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Hepatitis: HELP
Articles from Goethe Universitat Frankfurt
Based on 348 articles published since 2010

These are the 348 published articles about Hepatitis that originated from Goethe Universitat Frankfurt during 2010-2020.
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5 · 6 · 7 · 8 · 9 · 10 · 11 · 12 · 13 · 14
26 Review Development of sofosbuvir for the treatment of hepatitis C virus infection. 2015

Lawitz, Eric / Jacobson, Ira M / Nelson, David R / Zeuzem, Stefan / Sulkowski, Mark S / Esteban, Rafael / Brainard, Diana / McNally, John / Symonds, William T / McHutchison, John G / Dieterich, Douglas / Gane, Edward. ·Texas Liver Institute, University of Texas Health Science Center, San Antonio, Texas. · Icahn School of Medicine at Mount Sinai, New York, New York. · University of Florida, Gainesville, Florida. · Medical Center, Johann Wolfgang Goethe University, Frankfurt am Main, Germany. · Johns Hopkins University School of Medicine, Baltimore, Maryland. · Hospital Universitario Val d'Hebron, Barcelona, Spain. · Gilead Sciences, Foster City, California. · Mount Sinai School of Medicine, New York, New York. · Auckland City Hospital, Auckland, New Zealand. ·Ann N Y Acad Sci · Pubmed #26235748.

ABSTRACT: The nucleotide analog NS5B polymerase inhibitor sofosbuvir was approved by the U.S. Food and Drug Administration (FDA) in December 2013 for the treatment of chronic hepatitis C virus (HCV) infection in combination with ribavirin or peginterferon and ribavirin. Sofosbuvir was developed to meet an urgent medical need for shorter, safer, simplified, more effective HCV treatment regimens and to reduce or eliminate the need for peginterferon. New treatment regimens were especially required for patient populations with limited treatment options, including patients who had failed prior HCV therapy, those with compensated and decompensated cirrhosis, and those who were either intolerant of or had contraindications to interferon. Sofosbuvir plus ribavirin for patients with genotype 2 or 3 HCV infection was the first approved all-oral treatment option. Sofosbuvir is also the backbone of the first regimen available for patients awaiting liver transplantation to prevent HCV recurrence, as well as the first oral interferon-free regimen for patients coinfected with HCV and HIV. This paper describes the development of sofosbuvir up to its original FDA approval.

27 Review From non-A, non-B hepatitis to hepatitis C virus cure. 2015

Pawlotsky, Jean-Michel / Feld, Jordan J / Zeuzem, Stefan / Hoofnagle, Jay H. ·National Reference Center for Viral Hepatitis B, C and D, Department of Virology, Hôpital Henri Mondor, Université Paris-Est, Créteil, France; INSERM U955, Créteil, France. Electronic address: jean-michel.pawlotsky@hmn.aphp.fr. · Toronto Centre for Liver Disease, Sandra Rotman Centre for Global Health, University of Toronto, Toronto, Ontario, Canada. · Medizinische Klinik 1, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany. · Liver Disease Research Branch, Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States. ·J Hepatol · Pubmed #25920094.

ABSTRACT: The hepatitis C virus (HCV) was discovered in the late 1980s. Interferon (IFN)-α was proposed as an antiviral treatment for chronic hepatitis C at about the same time. Successive improvements in IFN-α-based therapy (dose finding, pegylation, addition of ribavirin) increased the rates of sustained virologic response, i.e. the rates of curing HCV infection. These rates were further improved by adding the first available direct-acting antiviral (DAA) drugs to the combination of pegylated IFN-α and ribavirin. An IFN-free era finally started in 2014, yielding rates of sustained virologic response over 90% in patients treated for 8 to 24 weeks with all-oral regimens. Major challenges however remain in implementation of these new treatment strategies, not only in low- to middle-income countries, but also in high-income countries where the price of these therapies is still prohibitive. Elimination of HCV infection through treatment in certain areas is possible but raises major public health issues.

28 Review An Update on Animal Models of Autoimmune Hepatitis: Are we There Yet? 2015

Christen, Urs / Hintermann, Edith. ·Pharmazentrum Frankfurt, Klinikum der Johann Wolfgang Goethe Universitat, Theodor-Stern Kai 7, 60590 Frankfurt am Main, Germany. christen@med.uni-frankfurt.de. ·Curr Pharm Des · Pubmed #25777755.

