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Hepatitis: HELP
Articles by Ulrich Spengler
Based on 94 articles published since 2008
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Between 2008 and 2019, U. Spengler wrote the following 94 articles about Hepatitis.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4
1 Guideline [Prophylaxis, diagnosis and therapy of hepatitis C virus (HCV) infection: the German guidelines on the management of HCV infection]. 2010

Sarrazin, C / Berg, T / Ross, R S / Schirmacher, P / Wedemeyer, H / Neumann, U / Schmidt, H H / Spengler, U / Wirth, S / Kessler, H H / Peck-Radosavljevic, M / Ferenci, P / Vogel, W / Moradpour, D / Heim, M / Cornberg, M / Protzer, U / Manns, M P / Fleig, W E / Dollinger, M M / Zeuzem, S. ·Medizinische Klinik I, Johann-Wolfgang-Goethe-Universität, Frankfurt am Main, Germany. ·Z Gastroenterol · Pubmed #20119896.

ABSTRACT: -- No abstract --

2 Review Direct antiviral agents (DAAs) - A new age in the treatment of hepatitis C virus infection. 2018

Spengler, Ulrich. ·Department of Internal Medicine 1, Rheinische Friedrich-Wilhelms-University of Bonn, Bonn, Germany. Electronic address: spengler@uni-bonn.de. ·Pharmacol Ther · Pubmed #29024739.

ABSTRACT: Hepatitis C virus (HCV) is a global health problem, because infection frequently leads to chronic hepatitis C eventually progressing to liver cirrhosis and liver cancer. Improved insights into the HCV replication cycle and the role of HCV non-structural proteins have recently enabled to identify drugs directly acting on specific HCV target structures. Agents from three drug classes have been developed and approved by the health authorities. Combinations of two or more drugs from different classes achieve high (>90%) HCV clearance rates and are well tolerated. This interferon-free DAA (direct antiviral agent) therapy has revolutionized antiviral therapy in hepatitis C so that successful hepatitis C treatment can be offered to virtually all patients irrespective of their co-morbidity. This review provides an overview over currently approved regimens and outlines their use in clinical practice. In addition potential short-comings of the current therapeutic options such as drug-drug interactions and selection of viral resistance are addressed. DAA combination therapy has the potential to obtain global control over hepatitis C. However, easy access to DAAs, availability of reliable HCV diagnostics, and affordable costs remain still important goals, which must be reached to globally eliminate hepatitis C.

3 Review Between Scylla and Charybdis: the role of the human immune system in the pathogenesis of hepatitis C. 2013

Spengler, Ulrich / Nischalke, Hans Dieter / Nattermann, Jacob / Strassburg, Christian P. ·Ulrich Spengler, Hans Dieter Nischalke, Jacob Nattermann, Christian P Strassburg, Department of Internal Medicine 1, University of Bonn, 53105 Bonn, Germany. ·World J Gastroenterol · Pubmed #24307779.

ABSTRACT: Hepatitis C virus (HCV) frequently elicits only mild immune responses so that it can often establish chronic infection. In this case HCV antigens persist and continue to stimulate the immune system. Antigen persistence then leads to profound changes in the infected host's immune responsiveness, and eventually contributes to the pathology of chronic hepatitis. This topic highlight summarizes changes associated with chronic hepatitis C concerning innate immunity (interferons, natural killer cells), adaptive immune responses (immunoglobulins, T cells, and mechanisms of immune regulation (regulatory T cells). Our overview clarifies that a strong anti-HCV immune response is frequently associated with acute severe tissue damage. In chronic hepatitis C, however, the effector arms of the immune system either become refractory to activation or take over regulatory functions. Taken together these changes in immunity may lead to persistent liver damage and cirrhosis. Consequently, effector arms of the immune system will not only be considered with respect to antiviral defence but also as pivotal mechanisms of inflammation, necrosis and progression to cirrhosis. Thus, avoiding Scylla - a strong, sustained antiviral immune response with inital tissue damage - takes the infected host to virus-triggered immunopathology, which ultimately leads to cirrhosis and liver cancer - the realm of Charybdis.

4 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.

5 Review Management of end-stage liver disease in HIV/hepatitis C virus co-infection. 2011

Spengler, Ulrich. ·Department of Internal Medicine 1, University of Bonn, Bonn, Germany. Spengler@uni-bonn.de ·Curr Opin HIV AIDS · Pubmed #21918437.

ABSTRACT: PURPOSE OF REVIEW: Highly active antiretroviral therapy has improved prognosis of HIV infection and substantially reduced the incidence of opportunistic diseases. However, hepatitis viruses and HIV share the same routes of transmission. Thus, chronic viral hepatitis is found frequently in HIV-infected patients. Antiretroviral drugs do not directly interact with the hepatitis C virus (HCV), so that end-stage liver disease (ESLD) in HCV/HIV co-infected patients has become a leading clinical problem in many co-infected patients. RECENT FINDINGS: This review summarizes up-to-date guidelines in the management of ESLD and specifically addresses issues of cirrhosis in HCV/HIV co-infection. The most recent advances in the treatment of typical complication of ESLD such as esophageal varices (updated guidelines), variceal hemorrhage (early use of transjugular intrahepatic portosystemic shunt), ascites (updated guidelines), hepatorenal syndrome (vasopressor therapy, deleterious effects of beta-blockers), spontaneous bacterial peritonitis (primary prophylaxis) and hepatic encephalopathy (use of rifaximin) are discussed. This review also provides a basic outline on liver transplantation in HCV/HIV co-infected patients. SUMMARY: Thus, physicians involved in the management of ESLD in HCV/HIV co-infected patients will find a comprehensive overview over current treatment strategies in ESLD of HIV-positive patients as well as a valuable collection of pivotal references on the most recent advances in the treatment of ESLD due to HCV/HIV co-infection.

6 Review Challenges and controversies in haemophilia care in adulthood. 2009

Dolan, G / Hermans, C / Klamroth, R / Madhok, R / Schutgens, R E G / Spengler, U. ·Department of Haematology, Nottingham University Hospitals, Nottingham, UK. gerry.dolan@nottingham.ac.uk ·Haemophilia · Pubmed #19125937.

ABSTRACT: Overall life expectancy and quality of life among persons with haemophilia have increased in recent years, primarily because of the advances in factor replacement therapy and better treatment of infectious diseases. Older haemophilic patients now face aging co-morbidities that are common in the general male population, such as cardiovascular or metabolic diseases, prostate hypertrophy and hepatic, prostate and other cancers. The prevalence of cardiovascular disease and incidence of vascular events among older haemophilic patients can be expected to increase and haemophilic patients may become prone to some cardiovascular risk factors, warranting preventative measures. The treatment of long-term complications of hepatitis C virus infection such as liver cirrhosis and hepatic cancer can be expected to be required in a large portion of the older haemophilia population for some years to come. Appropriate antiviral treatment and close monitoring for possible disease advancement will constitute an important part of routine medical care, and special considerations may be appropriate in conjunction with invasive procedures, chemo- or radiotherapy. At the moment, hard data on which to base the management of these conditions are largely lacking, but can be expected to increase dramatically in the coming decades. In the meantime, the ageing population of haemophilia patients should be offered the same comprehensive health care offered to the general population, which may require a restructuring of health care delivery.

7 Review Atypical p-ANCA in PSC and AIH: a hint toward a "leaky gut"? 2009

Terjung, Birgit / Spengler, Ulrich. ·Department of Internal Medicine, University of Bonn, Sigmund-Freud-Strasse 25, 53105, Bonn, Germany. birgit.terjung@ukb.uni-bonn.de ·Clin Rev Allergy Immunol · Pubmed #18626795.

