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Hepatitis: HELP
Articles from Goethe Universitat Frankfurt
Based on 331 articles published since 2008
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These are the 331 published articles about Hepatitis that originated from Goethe Universitat Frankfurt during 2008-2019.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5 · 6 · 7 · 8 · 9 · 10 · 11 · 12 · 13 · 14
26 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.

27 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.

28 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.

29 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.

30 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.

31 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.

32 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.

33 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 --

34 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.

35 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.

36 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.

37 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.

38 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.

39 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.

40 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.

41 Review Recent publications in medical microbiology and immunology: a retrospective. 2012

Doerr, H W / Cinatl, J. ·Institute of Medical Virology, University Hospital of Frankfurt/M., Frankfurt/Main, Germany. H.W.Doerr@em.uni-frankfurt.de ·Med Microbiol Immunol · Pubmed #22033658.

ABSTRACT: A look back is done to some clinical and basic research activities recently published in medical microbiology and immunology. The review covers clinical experiences and in vitro experiments to understand the emergency, pathogenicity, epidemic spread, and vaccine-based prevention of avian and swine-origin flu. Some new developments and concepts in diagnosis, (molecular) epidemiology, and therapy of AIDS, viral hepatitis C, and herpesvirus-associated diseases are outlined. Regulation of immune system has been discussed in a special issue 2010 including some aspects of CNS affections (measles). Mycobacterial infection and its prevention by modern recombinant vaccines have reached new interest, as well as new concepts of vaccination and prophylaxis against several other bacteria. Adaptation to host niches enables immune escape (example brucella) and determines virulence (example N. meningitidis). Chlamydia pneumoniae, previously considered to trigger atherosclerosis, is hypothetically associated to Alzheimer disease, while CMV, another putative trigger of atherosclerosis, gains evidence of oncomodulation in CNS tumor diseases. In terms of globalization, exotic virus infections are increasingly imported from southern countries.

42 Review Mixing and matching drugs: what makes sense? 2011

Welzel, Tania M / Zeuzem, Stefan. ·Department of Medicine 1, JW Goethe University Hospital, Theodor-Stern-Kai 7, 60590 Frankfurt a.M., Germany. ·Clin Liver Dis · Pubmed #21867943.

ABSTRACT: The introduction and ongoing development of directly acting antiviral agents (DAAs) and drugs targeting host cell structures will change the management of patients with chronic hepatitis C virus (HCV) infection. The concomitant use of the protease inhibitors telaprevir or boceprevir with the standard of care, a combination of pegylated interferon (PegIFN) and ribavirin, will represent the new standard for the treatment of HCV genotype 1 infection. Contraindications and side effects limit the applicability of interferon-based therapies and motivate the investigation of PegIFN-sparing regimens. Different DAA combinations under investigation are reviewed in this article.

43 Review New hepatitis C therapies in clinical development. 2011

Vermehren, Johannes / Sarrazin, Christoph. ·Medizinische Klinik 1, Klinikum der J.W. Goethe-Universität, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. ·Eur J Med Res · Pubmed #21813371.

ABSTRACT: With the current standard of care for the treatment of chronic hepatitis C, a combination of pegylated interferon alfa and ribavirin, sustained virologic response rates can be achieved in approximately 50% of patients only. - Improved understanding of the viral life cycle has led to the identification of numerous potential targets for novel, direct-acting antiviral compounds. Inhibitors of the NS3/4A protease are currently the most advanced in clinical development. Recently completed phase 3 studies of the two protease inhibitors telaprevir and boceprevir, each given in combination with standard of care, yielded sustained virologic response rates in the range of 66-75% in treatment-naive patients and 59-66% in treatment-experienced patients with HCV genotype 1 infection. Studies of second-generation protease inhibitors, with the potential advantage of improved potency, drug metabolism and pharmacokinetics profile, are already underway. - Inhibitors of the HCV NS5A protein and NS5B polymerase are potentially active across different HCV genotypes and have shown promising antiviral efficacy in early clinical studies. Other emerging mechanisms include silymarin components and inhibitors of cell proteins required for HCV replication. - While improved formulations of current HCV therapies are also being developed, future hopes lie on the combination of direct-acting antivirals with the eventual possibility of interferon-free treatment regimens.

44 Review A new standard of care for the treatment of chronic HCV infection. 2011

Hofmann, Wolf Peter / Zeuzem, Stefan. ·Medizinische Klinik 1, Klinikum der Johann Wolfgang Goethe-Universität, Theodor Stern-Kai 7, Frankfurt am Main 60590, Germany. ·Nat Rev Gastroenterol Hepatol · Pubmed #21468124.