ABSTRACT: Autoimmune hepatitis is characterized by a progressive destruction of the liver parenchyma and a chronic fibrosis. Although the major targets of this autoimmune-mediated disease have been identified more than two decades ago, the current treatment of autoimmune hepatitis is still based on traditional therapies including a glucocorticoid treatment. One reason for this impasse is the limited availability of reliable animal models that reflect the clinical features of autoimmune hepatitis and allow for the identification of critical factors driving the autoimmune destruction and the evaluation of innovative therapies. However, the status of the liver as an immune privileged organ harbouring many immunosuppressing mechanisms hampers the development of such models. Here we will review the past and present attempts to develop a consistent animal model for autoimmune hepatitis.

29 Review Interferon-free antiviral combination therapies without nucleosidic polymerase inhibitors. 2014

Welzel, Tania Mara / Dultz, Georg / Zeuzem, Stefan. ·Department of Medicine 1, Johann Wolfgang Goethe-University Hospital, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. · Department of Medicine 1, Johann Wolfgang Goethe-University Hospital, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. Electronic address: zeuzem@em.uni-frankfurt.de. ·J Hepatol · Pubmed #25443350.

ABSTRACT: The establishment of robust HCV cell culture systems and characterization of the viral life cycle provided the molecular basis for highly innovative, successful years in HCV drug development. With the identification of direct-acting antiviral agents (DAAs), such as NS3/4A protease inhibitors, NS5A replication complex inhibitors, nucleotide and non-nucleoside polymerase inhibitors, as well as host cell targeting agents, novel therapeutic strategies were established and competitively entered clinical testing. The first-in-class NS3/4A protease inhibitors telaprevir and boceprevir, approved in 2011, were recently outpaced by the pan-genotypic nucleotide polymerase inhibitor sofosbuvir that in combination with pegylated interferon and ribavirin, further shortens therapy durations and also offers the first interferon-free HCV treatment option. In the challenging race towards the goal of interferon-free HCV therapies, however, several oral DAA regimens without nucleotide polymerase inhibitors that combine a NS3/4A protease inhibitor, a NS5A inhibitor and/or a non-nucleoside polymerase inhibitor yielded competitive results. Second generation NS3/4A protease and NS5A inhibitors promise an improved genotypic coverage and a high resistance barrier. Results of novel DAA combination therapies without the backbone of a nucleotide polymerase inhibitor, as well as treatment strategies involving host targeting agents are reviewed herein.

30 Review Decade in review-HCV: hepatitis C therapy-a fast and competitive race. 2014

Zeuzem, Stefan. ·Department of Medicine, J. W. Goethe University Hospital, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. ·Nat Rev Gastroenterol Hepatol · Pubmed #25223875.

ABSTRACT: -- No abstract --

31 Review Vitamin D level and sustained virologic response to interferon-based antiviral therapy in chronic hepatitis C: a systematic review and meta-analysis. 2014

Kitson, Matthew T / Sarrazin, Christoph / Toniutto, Pierluigi / Eslick, Guy D / Roberts, Stuart K. ·Department of Gastroenterology, Alfred Hospital, Melbourne, Australia; Department of Gastroenterology, Monash University, Melbourne, Australia. · Department of Gastroenterology & Hepatology, Johann Wolfgang Goethe-University Hospital, Frankfurt, Germany. · Department of Medicine, University of Udine, Udine, Italy. · Department of Surgery, University of Sydney, Sydney, Australia. · Department of Gastroenterology, Alfred Hospital, Melbourne, Australia; Department of Gastroenterology, Monash University, Melbourne, Australia. Electronic address: s.roberts@alfred.org.au. ·J Hepatol · Pubmed #25135863.

