“ der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS). ZEITSCHRIFT FUR GASTROENTEROLOGIE 2023; 61:1635-1653. [PMID: 38081179 DOI: 10.1055/a-2181-3046] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2023]
Affiliation(s)
- Lisa Sandmann
- Klinik für Gastroenterologie, Hepatologie, Infektiologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover, Deutschland
- D-SOLVE Consortium, Horizon Europe Project, partner-site Medizinische Hochschule Hannover, Hannover, Deutschland
| | - Thomas Berg
- Bereich Hepatologie, Medizinische Klinik II, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Katja Deterding
- Klinik für Gastroenterologie, Hepatologie, Infektiologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover, Deutschland
| | - Nadine Fischer
- Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS), Berlin, Deutschland
| | | | - Jörg Petersen
- IFI Institut für Interdisziplinäre Medizin an der Asklepios Klinik St Georg, Hamburg, Deutschland
| | - Frank Tacke
- Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Charité Universitätsmedizin Berlin, Berlin, Deutschland
| | - Markus Cornberg
- Klinik für Gastroenterologie, Hepatologie, Infektiologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover, Deutschland
- Centre for individualised infection Medicine (CiiM), Hannover, Deutschland
- Deutsches Zentrum für Infektionsforschung (DZIF), partner-site Hannover-Braunschweig, Deutschland
- D-SOLVE Consortium, Horizon Europe Project, partner-site Medizinische Hochschule Hannover, Hannover, Deutschland
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Sandmann L, Berg T, Deterding K, Fischer N, Hinrichsen H, Petersen J, Tacke F, Cornberg M. Antiviral Therapy of Chronic Hepatitis D Virus Infection - Addendum to the S3 Guideline "Prophylaxis, Diagnosis and Therapy of Hepatitis B Virus Infection" of the German Society for Gastroenterology, Digestive and Metabolic Diseases (DGVS). ZEITSCHRIFT FUR GASTROENTEROLOGIE 2023; 61:e715-e732. [PMID: 38081178 DOI: 10.1055/a-2181-3345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2023]
Affiliation(s)
- Lisa Sandmann
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- D-SOLVE Consortium, Horizon Europe Project, partner-site Hannover Medical School, Germany
| | - Thomas Berg
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
| | - Katja Deterding
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Nadine Fischer
- German Society for Gastroenterology, Digestive and Metabolic Diseases (DGVS), Berlin, Germany
| | | | - Jörg Petersen
- IFI Institute for Interdisciplinary Medicine at Asklepios Klinik St Georg, Hamburg, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- Centre for individualised infection Medicine (CiiM), Hannover, Germany
- German Center for Infection Research (DZIF), partner-site Hannover-Braunschweig, Germany
- D-SOLVE Consortium, Horizon Europe Project, partner-site Hannover Medical School, Germany
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Brunetto MR, Ricco G, Negro F, Wedemeyer H, Yurdaydin C, Asselah T, Papatheodoridis G, Gheorghe L, Agarwal K, Farci P, Buti M. EASL Clinical Practice Guidelines on hepatitis delta virus. J Hepatol 2023; 79:433-460. [PMID: 37364791 DOI: 10.1016/j.jhep.2023.05.001] [Citation(s) in RCA: 102] [Impact Index Per Article: 51.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 05/01/2023] [Indexed: 06/28/2023]
Abstract
Hepatitis D virus (HDV) is a defective virus that requires the hepatitis B virus to complete its life cycle and cause liver damage in humans. HDV is responsible for rare acute and chronic liver diseases and is considered the most aggressive hepatitis virus. Acute infection can cause acute liver failure, while persistent infection typically causes a severe form of chronic hepatitis which is associated with rapid and frequent progression to cirrhosis and its end-stage complications, hepatic decompensation and hepatocellular carcinoma. Major diagnostic and therapeutic innovations prompted the EASL Governing Board to commission specific Clinical Practice Guidelines on the identification, virologic and clinical characterisation, prognostic assessment, and appropriate clinical and therapeutic management of HDV-infected individuals.
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Schlaak JF. Current Therapy of Chronic Viral Hepatitis B, C and D. J Pers Med 2023; 13:964. [PMID: 37373953 DOI: 10.3390/jpm13060964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Revised: 05/22/2023] [Accepted: 06/06/2023] [Indexed: 06/29/2023] Open
Abstract
The majority of chronic viral hepatitis cases are induced via infection with the hepatitis B virus (HBV), hepatitis C virus (HCV), or hepatitis D virus (HDV). These patients are at increased risk for progressive liver disease leading to cirrhosis as well as hepatocellular carcinoma (HCC). HBV infection is well controlled by the currently available nucleosides as well as nucleotides, and the development of cirrhosis can be prevented. Additionally, it has been shown that HBV-induced liver fibrosis can regress during successful antiviral treatment; however, a "functional cure", i.e., loss of HBsAg, is a rare event when these drugs are used. Therefore, novel therapeutic strategies are aiming at the selective suppression of HBsAg levels in combination with immunostimulation. The development of directly acting antivirals (DAAs) has revolutionized HCV therapy, as almost all patients can be cured via this treatment. Additionally, DAA therapy has few, if any, side effects, and is generally well tolerated by patients. HDV remains the most challenging type of chronic viral hepatitis. Although novel therapeutic options have recently been approved, response rates are still less favorable compared to HBV and HCV. This review discusses current and future options for the treatment of chronic HBV, HCV, and HDV infection.
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Affiliation(s)
- Jörg F Schlaak
- Department of Internal Medicine, Ameos Hospital Oberhausen, Wilhelmstr. 34, 46145 Oberhausen, Germany
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Keskin O, Yurdaydin C. Emerging drugs for hepatitis D. Expert Opin Emerg Drugs 2023:1-12. [PMID: 37096555 DOI: 10.1080/14728214.2023.2205639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/26/2023]
Abstract
INTRODUCTION Chronic hepatitis delta (CHD) is the most severe form of chronic viral hepatitis. Until recently, its treatment consisted of pegylated interferon alfa (pegIFN) use. AREAS COVERED Current and new drugs for treating CHD. Virus entry inhibitor bulevirtide has received conditional approval by the European Medicines Agency. Prenylation inhibitor lonafarnib and pegIFN lambda are in phase 3 and nucleic acid polymers in phase 2 of drug development. EXPERT OPINION Bulevirtide appears to be safe. Its antiviral efficacy increases with treatment duration. Combining bulevirtide with pegIFN has the highest antiviral efficacy short-term. The prenylation inhibitor lonafarnib prevents hepatitis D virus assembly. It is associated with dose dependent gastrointestinal toxicity and is better used with ritonavir which increases liver lonafarnib concentrations. Lonafarnib also possesses immune modulatory properties which explains some post-treatment beneficial flare cases. Combining lonafarnib/ritonavir with pegIFN has superior antiviral efficacy. Nucleic acid polymers are amphipathic oligonucleotides whose effect appears to be a consequence of phosphorothioate modification of internucleotide linkages. These compounds led to HBsAg clearance in a sizeable proportion of patients. PegIFN lambda is associated with less IFN typical side effects. In a phase 2 study it led to 6 months off treatment viral response in one third of patients.
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Affiliation(s)
- Onur Keskin
- Department of Gastroenterology, Hacettepe University Medical School, Ankara, Turkey
| | - Cihan Yurdaydin
- Department of Gastroenterology & Hepatology, Koc University Medical School, Istanbul, Turkey
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Khalfi P, Kennedy PT, Majzoub K, Asselah T. Hepatitis D virus: Improving virological knowledge to develop new treatments. Antiviral Res 2023; 209:105461. [PMID: 36396025 DOI: 10.1016/j.antiviral.2022.105461] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 10/21/2022] [Accepted: 11/05/2022] [Indexed: 11/16/2022]
Abstract
Hepatitis delta virus (HDV), a satellite of hepatitis B virus (HBV), possesses the smallest viral genome known to infect animals. HDV needs HBV surface protein for secretion and entry into target liver cells. However, HBV is dispensable for HDV genome amplification, as it relies almost exclusively on cellular host factors for replication. HBV/HDV co-infections affect over 12 million people worldwide and constitute the most severe form of viral hepatitis. Co-infected individuals are at higher risk of developing liver cirrhosis and hepatocellular carcinoma compared to HBV mono-infected patients. Bulevirtide, an entry inhibitor, was conditionally approved in July 2020 in the European Union for adult patients with chronic hepatitis delta (CHD) and compensated liver disease. There are several drugs in development, including lonafarnib and interferon lambda, with different modes of action. In this review, we detail our current fundamental knowledge of HDV lifecycle and review antiviral treatments under development against this virus, outlining their respective mechanisms-of-action. Finally, we describe the antiviral effect these compounds are showing in ongoing clinical trials, discussing their promise and potential pitfalls for managing HDV infected patients.
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Affiliation(s)
- Pierre Khalfi
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS-UMR 5535, Montpellier 34293 cedex 5, France
| | - Patrick T Kennedy
- The Blizard Institute, Queen Mary University of London, The Royal London Hospital, Barts Health NHS Trust, London, UK
| | - Karim Majzoub
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS-UMR 5535, Montpellier 34293 cedex 5, France.
| | - Tarik Asselah
- Université de Paris, Cité CRI, INSERM UMR 1149, Department of Hepatology, AP-HP Hôpital Beaujon, Clichy, France.
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Yardeni D, Heller T, Koh C. Chronic hepatitis D-What is changing? J Viral Hepat 2022; 29:240-251. [PMID: 35122369 DOI: 10.1111/jvh.13651] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 01/03/2022] [Indexed: 01/04/2023]
Abstract
Hepatitis D virus (HDV) infection is a chronic viral disease of the liver that is still largely considered to be incurable due to lack of effective treatment options. Without treatment, the risk for the development of advanced liver disease, cirrhosis and hepatocellular carcinoma is significantly high. Currently, new therapeutic options are emerging out of ongoing phase 3 clinical trials, promising a new hope of cure for this devastating liver infection. Recently, bulevirtide, a first in its class HDV entry inhibitor, has received conditional authorization of use from the European Medicines Agency (EMA) and was also submitted for approval in the United States. Other novel therapeutic options in clincal trials include interferon lambda, the prenylation inhibitor lonafarnib and nucleic acidic polymers (NAPs). This review describes all recent advances and ongoing changes to the field of HDV therpaeutics.