ABSTRACT: Primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) are enigmatic chronic inflammatory diseases of the liver, which are frequently associated with chronic inflammatory bowel diseases. Both types of liver disease share various distinct autoantibodies such as atypical perinuclear antineutrophil cytoplasmic antibodies (p-ANCA), and thus are considered autoimmune disorders with atypical features. The discovery that atypical p-ANCA recognize both tubulin beta isoform 5 in human neutrophils and the bacterial cell division protein FtsZ has renewed the discussion on the potential role of microorganisms in the pathogenesis of both diseases. In this paper, we review the evidence for microbial infection in PSC and AIH and discuss new concepts how cross-recognition between microbial antigens in the gut and host components by the immune system along with stimulation of pattern recognition receptors might give rise to chronic hepatic inflammatory disorders with features of autoimmunity.

8 Review Host genetic factors and treatment of hepatitis C. 2008

Nattermann, Jacob / Leifeld, Ludger / Spengler, Ulrich. ·Department of Internal Medicine I, University of Bonn, Bonn, Germany. jacob.nattermann@ukb.uni-bonn.de ·Curr Mol Pharmacol · Pubmed #20021431.

ABSTRACT: Infection with the hepatitis C virus (HCV) is a major health problem worldwide due to the associated risk of developing liver cirrhosis and its sequelae. Approximately 200 million persons are chronically infected worldwide. Furthermore, about one third of HIV-infected individuals in Europe and the US are co-infected with HCV. Currently pegylated interferon-alpha in combination with ribavirin represents the backbone of HCV-specific therapy. However, with interferon-based combination therapy sustained virologic response (SVR) is achieved in only about 50% of HCV-infected patients in clinical studies and may be even lower in clinical practice. HCV genotype and viral load are major determinants of treatment response in HCV infection. However, emerging data suggest host genetic factors also influence response to treatment. These data might hold the keys to better understand and predict outcome of HCV-specific therapy and might help to develop novel anti-HCV strategies. Here, we review the role of genetic aspects including the role of cytokines, chemokines/ chemokine receptors, and MHC alleles with respect to HCV therapy that have been elucidated so far and offer suggestions for how to use these observations as platforms for future research to further understand differential response to antiviral therapy in HCV-infected patients.

9 Review [Liver biopsy at the intersection of clinical and pathological diagnosis]. 2008

Spengler, U / Fischer, H-P. ·Medizinische Klinik 1, Universität Bonn, 53127, Bonn. Ulrich.Spengler@ukb.uni-bonn.de ·Pathologe · Pubmed #18210109.

ABSTRACT: Liver biopsy plays an important role in the diagnosis of liver diseases. Nowadays, biochemical, immunological, functional and molecular tests allow the etiology of many liver diseases to be clarified. The liver biopsy contributes essential information about the stage and grade of inflammatory liver diseases on the basis of consensus criteria. These data influence treatment and help to assess the prognosis. In addition, the different patterns of fibrosis allow conclusions about the cause and progress of the underlying liver disease. Hepatitis C, autoimmune hepatitis, unexplained severe course of hepatitis B, differentiation of simple steatosis from steatohepatitis, the differential diagnosis of cholestatic diseases, unclear hepatopathy, transplant pathology and last but not least, hepatic masses are the focal points of liver biopsy diagnoses. Increased risk of hemorrhage due to coagulation defects can be minimized by a transjugular biopsy. Liver masses can be effectively located and identified by radiologically or ultrasound-guided biopsy. Regular periodic conferences between clinicians and pathologists help to clarify individual problematic cases and will promote the diagnostic competence of both partners in hepatology.

10 Clinical Trial Elbasvir/Grazoprevir for Patients With Hepatitis C Virus Infection and Inherited Blood Disorders: A Phase III Study. 2017

Hézode, Christophe / Colombo, Massimo / Bourlière, Marc / Spengler, Ulrich / Ben-Ari, Ziv / Strasser, Simone I / Lee, William M / Morgan, Leslie / Qiu, Jingjun / Hwang, Peggy / Robertson, Michael / Nguyen, Bach-Yen / Barr, Eliav / Wahl, Janice / Haber, Barbara / Chase, Robert / Talwani, Rohit / Marco, Vito Di / Anonymous4420898. ·Henri Mondor Hospital, Paris, France. · Humanitas Clinical and Research Center, Rozzano, Italy. · Hôpital Saint Joseph, Marseille, France. · University Hospital Bonn, Bonn, Germany. · Sheba Medical Center, Ramat Gan, Israel. · University of Sydney, Sydney, NSW, Australia. · University of Texas Southwestern Medical Center, Dallas, TX. · Merck & Co., Inc, Kenilworth, NJ. · University of Palermo, Palermo, Italy. ·Hepatology · Pubmed #28256747.

ABSTRACT: Direct-acting antiviral agents have not been studied exclusively in patients with inherited blood disorders and hepatitis C virus (HCV) infection. The objective of the randomized, placebo-controlled, phase III C-EDGE IBLD study was to assess the safety and efficacy of elbasvir/grazoprevir (EBR/GZR) in patients with inherited bleeding disorders and HCV infection. One hundred fifty-nine adults with HCV infection and sickle cell anemia, thalassemia, or hemophilia A/B or von Willebrand disease were enrolled at 31 study sites in the United States, Europe, Australia, Canada, Israel, and Thailand. Patients were given an oral, once-daily, fixed-dose combination of EBR/GZR 50 mg/100 mg for 12 weeks and randomized to the immediate-treatment group (ITG) or deferred-treatment group (DTG; placebo followed by active treatment). The primary endpoints were the proportion of patients in the ITG with unquantifiable HCV RNA 12 weeks posttreatment (sustained virological response 12 weeks after completion of study treatment; SVR12) and the comparison of safety in the ITG and DTG. In the ITG, 100 of 107 patients (93.5%) achieved SVR12, 6 relapsed, and 1 was lost to follow-up. SVR12 was achieved in 94.7% (18 of 19), 97.6% (40 of 41), and 89.4% (42 of 47) of patients with sickle cell disease, β-thalassemia, and hemophilia A/B or von Willebrand disease, respectively. Serious adverse events were reported by 2.8% (n = 3) and 11.5% (n = 6) of patients in the ITG and DTG, respectively. Hemoglobin levels and international normalized ratio values were similar in patients receiving EBR/GZR and placebo; among patients with hemoglobinopathies, change in mean hemoglobin levels was similar in those receiving EBR/GZR compared to those receiving placebo. CONCLUSION: These results add to the expanding pool of data available for EBR/GZR, indicating a high level of efficacy and favorable tolerability in patients with HCV infection. (Hepatology 2017;66:736-745).

11 Clinical Trial Ledipasvir plus sofosbuvir fixed-dose combination for 6 weeks in patients with acute hepatitis C virus genotype 1 monoinfection (HepNet Acute HCV IV): an open-label, single-arm, phase 2 study. 2017

Deterding, Katja / Spinner, Christoph D / Schott, Eckart / Welzel, Tania M / Gerken, Guido / Klinker, Hartwig / Spengler, Ulrich / Wiegand, Johannes / Schulze Zur Wiesch, Julian / Pathil, Anita / Cornberg, Markus / Umgelter, Andreas / Zöllner, Caroline / Zeuzem, Stefan / Papkalla, Armin / Weber, Kristina / Hardtke, Svenja / von der Leyen, Heiko / Koch, Armin / von Witzendorff, Dorothee / Manns, Michael P / Wedemeyer, Heiner / Anonymous551096. ·Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; HepNet Study-House, German Liver Foundation, Hannover, Germany. · Department of Medicine II, University Hospital Klinikum rechts der Isar, Munich, Germany. · Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany. · Department of Medicine, University Hospital Frankfurt, Frankfurt, Germany. · Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany. · Department of Internal Medicine II, Division of Infectious Diseases, University of Würzburg Medical Center, Würzburg, Germany. · Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany. · Department of Gastroenterology and Rheumatology, Section of Hepatology, University of Leipzig, Leipzig, Germany. · Department of Internal Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany. · Department of Internal Medicine IV, Gastroenterology and Hepatology, University Clinic of Heidelberg, Heidelberg, Germany. · Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; HepNet Study-House, German Liver Foundation, Hannover, Germany; German Centre for Infection Research (DZIF), partner site Hannover-Braunschweig, Germany. · Hannover Clinical Trial Center, Hannover, Germany. · Department of Biostatistics, Hannover Medical School, Hannover, Germany. · HepNet Study-House, German Liver Foundation, Hannover, Germany; German Centre for Infection Research (DZIF), partner site Hannover-Braunschweig, Germany. · HepNet Study-House, German Liver Foundation, Hannover, Germany. · Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; HepNet Study-House, German Liver Foundation, Hannover, Germany; German Centre for Infection Research (DZIF), partner site Hannover-Braunschweig, Germany. Electronic address: manns.michael@mh-hannover.de. · Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; HepNet Study-House, German Liver Foundation, Hannover, Germany; German Centre for Infection Research (DZIF), partner site Hannover-Braunschweig, Germany. Electronic address: wedemeyer.heiner@mh-hannover.de. ·Lancet Infect Dis · Pubmed #28029529.