ABSTRACT: BACKGROUND & AIMS: The baseline 25-hydroxyvitamin D (25[OH]D) level has recently been reported to be an independent predictor of sustained virologic response (SVR) to treatment with pegylated interferon (PEG-IFN) plus ribavirin (RBV) for chronic hepatitis C virus (HCV) infection. However, studies have yielded inconsistent results. Thus, we conducted a systematic review and meta-analysis to clarify any association between baseline 25(OH)D level and SVR in HCV therapy. METHODS: Two reviewers searched four electronic databases (Medline, Embase, PubMed, and Cochrane trials register) and relevant international conference proceedings up to March 2014 for studies treating chronic HCV infection with PEG-IFN plus RBV where baseline 25(OH)D level was tested. Studies involving patients with HIV co-infection, previous liver transplantation or those receiving vitamin D supplementation were excluded. The mean baseline 25(OH)D level was compared between those who achieved and those who failed to achieve SVR. Pooled standard difference in mean 25(OH)D level, odds ratios (OR) and 95% confidence intervals (CI) were calculated with the Comprehensive Meta-Analysis software (version 2.0) using a random effects model. RESULTS: 11 studies comprising 2605 patients were included in the meta-analysis. There was no significant association between the baseline mean 25(OH)D level and SVR (OR 1.44, 95% CI 0.92-2.26; p=0.11), either in patients infected with genotypes 1/4/5 (OR 1.48, 95% CI 0.94-2.34; p=0.09) or genotypes 2/3 (OR 1.51, 95% CI 0.26-8.87; p=0.65). CONCLUSIONS: The baseline 25(OH)D level is not associated with SVR to PEG-IFN plus RBV therapy in chronic HCV infection, regardless of genotype. Any effect of vitamin D supplementation on SVR is yet to be definitively determined.

32 Review Pathogen infection as a possible cause for autoimmune hepatitis. 2014

Christen, Urs / Hintermann, Edith. ·Pharmazentrum Frankfurt/ZAFES, Goethe University Hospital , Frankfurt am Main , Germany. ·Int Rev Immunol · Pubmed #24911790.

ABSTRACT: Autoimmune disorders afflicting the liver comprise the bona fide autoimmune diseases, primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis as well as drug-induced autoimmune-like diseases, such as halothane hepatitis. Whereas drug-induced forms of acute or chronic hepatitis often have a clear triggering factor, the etiology of classical autoimmune liver diseases is only poorly understood. Besides a genetic component present in disease susceptible individuals, environmental triggering factors are likely to play a role in the initiation and/or propagation of the disease. In this article, we will review on current evidence obtained from epidemiological associations, case studies, and findings in animal models for pathogens, to be involved in the etiology of autoimmune liver disease with a special focus on autoimmune hepatitis.

33 Review Interferon-free strategies without a nucleoside/nucleotide analogue. 2014

Welzel, Tania Mara / Zeuzem, Stefan. ·Department of Medicine 1, JW Goethe University Hospital, Frankfurt am Main, Germany. ·Semin Liver Dis · Pubmed #24782258.

ABSTRACT: The identification of viral and host factors involved in hepatitis C virus (HCV) replication was a key prerequisite for the discovery and further exploration of antiviral drug targets. As of today, numerous direct-acting antiviral agents (DAAs), as well as host-targeting agents (HTAs), have been developed and entered clinical testing. The goal to omit pegylated interferon due to its unfavorable side-effect profile from novel HCV therapeutic approaches led to an expedited design and competitive conduct of DAA combination trials striving for easily applicable, all-oral HCV treatments. Approval of several interferon-free regimens is awaited in the near future (2014/2015). Results of different DAA combination trials (without nucleos(t)ide polymerase inhibitors) and trials involving HTAs are reviewed herein.

34 Review Is there sufficient evidence to recommend antiviral therapy in hepatitis C? 2014

van der Meer, Adriaan J / Wedemeyer, Heiner / Feld, Jordan J / Hansen, Bettina E / Manns, Michael P / Zeuzem, S / Janssen, Harry L A. ·Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands. Electronic address: a.vandermeer@erasmusmc.nl. · Department of Gastroenterology, Hepatology, and Endocrinology, Medical School Hannover, Hannover, Germany. · Liver Centre, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada. · Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands. · Department of Gastroenterology, Hepatology, and Endocrinology, Medical School Hannover, Hannover, Germany; Medizinische Klinik 1, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany. · Medizinische Klinik 1, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany. · Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands; Liver Centre, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada. ·J Hepatol · Pubmed #23973931.