ABSTRACT: The introduction of direct acting antiviral agents (DAAs) will markedly change treatment options for individuals who have a chronic HCV infection. Within the next few months, licensing of two HCV protease inhibitors (boceprevir and telaprevir) for the treatment of patients with chronic hepatitis C as part of a triple therapy with PEG-IFN-α and ribavirin is anticipated in the USA, Europe and many other countries. Final results of pivotal phase III clinical trials in previously untreated and treatment-experienced patients with HCV genotype 1 infection were presented at the Annual Meeting of the American Association for the Study of the Liver 2010 held in Boston, MA, USA, and at the Annual Conference of the Asian Pacific Association for the Study of the Liver 2011, held in Bangkok, Thailand. This article summarizes the results of these phase III trials in consideration of accumulating data on important baseline and on-treatment predictive factors for treatment response, such as the host IL28B genotype and the rapid virologic response; the introduction of these new therapies into clinical practice is also covered. Furthermore, preliminary data on the combination of different classes of DAAs, such as HCV protease inhibitors and HCV polymerase inhibitors, without interferon α are discussed.

45 Review IL28B single nucleotide polymorphisms in the treatment of hepatitis C. 2011

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; Centre Hospitalier Universitaire Vaudois, University of Lausanne, Rue Bugnon 46, CH-1010 Lausanne, Switzerland. · Klinikum der J.W. Goethe-Universität Frankfurt am Main, Medizinische Klinik 1, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. Electronic address: zeuzem@em.uni-frankfurt.de. ·J Hepatol · Pubmed #21440591.

ABSTRACT: Recent genome-wide association studies (GWAS) have identified genetic variations near the IL28B gene which are strongly associated with spontaneous and treatment-induced clearance of hepatitis C virus (HCV) infection. Protective IL28B variations are strongly associated with on-treatment viral kinetics and approximately 2-fold increased sustained virologic response (SVR) rates in HCV genotype 1 and 4 patients. In HCV genotype 1 patients, IL28B variations were shown to be the strongest pre-treatment predictor of virologic response. In the treatment of HCV genotype 2 and 3 infected patients, IL28B variations play only a minor role. Preliminary data indicate that IL28B variations are also associated with treatment outcome of regimens, including directly acting antiviral (DAA) agents, though their impact seems to be attenuated compared to standard treatment. Here, we review these important findings and discuss possible implications for clinical decision making in the treatment of HCV infection.

46 Review [Current Guidelines for treatment of hepatitis C. The eradication of HCV as a goal]. 2011

Sarrazin, Christoph / Zeuzem, Stefan. ·Klinikum der J. W. Goethe-Universität Frankfurt am Main, Medizinische Klinik 1, Theodor-Stern-Kai 7, 60590 Frankfurt am Main. sarrazin@em.uni-frankfurt.de ·Pharm Unserer Zeit · Pubmed #21194083.

ABSTRACT: -- No abstract --

47 Review New HCV therapies on the horizon. 2011

Vermehren, J / Sarrazin, C. ·Medizinische Klinik 1, Klinikum der J. W. Goethe-Universität, Frankfurt am Main, Germany. ·Clin Microbiol Infect · Pubmed #21087349.

ABSTRACT: Improved understanding of the hepatitis C virus (HCV) life cycle has led to the discovery of numerous potential targets for antiviral therapy. HCV polyprotein processing and replication have been identified as the most promising viral targets. However, viral entry and fusion, RNA translation, virus assembly and release and several host cell factors may provide alternative attractive targets for future anti-HCV therapies. Inhibitors of the HCV NS3/4A protease are currently the most advanced in clinical development. Monotherapy with protease inhibitors has shown high antiviral activity, but is associated with frequent selection of resistant HCV variants, often resulting in viral breakthrough. However, there is encouraging evidence from phase 2/3 trials indicating that the addition of a protease inhibitor (e.g. telaprevir and boceprevir) to pegylated interferon-α/ribavirin substantially improves sustained virological response rates in both treatment-naïve and treatment-experienced patients with HCV genotype 1. Nucleos(t)ide inhibitors of the HCV NS5B polymerase have shown variable antiviral activity against different HCV genotypes, but seem to have a higher genetic barrier to resistance than protease inhibitors. In addition, several allosteric binding sites have been identified for non-nucleoside inhibitors of the NS5B polymerase. However, the development of a substance with high antiviral activity and a high genetic barrier to resistance seems to be difficult. Among the different host cell-targeting compounds in early clinical development, cyclophilin inhibitors have shown the most promising results. Although advances have also been made in improving interferons, combinations of antiviral agents with different mechanisms of action may lead to the eventual possibility of interferon-free regimens.

48 Review [Chronic hepatitis C]. 2010

Grammatikos, G / Sarrazin, C. ·Medizinische Klinik 1, Klinikum der J. W. Goethe-Universität, Frankfurt am Main. ·Dtsch Med Wochenschr · Pubmed #21140330.