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Affiliation(s)
- David Yardeni
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Theo Heller
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Christopher Koh
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
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Scheller L, Hilgard G, Anastasiou O, Dittmer U, Kahraman A, Wedemeyer H, Deterding K. Poor clinical and virological outcome of nucleos(t)ide analogue monotherapy in HBV/HDV co-infected patients. Medicine (Baltimore) 2021; 100:e26571. [PMID: 34260535 PMCID: PMC8284709 DOI: 10.1097/md.0000000000026571] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 06/08/2021] [Indexed: 01/04/2023] Open
Abstract
Co-infection of Hepatitis B (HBV) and Delta viruses (HDV) represent the most severe form of viral hepatitis. While treatment with pegylated Interferon alpha (PEG-IFNα) is well established, therapy with nucleoside or nucleotide analogues (NA) has been a matter of debate. We aimed to investigate the role of NA treatment in a well-defined single centre cohort.In a retrospective approach, we observed 53 HDV RNA positive and/or anti-HDV-positive patients recruited at a German referral centre between 2000 and 2019. Patients were followed for at least 3 months (mean time of follow up: 4.6 years; range: 0.2-14.1 years). Patients who had liver transplantation or hepatocellular carcinoma at the time of presentation were excluded. 43% (n = 23) were treated with NA, 43% (n = 23) received IFNα-based therapies and 13% (n = 7) were untreated.Liver cirrhosis was already present in 53% (28/53) of patients at first presentation. During follow-up, liver-related endpoints developed in 44% of all patients (n = 23). NA-treatment was associated with a significantly worse clinical outcome (P = .01; odds ratio [OR] = 4.92; CI = 1.51-16.01) compared to both, untreated (P = .38; OR = 0.46; CI = 0.80-2.61) and IFNα-based-treated patients (P = .04; OR = 0.29; CI = 0.89-0.94) in univariate logistic regression analysis. HBsAg levels declined by more than 50% during NA-based therapy in only 7 cases (7/23; mean time: 3.6 years; range: 0.8-8.5 years) and during IFNα-based therapy in 14 cases (14/23; mean time: 2.8 years, range 0.7-8.5 years). HDV RNA became undetectable during follow up in 30% of patients receiving NA alone (7/23; mean time: 5.0 years; range: 0.6-13.5 years), in 35% of patients receiving IFNα-based therapy (8/23; mean time: 2.9 years, range: 0.3-7.6 years).The effect of NA in patients with HBV/HDV co-infection is limited. Treatment with NA was associated with a higher likelihood of clinical disease progression. Interferon alpha therapy was beneficial in reducing liver complications and improves long-term outcome.
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Affiliation(s)
- Laura Scheller
- Department of Gastroenterology and Hepatology, University Hospital Essen, Germany
| | - Gudrun Hilgard
- Department of Gastroenterology and Hepatology, University Hospital Essen, Germany
| | | | - Ulf Dittmer
- Institute of Virology, University Hospital Essen, Germany
| | - Alisan Kahraman
- Department of Gastroenterology and Hepatology, University Hospital Essen, Germany
- Department of Gastroenterology, Max Grundig Clinic, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology and Hepatology, University Hospital Essen, Germany
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany
| | - Katja Deterding
- Department of Gastroenterology and Hepatology, University Hospital Essen, Germany
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany
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Cornberg M, Sandmann L, Protzer U, Niederau C, Tacke F, Berg T, Glebe D, Jilg W, Wedemeyer H, Wirth S, Höner Zu Siederdissen C, Lynen-Jansen P, van Leeuwen P, Petersen J. S3-Leitlinie der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) zur Prophylaxe, Diagnostik und Therapie der Hepatitis-B-Virusinfektion – (AWMF-Register-Nr. 021-11). ZEITSCHRIFT FUR GASTROENTEROLOGIE 2021; 59:691-776. [PMID: 34255317 DOI: 10.1055/a-1498-2512] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Markus Cornberg
- Deutsches Zentrum für Infektionsforschung (DZIF), Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover; Centre for individualised infection Medicine (CiiM), Hannover.,Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover
| | - Lisa Sandmann
- Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover
| | - Ulrike Protzer
- Institut für Virologie, Technische Universität München/Helmholtz Zentrum München, München
| | | | - Frank Tacke
- Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Charité Universitätsmedizin Berlin, Berlin
| | - Thomas Berg
- Klinik und Poliklinik für Gastroenterologie und Rheumatologie, Universitätsklinikum Leipzig, Leipzig
| | - Dieter Glebe
- Institut für Medizinische Virologie, Nationales Referenzzentrum für Hepatitis-B-Viren und Hepatitis-D-Viren, Justus-Liebig-Universität Gießen, Gießen
| | - Wolfgang Jilg
- Institut für Medizinische Mikrobiologie und Hygiene, Universität Regensberg, Regensburg
| | - Heiner Wedemeyer
- Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover
| | - Stefan Wirth
- Zentrum für Kinder- und Jugendmedizin, Helios Universitätsklinikum Wuppertal, Wuppertal
| | | | - Petra Lynen-Jansen
- Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS), Berlin
| | - Pia van Leeuwen
- Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS), Berlin
| | - Jörg Petersen
- IFI Institut für Interdisziplinäre Medizin an der Asklepios Klinik St. Georg, Hamburg
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Sagnelli C, Sagnelli E, Russo A, Pisaturo M, Occhiello L, Coppola N. HBV/HDV Co-Infection: Epidemiological and Clinical Changes, Recent Knowledge and Future Challenges. Life (Basel) 2021; 11:life11020169. [PMID: 33671730 PMCID: PMC7926847 DOI: 10.3390/life11020169] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 02/18/2021] [Accepted: 02/18/2021] [Indexed: 02/06/2023] Open
Abstract
Several investigations have been published on Hepatitis Delta Virus (HDV) infection in recent years, from which we have drawn the salient data to provide readers with useful information to improve their knowledge on the subject. HDV genotypes 5–8 have been recently imported to Western countries from central Africa, whose clinical relevance deserves further investigation. Ongoing HDV replication has been identified as an independent predictor of progression to cirrhosis and HCC for patients with HDV chronic hepatitis (HDV-CH). Long-term treatments of HDV-CH with standard or pegylated interferon alfa (peg-IFN-α) have all been unsatisfactory, leading to a sustained virological response (SVR) only in 20–30% of patients treated, faced with a poor tolerability and frequent serious adverse reactions; the addition of HBV nucleo(s)tide analogues to peg-IFN- α did not improve the rate of SVR. The improved knowledge of the HDV life cycle has allowed the development of direct acting agents towards key-points of the HDV life cycle, namely bulevirtide, lonafarnib and nucleic acid polymers. Preliminary data have shown that these drugs are more effective than interferon-based therapies, but adverse reactions are also common, which however seem toned down in combination therapy with other antivirals.
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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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Baskiran A, Akbulut S, Sahin TT, Koc C, Karakas S, Ince V, Yurdaydin C, Yilmaz S. Effect of HBV-HDV co-infection on HBV-HCC co-recurrence in patients undergoing living donor liver transplantation. Hepatol Int 2020; 14:869-880. [PMID: 32895876 DOI: 10.1007/s12072-020-10085-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 08/20/2020] [Indexed: 02/07/2023]
Abstract
PURPOSE To evaluate the effect of hepatitis D virus (HDV) on hepatitis B virus-hepatocellular carcinoma (HBV-HCC) co-recurrence in patients undergoing living donor liver transplantation (LDLT) for HBV alone or HBV-HDV coinfection. METHODS Between 2002 and 2019, 254 HBV-HCC patients underwent LDLT. The patients were divided into two groups after the application of the exclusion criteria: HBV-HCC (Group B; n = 163) and HBV-HDV-HCC (Group D; n = 31). First, the B and D groups were compared in terms of demographic and clinical parameters. Second, patients with (n = 16) and without (n = 178) post-transplant HBV-HCC co-recurrences were grouped and compared in terms of the same parameters. RESULTS Although the risk of HBV-HCC co-recurrence in group D was 4.99-fold higher than in group B, the risk of HBV recurrence alone in group D was 12.5-fold lower than in group B. The AFP (OR = 4.4), Milan criteria (beyond; OR = 18.8), and HDV (OR = 8.1) were identified as the independent risk factors affecting post-transplant HBV-HCC co-recurrence. The Milan criteria (OR = 2.1) and HBV-HCC co-recurrence (OR = 10.9) were identified as the risk factors affecting post-transplant mortality. HBV-HCC co-recurrence developed in 26.5% of patients in Group B and 100% in Group D (OR = 40; p = 0.001). HCC recurrence alone developed in 10% of patients without HBV recurrence in group B and 0% of patients without HBV recurrence in group D (OR = 5.7). CONCLUSION This study showed that the risk of HBV recurrence alone was reduced by 12.5-fold in the presence of HDV; however, the HCC recurrence occurred in all patients with HDV when HBV recurrence developed.
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Affiliation(s)
- Adil Baskiran
- Department of Surgery, Faculty of Medicine, Liver Transplant Institute, Inonu University, Elazig Yolu 10. Km, 44280, Malatya, Turkey
| | - Sami Akbulut
- Department of Surgery, Faculty of Medicine, Liver Transplant Institute, Inonu University, Elazig Yolu 10. Km, 44280, Malatya, Turkey.
| | - Tevfik Tolga Sahin
- Department of Surgery, Faculty of Medicine, Liver Transplant Institute, Inonu University, Elazig Yolu 10. Km, 44280, Malatya, Turkey
| | - Cemalettin Koc
- Department of Surgery, Faculty of Medicine, Liver Transplant Institute, Inonu University, Elazig Yolu 10. Km, 44280, Malatya, Turkey
| | - Serdar Karakas
- Department of Surgery, Faculty of Medicine, Liver Transplant Institute, Inonu University, Elazig Yolu 10. Km, 44280, Malatya, Turkey
| | - Volkan Ince
- Department of Surgery, Faculty of Medicine, Liver Transplant Institute, Inonu University, Elazig Yolu 10. Km, 44280, Malatya, Turkey
| | - Cihan Yurdaydin
- Department of Gastroenterology, Faculty of Medicine, Koc University, 34450, Istanbul, Turkey
| | - Sezai Yilmaz
- Department of Surgery, Faculty of Medicine, Liver Transplant Institute, Inonu University, Elazig Yolu 10. Km, 44280, Malatya, Turkey
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Abstract
Chronic hepatitis D (CHD) results from an infection with the hepatitis B virus and hepatitis D virus (HDV). CHD is the most severe form of human viral hepatitis. Current treatment options consist of interferon alfa, which is effective only in a minority of patients. Study of HDV molecular virology has resulted in new approaches entering clinical trials, with phase-3 studies the most advanced. These include the entry inhibitor bulevirtide, the nucleic acid polymer REP 2139-Ca, the farnesyltransferase inhibitor lonafarnib, and pegylated interferon lambda. This article summarizes the available data on these emerging therapeutics.