ABSTRACT: While patients with chronic hepatitis C virus (HCV) infection are treated in order to prevent liver-related morbidity and mortality, we rely on sustained virological response (SVR) as a virological biomarker to evaluate treatment efficacy in both clinical practice as well as in drug development. However, conclusive evidence for the clinical benefit of antiviral therapy or validity of SVR as surrogate marker, as derived from trials randomizing patients to a treatment or control arm, is lacking. In fact, the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C) trial recently showed an increased mortality rate among interferon-treated patients compared to untreated controls. Consequently, the recommendation to treat patients with chronic HCV infection was challenged. Here, we argue that the possible harmful effect of long-term low-dose pegylated interferon mono therapy, as was observed in the HALT-C trial cohort, cannot be extrapolated to potentially curative short-term treatment regimens. Furthermore, we discuss SVR as a surrogate biomarker, based on numerous studies which indicated an association between SVR and improvements in health-related quality of life, hepatic inflammation and fibrosis, and portal pressure as well as a reduced risk for hepatocellular carcinoma (HCC), liver failure and mortality.

35 Review The importance of HCV RNA measurement for tailoring treatment duration. 2013

Peiffer, Kai-Henrik / Sarrazin, Christoph. ·Klinikum der J. W. Goethe-Universität, Medizinische Klinik 1, Theodor-Stern-Kai 7, Frankfurt am Main, Germany. ·Dig Liver Dis · Pubmed #24091111.

ABSTRACT: The introduction of telaprevir and boceprevir in the treatment of chronically HCV genotype 1 infected patients has led to substantially improved sustained virologic response rates and shorter treatment duration for a growing group of patients. Management and monitoring of patients receiving protease inhibitor-based triple therapy is of major importance and has become more complicated. Close monitoring of HCV RNA levels for patients on protease inhibitor-based therapy to identify subjects who are eligible for shortening of treatment duration, are virological non-responders or are in danger of experiencing a viral breakthrough is strongly recommended. Several virological tools including qualitative and quantitative HCV RNA assays for detection and quantification of HCV RNA are commercially available. We review these methods and their implications for HCV therapy as well as current sustained virologic response definition, stopping rules and recommendations for protease inhibitor-based treatment durations.

36 Review Hepatitis C-associated B-cell non-Hodgkin lymphomas. Epidemiology, molecular signature and clinical management. 2013

Peveling-Oberhag, Jan / Arcaini, Luca / Hansmann, Martin-Leo / Zeuzem, Stefan. ·Department of Internal Medicine 1, J.W. Goethe-University Hospital, Frankfurt, Germany. jan.peveling-oberhag@kgu.de ·J Hepatol · Pubmed #23542089.

ABSTRACT: There is ample epidemiologic evidence for an association of chronic hepatitis C virus (HCV) infection with B-cell non-Hodgkin lymphoma (B-NHL). B-NHL subtypes most frequently associated with HCV are marginal zone lymphoma and diffuse large B-cell lymphoma. The most convincing evidence for a causal relationship between HCV infection and lymphoma development is the observation of B-NHL regression after HCV eradication by antiviral therapy (AVT). In fact, for indolent HCV-associated B-NHL, first-line AVT instead of standard immune-chemotherapy might be considered. Molecular mechanisms of HCV-NHL development are still poorly understood. Three general theories have emerged to understand the HCV-induced lymphomagenesis: (1) continuous external stimulation of lymphocyte receptors by viral antigens and consecutive proliferation; (2) HCV replication in B cells with oncogenic effect mediated by intracellular viral proteins; (3) permanent B-cell damage, e.g., mutation of tumor suppressor genes, caused by a transiently intracellular virus ("hit and run" theory). This review systematically summarizes the data on epidemiology, interventional studies, and molecular mechanisms of HCV-associated B-NHL.

37 Review The role of autoantibodies in autoimmune hepatitis type 2. 2013

Christen, Urs. ·Pharmazentrum Frankfurt/ZAFES, Goethe University Hospital Frankfurt, Theodor-Stern Kai 7, 60590 Frankfurt am Main, Germany. christen@med.uni-frankfurt.de ·Immunotherapy · Pubmed #23444954.

ABSTRACT: Antibodies play an important role in autoimmune liver diseases, such as autoimmune hepatitis (AIH). On the one hand, they are essential diagnostic markers to identify not only the presentation of AIH, but also the AIH subtype characterized by the presence of particular antibodies to target autoantigens in the liver. On the other hand, such autoantibodies might be directly involved in the etiology and/or pathogenesis of AIH. This review will reflect on the evidence of how specific autoantibodies influence AIH and will further provide insight into the necessities for generating therapeutic antibodies to treat AIH in the future.