ABSTRACT: Chronic hepatitis C virus (HCV) infection is an important, global pathognomonic causal factor for development of liver cirrhosis and hepatocellular carcinoma. After parenteral transmission of the virus the majority of cases develop a chronic infection. Nowadays, the diagnosis of HCV-infection is made frequently in an advanced disease-stage due to an increasing number of patients with long durations of chronic infection and typically asymptomatic disease progression. The detection of HCV antibodies is suitable for the initial screening in the diagnosis of chronic Hepatitis C-infection. In patients with positive HCV antibodies, testing for HCV RNA by a sensitive assay is required to differentiate between an ongoing and a past infection. Prior to initiation of antiviral therapy, HCV genotype and HCV viral load should be determined together with a comprehensive diagnostic framework (including determination of the extent of liver fibrosis, exclusion of hepatocellular carcinoma and a concomitant liver disease). All treatment-naive patients with chronic hepatitis C should be considered for antiviral treatment since the eradication of the virus is associated with reduction of HCV related mortality and increasing age as well as increasing fibrosis is associated with reduced virologic response rates. In pretreated patients, decision on retreatment should be based on the potential for optimization of conditions for a second treatment in each individual case. Based mainly on the viral load before treatment initiation and virologic response during antiviral therapy rules for early treatment discontinuations in non-responders as well as for individualized durations of treatment for virologic responders have been established. Currently, approximately 50 % of treatment-naïve patients with genotype 1 infection and 80 % of patients with genotype 2/3 infection achieve a sustained virologic response with eradication of the virus. With the approval of triple therapies of HCV protease inhibitors (telaprevir and boceprevir) together with the current standard of care in 2011/2012 sustained virologic response rates of HCV genotype 1 patients will be improved by approximately 30 %.

49 Review Pegylated-interferon plus ribavirin therapy in the treatment of CHC: individualization of treatment duration according to on-treatment virologic response. 2010

Zeuzem, Stefan / Poordad, Fred. ·Department of Medicine I, J.W. Goethe University Hospital, Frankfurt, Germany. zeuzem@em.uni-frankfurt.de ·Curr Med Res Opin · Pubmed #20482242.

ABSTRACT: BACKGROUND: Standard treatment of chronic hepatitis C (CHC) is peginterferon alfa (PEG-IFN alfa) plus ribavirin (RBV) for 48 weeks in patients infected with genotype 1, and 24 weeks for those infected with genotype 2 or 3. However, recent studies have shown that on-treatment markers of virologic response can be used to tailor treatment duration according to each patient's response to therapy. AIM: To discuss the rationale for assessing on-treatment markers of virologic response to PEG-IFN alfa plus RBV. METHODS: A literature search was conducted using MEDLINE and conference proceedings for clinical studies of reduced and extended treatment durations in the treatment of CHC. FINDINGS: Patients infected with genotype 1 and low baseline viral load who have undetectable HCV RNA by week 4 can be effectively treated for 24 weeks without any decline in efficacy. Extended treatment duration of 72 weeks has been studied in various selected patient groups with genotype 1 infection who are slow to respond to treatment; however, data are conflicting regarding the patient subgroup that may benefit most from this strategy. Finally, selected HCV genotype 2 or 3 patients with undetectable HCV RNA at week 4 and other favorable prognostic features may be effectively managed with shorter (12 to 16 weeks) treatment duration. Further work is required to determine how the findings of this review relate to patients who do not fit with the enrollment criteria of randomized clinical trials or who require dose adjustment based on adverse tolerability. Care should also be exercised when comparing data between studies because of differences in design and patient populations. CONCLUSION: Evaluation of on-treatment markers of virologic response has revolutionized the treatment of CHC: implementation of these assessments in clinical practice is strongly supported by data from recent clinical studies, even in advance of formal recognition in treatment guidelines.

50 Review Review article: specifically targeted anti-viral therapy for hepatitis C - a new era in therapy. 2010

Lange, C M / Sarrazin, C / Zeuzem, S. ·Department of Medicine, Johann Wolfgang Goethe University, Frankfurt am Main, Germany. ·Aliment Pharmacol Ther · Pubmed #20374226.

ABSTRACT: BACKGROUND: Novel, directly acting anti-viral agents, also named 'specifically targeted anti-viral therapy for hepatitis C' (STAT-C) compounds, are currently under development. AIM: To review the potential of STAT-C agents which are currently under clinical development, with a focus on agents that target HCV proteins. METHODS: Studies evaluating STAT-C compounds were identified by systematic literature search using PubMed as well as databases of abstracts presented in English at recent liver and gastroenterology congresses. RESULTS: Numerous directly-acting anti-viral agents are currently under clinical phase I-III evaluation. Final results of phase II clinical trials evaluating the most advanced compounds telaprevir and boceprevir indicate that the addition of these NS3/4A protease inhibitors to pegylated interferon-alfa and ribavirin strongly improves the chance to achieve a SVR in treatment-naive HCV genotype 1 patient as well as in prior nonresponders and relapsers to standard therapy. Monotherapy with directly acting anti-virals is not suitable. NS5B polymerase inhibitors in general have a lower anti-viral efficacy than protease inhibitors. CONCLUSIONS: STAT-C compounds in addition to pegylated interferon-alfa and ribavirin can improve SVR rates at least in HCV genotype 1 patients. Future research needs to evaluate whether a SVR can be achieved by combination therapies of STAT-C compounds in interferon-free regimens.

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