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Affiliation(s)
- Christopher Koh
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Ben L. Da
- Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Jeffrey S. Glenn
- Departments of Medicine and Microbiology & Immunology, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
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Da BL, Heller T, Koh C. Hepatitis D infection: from initial discovery to current investigational therapies. Gastroenterol Rep (Oxf) 2019; 7:231-245. [PMID: 32477569 DOI: 10.1093/gastro/goz023] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Revised: 03/15/2019] [Accepted: 05/09/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatitis D is the most severe form of viral hepatitis associated with a more rapid progression to cirrhosis and an increased risk of hepatocellular carcinoma and mortality compared with hepatitis B mono-infection. Although once thought of as a disappearing disease, hepatitis D is now becoming recognized as a serious worldwide issue due to improvement in diagnostic testing and immigration from endemic countries. Despite these concerns, there is currently only one accepted medical therapy (pegylated-interferon-α) for the treatment of hepatitis D with less than desirable efficacy and significant side effects. Due to these reasons, many patients never undergo treatment. However, increasing knowledge about the virus and its life cycle has led to the clinical development of multiple promising new therapies that hope to alter the natural history of this disease and improve patient outcome. In this article, we will review the literature from discovery to the current investigational therapies.
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Affiliation(s)
- Ben L Da
- Digestive Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Theo Heller
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Christopher Koh
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
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Yurdaydin C. New treatment options for delta virus: Is a cure in sight? J Viral Hepat 2019; 26:618-626. [PMID: 30771261 DOI: 10.1111/jvh.13081] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Accepted: 01/25/2019] [Indexed: 12/12/2022]
Abstract
Current treatment of chronic hepatitis D viral infection with interferons is poorly tolerated and effective only in a minority of patients. Despite delta virus causing the most severe form of chronic viral hepatitis, no other treatments are available. After many years of inactivity, there is now hope for new treatment approaches for delta virus and some are likely to enter clinical practice in the near future. Four new treatment approaches are currently being evaluated in phase 2 studies. These involve the hepatocyte entry inhibitor myrcludex B, the farnesyl transferase inhibitor lonafarnib, the nucleic acid inhibitor REP 2139 Ca and pegylated interferon lambda. Results obtained so far are promising, and phase 3 studies are expected shortly. This review summarizes the available data on the efficacy and safety of these new drugs.
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Affiliation(s)
- Cihan Yurdaydin
- Department of Gastroenterology, Ankara University Medical School, Ankara, Turkey.,Department of Gastroenterology and Hepatology, Koc University, Istanbul, Turkey
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16
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Mentha N, Clément S, Negro F, Alfaiate D. A review on hepatitis D: From virology to new therapies. J Adv Res 2019; 17:3-15. [PMID: 31193285 PMCID: PMC6526199 DOI: 10.1016/j.jare.2019.03.009] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Revised: 03/21/2019] [Accepted: 03/22/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatitis delta virus (HDV) is a defective virus that requires the hepatitis B virus (HBV) to complete its life cycle in human hepatocytes. HDV virions contain an envelope incorporating HBV surface antigen protein and a ribonucleoprotein containing the viral circular single-stranded RNA genome associated with both forms of hepatitis delta antigen, the only viral encoded protein. Replication is mediated by the host cell DNA-dependent RNA polymerases. HDV infects up to72 million people worldwide and is associated with an increased risk of severe and rapidly progressive liver disease. Pegylated interferon-alpha is still the only available treatment for chronic hepatitis D, with poor tolerance and dismal success rate. Although the development of antivirals inhibiting the viral replication is challenging, as HDV does not possess its own polymerase, several antiviral molecules targeting other steps of the viral life cycle are currently under clinical development: Myrcludex B, which blocks HDV entry into hepatocytes, lonafarnib, a prenylation inhibitor that prevents virion assembly, and finally REP 2139, which is thought to inhibit HBsAg release from hepatocytes and interact with hepatitis delta antigen. This review updates the epidemiology, virology and management of HDV infection.
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Affiliation(s)
- Nathalie Mentha
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
| | - Sophie Clément
- Division of Clinical Pathology, Geneva University Hospitals, 1211 Geneva, Switzerland
| | - Francesco Negro
- Division of Clinical Pathology, Geneva University Hospitals, 1211 Geneva, Switzerland
- Division of Gastroenterology and Hepatology, Geneva University Hospitals, 1205 Geneva, Switzerland
| | - Dulce Alfaiate
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
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17
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Abstract
Hepatitis delta virus (HDV) is a defective RNA virus that depends on the presence of hepatitis B virus (HBV) for the creation of new virions and propagation of the infection to hepatocytes. Chronic infection with HDV is usually associated with a worsening of HBV infection, leading more frequently to cirrhosis, increased risk of liver decompensation and hepatocellular carcinoma (HCC) occurrence. In spite of a progressive declining prevalence of both acute and chronic HDV infection observed over several years, mainly due to increased global health policies and mass vaccination against HBV, several European countries have more recently observed stable HDV prevalence mainly due to migrants from non-European countries. Persistent HDV replication has been widely demonstrated as associated with cirrhosis development and, as a consequence, development of liver decompensation and occurrence of HCC. Several treatment options have been attempted with poor results in terms of HDV eradication and improvement of long-term prognosis. A global effort is deemed urgent to enhance the models already existing as well as to learn more about HDV infection and correlated tumourigenesis mechanisms.
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18
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Botelho-Souza LF, Vasconcelos MPA, Dos Santos ADO, Salcedo JMV, Vieira DS. Hepatitis delta: virological and clinical aspects. Virol J 2017; 14:177. [PMID: 28903779 PMCID: PMC5597996 DOI: 10.1186/s12985-017-0845-y] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Accepted: 09/05/2017] [Indexed: 02/06/2023] Open
Abstract
There are an estimated 400 million chronic carriers of HBV worldwide; between 15 and 20 million have serological evidence of exposure to HDV. Traditionally, regions with high rates of endemicity are central and northern Africa, the Amazon Basin, eastern Europe and the Mediterranean, the Middle East and parts of Asia. There are two types of HDV/HBV infection which are differentiated by the previous status infection by HBV for the individual. Individuals with acute HBV infection contaminated by HDV is an HDV/HBV co-infection, while individuals with chronic HBV infection contaminated by HDV represent an HDV/HBV super-infection. The appropriate treatment for chronic hepatitis delta is still widely discussed since it does not have an effective drug. Alpha interferon is currently the only licensed therapy for the treatment of chronic hepatitis D. The most widely used drug is pegylated interferon but only approximately 25% of patients maintain a sustained viral response after 1 year of treatment. The best marker of therapeutic success would be the clearance of HBsAg, but this data is rare in clinical practice. Therefore, the best way to predict a sustained virologic response is the maintenance of undetectable HDV RNA levels.
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Affiliation(s)
- Luan Felipo Botelho-Souza
- Laboratório de Virologia Molecular - FIOCRUZ - RONDÔNIA, Rua da Beira, 7671 - BR 364, Km 3,5 Bairro Lagoa, CEP: 76812, Porto Velho, RO, CEP: 76812-329, Brazil.
- Ambulatório de Hepatites Virais, Fundação Oswaldo Cruz Rondônia e Centro de Pesquisa em Medicina Tropical - CEPEM, Avenida Guaporé, 215, anexo Hospital CEMETRON, Agenor M de Carvalho, Porto Velho, RO, CEP: 76812-329, Brazil.
- Programa de Pós-Graduação em Biologia Experimental - PGBioExp, Rodovia Br-364, KM 9, CAMPUS UNIR, Porto Velho, RO, CEP: 76801-974, Brazil.
| | | | - Alcione de Oliveira Dos Santos
- Laboratório de Virologia Molecular - FIOCRUZ - RONDÔNIA, Rua da Beira, 7671 - BR 364, Km 3,5 Bairro Lagoa, CEP: 76812, Porto Velho, RO, CEP: 76812-329, Brazil
- Ambulatório de Hepatites Virais, Fundação Oswaldo Cruz Rondônia e Centro de Pesquisa em Medicina Tropical - CEPEM, Avenida Guaporé, 215, anexo Hospital CEMETRON, Agenor M de Carvalho, Porto Velho, RO, CEP: 76812-329, Brazil
- Programa de Pós-Graduação em Biologia Experimental - PGBioExp, Rodovia Br-364, KM 9, CAMPUS UNIR, Porto Velho, RO, CEP: 76801-974, Brazil
| | - Juan Miguel Villalobos Salcedo
- Laboratório de Virologia Molecular - FIOCRUZ - RONDÔNIA, Rua da Beira, 7671 - BR 364, Km 3,5 Bairro Lagoa, CEP: 76812, Porto Velho, RO, CEP: 76812-329, Brazil
- Ambulatório de Hepatites Virais, Fundação Oswaldo Cruz Rondônia e Centro de Pesquisa em Medicina Tropical - CEPEM, Avenida Guaporé, 215, anexo Hospital CEMETRON, Agenor M de Carvalho, Porto Velho, RO, CEP: 76812-329, Brazil
- Programa de Pós-Graduação em Biologia Experimental - PGBioExp, Rodovia Br-364, KM 9, CAMPUS UNIR, Porto Velho, RO, CEP: 76801-974, Brazil
| | - Deusilene Souza Vieira
- Laboratório de Virologia Molecular - FIOCRUZ - RONDÔNIA, Rua da Beira, 7671 - BR 364, Km 3,5 Bairro Lagoa, CEP: 76812, Porto Velho, RO, CEP: 76812-329, Brazil
- Ambulatório de Hepatites Virais, Fundação Oswaldo Cruz Rondônia e Centro de Pesquisa em Medicina Tropical - CEPEM, Avenida Guaporé, 215, anexo Hospital CEMETRON, Agenor M de Carvalho, Porto Velho, RO, CEP: 76812-329, Brazil
- Programa de Pós-Graduação em Biologia Experimental - PGBioExp, Rodovia Br-364, KM 9, CAMPUS UNIR, Porto Velho, RO, CEP: 76801-974, Brazil
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19
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Wranke A, Serrano BC, Heidrich B, Kirschner J, Bremer B, Lehmann P, Hardtke S, Deterding K, Port K, Westphal M, Manns MP, Cornberg M, Wedemeyer H. Antiviral treatment and liver-related complications in hepatitis delta. Hepatology 2017; 65:414-425. [PMID: 27770553 DOI: 10.1002/hep.28876] [Citation(s) in RCA: 88] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2016] [Accepted: 09/22/2016] [Indexed: 12/14/2022]
Abstract
UNLABELLED Hepatitis delta virus (HDV) is the most severe form of viral hepatitis. Pegylated interferon alfa (PEG-IFNα) is effective in only 25%-30% of patients and is associated with frequent side effects. The aim of this study was to analyze the clinical long-term outcome of hepatitis delta in relation to different antiviral treatment strategies. We studied 136 anti-HDV-positive patients who were followed for at least 6 months in a retrospective single-center cohort (mean time of follow-up, 5.2 years; range, 0.6-18.8). Liver cirrhosis was already present in 62 patients at first presentation. Twenty-nine percent of patients did not receive any antiviral treatment, 38% were treated with interferon alfa (IFNα)-based therapies, and 33% received nucleos(t)ide analogues (NAs) only. Clinical endpoints defined as hepatic decompensation (ascites, encephalopathy, and variceal bleeding), hepatocellular carcinoma, liver transplantation, and liver-related death developed in 55 patients (40%). Patients who received IFNα-based therapies developed clinical endpoints less frequently than those treated with NA (P = 0.02; HR, 4.0) or untreated patients (P = 0.05; HR, 2.2; 17%, 64%, and 44%), respectively, which was significant in both chi-square and Kaplan-Meier analysis. In addition, considering various clinical and virological parameters, IFNα therapy was independently associated with a more benign clinical long-term outcome in multivariate logistic regression analysis (P = 0.04; odds ratio, 0.25; 95% confidence interval, 0.07-0.9). Loss of HDV RNA during follow-up was more frequent in IFNα-treated patients and strongly linked with a lower likelihood to experience liver-related complications. CONCLUSION IFNα-based antiviral therapy of hepatitis delta was independently associated with a lower likelihood for clinical disease progression. Durable undetectability of HDV RNA is a valid surrogate endpoint in the treatment of hepatitis delta. (Hepatology 2017;65:414-425).