38 Review Herbal hepatotoxicity and WHO global introspection method. 2013

Teschke, Rolf / Eickhoff, Axel / Wolff, Albrecht / Frenzel, Christian / Schulze, Johannes. ·Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Academic Teaching Hospital of the Medical Faculty of the Goethe University Frankfurt, Main, Germany. rolf.teschke@gmx.de ·Ann Hepatol · Pubmed #23293189.

ABSTRACT: Herbal hepatotoxicity is a rare but highly disputed disease because numerous confounding variables may complicate accurate causality assessment. Case evaluation is even more difficult when the WHO global introspection method (WHO method) is applied as diagnostic algorithm. This method lacks liver specificity, hepatotoxicity validation, and quantitative items, basic qualifications required for a sound evaluation of hepatotoxicity cases. Consequently, there are no data available for reliability, sensitivity, specificity, positive and negative predictive value. Its scope is also limited by the fact that it cannot discriminate between a positive and a negative causality attribution, thereby stimulating case overdiagnosing and overreporting. The WHO method ignores uncertainties regarding daily dose, temporal association, start, duration, and end of herbal use, time to onset of the adverse reaction, and course of liver values after herb discontinuation. Insufficiently considered or ignored are comedications, preexisting liver diseases, alternative explanations upon clinical assessment, and exclusion of infections by hepatitis A-C, cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus (HSV), and varicella zoster virus (VZV). We clearly prefer as alternative the scale of CIOMS (Council for International Organizations of Medical Sciences) which is structured, quantitative, liver specific, and validated for hepatotoxicity. In conclusion, causality of herbal hepatotoxicity is best assessed by the liver specific CIOMS scale validated for hepatotoxicity rather than the obsolete WHO method that is liver unspecific and not validated for hepatotoxicity. CIOMS based assessments will ensure the correct diagnosis and exclude alternative diagnosis that may require other specific therapies.

39 Review New therapeutic strategies in HCV: polymerase inhibitors. 2013

Gerber, Ludmila / Welzel, Tania M / Zeuzem, Stefan. ·Klinikum der J.W. Goethe Universität, Frankfurt am Main, Germany. ·Liver Int · Pubmed #23286851.

ABSTRACT: The characterization of the viral life cycle facilitated the development of directly acting antiviral drugs. Among those, several inhibitors of the viral RNA-dependent RNA polymerase have proven effectiveness in clinical trials. The characteristics of different nucleos(t)ide and non-nucleoside polymerase inhibitors, as well as their clinical applications and combinations with other classes of directly acting antiviral drugs are reviewed herein.

40 Review Perspectives and challenges of interferon-free therapy for chronic hepatitis C. 2013

Lange, Christian M / Zeuzem, Stefan. ·Klinikum der J W Goethe-Universität Frankfurt am Main, Medizinische Klinik 1, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. christian.lange@kgu.de ·J Hepatol · Pubmed #23104162.

ABSTRACT: Recent data have clearly shown that a sustained virologic response can be achieved in different HCV infected patient populations with various interferon-free treatment regimens. Despite the successful implementation of telaprevir- and boceprevir-based triple therapies, all-oral regimens will certainly become a first choice for a number of HCV-infected patients in the very near future, as triple therapy approaches are burdened with significant side-effects and limited success in patients with advanced liver fibrosis and prior null-response to pegylated interferon-α (pegIFN-α)/ribavirin therapy. However, available data from phase I and II clinical trials evaluating interferon-free regimens have not yet revealed a clearly outstanding all-oral combination, and numerous challenges remain to be addressed by intensive ongoing and future research. In particular, thus far evaluated all-oral regimens did not cure a satisfactory percentage of patients with unfavorable baseline characteristics, namely patients infected with HCV genotype 1a, previous null-response to pegIFN-α/ribavirin, or liver cirrhosis. In this review, we summarize available data of interferon-free regimens for the treatment of chronic hepatitis C and assess implications for perspectives and challenges in the further development of all-oral therapies.

41 Review The role of resistance in HCV treatment. 2012

Vermehren, Johannes / Sarrazin, Christoph. ·Medizinische Klinik 1, Klinikum der J. W. Goethe-Universität, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. ·Best Pract Res Clin Gastroenterol · Pubmed #23199507.