ABSTRACT: BACKGROUND: Early treatment of acute hepatitis C virus (HCV) infection with interferon alfa is highly effective, but can be associated with frequent side-effects. We investigated the safety and efficacy of an interferon-free regimen for treatment of acute HCV infection. METHODS: In this prospective, open-label, multicentre, single-arm pilot study, we enrolled adults (≥18 years) with acute HCV genotype 1 monoinfection from ten centres in Germany. Patients were given ledipasvir (90 mg) plus sofosbuvir (400 mg) as a fixed-dose combination tablet once daily for 6 weeks. The primary efficacy outcome was the proportion of patients with sustained virological response (defined as undetectable HCV RNA 12 weeks after the end of treatment; other primary outcomes were safety and tolerability of ledipasvir plus sofosbuvir. The primary analysis population consisted of all patients who received at least one dose of study drug. Safety was also assessed in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov, number NCT02309918. FINDINGS: Between Nov 19, 2014, and Nov 10, 2015, we enrolled 20 patients. Median HCV RNA viral load at baseline was 4·04 log INTERPRETATION: Treatment for 6 weeks with ledipasvir plus sofosbuvir was well tolerated and highly effective in patients with acute HCV genotype 1 monoinfection. Short-duration treatment of acute hepatitis C might prevent the spread of HCV in high-risk populations. FUNDING: Gilead Sciences, HepNet Study-House/German Liver Foundation, and German Centre for Infection Research (DZIF).

12 Clinical Trial Delayed versus immediate treatment for patients with acute hepatitis C: a randomised controlled non-inferiority trial. 2013

Deterding, Katja / Grüner, Norbert / Buggisch, Peter / Wiegand, Johannes / Galle, Peter R / Spengler, Ulrich / Hinrichsen, Holger / Berg, Thomas / Potthoff, Andrej / Malek, Nisar / Großhennig, Anika / Koch, Armin / Diepolder, Helmut / Lüth, Stefan / Feyerabend, Sandra / Jung, Maria Christina / Rogalska-Taranta, Magdalena / Schlaphoff, Verena / Cornberg, Markus / Manns, Michael P / Wedemeyer, Heiner / Anonymous5580753. ·Hep-Net: German Network of Competence on Viral Hepatitis, Hannover, Germany. ·Lancet Infect Dis · Pubmed #23523674.

ABSTRACT: BACKGROUND: Early treatment of acute hepatitis C virus (HCV) infection with interferon alfa monotherapy is very effective, with cure rates of greater than 85%. However, spontaneous clearance of HCV occurs in 10-50% of cases. We aimed to assess an alternative treatment strategy of delayed antiviral therapy in patients who do not eliminate the virus spontaneously compared with immediate treatment. METHODS: In our open-label phase 3 non-inferiority trial, we enrolled adults (≥18 years) with acute hepatitis C but no HIV or hepatitis B co-infection at 72 centres in Germany. We randomly allocated patients with symptomatic acute hepatitis C (1:1) to receive immediate pegylated interferon alfa-2b treatment for 24 weeks or delayed treatment with pegylated interferon alfa-2b plus ribavirin (for 24 weeks) starting 12 weeks after randomisation if HCV RNA remained positive. We used a computer-generated randomisation sequence and block sizes of eight, stratified by bilirubin concentration. We assigned all asymptomatic patients to immediate treatment with pegylated interferon alfa-2b for 24 weeks. The primary endpoint was sustained HCV RNA negativity in all randomly allocated participants who completed screening (intention-to-treat analysis), with a non-inferiority margin of 10%. For the primary analysis, we calculated the virological response of patients in the immediate and delayed treatment groups and an absolute risk difference stratified by bilirubin status. The trial was stopped early on advice from the study advisory committee because of slow recruitment of participants. This study is registered, number ISRCTN88729946. FINDINGS: Between April, 2004, and February, 2010, we recruited 107 symptomatic and 25 asymptomatic patients. 37 (67%) of 55 symptomatic patients randomly allocated to receive immediate treatment and 28 (54%) of 52 symptomatic patients randomly allocated to receive delayed treatment had a sustained virological response (difference 13·7%, 95% CI -4·6 to 32·0; p=0·071). 18 (72%) of 25 asymptomatic patients had a sustained virological response. 22 (42%) of 52 symptomatic patients allocated to receive delayed treatment did not complete follow-up compared with 20 (25%) of 80 symptomatic or asymptomatic patients assigned immediate treatment (p=0·037). 11 symptomatic patients (21%) assigned delayed treatment had spontaneous HCV clearance. 14 patients who received delayed pegylated interferon alfa-2b plus ribavirin treatment and completed follow-up achieved sustained virological response. INTERPRETATION: Delayed treatment is effective although not of equal efficacy to immediate treatment; coupled with the rate of spontaneous clearance it can reduce unnecessary treatment in closely monitored populations. Immediate treatment seems preferable in populations where loss to follow-up is great. FUNDING: German Network of Competence on Viral Hepatitis (HepNet, funded by the German Federal Ministry of Education and Research, grants 01KI0102, 01KI0401, and 01KI0601), MSD, Schering-Plough.

13 Clinical Trial Budesonide induces remission more effectively than prednisone in a controlled trial of patients with autoimmune hepatitis. 2010

Manns, Michael P / Woynarowski, Marek / Kreisel, Wolfgang / Lurie, Yoav / Rust, Christian / Zuckerman, Elimelech / Bahr, Matthias J / Günther, Rainer / Hultcrantz, Rolf W / Spengler, Ulrich / Lohse, Ansgar W / Szalay, Ferenc / Färkkilä, Martti / Pröls, Markus / Strassburg, Christian P / Anonymous6530664. ·Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. manns.michael@mh-hannover.de ·Gastroenterology · Pubmed #20600032.

ABSTRACT: BACKGROUND & AIMS: Autoimmune hepatitis (AIH) is a chronic liver disease associated with cirrhosis and liver failure. Corticosteroid therapy induces long-term remission but has many side effects. We compared the effects of budesonide (a steroid that is rapidly metabolized, with low systemic exposure) and prednisone, both in combination with azathioprine. METHODS: We performed a 6-month, prospective, double-blind, randomized, active-controlled, multicenter, phase IIb trial of patients with AIH without evidence of cirrhosis who were given budesonide (3 mg, three times daily or twice daily) or prednisone (40 mg/d, tapered to 10 mg/d); patients also received azathioprine (1-2 mg/kg/d). Treatment was followed by a 6-month, open-label phase during which all patients received budesonide in addition to azathioprine. The primary end point was complete biochemical remission, defined as normal serum levels of aspartate aminotransferase and alanine aminotransferase, without predefined steroid-specific side effects, at 6 months. RESULTS: The primary end point was achieved in 47/100 patients given budesonide (47.0%) and in 19/103 patients given prednisone (18.4%) (P < .001; 97.5% 1-side confidence interval [CI] = 16.2). At 6 months, complete biochemical remission occurred in 60% of the patients given budesonide versus 38.8% of those given prednisone (P = .001; CI: 7.7); 72.0% of those in the budesonide group did not develop steroid-specific side effects versus 46.6% in the prednisone group (P < .001; CI = 12.3). Among 87 patients who were initially given prednisone and then received budesonide after 6 months, steroid-specific side effects decreased from 44.8% to 26.4% at month 12 (P < .002). CONCLUSIONS: Oral budesonide, in combination with azathioprine, induces and maintains remission in patients with noncirrhotic AIH, with a low rate of steroid-specific side effects.