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Affiliation(s)
- Anika Wranke
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Beatriz Calle Serrano
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Benjamin Heidrich
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Partner Side Hannover Medical School, Hannover, Germany
| | - Janina Kirschner
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Birgit Bremer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Patrick Lehmann
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Svenja Hardtke
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Partner Side Hannover Medical School, Hannover, Germany
| | - Katja Deterding
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Kerstin Port
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Max Westphal
- Institute for Biometry, Hannover Medical School, Germany
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Partner Side Hannover Medical School, Hannover, Germany.,Integrated Research and Treatment Center Transplantation, Hannover Medical School, Germany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Partner Side Hannover Medical School, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Partner Side Hannover Medical School, Hannover, Germany.,Integrated Research and Treatment Center Transplantation, Hannover Medical School, Germany
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20
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Affiliation(s)
| | - Abdurrahman Sahin
- Department of Gastroenterology, Medicine Faculty, Firat University, Elazig, Turkey
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21
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Wranke A, Heidrich B, Hardtke S, Wedemeyer H. Current Management of HBV/HDV Coinfection and Future Perspectives. ACTA ACUST UNITED AC 2015. [DOI: 10.1007/s11901-015-0280-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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22
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Romeo R, Perbellini R. Hepatitis delta virus: Making the point from virus isolation up to 2014. World J Hepatol 2015; 7:2389-2395. [PMID: 26464754 PMCID: PMC4598609 DOI: 10.4254/wjh.v7.i22.2389] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2015] [Accepted: 09/18/2015] [Indexed: 02/06/2023] Open
Abstract
Chronic infection with hepatitis delta virus (HDV) has lately regained clinical importance because of the recent evidence of increasing prevalence in several European countries, due to immigration from highly endemic areas. HDV requires the mandatory presence of hepatitis B virus (HBV) for propagation to hepatocytes. It is transmitted by the same routes of HBV and it can be acquired either by co-infection (simultaneous transmission of the two viruses) or super-infection (acquisition of HDV by an already chronic carrier of HBV). As a consequence, every HBV carrier is potentially at risk for HDV superinfection. Since the clinical course of super-infection can be severe, early diagnosis of HDV infection is necessary.
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23
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Abstract
Hepatitis D virus (HDV) is an uncommon, defective, single-stranded circular RNA virus that is dependent on the hepatitis B virus' surface antigen envelope proteins for transmission. It is highly pathogenic and associated with high rates of progression to cirrhosis and associated complications. HDV continues to ravage endemic parts of Asia and Europe, and its prevalence in the United States, although low, has not decreased in frequency, despite universal hepatitis B virus vaccination, because of lack of testing and underrecognition. There are few reports on the prevalence and characteristics of HDV infection in the pediatric population. We present 2 patients with HDV infection at our institution; both were from eastern Europe and were treated with pegylated interferon-α. The present standard of care treatment for HDV yields suboptimal results, but insights into the virology of hepatitis D are stimulating the search for novel therapeutic approaches, particularly the development of prenylation inhibitors and viral entry inhibitors.
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24
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Abstract
Delta hepatitis is the less frequently encountered but most severe form of viral hepatitis. Acute delta hepatitis, as a result of coinfection with hepatitis B and hepatitis delta, is rare, but may lead to fulminant hepatitis, and no therapy exists for this form. Chronic delta hepatitis (CDH) mostly develops as a result of superinfection of a hepatitis B surface antigen (HBsAg) carrier with hepatitis delta virus (HDV). In general, HDV is the dominant virus. However, a dynamic shift of the dominant virus may occur with time in rare instances, and hepatitis B virus (HBV) may become the dominant virus, at which time nucleos(t)ide analog therapy may be indicated. Otherwise, the only established management of CDH consists of conventional or pegylated interferon therapy, which has to be administered at doses used for hepatitis B for a duration of at least 1 year. Posttreatment week-24 virologic response is the most widely used surrogate marker of treatment efficacy, but it does not represent a sustained virologic response, and late relapse can occur. As an easy-to-use simple serological test, anti-HDV-immunoglobulin M (IgM) correlates with histological inflammatory activity and clinical long-term outcome; however, it is not as sensitive as HDV RNA in assessing treatment response. No evidence-based rules for treating CDH exist, and treatment duration needs to be individualized based on virologic response at end of treatment or end of follow-up. Effective treatment may decrease liver-related complications, such as decompensation or liver-related mortality. In patients with decompensated cirrhosis, interferons are contraindicated and liver transplantation has to be considered. Alternative treatment options are an urgent need in CDH. New treatment strategies targeting different steps of the HDV life cycle, such as hepatocyte entry inhibitors or prenylation inhibitors, are emerging and provide hope for the future.
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Affiliation(s)
- Cihan Yurdaydin
- Department of Gastroenterology, University of Ankara Medical School, Ankara 06100, Turkey Hepatology Institute, University of Ankara, Ankara 06100, Turkey
| | - Ramazan Idilman
- Department of Gastroenterology, University of Ankara Medical School, Ankara 06100, Turkey
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25
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Bahcecioglu IH, Ispiroglu M, Demirel U, Yalniz M. Pegylated Interferon α Therapy in Chronic Delta Hepatitis: A One-Center Experience. HEPATITIS MONTHLY 2015; 15:e24366. [PMID: 25861318 PMCID: PMC4385268 DOI: 10.5812/hepatmon.24366] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/06/2014] [Revised: 02/06/2015] [Accepted: 02/21/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND The only established therapy for chronic viral delta hepatitis, the most severe form of viral hepatitis is treatment with pegylated-interferon α (Peg IFN α). OBJECTIVES In this study, we aimed to determine the efficacy of pegylated-interferon α 2a (Peg-IFN α 2a) and 2b (Peg IFN α 2b) in the treatment of patients infected with chronic delta hepatitis virus. PATIENTS AND METHODS The sample size was based on available patients potentially to be recruited. Data of 63 patients receiving either Peg IFN alpha 2a or Peg IFN alpha 2b were retrospectively assessed in the present cohort study performed in Turkey. Of 56 patients completed the study, 41 received Peg IFN α 2a and 15 received Peg IFN α 2b for 12 months. Patients were evaluated for biochemical and virological responses at the end of given treatment and six months after the treatment. RESULTS Stage of fibrosis was found high in both groups (85.4% vs. 86.7%), while cirrhosis was higher in the group of Peg IFN α 2b (53.3% vs. 34.1%). At the end of treatment, either hepatitis delta virus RNA (HDV RNA) alone or both HDV RNA and hepatitis b virus DNA (HBV DNA) had negative results in 32% of patients. Although HDV RNA negativity was sustained in 30.3% of patients, negativity of both HDV RNA and HBV DNA was decreased to 19.6% six months after completion of the treatment. HBV DNA became positive in one third of patients with response at six months after completion of the treatment (10.7% of all patients). HDV RNA negativity at month six was found as a predictor of positive response. No significant difference was found between Peg IFN α 2a and Peg IFN α 2b for virological response rate. CONCLUSIONS Treatment with Peg IFN α achieved a sustained negativity of HDV RNA in about one third of patients. Duration of Peg IFN α therapy might be prolonged to at least 24 months or more to prevent the occurrence of Hepatitis B virus (HBV) relapse encountered six months after completion of the treatment.
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Affiliation(s)
- Ibrahim Halil Bahcecioglu
- Department of Gastroenterology, Faculty of Medicine, Firat University, Elazig, Turkey
- Corresponding Author: Ibrahim Halil Bahcecioglu, Department of Gastroenterology, Faculty of Medicine, Firat University, Elazig, Turkey. Tel: +90-4242333555, Fax: +90-4242388096, E-mail:
| | - Murat Ispiroglu
- Department of Gastroenterology, Faculty of Medicine, Firat University, Elazig, Turkey
| | - Ulvi Demirel
- Department of Gastroenterology, Faculty of Medicine, Firat University, Elazig, Turkey
| | - Mehmet Yalniz
- Department of Gastroenterology, Faculty of Medicine, Firat University, Elazig, Turkey
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Kabaçam G, Wedemeyer H, Savaş B, Keskin O, Dalekos G, Tabak F, Idilman R, Erhardt A, Yalçın K, Bozdayi MA, Bozkaya H, Manns M, Dienes H, Yurdaydın C. Role of immunohistochemistry for hepatitis D and hepatitis B virus in hepatitis delta. Liver Int 2014; 34:1207-15. [PMID: 24308704 DOI: 10.1111/liv.12376] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2013] [Accepted: 10/31/2013] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS Immunohistochemical assessment of liver tissue in chronic delta hepatitis (CDH) is underinvestigated. Aim of the study was (i) to assess variables associated with hepatitis D antigen (HDAg), hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg) staining in the liver. METHODS Demographic, biochemical and virologic data collected from the HIDIT 1 study were used. HBsAg, HBcAg and HDAg immunohistochemical (IHC) staining was semiquantitatively assessed. RESULTS Hepatitis D antigen immunohistochemical staining displayed positive correlations with age and alanine aminotransferase (ALT) and negative correlations with serum HBsAg (P = 0.01 for all). HBsAg IHC displayed a negative correlation with gamma glutamyl transferase and positive correlations with serum HBV DNA, serum HBsAg levels and HBeAg serology (P < 0.001, P = 0.02 and P = 0.007 respectively). HBcAg staining was mainly nuclear and displayed negative correlations with serum HBsAg and histologic activity (P = 0.002 and P = 0.02 respectively). Pegylated IFN based treatment led to a decline of all IHC markers, however, these markers had no impact on treatment outcome. CONCLUSIONS These data suggest an association of liver injury with HDAg expression in CDH whereas the negative correlation between HBcAg expression and liver injury and the overall nuclear localization of HBcAg suggest that HBcAg does not contribute to liver injury in CDH. HDV cases with high level of HBV replication, high serum HBsAg levels, HBeAg positivity, that are probably in the earlier stages of disease (low gamma-glutamyl transferase), had a more intense HBsAg staining profile. Overall, the data enforce the importance of HDAg and HBsAg in different phases of CDH infection.