ABSTRACT: The recent development of small molecule compounds that directly inhibit the viral life cycle represents a major milestone for the treatment of chronic hepatitis C virus (HCV) infection. These new drugs that are collectively termed direct-acting antivirals (DAA) include a range of inhibitors of the non-structural (NS) 3/4A protease, NS5B polymerase and NS5A protein. Two NS3/4A protease inhibitors (boceprevir and telaprevir) in combination with pegylated interferon and ribavirin have now been approved for the treatment of chronic HCV genotype 1 infection and cure rates could be increased by 20-30%. However, the majority of DAAs is still in early clinical development. The rapid replication rate of HCV, along with the error-prone polymerase activity leads to a high genetic diversity among HCV virions that includes mutants with reduced susceptibility to DAA-therapy. These resistance-associated variants often occur at very low frequencies. However, during DAA-based treatment, rapid selection of resistance mutations may occur, eventually leading to viral break-through. A number of variants with different levels of resistance have been described in vitro and in vivo for virtually all DAAs. We review the parameters that determine DAA resistance as well as the clinical implications of resistance testing. In addition, the most recent literature and conference data on resistance profiles of DAAs in clinical development and future strategies to avoid the emergence of viral resistance are also discussed.

42 Review Clinical relevance of HCV antiviral drug resistance. 2012

Welsch, C / Zeuzem, S. ·J. W. Goethe University Hospital, Department of Internal Medicine I, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. christophwelsch@gmx.net ·Curr Opin Virol · Pubmed #23006585.

ABSTRACT: The approval of direct-acting antiviral agents (DAAs) against the hepatitis C virus (HCV) NS3 protease revolutionized antiviral therapy in chronic hepatitis C. They mark the beginning of an era with drugs designed to inhibit specific viral proteins involved in the virus life cycle rather than the nonspecific antiviral activity of interferon. Upcoming generations of antivirals are expected that lead to viral eradication in most patients who undergo treatment with hope held for years that HCV can be cured without interferon. Antiviral drug resistance plays a key role in DAA-treatment failure. Knowledge on molecular escape mechanisms of resistant variants, their time to wild-type reversal and potential persistence is of upmost importance to design treatment strategies for patients with previous DAA-treatment failure.

43 Review [Chronic hepatitis C: improved cure rates with new approved medications]. 2012

Grammatikos, Georgios / Vermehren, Johannes / Zeuzem, Stefan. ·Medizinische Klinik I, Gastroenterologie/Hepatologie Klinikum der J.W. Goethe-Universität Frankfurt, Frankfurt am Main. Georgios.Grammatikos@kgu.de ·MMW Fortschr Med · Pubmed #22916428.

ABSTRACT: -- No abstract --

44 Review New antiviral therapies in the management of HCV infection. 2012

Farnik, Harald / Zeuzem, Stefan. ·Medizinische Klinik 1, Klinikum der JW Goethe-Universität, Frankfurt am Main, Germany. ·Antivir Ther · Pubmed #22626842.

ABSTRACT: Improved knowledge of the HCV life cycle and of structural features of HCV proteins have led to the discovery of numerous potential targets for antiviral therapy. Viral replication and polyprotein processing have been tagged as promising viral targets. Clathrin-mediated endocytosis, fusion of HCV with cellular membranes, translation of viral RNA, virus production and release as well as several host cell factors may provide alternative targets for future anti-HCV therapies. Several compounds are currently under investigation in clinical trials and showed high antiviral activity in patients with chronic hepatitis C. Recently, Phase III studies for two protease inhibitors, telaprevir and boceprevir, each given in combination with pegylated interferon (standard of care [SOC]), were completed. In HCV-genotype-1-infected patients, the addition of telaprevir or boceprevir to SOC increased sustained virological response rates from <50% to >70%. Nucleoside/nucleotide inhibitors of the HCV NS5B polymerase have shown antiviral activity against different HCV genotypes, and have a higher barrier to resistance than protease inhibitors. In addition, several allosteric binding sites have been identified for non-nucleoside inhibitors of the NS5B polymerase. Inhibitors of NS5A are potentially active against all HCV genotypes. Among the different host cell-targeting compounds, cyclophilin inhibitors have shown promising results. Future hope lies in the combination of direct-acting antiviral agents with the possibility of interferon-free treatment regimens.

45 Review New direct-acting antiviral agents for the treatment of hepatitis C virus infection and perspectives. 2012

Welsch, Christoph / Jesudian, Arun / Zeuzem, Stefan / Jacobson, Ira. ·Department of Internal Medicine I, J W Goethe University Hospital, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany. christophwelsch@gmx.net ·Gut · Pubmed #22504918.