14 Article Successful direct acting antiviral (DAA) treatment of HCV/HIV-coinfected patients before and after liver transplantation. 2018

Grottenthaler, Julia M / Werner, Christoph R / Steurer, Martina / Spengler, Ulrich / Berg, Thomas / Engelmann, Cornelius / Wedemeyer, Heiner / von Hahn, Thomas / Stremmel, Wolfgang / Pathil, Anita / Seybold, Ulrich / Schott, Eckart / Blessin, Usha / Sarrazin, Christoph / Welker, Martin-Walter / Harrer, Ellen / Scholten, Stefan / Hinterleitner, Clemens / Lauer, Ulrich M / Malek, Nisar P / Berg, Christoph P. ·Department of Gastroenterology, Hepatology, and Infectiology, University Hospital Tuebingen, Tuebingen, Germany. · German Center for Infection Research (DZIF) partner site, Tuebingen, Bonn, Hannover, Heidelberg, Munich, Germany. · Department of Internal Medicine I, University of Bonn, Bonn, Germany. · Division of Gastroenterology and Hepatology, University Hospital Leipzig, Leipzig, Germany. · Department of Gastroenterology, Hepatology, and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany. · Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany. · Division of Infectious Diseases, Medizinische Poliklinik-Innenstadt, University of Munich, Munich, Germany. · Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany. · Department of Gastroenterology and Hepatology, University Hospital Frankfurt, Frankfurt, Germany. · Department of Internal Medicine 3, Institute of Clinical Immunology, University Hospital Erlangen, Erlangen, Germany. · Praxis Hohenstaufenring, Cologne, Germany. · Department of Medical Oncology, Haematology, Immunology, Rheumatology and Pulmology, University Hospital Tuebingen, Tuebingen, Germany. · Department of Clinical Tumor Biology, University Hospital Tuebingen, Tuebingen, Germany. ·PLoS One · Pubmed #29874250.

ABSTRACT: OBJECTIVES: The aim of this multicenter retrospective study was to investigate safety and efficacy of direct acting antiviral (DAA) treatment in the rare subgroup of patients with HCV/HIV-coinfection and advanced liver cirrhosis on the liver transplant waiting list or after liver transplantation, respectively. METHODS: When contacting 54 German liver centers (including all 23 German liver transplant centers), 12 HCV/HIV-coinfected patients on antiretroviral combination therapy were reported having received additional DAA therapy while being on the waiting list for liver transplantation (patient characteristics: Child-Pugh A (n = 6), B (n = 5), C (n = 1); MELD range 7-21; HCC (n = 2); HCV genotype 1a (n = 8), 1b (n = 2), 4 (n = 2)). Furthermore, 2 HCV/HIV-coinfected patients were denoted having received DAA therapy after liver transplantation (characteristics: HCV genotype 1a (n = 1), 4 (n = 1)). RESULTS: Applied DAA regimens were SOF/DAC (n = 7), SOF/LDV/RBV (n = 3), SOF/RBV (n = 3), PTV/r/OBV/DSV (n = 1), or PTV/r/OBV/DSV/RBV (n = 1), respectively. All patients achieved SVR 12, in the end. In one patient, HCV relapse occurred after 24 weeks of SOF/DAC therapy; subsequent treatment with 12 weeks PTV/r/OBV/DSV achieved SVR 12. One patient underwent liver transplantation while on DAA treatment. Analysis of liver function revealed either stable parameters or even significant improvement during DAA therapy and in follow-up. MELD scores were found to improve in 9/13 therapies in patients on the waiting list for liver transplantation; in only 2 patients a moderate increase of MELD scores persisted at the end of follow-up. CONCLUSION: DAA treatment was safe and highly effective in this nation-wide cohort of patients with HCV/HIV-coinfection awaiting liver transplantation or being transplanted.

15 Article Patterns of Resistance-Associated Substitutions in Patients With Chronic HCV Infection Following Treatment With Direct-Acting Antivirals. 2018

Dietz, Julia / Susser, Simone / Vermehren, Johannes / Peiffer, Kai-Henrik / Grammatikos, Georgios / Berger, Annemarie / Ferenci, Peter / Buti, Maria / Müllhaupt, Beat / Hunyady, Bela / Hinrichsen, Holger / Mauss, Stefan / Petersen, Jörg / Buggisch, Peter / Felten, Gisela / Hüppe, Dietrich / Knecht, Gaby / Lutz, Thomas / Schott, Eckart / Berg, Christoph / Spengler, Ulrich / von Hahn, Thomas / Berg, Thomas / Zeuzem, Stefan / Sarrazin, Christoph / Anonymous5030927. ·Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt, Germany, German Center for Infection Research (DZIF), External Partner Site Frankfurt, Germany. · Institute for Medical Virology, University Hospital Frankfurt, Frankfurt, Germany. · Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria. · Hospital Universitario Valle Hebron and Ciberehd del Instituto Carlos III, Barcelona, Spain. · Swiss Hepato-Pancreato-Biliary Center and Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland. · Somogy County Kaposi Mór Teaching Hospital, Kaposvár, Hungary. · Practice of Gastroenterology, Kiel, Germany. · Practice of Gastroenterology, Düsseldorf, Germany. · Institute for Interdisciplinary Medicine IFI, Hamburg, Germany. · Practice of Hepatology, Herne, Germany. · Infektiologikum, Frankfurt, Germany. · Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany. · Department of Internal Medicine I, University of Tübingen, Tübingen, Germany. · Department of Internal Medicine I, University of Bonn, Bonn, Germany. · Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany; German Center for Infection Research (DZIF), Hannover-Braunschweig Site, Germany. · Department of Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany. · Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt, Germany, German Center for Infection Research (DZIF), External Partner Site Frankfurt, Germany; Medizinische Klinik II, St. Josefs-Hospital, Wiesbaden, Germany. Electronic address: sarrazin@em.uni-frankfurt.de. ·Gastroenterology · Pubmed #29146520.

ABSTRACT: BACKGROUND & AIMS: Little is known about substitutions that mediate resistance of hepatitis C virus (HCV) to direct-acting antivirals (DAAs), due to the small number of patients with treatment failure in approval studies. It is important to identify resistance patterns to select effective salvage treatments. METHODS: We performed a comprehensive analysis for resistance-associated substitutions (RASs) in HCV genes (nonstructural protein [NS]3, NS5A, NS5B) targeted by DAAs. We compared NS3, NS5A, and NS5B sequences from 626 patients in Europe with DAA failure with sequences from 2322 DAA-naïve patients, infected with HCV genotypes 1 to 4. We considered RASs to be relevant if they were associated with DAA failure in patients or conferred a greater than twofold change in susceptibility compared with a reference strain in in vitro replicon assays. Data were collected on pretreatment status, DAA regimen, the treatment initiation date and duration, and virologic response. Patients who received at least 4 weeks of antiviral treatment were included in the analysis. RESULTS: RASs in NS3 associated with simeprevir or paritaprevir failure include R155K and D168E/V. In addition, several RASs were specifically associated with failure of simeprevir (Q80K/R in patients with genotype 1a or 4) or paritaprevir (Y56H in combination with D168V in patients with genotype 1b). Y93H in NS5A was the RAS most frequently associated with failure of daclatasvir, ledipasvir, or ombitasvir in patients with genotype 1b infection, and L31M was associated with failure of daclatasvir or ledipasvir, but not ombitasvir. RASs in NS5A were heterogeneous among patients with HCV genotype 1a or genotype 4 infections. In patients with HCV genotype 3, Y93H was associated with resistance to daclatasvir, but no RASs were associated with ledipasvir failure, pointing to a limited efficacy of ledipasvir in patients with genotype 3. Among patients failed by sofosbuvir-containing regimens, L159F was enriched in patients with genotype 1b (together with C316N) or genotype 3 infection, whereas the RAS S282T was rarely observed. CONCLUSIONS: We compared RASs in NS3, NS5A, and NS5B among patients failed by DAA therapy. Theses varied with the HCV genotype and subtype, and the different drug classes. These findings might be used to select salvage therapies.