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Affiliation(s)
- Gökhan Kabaçam
- Department of Gastroenterology, University of Ankara Medical School, Ankara, Turkey
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Noureddin M, Gish R. Hepatitis delta: epidemiology, diagnosis and management 36 years after discovery. Curr Gastroenterol Rep 2014; 16:365. [PMID: 24293018 PMCID: PMC3918112 DOI: 10.1007/s11894-013-0365-x] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/02/2023]
Abstract
With recent studies showing increased prevalence of hepatitis delta (HDV) even in the US, Australia, and some countries in Europe, and very high prevalence in endemic regions, HDV infection is far from being a disappearing disease. Although immigrants from endemic countries have been shown to have increased risk, studies have clearly shown that the disease is not solely appearing in traditional high-risk groups. Recent studies provide increasing evidence that sexual transmission may be an important factor in HDV infection spread. Based on the totality of evidence showing increased disease progression and substantially increased risk of cirrhosis in HDV-infected CHB patients, and the current studies showing higher than expected prevalence, it is time to call for HDV screening of all CHB patients. HDV viral load detection and measurement should be considered in all patients whether or not they are anti-HDV-positive. With universal screening of CHB patients for HDV, earlier diagnosis and consideration of treatment would be possible. Current treatment of HDV is IFN-based therapy with or without HBV antivirals, but current research indicates the possibility that prenylation inhibitors, entry inhibitors, HBsAg release inhibitors, or other therapies currently in the pipeline may provide more effective therapy in the future. In addition, universal screening would serve the important public health goal of allowing patients to be educated on their status and on the need for HDV-negative patients to protect themselves against superinfection and for HDV-infected patients to protect against transmission to others. Further studies and global awareness of HDV infection are needed.
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Affiliation(s)
- Mazen Noureddin
- Division of Gastroenterology and Hepatology, Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, HMR 101, Los Angeles, CA 90033 USA
| | - Robert Gish
- Robert G. Gish Consultants, LLC, San Diego, CA USA
- St. Joseph’s Hospital and Medical Center, Phoenix, AZ USA
- University of Nevada, Las Vegas, 6022 La Jolla Mesa Drive, San Diego, CA 92037 USA
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28
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Lunemann S, Grabowski J, Wedemeyer H. Immunopathogenesis of Hepatitis D. LIVER IMMUNOLOGY 2014:231-241. [DOI: 10.1007/978-3-319-02096-9_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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29
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Hepatitis delta virus: a peculiar virus. Adv Virol 2013; 2013:560105. [PMID: 24198831 PMCID: PMC3807834 DOI: 10.1155/2013/560105] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2013] [Revised: 08/29/2013] [Accepted: 08/29/2013] [Indexed: 02/07/2023] Open
Abstract
The hepatitis delta virus (HDV) is distributed worldwide and related to the most severe form of viral hepatitis. HDV is a satellite RNA virus dependent on hepatitis B surface antigens to assemble its envelope and thus form new virions and propagate infection. HDV has a small 1.7 Kb genome making it the smallest known human virus. This deceivingly simple virus has unique biological features and many aspects of its life cycle remain elusive. The present review endeavors to gather the available information on HDV epidemiology and clinical features as well as HDV biology.
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30
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Ghamari S, Alavian SM, Rizzetto M, Olivero A, Smedile A, Khedive A, Alavian SE, Zolfaghari MR, Jazayeri SM. Prevalence of hepatitis delta virus (HDV) infection in chronic hepatitis B patients with unusual clinical pictures. HEPATITIS MONTHLY 2013; 13:e6731. [PMID: 24098308 PMCID: PMC3787685 DOI: 10.5812/hepatmon.6731] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/10/2012] [Revised: 06/29/2013] [Accepted: 07/15/2013] [Indexed: 12/11/2022]
Abstract
BACKGROUND Probably 5% of the HBV carriers have HDV super infection. The risk of fulminant hepatitis, cirrhosis and hepatocellular carcinoma is higher in superinfection than the settings when HBV is alone. OBJECTIVES The aim of this study was to evaluate the prevalence of HDV in Iranian HBV isolates and to compare their clinical and virological pictures as well as their HDV genetic variations with other worldwide isolates. PATIENTS AND METHODS 81 carriers with positive results for HBsAg with upper limit ranges of ALT and low or undetectable levels of HBV viral load who did not respond to HBV therapy were selected. After RT amplification of HDV Delta antigen, direct sequencing and phylogenetic study were performed to explore the genotype(s) and nucleotide/amino acid variations. RESULTS 12 (14.8%) patients had positive results for both HDV RNA and anti-HDV. The mean ALT level was higher in HDV positive patients (75.9 U/ML) than HBV-mono-infected individuals; however, the mean HBV viral load was lower in coinfected patients than HBV-mono-infected patients. Phylogenetically, genotype I was the only detected genotype, and the most closely related isolates were of Turkish, Italian and Mongolian origin. Within the delta Ag, there were 326 nucleotide mutations, of which 111 and 215 were silent and missense, respectively. The total number of amino acid substitution was 148; most were located in known functional/epitopic domains. There was no correlation between the numbers of amino acid mutations, with clinical, virological status of the patients. CONCLUSIONS HDV should be suspected in HBV carriers with unusual clinical and virological pictures. Relatedness of Iranian HDV isolates to Italian and Turkish sequences proposed a common Caucasian origin for the distribution of HDV genotype I in this ethnic group.
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Affiliation(s)
- Shiva Ghamari
- Hepatitis B Molecular Laboratory, Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, IR Iran
| | - Seyed Moayed Alavian
- Baqiyatallah University of Medical Sciences, Baqiyatallah Research Centre for Gastroenterology and Liver Disease, Tehran, IR Iran
- Middle East Liver Diseases Center, Tehran, IR Iran
| | - Mario Rizzetto
- Department of Gastroenterology and Hepatology, San Giovanni Battista University Hospital (Molinette), Turin, Italy
| | - Antonella Olivero
- Department of Gastroenterology and Hepatology, San Giovanni Battista University Hospital (Molinette), Turin, Italy
| | - Antonina Smedile
- Department of Gastroenterology and Hepatology, San Giovanni Battista University Hospital (Molinette), Turin, Italy
| | - Abulfazl Khedive
- Hepatitis B Molecular Laboratory, Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, IR Iran
| | - Seyed Ehsan Alavian
- Baqiyatallah University of Medical Sciences, Baqiyatallah Research Centre for Gastroenterology and Liver Disease, Tehran, IR Iran
- Middle East Liver Diseases Center, Tehran, IR Iran
| | | | - Seyed Mohammad Jazayeri
- Hepatitis B Molecular Laboratory, Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, IR Iran
- Corresponding author: Seyed Mohammad Jazayeri, Hepatitis B Molecular Laboratory, Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, IR Iran. Tel/Fax: +98-2188992660, E-mail:
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Stokowa-Sołtys K, Gaggelli N, Nagaj J, Szczepanik W, Ciesiołka J, Wrzesiński J, Górska A, Gaggelli E, Valensin G, Jeżowska-Bojczuk M. High affinity of copper(II) towards amoxicillin, apramycin and ristomycin. Effect of these complexes on the catalytic activity of HDV ribozyme. J Inorg Biochem 2013; 124:26-34. [DOI: 10.1016/j.jinorgbio.2013.03.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2012] [Revised: 02/28/2013] [Accepted: 03/04/2013] [Indexed: 12/18/2022]
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Abstract
Hepatitis delta virus (HDV) is a defective RNA virus that depends on hepatitis B virus (HBV) for its lifecycle. Treatment of chronic HDV infection is difficult as it does not have an enzymatic function as a target, such as polymerases and proteases of HBV and hepatitis C virus. Recently, it has been suggested that farnesyl transferase could be an enzymatic target. Currently, interferon is the only agent against HDV infection. Virological response has risen to 20-47% with pegylated interferon. Monotherapy of nucleos(t)ide analogs are ineffective against the HDV infection, but adefovir and pegylated interferon combination therapy have had some advantages for reduction of HBV surface antigen (HBsAg) levels. Recent studies suggest that measuring HBsAg levels during treatment could be more meaningful than HDV RNA negativity to predict virological response. Prenylation inhibitors that can affect the interactions between the large HDV antigen and HBsAg in the HDV virion are expected treatments for HDV infection. More studies are needed to understand the molecular mechanisms of HDV to manage the disease.
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Affiliation(s)
- Fulya Gunsar
- Department of Gastroenterology, Ege University, Bornova, Izmir 35100, Turkey.
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Abstract
The hepatitis D virus (HDV), the smallest virus known to infect man, causes the most severe form of chronic viral hepatitis, hepatitis delta. It is estimated that about 15 to 20 million people are suffering from chronic HDV infection. HDV is a defective satellite virus depending on the hepatitis B surface antigen (HBsAg) for transmission. Chronic hepatitis delta is associated with a rapid progression of liver fibrosis and a high prevalence of liver cirrhosis, even in younger patients. Immunization against hepatitis B virus (HBV) protects from HDV infection, but there is no specific vaccine against HDV available for HBsAg-positive individuals. Treatment options for hepatitis delta patients are limited. So far, only interferon-alpha has shown an antiviral efficacy against HDV. Recent trials showed sustained virological response rates concerning HDV in 25 %-30 % of patients treated with pegylated interferons. HDV is dominant over HBV in the majority of cases, but HBV DNA-positive subjects should be treated with HBV polymerase inhibitors. Combination therapy of pegylated interferon-alpha and adefovir showed a more pronounced HBsAg decline, but the exact role of combination therapies in hepatitis delta requires further investigation. Alternative future treatment strategies may include prenylation inhibitors and HBV entry inhibitors, which are in early clinical development.