ABSTRACT: Until recently, the standard of care (SOC) for patients with chronic hepatitis C virus (HCV) infection has consisted of a combination of pegylated interferon-α [corrected] plus ribavirin, administered for 24- to 48-weeks depending on the HCV genotype. The sustained virologic response rate for this SOC has been only about 50% in patients infected with genotype 1 HCV, the most prevalent genotype in Europe and North America. HCV therapy has been revolutionised recently by the approval of two direct-acting antiviral agents (DAA) against the NS3/4A serine protease for use in genotype 1 HCV, the ketoamide inhibitors boceprevir and telaprevir. The novel SOC marks the beginning of an extraordinary new era in HCV therapy. We review this new SOC with an emphasis on practical issues related to protease inhibitors, e.g. prescribing guidelines, futility rules and management of adverse events. We also give a perspective on what to expect in the coming years. Newer DAA with simplified dosing regimens and/or minimal toxicity which, when used in combination, will lead to viral eradication in most if not all CHC patients who undergo treatment. The novel agents in clinical development are paving the way for future interferon-sparing regimens.

46 Review [Antiviral treatment of chronic hepatitis C]. 2012

Berger, Annemarie. ·Institut für Medizinische Virologie, Klinikum der Johann Wolfgang Goethe-Universität, Paul-Ehrlich-Str 40, 60596 Frankfurt am Main. Annemarie.Berger@em.uni-frankfurt.de ·Med Monatsschr Pharm · Pubmed #22400430.

ABSTRACT: The therapy of the chronically hepatitis C virus infection is still a major challenge for the attending physician. Standard therapy regimen implements the combination of pegylated interferon alpha and ribavirin. Duration of therapy is individualized according to the infecting HCV genotype and on the viral response. However, only in 50-80% (dependent on the HCV genotype) treatment will be successful. The development of so called "direct-acting antivirals"(DAA) will provide new options and this was achieved by the approval of two inhibitors of the HCV protease. Boceprevir and telaprevir give hope especially for patients infected with the worse to treat HCV genotype 1. In order to reduce the risk of antiviral resistance these drugs are given in combination with pegylated interferon and ribavirin only.

47 Review Telaprevir for the treatment of hepatitis C. 2012

Forestier, Nicole / Zeuzem, Stefan. ·J. W. Goethe University Hospital, Department of Medicine, 1, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany. ·Expert Opin Pharmacother · Pubmed #22332992.

ABSTRACT: INTRODUCTION: More than 180 million people worldwide are infected with the chronic hepatitis C virus (HCV), a major cause of liver cirrhosis, and its life-threatening complications including liver failure, portal hypertension and hepatocellular carcinoma. For patients infected with HCV genotype 1, the chances of a sustained virologic response (SVR) with the previous standard of care treatment (Peg-IFN-α + ribavirin) are only 40 - 50%. Neither drug targets a specific HCV protein, and treatment is not only compromised by insufficient SVR rates but also associated with several side effects. With a better understanding of the HCV life-cycle, and of the structural features of HCV proteins, several promising direct antiviral drugs (DAAs) have entered clinical development. AREAS COVERED: This review summarizes the clinical development of telaprevir and discusses the possible role of telaprevir in combination with Peg-IFN-α and ribavirin as a new standard treatment against HCV infection, as well as any possible challenges in the future. EXPERT OPINION: Triple therapy, with telaprevir in combination with Peg-IFN-α + ribavirin, is the new standard for chronic hepatitis C treatment in genotype 1-infected patients. At present, there are several next-generation DAAs in clinical development in combination with Peg-IFN-α. The future, however, may also include new treatment strategies, such as oral DAA combinations.

48 Review Antiviral strategies in hepatitis C virus infection. 2012

Sarrazin, Christoph / Hézode, Christophe / Zeuzem, Stefan / Pawlotsky, Jean-Michel. ·Klinikum der JW Goethe-Universität, Medizinische Klinik 1, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. ·J Hepatol · Pubmed #22300469.