16 Article IFN-λ3, not IFN-λ4, likely mediates IFNL3-IFNL4 haplotype-dependent hepatic inflammation and fibrosis. 2017

Eslam, Mohammed / McLeod, Duncan / Kelaeng, Kebitsaone Simon / Mangia, Alessandra / Berg, Thomas / Thabet, Khaled / Irving, William L / Dore, Gregory J / Sheridan, David / Grønbæk, Henning / Abate, Maria Lorena / Hartmann, Rune / Bugianesi, Elisabetta / Spengler, Ulrich / Rojas, Angela / Booth, David R / Weltman, Martin / Mollison, Lindsay / Cheng, Wendy / Riordan, Stephen / Mahajan, Hema / Fischer, Janett / Nattermann, Jacob / Douglas, Mark W / Liddle, Christopher / Powell, Elizabeth / Romero-Gomez, Manuel / George, Jacob / Anonymous7690902. ·Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, New South Wales, Australia. · Department of Anatomical Pathology, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, Sydney, New South Wales, Australia. · Division of Hepatology, Ospedale Casa Sollievo della Sofferenza, IRCCS, San Giovanni Rotondo, Italy. · Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Clinic Leipzig, Leipzig, Germany. · Biochemistry Department, Faculty of Pharmacy, Minia University, Minia, Egypt. · NIHR Biomedical Research Unit in Gastroenterology and the Liver, University of Nottingham, Nottingham, UK. · Kirby Institute, University of New South Wales, Sydney, New South Wales, Australia. · Institute of Translational and Stratified Medicine, Plymouth University, Plymouth, UK. · Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark. · Division of Gastroenterology and Hepatology, Department of Medical Science, University of Turin, Turin, Italy. · Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark. · Department of Internal Medicine I, University of Bonn, Bonn, Germany. · UCM IC Digestive Diseases and ciberehd. University Hospital Virgen del Rocio, Institute of Biomedicine of Seville, Seville, Spain. · Institute of Immunology and Allergy Research, Westmead Hospital and Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia. · Department of Gastroenterology and Hepatology, Nepean Hospital, Sydney, New South Wales, Australia. · Department of Gastroenterology and Hepatology, Fremantle Hospital, Fremantle, Western Australia, Australia. · Department of Gastroenterology and Hepatology, Royal Perth Hospital, Perth, Western Australia, Australia. · Gastrointestinal and Liver Unit, Prince of Wales Hospital and University of New South Wales, Sydney, New South Wales, Australia. · Centre for Infectious Diseases and Microbiology, Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney at Westmead Hospital, Westmead, New South Wales, Australia. · University of Queensland, School of Medicine, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia. ·Nat Genet · Pubmed #28394349.

ABSTRACT: Genetic variation in the IFNL3-IFNL4 (interferon-λ3-interferon-λ4) region is associated with hepatic inflammation and fibrosis. Whether IFN-λ3 or IFN-λ4 protein drives this association is not known. We demonstrate that hepatic inflammation, fibrosis stage, fibrosis progression rate, hepatic infiltration of immune cells, IFN-λ3 expression, and serum sCD163 levels (a marker of activated macrophages) are greater in individuals with the IFNL3-IFNL4 risk haplotype that does not produce IFN-λ4, but produces IFN-λ3. No difference in these features was observed according to genotype at rs117648444, which encodes a substitution at position 70 of the IFN-λ4 protein and reduces IFN-λ4 activity, or between patients encoding functionally defective IFN-λ4 (IFN-λ4-Ser70) and those encoding fully active IFN-λ4-Pro70. The two proposed functional variants (rs368234815 and rs4803217) were not superior to the discovery SNP rs12979860 with respect to liver inflammation or fibrosis phenotype. IFN-λ3 rather than IFN-λ4 likely mediates IFNL3-IFNL4 haplotype-dependent hepatic inflammation and fibrosis.

17 Article Alterations of the NK cell pool in HIV/HCV co-infection. 2017

Kaczmarek, Dominik J / Kokordelis, Pavlos / Krämer, Benjamin / Glässner, Andreas / Wolter, Franziska / Goeser, Felix / Lutz, Philipp / Schwarze-Zander, Carolynne / Boesecke, Christoph / Strassburg, Christian P / Rockstroh, Jürgen K / Spengler, Ulrich / Nattermann, Jacob. ·Department of Internal Medicine I, University of Bonn, Bonn, Germany. · German Center for Infection Research (DZIF), Bonn, Germany. ·PLoS One · Pubmed #28380039.

ABSTRACT: BACKGROUND: A relevant proportion of human immunodeficiency virus (HIV) infected patients is co-infected with the hepatitis C virus (HCV). HCV co-infection in HIV-positive patients is associated with faster progression of liver disease in comparison to HCV mono-infection. Natural killer (NK) cells critically modulate the natural course of HCV infection. Both HIV and HCV mono-infection are associated with alterations of the NK cell pool. However, little data is available concerning phenotype and function of NK cells in HIV/HCV co-infection. METHODS: A total of 34 HIV/HCV co-infected, 35 HIV and 39 HCV mono-infected patients and 43 healthy control persons were enrolled into this study. All HIV-positive patients were under effective antiretroviral therapy. NK cell phenotype, IFN-γ production and degranulation were studied by flow cytometry. RESULTS: NK cell frequency in HIV/HCV co-infection was significantly lower than in healthy individuals but did not differ from HIV and HCV mono-infection. HIV/HCV co-infection was associated with significantly decreased expression of the maturation/differentiation markers CD27/62L/127 on NK cells but increased expression of CD57 compared to healthy controls. Of note, expression also differed significantly from HCV mono-infection but was similar to HIV mono-infection, suggesting a pronounced impact of HIV on these alterations. Similar findings were made with regard to the NK cell receptors NKG2A/C and NKp30. More importantly, NK cells in co-infection displayed a highly impaired functional activity with significantly lower IFN-γ production and degranulation than in healthy donors as well as HIV and HCV mono-infection, suggesting a synergistic effect of both viruses. CONCLUSIONS: Our data indicate that HIV/HCV co-infection is associated with significant alterations of the NK cell pool, which might be involved in the rapid progression of liver disease in co-infected patients and which mainly reflect alterations observed in HIV mono-infection.

18 Article Increased peripheral CD4 2017

Langhans, Bettina / Nischalke, Hans Dieter / Krämer, Benjamin / Hausen, Annekristin / Dold, Leona / van Heteren, Peer / Hüneburg, Robert / Nattermann, Jacob / Strassburg, Christian P / Spengler, Ulrich. ·Department of Internal Medicine I, University of Bonn, Bonn, Germany, and the German Center for Infection Research (DZIF), Partner Site Cologne-Bonn, Bonn, Germany. Electronic address: bettina.langhans@ukb.uni-bonn.de. · Department of Internal Medicine I, University of Bonn, Bonn, Germany, and the German Center for Infection Research (DZIF), Partner Site Cologne-Bonn, Bonn, Germany. ·J Hepatol · Pubmed #28040549.