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Gaballa AS, Teleb SM, Nour EM. Preparation and spectroscopic studies on charge-transfer complexes of famciclovir drug with different electron acceptors. J Mol Struct 2012. [DOI: 10.1016/j.molstruc.2012.04.092] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Lamers MH, Kirgiz ÖÖ, Heidrich B, Wedemeyer H, Drenth JPH. Interferon-α for patients with chronic hepatitis delta: a systematic review of randomized clinical trials. Antivir Ther 2012; 17:1029-37. [PMID: 22892440 DOI: 10.3851/imp2306] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/22/2012] [Indexed: 10/28/2022]
Abstract
BACKGROUND Hepatitis delta virus (HDV) infection therapy is unclear. This systematic analysis aimed to clarify the evidence on the efficacy of interferon (IFN)-α-based therapy in HDV. METHODS We performed a systematic search on electronic databases including MEDLINE (1970 to January 2011), Web of Science, The Cochrane Library and ClinicalTrials.gov. Randomized clinical trials (RCTs) comparing IFN-α-based therapy with either another drug, placebo or no intervention were included. We excluded paediatric studies. We calculated relative risks (RRs) for comparison of treatment options on the primary outcome measure, which was defined as undetectable levels of HDV RNA and normal alanine aminotransferase at end of treatment (EOT; 1 year). RESULTS Nine RCTs were included. Seven trials evaluated the treatment with IFN-α (n=132). The remaining two trials evaluated treatment with pegylated (PEG)-IFN-α (n=45). We found that 1-year treatment with high-dose IFN-α achieved better primary outcome rates than with PEG-IFN-α (RR=4.14, 95% CI 1.00, 17.14). Data for 1-year treatment with low-dose IFN-α compared with PEG-IFN-α were similar (RR=2.83, 95% CI 0.65, 12.40), as were low-dose IFN-α versus high-dose IFN-α (RR=0.68, 95% CI 0.31, 1.50). High-dose IFN-α and PEG-IFN-α reached similar HDV RNA suppression 24 weeks after EOT (RR=1.00, 95% CI 0.51, 1.97). None of the 55 patients assigned to no intervention obtained undetectable levels of HDV RNA and only one patient achieved normalization of alanine aminotransferase level. CONCLUSIONS Based on available RCTs, 1-year high-dose IFN-α monotherapy appears to be more effective than PEG-IFN-α for treatment of HDV patients, with efficacy rates of approximately 30%. There is a lack of head-to-head comparisons. Combination therapies and longer treatment duration need to be investigated.
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Affiliation(s)
- Mieke H Lamers
- Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
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Dastgerdi ES, Herbers U, Tacke F. Molecular and clinical aspects of hepatitis D virus infections. World J Virol 2012; 1:71-8. [PMID: 24175212 PMCID: PMC3782269 DOI: 10.5501/wjv.v1.i3.71] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2011] [Revised: 05/12/2012] [Accepted: 05/20/2012] [Indexed: 02/05/2023] Open
Abstract
Hepatitis D virus (HDV) is a defective virus with circular, single-stranded genomic RNA which needs hepatitis B virus (HBV) as a helper virus for virion assembly and infectivity. HDV virions are composed of a circular shape HDV RNA and two types of viral proteins, small and large HDAgs, surrounded by HBV surface antigen (HBsAg). The RNA polymerase II from infected hepatocytes is responsible for synthesizing RNAs with positive and negative polarities for HDV, as the virus does not code any enzyme to replicate its genome. HDV occurs as co-infection or super-infection in up to 5% of HBsAg carriers. A recent multi-center study highlighted that pegylated interferon α-2a (PEG-IFN) is currently the only treatment option for delta hepatitis. Nucleotide/nucleoside analogues, which are effective against HBV, have no relevant effects on HDV. However, additional clinical trials combining PEG-IFN and tenofovir are currently ongoing. The molecular interactions between HDV and HBV are incompletely understood. Despite fluctuating patterns of HBV viral load in the presence of HDV in patients, several observations indicate that HDV has suppressive effects on HBV replication, and even in triple infections with HDV, HBV and HCV, replication of both concomitant viruses can be reduced. Additional molecular virology studies are warranted to clarify how HDV interacts with the helper virus and which key cellular pathways are used by both viruses. Further clinical trials are underway to optimize treatment strategies for delta hepatitis.
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Affiliation(s)
- Elham Shirvani Dastgerdi
- Elham Shirvani Dastgerdi, Ulf Herbers, Frank Tacke, Department of Medicine III, RWTH-University Hospital Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany
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Wedemeyer H, Hardtke S, Manns MP. Update on the Management of HBV-HDV Coinfection. CURRENT HEPATITIS REPORTS 2012; 11:95-101. [DOI: 10.1007/s11901-012-0129-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Hartl J, Ott C, Kirchner G, Salzberger B, Wiest R. Successful treatment of HCV/HBV/HDV-coinfection with pegylated interferon and ribavirin. Clin Pract 2012; 2:e64. [PMID: 24765463 PMCID: PMC3981316 DOI: 10.4081/cp.2012.e64] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2011] [Revised: 04/26/2012] [Accepted: 05/07/2012] [Indexed: 12/12/2022] Open
Abstract
Dual and triple infections with hepatitis virus C (HCV), B (HBV) and D (HDV) frequently lead to severe liver damage. Hereby we describe a 38-year-old Caucasian male coinfected with HCV (genotype 3a), HBV [positive hepatitis B surface antigen (HbsAg) and antibody to hepatitis B core antigen; negative hepatitis B e antigen (HbeAg) and antibody to hepatitis B e antigen (anti-HBe)] and HDV. Laboratory diagnostics revealed increased liver enzymes and histological examination of the liver showed signs of fibrosis with moderate inflammation. On therapy with pegIFN-α2b and ribavirin HCV-RNA was undetectable at week 8. After week 24 the antiviral therapy was stopped because of a HBs-seroconversion, the loss of HbeAg and the detection of anti-HBe. Furthermore the HCV-RNA was negative. Six months after successful treatment of the triple-infection, HCV- and HDV-RNA and HbsAg remained negative and the liver enzymes had been completely normalized. In conclusion, pegylated-interferon plus ribavirin may be an effective therapy for HCV, HBV and HDV-coinfected patients.
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Affiliation(s)
- Janine Hartl
- Internal Medicine 1, University Hospital of Regensburg, Germany
| | - Claudia Ott
- Internal Medicine 1, University Hospital of Regensburg, Germany
| | | | | | - Reiner Wiest
- Internal Medicine 1, University Hospital of Regensburg, Germany
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Kabaçam G, Onder FO, Yakut M, Seven G, Karatayli SC, Karatayli E, Savas B, Idilman R, Bozdayi AM, Yurdaydin C. Entecavir treatment of chronic hepatitis D. Clin Infect Dis 2012; 55:645-50. [PMID: 22573857 DOI: 10.1093/cid/cis459] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatitis D virus (HDV) requires hepatitis B surface antigen (HBsAg) to propagate infection and cause disease. Entecavir is a nucleoside analog with potent antiviral efficacy, and in the woodchuck animal model it also decreased hepatitis B virus (HBV) cccDNA and woodchuck surface antigen. The aim of this study was to investigate the efficacy of entecavir in chronic hepatitis D (CHD). METHODS This single-center study was conducted in patients with compensated liver disease. All patients had to have detectable hepatitis HDV RNA and elevated levels of alanine aminotransferase (ALT). Entecavir was given at a dosage of 1 mg/d for 1 year. The primary end point was achievement of undetectable HDV RNA at the end of treatment. RESULTS Thirteen consecutive patients were assessed. All patients had detectable HDV RNA, and 8 had detectable HBV DNA at baseline. At the end of treatment, HBV DNA became undetectable in all patients (P = .001). No significant decline in HDV RNA, ALT, or quantitative HBsAg levels was observed. The primary end point of undetectable HDV RNA at the end of treatment was achieved in 3 patients who had significantly lower baseline HDV RNA levels than nonresponders (2.99 log(10) copies/mL ± .70 vs 4.68 ± .97; P = .0185). In all 3 patients, ALT levels were also normal at the end of treatment. CONCLUSIONS One year of entecavir treatment is ineffective in CHD. Any generalized beneficial effect of nucleoside/nucleotide analog treatment may necessitate prolonged treatment. Patients with CHD with HBV dominance, which is likely to occur in the later phases of CHD, may be a reasonable patient cohort in which to target nucleoside/nucleotide analog therapy.
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Affiliation(s)
- Gökhan Kabaçam
- Departments of Gastroenterology, University of Ankara Medical School, Dikimevi 06100, Ankara, Turkey
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Triantos C, Kalafateli M, Nikolopoulou V, Burroughs A. Meta-analysis: antiviral treatment for hepatitis D. Aliment Pharmacol Ther 2012; 35:663-73. [PMID: 22273482 DOI: 10.1111/j.1365-2036.2012.04993.x] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2011] [Revised: 11/21/2011] [Accepted: 01/01/2012] [Indexed: 02/06/2023]
Abstract
BACKGROUND There is no satisfactory treatment for patients with hepatitis D (HDV). AIM To evaluate treatment for HDV using meta-analysis. METHODS Medline, Scopus, Cochrane Library and ISI Web of Knowledge searches using the textwords 'Hepatitis D', 'therapy', "interferon", "peginterferon", "pegylated interferon", "lamivudine", "pegifn", "ifn" and "Hepatitis D", and abstracts from major Gastroenterology/Liver meetings. ENDPOINTS end of treatment biochemical (biochemical EOT) and virological response (virological EOT), end of follow-up virological response (EOFUP VR), histological improvement and intrahepatic HDAg clearance. RESULTS We included randomised clinical trials (RCTs) comparing Group A: interferon-A (IFNa) vs. no treatment (three RCTs, n ;= ;137 patients), Group B: low dose vs. high dose IFNa (two RCTs, n ;= ;60), Group C: IFNa ;+ ;lamivudine vs. IFNa (two RCTs, n ;= ;48) and Group D: pegylated IFNa (PEG-IFNa) vs. other medications (two RCTs, n ;= ;157). Group A. IFNa was better for biochemical EOT [OR, 0.11 (95% CI, 0.04-0.2)] and virological EOT [OR, 0.08 (95% CI, 0.03-0.2)], but not for EOFUP VR. Group B. High dose IFNa was better for biochemical EOT [OR, 0.24 (95% CI,0.08-0.73)] and virological EOT [OR, 0.27 (95% CI, 0.1-0.74)]. Group C. There was a trend favouring histological improvement [OR, 2.9 (95% CI, 0.6-13.4)]. Group D. PEG-IFNa was better for virological EOT [OR, 0.419 (95% CI, 0.18-0.974)], EOFUP VR [OR, 0.404 (95% CI, 0.189-0.866)] and improvement in necroinflammatory activity [OR, 0.308 (95% CI, 0.129-0.732)]. CONCLUSIONS Long-term suppression of HDV RNA by IFNa is not maintained despite an end of treatment response; adding lamivudine is not beneficial. PEG-IFNa is superior to other medications with respect to EOT and EOFUP. New RCTs should test combinations of PEG-IFNa and newest antivirals.