ABSTRACT: Resolution of the three-dimensional structures of several hepatitis C virus (HCV) proteins, together with the development of replicative cell culture systems, has led to the identification of a number of potential targets for direct-acting antiviral (DAA) agents. Numerous families of drugs that potently inhibit the HCV lifecycle in vitro have been identified, and some of these molecules have reached early to late clinical development. Two NS3/4A protease inhibitors, telaprevir and boceprevir, were approved in Europe and the United States in 2011 in combination with pegylated interferon (IFN)-α and ribavirin for the treatment of chronic hepatitis C related to HCV genotype 1, in both treatment-naïve and treatment-experienced patients. Sustained virological response rates in the range of 6675% and 5966% (2988% if the response to the first course of therapy is taken into account) have been achieved in these two patient populations, respectively, with treatment durations of 24 to 48 weeks. A number of other DAAs are at the clinical developmental stage in combination with pegylated IFN-α and ribavirin or with other DAAs in IFN-free regimens, with or without ribavirin. They include second-wave, first-generation, and second-generation NS3/4A protease inhibitors, nucleoside/nucleotide analogue inhibitors and non-nucleoside inhibitorsof HCVRNA-dependent RNA polymerase, inhibitors of nonstructural protein 5A (NS5A) and host-targeted compounds, such as cyclophilin inhibitors and silibinin. The proof of concept that IFN-free regimens may lead to HCV eradication has recently been brought. However, new drugs may be associated with troublesome side effects and drugdrug interactions, and the ideal IFN-free DAA combination remains to be found.

49 Review [Expert opinion on boceprevir- and telaprevir-based triple therapies of chronic hepatitis C]. 2012

Sarrazin, C / Berg, T / Cornberg, M / Dollinger, M / Ferenci, P / Hinrichsen, H / Klinker, H / Kraus, M / Manns, M / Mauss, S / Peck-Radosavljevic, M / Schmidt, H / Spengler, U / Wedemeyer, H / Wirth, S / Zeuzem, S. ·Klinikum der Goethe-Universität, Medizinische Klinik 1, Frankfurt am Main. ·Z Gastroenterol · Pubmed #22222799.

ABSTRACT: With the approval of boceprevir and telaprevir the standard treatment of chronic hepatitis C virus (HCV) genotype 1 infection will be the triple therapy of a HCV protease inhibitor together with pegylated interferon alfa and ribavirin. In clinical studies a significant increase of sustained virological response rates from 38 - 44 % to 63 - 75 % for treatment-naïve and from 17 - 21 % to 59 - 66 % in treatment-experienced patients in comparison to the dual combination therapy with pegylated interferon alfa and ribavirin alone has been demonstrated. In addition, a large number of treatment-naïve patients and relapsers benefit from shorten treatment durations to 24 - 28 weeks. However, important differences exist between the administration of boceprevir and telaprevir in terms of a pegylated interferon alfa/ribavirin lead-in phase, the duration of dosing of the protease inhibitor, the overall treatment duration, HCV RNA measurements for response guided treatment durations and stopping rules. Furthermore, triple therapies with boceprevir and telaprevir may be associated with selection of resistant viral variants, new adverse events and clinically relevant drug-drug interactions. The present review gives an overview on the results of underlying clinical studies together with a guideline for the practical management of boceprevir- and telaprevir-based triple therapies.

50 Review Triple therapy with telaprevir: results in hepatitis C virus-genotype 1 infected relapsers and non-responders. 2012

Forestier, Nicole / Zeuzem, Stefan. ·Department of Internal Medicine, J. W. Goethe University Hospital, Frankfurt am Main, Germany. ·Liver Int · Pubmed #22212571.

ABSTRACT: Treatment for chronic hepatitis C virus (HCV) infection has evolved considerably in the last few years. Combination therapy with pegylated interferon (PEG-IFN)-α plus ribavirin (RBV) has been the standard of care (SoC) treatment in the past few years. Several viral and host factors have been associated with treatment failure, including age, male gender, ethnicity, genotype, IL28B genotype, steatosis, obesity and insulin resistance. Several studies have also shown that in patients who fail treatment, several interferon-stimulated genes are upregulated before treatment. Recently, the NS3/4A protease inhibitors telaprevir and boceprevir have been approved and are considered the new SoC therapy in combination with PEG-IFN-α/RBV in HCV genotype 1 treatment-naïve patients, as well as in previously treated patients, with significant improvements in SVR rates. The REALIZE phase III trial with telaprevir in previously treated patients showed SVR rates of 83-88% in prior relapsers, 54-58% in prior partial responders and, 29-33% in prior non-responders.

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