ABSTRACT: BACKGROUND & AIMS: CD4 METHODS: We analyzed Tregs before (baseline), at end of therapy (EOT), 12 and 24weeks (SVR12, SVR24) and long-term (51±14weeks) after EOT in 26 genotype-1-infected patients who were successfully treated with sofosbuvir (SOF) plus interferon (IFN)/ribavirin (n=12) and IFN-free DAA regimens (SOF plus daclatasvir or simeprevir; n=14). Frequency, phenotype and suppressor function of peripheral Foxp3 RESULTS: Frequencies and activation status of Foxp3 CONCLUSION: Although IFN-based DAA therapy induced transient expansion of activated Foxp3 LAY SUMMARY: In chronic hepatitis C virus (HCV) infection, CD4

19 Article Real-world experience with daclatasvir plus sofosbuvir ± ribavirin for post-liver transplant HCV recurrence and severe liver disease. 2017

Herzer, Kerstin / Welzel, Tania M / Spengler, Ulrich / Hinrichsen, Holger / Klinker, Hartwig / Berg, Thomas / Ferenci, Peter / Peck-Radosavljevic, Markus / Inderson, Akin / Zhao, Yue / Jimenez-Exposito, Maria Jesus / Zeuzem, Stefan. ·Universitätsklinikum Essen, Essen, Germany. · Universitätsklinikum der Johann Wolfgang Goethe Universität, Frankfurt, Germany. · Universitätsklinikum Bonn, Bonn, Germany. · Gastroenterologisch-Hepatologisches Zentrum Kiel, Kiel, Germany. · Universitätsklinikum Würzburg, Würzburg, Germany. · Universitätsklinikum Leipzig, Leipzig, Germany. · Medical University of Vienna, Vienna, Austria. · Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria. · Leiden University Medical Center, Leiden, The Netherlands. · Bristol-Myers Squibb, Princeton, NJ, USA. ·Transpl Int · Pubmed #28012215.

ABSTRACT: Optimizing therapy of post-transplant HCV recurrence remains important, especially in advanced liver disease. We evaluated daclatasvir (DCV) plus sofosbuvir (SOF), with or without ribavirin (RBV), in patients with post-liver transplant recurrence in a real-world European cohort at high risk of decompensation or death within 12 months. Recommended treatment was DCV 60 mg plus SOF 400 mg once daily for 24 weeks; RBV use/shorter treatment duration was at physicians' discretion. Patients (N = 87) were 70% male, 93% white, and mostly infected with HCV genotypes 1b (48%), 1a (32%), or 3 (9%); 37 (43%) had cirrhosis (16 decompensated), five had fibrosing cholestatic hepatitis. Sustained virologic response at post-treatment week 12 (SVR12) was 94% (80/85) in a modified intention-to-treat analysis: 95% (58/61) without RBV and 92% (22/24) with RBV, with no virologic failures. SVR12 was 100% (80/80) in an as-observed analysis excluding five nonvirologic failures. Four patients (5%) discontinued therapy for adverse events (AEs); 16 (18%) experienced serious AEs. One patient died on treatment and five during follow-up. Most AEs were associated with advanced liver disease and unrelated to therapy. No clinically significant drug-drug interactions were observed. DCV + SOF ± RBV was well tolerated and achieved high SVR12 (94%) in patients with post-transplant HCV recurrence, including patients with severe liver disease.

20 Article Sex-specific effects of TLR9 promoter variants on spontaneous clearance of HCV infection. 2017

Fischer, Janett / Weber, Alexander N R / Böhm, Stephan / Dickhöfer, Sabine / El Maadidi, Souhayla / Deichsel, Danilo / Knop, Viola / Klinker, Hartwig / Möller, Bernd / Rasenack, Jens / Wang, Lisa / Sharma, Manu / Hinrichsen, Holger / Spengler, Ulrich / Buggisch, Peter / Sarrazin, Christoph / Pawlita, Michael / Waterboer, Tim / Wiese, Manfred / Probst-Müller, Elsbeth / Malinverni, Raffaele / Bochud, Pierre-Yves / Gardiner, Clair / O'Farrelly, Cliona / Berg, Thomas. ·Department of Gastroenterology and Rheumatology, Section of Hepatology, University Hospital, Leipzig, Germany. · Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany. · Medical Department 1, Goethe-University Hospital Frankfurt/Main, Frankfurt, Germany. · Department of Internal Medicine II, University of Würzburg, Würzburg, Germany. · Department of Medical Practice, Charlottenstraße 81, Berlin, Germany. · Medical Department, Albert-Ludwigs University Freiburg, Freiburg, Germany. · Division of Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany. · Department of Gastroenterology, Gastroenterologische Schwerpunkt-Praxis, Kiel, Germany. · Department of Internal Medicine I, University of Bonn, Bonn, Germany. · Liver Unit, IFI Institute for Interdisciplinary Medicine, Asklepios Klinik St. Georg Hamburg, Hamburg, Germany. · Department of Genome Modifications and Carcinogenesis (F020), Research Program Infection and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany. · University Hospital, Zürich, Switzerland. · Pourtalès Hospital, Neuchâtel, Switzerland. · Infectious Diseases Service, University Hospital and University of Lausanne, Lausanne, Switzerland. · School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland. ·Gut · Pubmed #27196570.

ABSTRACT: OBJECTIVE: As pathogen sensors, Toll-like receptors (TLR) play a role in the first defence line during HCV infection. However, the impact of the DNA sensor TLR9 on the natural course of HCV infection is unknown. To address this, DESIGN: Therefore, the RESULTS: The

21 Article MBOAT7 rs641738 increases risk of liver inflammation and transition to fibrosis in chronic hepatitis C. 2016

Thabet, Khaled / Asimakopoulos, Anastasia / Shojaei, Maryam / Romero-Gomez, Manuel / Mangia, Alessandra / Irving, William L / Berg, Thomas / Dore, Gregory J / Grønbæk, Henning / Sheridan, David / Abate, Maria Lorena / Bugianesi, Elisabetta / Weltman, Martin / Mollison, Lindsay / Cheng, Wendy / Riordan, Stephen / Fischer, Janett / Spengler, Ulrich / Nattermann, Jacob / Wahid, Ahmed / Rojas, Angela / White, Rose / Douglas, Mark W / McLeod, Duncan / Powell, Elizabeth / Liddle, Christopher / van der Poorten, David / George, Jacob / Eslam, Mohammed / Anonymous2730881. ·Storr Liver Centre, Westmead Institute for Medical Research and Westmead Hospital, University of Sydney, Sydney, New South Wales 2145, Australia. · Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 6111, Egypt. · Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, Sydney, New South Wales 2145, Australia. · Nepean Genomic Research Group, ICU, Nepean Hospital, Kingswood, New South Wales 2747, Australia. · Unit for The Clinical Management of Digestive Diseases and CIBERehd, Hospital Universitario de Valme, 41014 Sevilla, Spain. · Division of Hepatology, Ospedale Casa Sollievo della Sofferenza, IRCCS, 71013 San Giovanni Rotondo, Italy. · NIHR Biomedical Research Unit in Gastroenterology and the Liver, University of Nottingham, Nottingham NG7 2UH, UK. · Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Clinic Leipzig, 04103 Leipzig, Germany. · Kirby Institute, The University of New South Wales, Sydney, New South Wales 2052, Australia. · Department of Hepatology and Gastroenterology, Aarhus University Hospital, DK-8000 Aarhus, Denmark. · Institute of Translational and Stratified Medicine, Plymouth University, Plymouth PL4 8AA, UK. · Division of Gastroenterology and Hepatology, Department of Medical Science, University of Turin, 10126 Turin, Italy. · Department of Gastroenterology and Hepatology, Nepean Hospital, Sydney, New South Wales 2747, Australia. · Department of Gastroenterology and Hepatology, Fremantle Hospital, Fremantle, Western Australia 6160, Australia. · Department of Gastroenterology and Hepatology, Royal Perth Hospital, Western Australia 6000, Australia. · Gastrointestinal and Liver Unit, Prince of Wales Hospital and University of New South Wales, Sydney, New South Wales 2031, Australia. · Department of Internal Medicine I, University of Bonn, 53105 Bonn, Germany. · Centre for Infectious Diseases and Microbiology, Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney at Westmead Hospital, Westmead, New South Wales 2145, Australia. · Department of Anatomical Pathology, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, Sydney, New South Wales 2145, Australia. · Princess Alexandra Hospital, School of Medicine, The University of Queensland, Woolloongabba, Queensland 4102, Australia. ·Nat Commun · Pubmed #27630043.