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Affiliation(s)
- C Triantos
- Department of Gastroenterology, University Hospital of Patras, Stamatopoulou 4, Patras, Greece.
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Rapid early HDV RNA decline in the peripheral blood but prolonged intrahepatic hepatitis delta antigen persistence after liver transplantation. J Hepatol 2012; 56:115-22. [PMID: 21762665 DOI: 10.1016/j.jhep.2011.06.016] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2010] [Revised: 05/30/2011] [Accepted: 06/01/2011] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIMS Chronic HDV infection is an inflammatory liver disease and liver transplantation (LTX) remains the only curative treatment option for most patients. The hepatitis D virus (HDV) uses HBsAg as its surface protein, however, it is controversial to what extend HDV may be detected independently of HBsAg in blood and liver after LTX. The aims of this study were to investigate kinetics of HDV RNA and HBsAg early after LTX, to apply the data to a mathematical model and to study long-term persistence of HDV after LTX. METHODS We retrospectively analyzed 26 patients with chronic hepatitis delta who underwent LTX between 1994 and 2009. Blood samples were obtained every 1-3 days during the first 14 days after LTX. Data were applied to a mathematical model to study viral kinetics. Available liver biopsy samples were stained for HBV and HDV viral antigens and tested for HBV DNA/cccDNA. RESULTS HBsAg and HDV RNA became negative after a median of 5 days (range 1-13) and 4 days (range 1-10), respectively. Early HDV RNA and HBsAg decline paralleled almost exactly in all patients; however the mathematical model showed a high variability of virion death. HDAg stained positive in transplanted livers in six patients in the absence of liver HBV DNA/cccDNA, serum-HBsAg, and HDV RNA for up to 19 months after LTX. CONCLUSIONS HDV RNA and HBsAg decline follow almost identical kinetic patterns within the first days after LTX. Nevertheless, intrahepatic latency of HDAg has to be considered when exploring novel concepts to withdraw HBIG.
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Abstract
BACKGROUND Hepatitis D virus is a small defective RNA virus that requires the presence of hepatitis B virus infection to infect a person. Hepatitis D is a difficult-to-treat infection. Several clinical trials have been published on the efficacy of interferon alpha for hepatitis D virus (HDV) infection. However, there are few randomised trials evaluating the effects of interferon alpha, and it is difficult to judge any benefit of this intervention from the individual trials. OBJECTIVES To evaluate the beneficial and harmful effects of interferon alpha for patients with chronic hepatitis D. SEARCH METHODS We identified relevant for the review randomised clinical trials by electronic searches in the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded until May 2011. We also checked the bibliographic references of identified randomised trials, textbooks, and review articles in order to find randomised trials not identified by the electronic searches. SELECTION CRITERIA Randomised clinical trials evaluating interferon alpha versus placebo or no intervention for patients with chronic hepatitis D infection. DATA COLLECTION AND ANALYSIS Two authors assessed the trials and extracted data on mortality, virologic, biochemical, and histological response as well as adverse events at end of treatment and six months or more after completing treatment. The analyses were performed using the intention-to-treat principle including all randomised participants irrespective of follow-up. Drop-outs, withdrawals, and non-compliance were considered as treatment failures. Data were analysed with fixed- and random-effects models. Reported results were based on fixed-effect model except in cases where statistical significance varied between the two models. MAIN RESULTS Six randomised trials fulfilled the inclusion criteria. Two hundred and one randomised participants (male = 174) were included. The risk of bias in all the included trials was high. Five trials compared interferon alpha with no treatment in the control group. One of these trials had two treatment arms with a higher dose and lower dose of interferon alpha and a no-treatment control group. We analysed both treatment regimens as a single group in a primary analysis and as separate groups in the subgroup analysis of different interferon dosages. The sixth trial compared only a higher dose of interferon alpha with a lower dose.Meta-analysis of five trials comparing interferon alpha with no-treatment control group included 169 participants. There were seven drop-outs in the treatment group and nine in the control group. One patient out of 92 (1.1%) died in the interferon alpha group compared with zero out of 77 (0.0%) in the no-intervention control group (risk ratio (RR)) 3.00; 95% confidence interval (CI) 0.14 to 66.5). Interferon alpha led to failure of end of treatment virological response in 62/92 (67.4%) of the patients compared with 71/77 (92.2%) in the untreated controls (RR 0.76, 95% CI 0.66 to 0.87, P = 0.0001 by fixed-effect model and RR 0.71, 95% CI 0.43 to 1.16, P = 0.17 by random-effects model). Failure of normalisation of alanine aminotransferase (ALT) at the end of treatment was seen in 60/92 (65.2%) patients treated with interferon alpha versus 76/77 (98.7%) in the control group (RR 0.69, 95% CI 0.59 to 0.80, P < 0.00001). Sustained virological response was not achieved in 76/92 (82.6%) of patients on interferon compared with 73/77 (94.8%) of controls (RR 0.89, 95% CI 0.80 to 0.98, P = 0.02). Serum alanine aminotransferase was abnormal in 81/92 (88.0%) treated with interferon alpha patients at six months post-treatment follow-up compared with 76/77 (98.7%) in controls (RR 0.92, 95% CI 0.84 to 0.99, P = 0.04). There was no significant histological improvement in 67/92 (72.8%) patients treated with interferon alpha compared with 65/77 (84.4%) in controls (RR 0.86, 95% CI 0.74 to 1.00, P = 0.06).Two trials comparing a higher dose of interferon alpha with the lower dose showed no significant difference in sustained virological response (76.7% compared with 90.0%) (RR 0.85, 95% CI 0.68 to 1.07, P = 0.16). Adverse events such as flu-like symptoms, asthenia, weight loss, alopecia, thrombocytopenia, and leukopenia were reported in all these trials and the adverse events were related to interferon alpha. These were common and sometimes severe. One patient in the treatment group was reported to have died by suicide towards the end of the study period. AUTHORS' CONCLUSIONS Interferon alpha does not seem to cure hepatitis D in most patients. The agent seems effective in suppressing viral and liver disease activity in some patients, but this improvement is not sustained in the majority of patients. We cannot exclude overestimation of benefits and underestimation of harms due to high risk of bias (systematic errors) and high risk play of chance (random errors). Therefore, more randomised trials with large sample sizes and less risk of bias are needed before interferon can be recommended or refuted.
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Affiliation(s)
- Zaigham Abbas
- Sindh Institute of Urology and TransplantationDepartment of HepatogastroenterologyDiwan ComplexChand Bibi RoadKarachiPakistan
| | - Muhammad Arsalan Khan
- Sindh Institute of Urology and TransplantationDepartment of Hepatobiliary SurgeryOff Chand Bibi RoadKarachiPakistan
| | - Mohammad Salih
- Aga Khan University HospitalDepartment of MedicineStadium RoadPO Box 3500KarachiPakistan74800
| | - Wasim Jafri
- Aga Khan University HospitalDepartment of MedicineStadium RoadPO Box 3500KarachiPakistan74800
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Abstract
Hepatitis delta virus (HDV) is a small, defective RNA virus that can infect only individuals who have hepatitis B virus (HBV); worldwide more than 15 million people are co-infected. There are eight reported genotypes of HDV with unexplained variations in their geographical distribution and pathogenicity. The hepatitis D virion is composed of a coat of HBV envelope proteins surrounding the nucleocapsid, which consists of a single-stranded, circular RNA genome complexed with delta antigen, the viral protein. HDV is clinically important because although it suppresses HBV replication, it causes severe liver disease with rapid progression to cirrhosis and hepatic decompensation. The range of clinical presentation is wide, varying from mild disease to fulminant liver failure. The prevalence of HDV is declining in some endemic areas but increasing in northern and central Europe because of immigration. Treatment of HDV is with pegylated interferon alfa; however, response rates are poor. Increased understanding of the molecular virology of HDV will identify novel therapeutic targets for this most severe form of chronic viral hepatitis.
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Affiliation(s)
- Sarah A Hughes
- Institute of Liver Studies, King's College Hospital, London, UK
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Wedemeyer H, Yurdaydìn C, Dalekos GN, Erhardt A, Çakaloğlu Y, Değertekin H, Gürel S, Zeuzem S, Zachou K, Bozkaya H, Koch A, Bock T, Dienes HP, Manns MP. Peginterferon plus adefovir versus either drug alone for hepatitis delta. N Engl J Med 2011; 364:322-31. [PMID: 21268724 DOI: 10.1056/nejmoa0912696] [Citation(s) in RCA: 325] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Chronic infection with hepatitis B virus and hepatitis delta virus (HDV) results in the most severe form of viral hepatitis. There is no currently approved treatment. We investigated the safety and efficacy of 48 weeks of treatment with peginterferon alfa-2a plus adefovir dipivoxil, peginterferon alfa-2a alone, and adefovir dipivoxil alone. METHODS We conducted a randomized trial in which 31 patients with HDV infection received treatment with 180 μg of peginterferon alfa-2a weekly plus 10 mg of adefovir daily, 29 received 180 μg of peginterferon alfa-2a weekly plus placebo, and 30 received 10 mg of adefovir alone weekly for 48 weeks. Follow-up was conducted for an additional 24 weeks. Efficacy end points included clearance of HDV RNA, normalization of alanine aminotransferase levels, and a decline in levels of hepatitis B surface antigen (HBsAg). RESULTS The primary end point--normalization of alanine aminotransferase levels and clearance of HDV RNA at week 48--was achieved in two patients in the group receiving peginterferon alfa-2a plus adefovir and two patients in the group receiving peginterferon alfa-2a plus placebo but in none of the patients in the group receiving adefovir alone. At week 48, the test for HDV RNA was negative in 23% of patients in the first group, 24% of patients in the second, and none of those in the third (P = 0.006 for the comparison of the first and third groups; P = 0.004 for the comparison of the second and third). The efficacy of peginterferon alfa-2a was sustained for 24 weeks after treatment, with 28% of the patients receiving peginterferon alfa-2a plus adefovir or peginterferon alfa-2a alone having negative results on HDV-RNA tests; none of the patients receiving adefovir alone had negative results. A decline in HBsAg levels of more than 1 log(10) IU per milliliter from baseline to week 48 was observed in 10 patients in the first group, 2 in the second, and none in the third (P<0.001 for the comparison of the first and third groups and P = 0.01 for the comparison of the first and second). CONCLUSIONS Treatment with peginterferon alfa-2a for 48 weeks, with or without adefovir, resulted in sustained HDV RNA clearance in about one quarter of patients with HDV infection. (Current Controlled Trials number, ISRCTN83587695.).