ABSTRACT: Cirrhosis likely shares common pathophysiological pathways despite arising from a variety of liver diseases. A recent GWAS identified rs641738, a polymorphism in the MBOAT7 locus, as being associated with the development of alcoholic cirrhosis. Here we explore the role of this variant on liver inflammation and fibrosis in two cohorts of patients with chronic hepatitis C. In 2,051 patients, rs641738 associated with severe hepatic inflammation and increased risk of fibrosis, as well as fast fibrosis progression. At functional level, rs641738 associated with MBOAT7 transcript and protein levels in liver and blood, and with serum inflammatory, oxidative stress and macrophage activation markers. MBOAT7 was expressed in immune cell subsets, implying a role in hepatic inflammation. We conclude that the MBOAT7 rs641738 polymorphism is a novel risk variant for liver inflammation in hepatitis C, and thereby for liver fibrosis.

22 Article Daclatasvir plus sofosbuvir, with or without ribavirin, achieved high sustained virological response rates in patients with HCV infection and advanced liver disease in a real-world cohort. 2016

Welzel, Tania M / Petersen, Jörg / Herzer, Kerstin / Ferenci, Peter / Gschwantler, Michael / Wedemeyer, Heiner / Berg, Thomas / Spengler, Ulrich / Weiland, Ola / van der Valk, Marc / Rockstroh, Jürgen / Peck-Radosavljevic, Markus / Zhao, Yue / Jimenez-Exposito, Maria Jesus / Zeuzem, Stefan. ·Universitätsklinikum der Johann Wolfgang Goethe Universität, Frankfurt am Main, Germany. · IFI Institut für Interdisziplinäre Medizin, Hamburg, Germany. · Universitätsklinikum Essen (AöR), Essen, Germany. · Department of Internal Medicine III, Medizinische Universität Wien, Vienna, Austria. · Wilhelminenspital, Vienna, Austria. · Medizinische Hochschule Hannover, Hannover, Germany. · Universitätsklinikum Leipzig, Leipzig, Germany. · Universitätsklinikum Bonn, Bonn, Germany. · Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden. · Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. · Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria. · Bristol-Myers Squibb, Princeton, New Jersey, USA. ·Gut · Pubmed #27605539.

ABSTRACT: OBJECTIVE: We assessed the effectiveness and safety of daclatasvir (DCV) plus sofosbuvir (SOF), with or without ribavirin (RBV), in a large real-world cohort, including patients with advanced liver disease. DESIGN: Adults with chronic HCV infection at high risk of decompensation or death within 12 months and with no available treatment options were treated in a European compassionate use programme. The recommended regimen was DCV 60 mg plus SOF 400 mg for 24 weeks; RBV addition or shorter duration was allowed at physicians' discretion. The primary endpoint was sustained virological response at post-treatment week 12 (SVR12). RESULTS: Of the 485 evaluable patients, 359 received DCV+SOF and 126 DCV+SOF+RBV. Most patients were men (66%), white (93%) and treatment-experienced (70%). The most frequent HCV genotypes were 1b (36%), 1a (33%) and 3 (21%), and 80% of patients had cirrhosis (42% Child-Pugh B/C; 46% Model for End-Stage Liver Disease score >10). SVR12 (modified intention-to-treat) was achieved by 91% of patients (419/460); 1 patient had virological breakthrough and 13 patients relapsed. Virological failure was not associated with treatment group (adjusted risk difference DCV+SOF minus DCV+SOF+RBV: 1.06%; 95% CI -2.22% to 4.35%). High SVR12 was observed regardless of HCV genotype or cirrhosis, liver transplant or HIV/HCV coinfection status. Twenty eight patients discontinued treatment due to adverse events (n=18) or death (n=10) and 18 died during follow-up. Deaths and most safety events were associated with advanced liver disease and not considered treatment related. CONCLUSIONS: DCV+SOF with or without RBV achieved high SVR12 and was well tolerated in a diverse cohort of patients with severe liver disease. TRIAL REGISTRATION NUMBER: NCT02097966.

23 Article IL-28B Genetic Variants Determine the Extent of Monocyte-Induced Activation of NK Cells in Hepatitis C. 2016

Krämer, Benjamin / Finnemann, Claudia / Sastre, Beatriz / Lutz, Philipp / Glässner, Andreas / Wolter, Franziska / Goeser, Felix / Kokordelis, Pavlos / Kaczmarek, Dominik / Nischalke, Hans-Dieter / Strassburg, Christian P / Spengler, Ulrich / Nattermann, Jacob. ·Department of Internal Medicine I, University of Bonn, Bonn, Germany. · German Center for Infection Research (DZIF), Bonn, Germany. · Department of Infectious Diseases, Institute for Health Research (IRYCIS), University Hospital Ramón y Cajal, Madrid, Spain. · AIDS Research Network (RIS-RETICS), Madrid, Spain. ·PLoS One · Pubmed #27583440.

ABSTRACT: BACKGROUND: Immuno-genetic studies suggest a functional link between NK cells and λ-IFNs. We recently showed that NK cells are negative for the IFN-λ receptor IFN-λR1 and do not respond to IFN-λ, suggesting a rather indirect association between IL-28B genotype and NK cell activity. METHODS: A total of 75 HCV(+) patients and 67 healthy controls were enrolled into this study. IL-28B (rs12979860) and IFNL-4 (rs368234815) genotypes were determined by rtPCR. Total PBMC, monocytes, and NK cells were stimulated with IL-29, the TLR-7/8 agonist R848, or a combination of both. NK cell IFN-γ response was analysed by FACS. IL-12 and IL-18 secretion of monocytes was studied by ELISA. In blocking experiments anti-IL-12/anti-IL-18 were used. RESULTS: Following stimulation of total PBMCs with R848 we found NK cell IFN- γ responses to vary with the IL-28B genotype, with carriers of a T/T genotype displaying the lowest frequency of IFN-γ(+)NK cells. When isolated NK cells were studied no such associations were observed, indicating an indirect association between IL-28B genotype and NK cell activity. Accordingly, we found R848-stimulated monocytes of patients with a T/T genotype to be significantly less effective in triggering NK cell IFN- γ production than monocytes from carriers of a non-T/T genotype. In line with these findings we observed monocytes from T/T patients to secrete significantly lower concentrations of IL-12 than monocytes from non-T/T individuals. CONCLUSIONS: Our data indicate that monocytes from carriers of an IL-28B T/T genotype display a reduced ability to stimulate NK cell activity and, thus, provide a link between IL-28B genotype and NK functions.

24 Article Diverse impacts of the rs58542926 E167K variant in TM6SF2 on viral and metabolic liver disease phenotypes. 2016

Eslam, Mohammed / Mangia, Alessandra / Berg, Thomas / Chan, Henry Lik Yuen / Irving, William L / Dore, Gregory J / Abate, Maria Lorena / Bugianesi, Elisabetta / Adams, Leon A / Najim, Mustafa A M / Miele, Luca / Weltman, Martin / Mollison, Lindsay / Cheng, Wendy / Riordan, Stephen / Fischer, Janett / Romero-Gomez, Manuel / Spengler, Ulrich / Nattermann, Jacob / Rahme, Antony / Sheridan, David / Booth, David R / McLeod, Duncan / Powell, Elizabeth / Liddle, Christopher / Douglas, Mark W / van der Poorten, David / George, Jacob / Anonymous5210856. ·Storr Liver Centre, Westmead Millennium Institute and Westmead Hospital, University of Sydney, NSW, Australia. · Division of Hepatology, Ospedale Casa Sollievo della Sofferenza, IRCCS, San Giovanni Rotondo, Italy. · Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Clinic Leipzig, Leipzig, Germany. · Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China. · NIHR Biomedical Research Unit in Gastroenterology and the Liver, University of Nottingham, Nottingham, UK. · Kirby Institute, The University of New South Wales, Sydney, NSW, Australia. · St. Vincent's Hospital, Sydney, NSW, Australia. · Division of Gastroenterology and Hepatology, Department of Medical Science, University of Turin, Turin, Italy. · School of Medicine and Pharmacology, Sir Charles Gairdner Hospital Unit, University of Western Australia, Nedlands, WA, Australia. · Department of Medical Laboratories Technology, Faculty of Applied Medical Sciences, Taibah University, Medina, Saudi Arabia. · Department of Internal Medicine, Catholic University of the Sacred Heart, Rome, Italy. · Department of Gastroenterology and Hepatology, Nepean Hospital, Sydney, NSW, Australia. · Department of Gastroenterology and Hepatology, Fremantle Hospital, Fremantle, WA, Australia. · Department of Gastroenterology & Hepatology, Royal Perth Hospital, WA, Australia. · Gastrointestinal and Liver Unit, Prince of Wales Hospital and University of New South Wales, Sydney, NSW, Australia. · Unit for the Clinical Management of Digestive Diseases and CIBERehd, Hospital Universitario de Valme, Sevilla, Spain. · Department of Internal Medicine I, University of Bonn, Bonn, Germany. · Institute of Translational and Stratified Medicine, Plymouth University, UK. · Institute of Immunology and Allergy Research, Westmead Hospital and Westmead Millennium Institute, University of Sydney, NSW, Australia. · Department of Anatomical Pathology, Institute of Clinical Pathology and Medical Research, Westmead Hospital, Sydney, Australia. · The University of Queensland, School of Medicine, Princess Alexandra Hospital, Woolloongabba, QLD, Australia. · Centre for Infectious Diseases and Microbiology, Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney at Westmead Hospital, Westmead, NSW, Australia. ·Hepatology · Pubmed #26822232.

ABSTRACT: CONCLUSION: The TM6SF2 E167K substitution promotes steatosis and lipid abnormalities in part by altering TM6SF2 and microsomal triglyceride transfer protein expression and differentially impacts CHC and chronic hepatitis B viral load, while effects on fibrosis are marginal. (Hepatology 2016;64:34-46).

25 Article FibroGENE: A gene-based model for staging liver fibrosis. 2016

Eslam, Mohammed / Hashem, Ahmed M / Romero-Gomez, Manuel / Berg, Thomas / Dore, Gregory J / Mangia, Alessandra / Chan, Henry Lik Yuen / Irving, William L / Sheridan, David / Abate, Maria Lorena / Adams, Leon A / Weltman, Martin / Bugianesi, Elisabetta / Spengler, Ulrich / Shaker, Olfat / Fischer, Janett / Mollison, Lindsay / Cheng, Wendy / Nattermann, Jacob / Riordan, Stephen / Miele, Luca / Kelaeng, Kebitsaone Simon / Ampuero, Javier / Ahlenstiel, Golo / McLeod, Duncan / Powell, Elizabeth / Liddle, Christopher / Douglas, Mark W / Booth, David R / George, Jacob / Anonymous4060849. ·Storr Liver Centre, The Westmead Millennium Institute for Medical Research and Westmead Hospital, The University of Sydney, NSW, Australia. · Department of Systems and Biomedical Engineering, Faculty of Engineering, Minia University, Minia, Egypt. · Unit for The Clinical Management of Digestive Diseases and CIBERehd, Hospital Universitario de Valme, Sevilla, Spain. · Medizinische Klinik m.S. Hepatologie und Gastroenterologie, Charite, Campus Virchow-Klinikum, Universitätsmedizin Berlin, Germany; Department of Hepatology, Clinic for Gastroenterology and Rheumatology, University Clinic Leipzig, Leipzig, Germany. · Kirby Institute, The University of New South Wales, Sydney, NSW, Australia; St Vincent's Hospital, Sydney, NSW, Australia. · Division of Hepatology, Ospedale Casa Sollievo della Sofferenza, IRCCS, San Giovanni Rotondo, Italy. · Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China. · NIHR Biomedical Research Unit in Gastroenterology and the Liver, University of Nottingham, Nottingham, United Kingdom. · Liver Research Group, Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom; Institute of Translational and Stratified Medicine, Plymouth University, United Kingdom. · Division of Gastroenterology and Hepatology, Department of Medical Science, University of Turin, Turin, Italy. · School of Medicine and Pharmacology, Sir Charles Gairdner Hospital Unit, University of Western Australia, Nedlands, WA, Australia. · Department of Gastroenterology and Hepatology, Nepean Hospital, Sydney, NSW, Australia. · Department of Internal Medicine I, University of Bonn, Bonn, Germany. · Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University, Cairo, Egypt. · Medizinische Klinik m.S. Hepatologie und Gastroenterologie, Charite, Campus Virchow-Klinikum, Universitätsmedizin Berlin, Germany. · School of Medicine and Pharmacology, Fremantle Hospital, UWA, Fremantle, WA, Australia. · Department of Gastroenterology & Hepatology, Royal Perth Hospital, WA, Australia. · Gastrointestinal and Liver Unit, Prince of Wales Hospital and University of New South Wales, Sydney, NSW, Australia. · Department of Internal Medicine, Catholic University of the Sacred Heart, Rome, Italy. · Department of Anatomical Pathology, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, Sydney, Australia. · Princess Alexandra Hospital, Department of Gastroenterology and Hepatology, Woolloongabba, QLD, Australia; The University of Queensland, School of Medicine, Princess Alexandra Hospital, Woolloongabba, QLD, Australia. · Institute of Immunology and Allergy Research, Westmead Hospital and Westmead Millennium Institute, University of Sydney, NSW, Australia. · Storr Liver Centre, The Westmead Millennium Institute for Medical Research and Westmead Hospital, The University of Sydney, NSW, Australia. Electronic address: jacob.george@sydney.edu.au. ·J Hepatol · Pubmed #26592354.

ABSTRACT: BACKGROUND & AIMS: The extent of liver fibrosis predicts long-term outcomes, and hence impacts management and therapy. We developed a non-invasive algorithm to stage fibrosis using non-parametric, machine learning methods designed for predictive modeling, and incorporated an invariant genetic marker of liver fibrosis risk. METHODS: Of 4277 patients with chronic liver disease, 1992 with chronic hepatitis C (derivation cohort) were analyzed to develop the model, and subsequently validated in an independent cohort of 1242 patients. The model was assessed in cohorts with chronic hepatitis B (CHB) (n=555) and non-alcoholic fatty liver disease (NAFLD) (n=488). Model performance was compared to FIB-4 and APRI, and also to the NAFLD fibrosis score (NFS) and Forns' index, in those with NAFLD. RESULTS: Significant fibrosis (⩾F2) was similar in the derivation (48.4%) and validation (47.4%) cohorts. The FibroGENE-DT yielded the area under the receiver operating characteristic curve (AUROCs) of 0.87, 0.85 and 0.804 for the prediction of fast fibrosis progression, cirrhosis and significant fibrosis risk, respectively, with comparable results in the validation cohort. The model performed well in NAFLD and CHB with AUROCs of 0.791, and 0.726, respectively. The negative predictive value to exclude cirrhosis was>0.96 in all three liver diseases. The AUROC of the FibroGENE-DT performed better than FIB-4, APRI, and NFS and Forns' index in most comparisons. CONCLUSION: A non-invasive decision tree model can predict liver fibrosis risk and aid decision making.

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