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Abstract
More than 30 years after Mario Rizzetto and colleagues described a new antigen in livers of HBsAg-positive patients called the "delta antigen", a re-emerging interest in hepatitis delta is currently observed. The state-of-the art on basic and clinical research on hepatitis delta was presented during a monothematic conference organized by the European Association for the Study of the Liver (EASL) in September 2010. Hepatitis delta is caused by infection with the hepatitis D virus (HDV) which requires presence of HBsAg for complete replication and transmission. Recent data confirmed the severe long-term course of HDV infection with high rates of hepatic decompensation while controversial data on the risk for the development of hepatocellular carcinoma were reported. Pegylated interferon alpha can lead to sustained HDV RNA elimination in about one quarter of patients while HBV polymerase inhibitors are ineffective against HDV. Novel treatment options include prenylation inhibitors and HBV entry inhibitors which are currently in early clinical development.
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Affiliation(s)
- Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany.
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Abstract
Hepatitis D virus (HDV) infection involves a distinct subgroup of individuals simultaneously infected with the hepatitis B virus (HBV) and characterized by an often severe chronic liver disease. HDV is a defective RNA agent needing the presence of HBV for its life cycle. HDV is present worldwide, but the distribution pattern is not uniform. Different strains are classified into eight genotypes represented in specific regions and associated with peculiar disease outcome. Two major specific patterns of infection can occur, i.e. co-infection with HDV and HBV or HDV superinfection of a chronic HBV carrier. Co-infection often leads to eradication of both agents, whereas superinfection mostly evolves to HDV chronicity. HDV-associated chronic liver disease (chronic hepatitis D) is characterized by necro-inflammation and relentless deposition of fibrosis, which may, over decades, result in the development of cirrhosis. HDV has a single-stranded, circular RNA genome. The virion is composed of an envelope, provided by the helper HBV and surrounding the RNA genome and the HDV antigen (HDAg). Replication occurs in the hepatocyte nucleus using cellular polymerases and via a rolling circle process, during which the RNA genome is copied into a full-length, complementary RNA. HDV infection can be diagnosed by the presence of antibodies directed against HDAg (anti-HD) and HDV RNA in serum. Treatment involves the administration of pegylated interferon-α and is effective in only about 20% of patients. Liver transplantation is indicated in case of liver failure.
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Affiliation(s)
- Stéphanie Pascarella
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
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Abstract
Chronic delta hepatitis (CDH) represents a severe form of chronic viral hepatitis, induced by the hepatitis delta virus (HDV) in conjunction with the hepatitis B virus (HBV). Delta hepatitis may lead to disease in humans through co-infection. The former leads to acute hepatitis which clinically can range from mild hepatitis to fulminant hepatitis and death. Severe or fulminant hepatitis is more often observed with HBV-HDV co-infection compared to HBV mono-infection. Chronic infection after acute hepatitis B + D co-infection is infrequent and similar to the rate in mono-infected patients. CDH develops in 70-90% of patients with superinfection. CDH runs a more progressive course than chronic hepatitis B and may lead to cirrhosis within 2 years in 10-15% of patients. However, as with any immune-mediated disease, different patterns of progression, ranging from mild to severe progressive disease, are observed. Active replication of both HBV and HDV may be associated with a more progressive disease pattern. Further, different HDV and HBV genotypes may contribute to various disease outcomes. CDH may be frequently associated with hepatocellular carcinoma development although recent studies provided conflicting results. The only established therapy for CDH is treatment with interferons for a duration of at least 1 year. On treatment, 6 month HDV RNA assessment may give clues as to whether to stop treatment at 1 year or continue beyond 1 year. New approaches to treatment of CDH are an urgent need of which the use of prenylation inhibitors appears the most promising.
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Affiliation(s)
- C Yurdaydın
- Gastroenterology Department, University of Ankara Medical School, Hepatology Institute, University of Ankara, Ankara, Turkey.
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de Sousa BC, Cunha C. Development of mathematical models for the analysis of hepatitis delta virus viral dynamics. PLoS One 2010; 5:e12512. [PMID: 20862328 PMCID: PMC2940762 DOI: 10.1371/journal.pone.0012512] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2010] [Accepted: 08/09/2010] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Mathematical models have shown to be extremely helpful in understanding the dynamics of different virus diseases, including hepatitis B. Hepatitis D virus (HDV) is a satellite virus of the hepatitis B virus (HBV). In the liver, production of new HDV virions depends on the presence of HBV. There are two ways in which HDV can occur in an individual: co-infection and super-infection. Co-infection occurs when an individual is simultaneously infected by HBV and HDV, while super-infection occurs in persons with an existing chronic HBV infection. METHODOLOGY/PRINCIPAL FINDINGS In this work a mathematical model based on differential equations is proposed for the viral dynamics of the hepatitis D virus (HDV) across different scenarios. This model takes into consideration the knowledge of the biology of the virus and its interaction with the host. In this work we will present the results of a simulation study where two scenarios were considered, co-infection and super-infection, together with different antiviral therapies. Although, in general the predicted course of HDV infection is similar to that observed for HBV, we observe a faster increase in the number of HBV infected cells and viral load. In most tested scenarios, the number of HDV infected cells and viral load values remain below corresponding predicted values for HBV. CONCLUSIONS/SIGNIFICANCE The simulation study shows that, under the most commonly used and generally accepted therapy approaches for HDV infection, such as lamivudine (LMV) or ribavirine, peggylated alpha-interferon (IFN) or a combination of both, LMV monotherapy and combination therapy of LMV and IFN were predicted to more effectively reduce the HBV and HDV viral loads in the case of super-infection scenarios when compared with the co-infection. In contrast, IFN monotherapy was found to reduce the HDV viral load more efficiently in the case of super-infection while the effect on the HBV viral load was more pronounced during co-infection. The results suggest that there is a need for development of high efficacy therapeutic approaches towards the specific inhibition of HDV replication. These approaches may additionally be directed to the reduction of the half-life of infected cells and life-span of newly produced circulating virions.
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Affiliation(s)
- Bruno C de Sousa
- Centre for Malaria and Tropical Diseases, Associated Laboratory, Unit of Epidemiology and Biostatistics, Instituto de Higiene e Medicina Tropical-Universidade Nova de Lisboa, Lisbon, Portugal.
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Establishment of a novel quantitative hepatitis D virus (HDV) RNA assay using the Cobas TaqMan platform to study HDV RNA kinetics. J Clin Microbiol 2010; 48:2022-9. [PMID: 20351206 DOI: 10.1128/jcm.00084-10] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Determination of hepatitis D virus (HDV) viremia represents the "gold standard" for the diagnosis of HDV infection. Hepatitis B virus (HBV)-HDV coinfection frequently leads to end-stage liver disease and hepatocellular carcinoma. No commercial assay for HDV RNA quantification that includes automated nucleic acid extraction is available, and in-house PCR tests are not well standardized. However, knowledge of HDV RNA levels may give important information for patient management and could be a useful tool for monitoring the response to antiviral therapies. One platform that is widely used for HBV DNA or HCV RNA quantification is the Cobas Ampliprep/TaqMan system. Using the utility channel of this platform, we established a novel protocol for TaqMan-based HDV RNA quantification after automatic extraction of RNA by the Ampliprep system. The assay was specific and showed linearity over a wide range from 3 x 10(2) to 10(7) copies/ml. Reproducibility was demonstrated by determination of the interrun and intrarun variabilities, which were similar to those achieved with the commercially available Cobas TaqMan assays for HCV RNA and HBV DNA. HDV RNA levels were stable in whole blood (n = 4), plasma (n = 3), and serum (n = 3) samples at room temperature for up to 6 days. Importantly, HDV RNA viremia showed only minor fluctuations, with the log(10) coefficient of variation being between 1.3 and 11.2% for hepatitis delta patients studied every 2 weeks for up to 3 months (n = 6), while a rapid viral decline was observed early during treatment with pegylated alfa-2a interferon (n = 6). In conclusion, this novel automated HDV RNA assay is a useful tool for monitoring HDV-infected patients both before and during antiviral therapy.
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Zachou K, Yurdaydin C, Drebber U, Dalekos GN, Erhardt A, Cakaloglu Y, Degertekin H, Gurel S, Zeuzem S, Bozkaya H, Schlaphoff V, Dienes HP, Bock TC, Manns MP, Wedemeyer H. Quantitative HBsAg and HDV-RNA levels in chronic delta hepatitis. Liver Int 2010; 30:430-7. [PMID: 19840253 DOI: 10.1111/j.1478-3231.2009.02140.x] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
UNLABELLED Abstract Background: Hepatitis delta virus (HDV) causes severe liver disease. AIMS To investigate the quantitative HDV-RNA, HBsAg and hepatitis B virus (HBV)DNA levels in correlation to histological, biochemical and demographical parameters in patients with chronic HDV infection as similar data in a large series of HDV patients are missing. METHODS Eighty HDV patients were recruited in Germany, Turkey and Greece; quantitative determination of HDV-RNA, HBsAg and HBV-DNA was performed by real-time polymerase chain reaction, the Architect HBsAg assay and Cobas TaqMan HBV test respectively. RESULTS All patients were infected with HDV-genotype 1. Thirty-five patients (48%) had significant fibrosis (Ishak 3-4) and 15 (20.5%) had cirrhosis. HDV viraemia ranged from 1.1 x 10(3) to 8.4 x 10(7) copies/ml with 60% of patients showing HDV-RNA levels above 10(5) copies/ml accompanied by low HBV viraemia (<10(5) copies/ml). However, HDV-RNA and HBV-DNA levels showed no direct inverse correlation. HDV-RNA correlated positively with HBsAg and negatively with age. HBsAg correlated negatively with age and positively with histological grading. Only gamma-glutamyltranspeptidase was independently associated with cirrhosis (P=0.032), while no biochemical parameter was associated with grading. CONCLUSIONS (i) HBsAg levels correlated with HDV viraemia in chronic HDV. (ii) Biochemical parameters did not accurately indicate the stage and grade of liver disease in chronic HDV and thus liver biopsy seems to remain the major tool for the evaluation of delta hepatitis patients.
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Affiliation(s)
- Kalliopi Zachou
- Department of Gastroenterology, Hepatology and Endocrinology, Hanover Medical School, Hanover, Germany
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