Darius Moradpour

University of Lausanne, Lausanne, Vaud, Switzerland

Are you Darius Moradpour?

Claim your profile

Publications (262)1388.47 Total impact

  • A Marot · E Trépo · C Doerig · C Moreno · D Moradpour · P Deltenre ·
    [Show abstract] [Hide abstract]
    ABSTRACT: Background The prognosis of patients with cirrhosis and acute variceal bleeding is very poor when the standard-of-care fails to control bleeding. New treatment modalities are needed in these patients.AimTo synthesise the available evidence on the efficacy of self-expanding metal stents (SEMS) in patients with cirrhosis and severe or refractory oesophageal variceal bleeding.Methods Meta-analysis of trials evaluating SEMS in patients with cirrhosis and severe or refractory oesophageal variceal bleeding.ResultsThirteen studies were included. The pooled estimate rates were 0.40 (95% confidence interval, CI = 0.31–0.49) for death, 0.41 (95% CI = 0.29–0.53) for liver-related death and 0.36 (95% CI = 0.26–0.47) for death at day 30, with low heterogeneity between studies. The pooled estimate rates were 0.12 (95% CI = 0.07–0.21) for mortality related to variceal bleeding, and 0.18 (95% CI = 0.11–0.29) for failure to control bleeding with SEMS, with no or low heterogeneity between studies. The pooled estimate rate were 0.16 (95% CI = 0.04–0.48) for rebleeding after stent removal and 0.28 (95% CI = 0.17–0.43) for stent migration, with high heterogeneity. A significant proportion of patients had access to liver transplantation or to TIPSS [pooled estimate rate 0.10 (95% CI = 0.04–0.21) and 0.26 (95% CI = 0.18–0.36), respectively].Conclusions Fewer than 40% of patients treated with SEMS were dead at 1 month. SEMS can be used as a bridge to TIPSS or to liver transplantation in a significant proportion of patients. Additional studies are required to identify potential risk factors leading to a poor prognosis in patients with acute variceal bleeding in whom the use of SEMS could be considered.
    Alimentary Pharmacology & Therapeutics 10/2015; DOI:10.1111/apt.13424 · 5.73 Impact Factor
  • Source

    Gastroenterology 09/2015; · 16.72 Impact Factor
  • Beat Müllhaupt · Darius Moradpour ·

    Revue médicale suisse 06/2015; 11(471):907-8.
  • [Show abstract] [Hide abstract]
    ABSTRACT: There is conflicting evidence on the benefit of early transjugular intrahepatic portosystemic shunt (TIPSS) on the survival of patients with acute variceal bleeding (AVB). To assess the effect of early TIPSS on patient prognosis. We carried out a meta-analysis of trials evaluating early TIPSS in cirrhotic patients with AVB. Four studies were included. Early TIPSS was associated with fewer deaths [odds ratio (OR)=0.38, 95% confidence interval (CI)=0.17-0.83, P=0.02], with moderate heterogeneity between studies (P=0.15, I=44%). Early TIPSS was not significantly associated with fewer deaths among Child-Pugh B patients (OR=0.35, 95% CI=0.10-1.17, P=0.087) nor among Child-Pugh C patients (OR=0.34, 95% CI=0.10-1.11, P=0.074). There was no heterogeneity between studies in the Child-Pugh B analysis (P=0.6, I=0%), but there was a high heterogeneity in the Child-Pugh C analysis (P=0.06, I=60%). Early TIPSS was associated with lower rates of bleeding within 1 year (OR=0.08, 95% CI=0.04-0.17, P<0.001) both among Child-Pugh B patients, (OR=0.15, 95% CI=0.05-0.47, P=0.001) and among Child-Pugh C patients (OR=0.05, 95% CI=0.02-0.15, P<0.001), with no heterogeneity between studies. Early TIPSS was not associated with higher rates of encephalopathy (OR=0.84, 95% CI=0.50-1.42, P=0.5). Cirrhotic patients with AVB treated with early TIPSS had lower death rates and lower rates of clinically significant bleeding within 1 year compared with patients treated without early TIPSS. Additional studies are required to identify the potential risk factors leading to a poor prognosis after early TIPSS in patients with AVB and to determine the impact of the degree of liver failure on the patient's prognosis.
    European journal of gastroenterology & hepatology 06/2015; 62(9). DOI:10.1097/MEG.0000000000000403 · 2.25 Impact Factor
  • Darius Moradpour · Beat Müllhaupt ·
    [Show abstract] [Hide abstract]
    ABSTRACT: Hepatitis C virus (HCV) infection represents a major cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma worldwide. Great progress in the understanding of the molecular virology, pathogenesis and natural course as well as the prevention, diagnosis and treatment of hepatitis C have been made in over the last 25 years since the discovery of HCV. Here, we review recent advances and discuss them in the light of new challenges.
    Revue médicale suisse 04/2015; 11(471):896-901.
  • Darius Moradpour · Beat Müllhaupt ·
    [Show abstract] [Hide abstract]
    ABSTRACT: Treatment of chronic hepatitis C is currently being revolutionised, with the introduction of directly acting antivirals (DAA), including protease, NS5A and polymerase inhibitors. These can be combined in interferon-free oral therapies with unprecedented efficacy and good tolerance. Here, we review the current therapy of chronic hepatitis C, with a particular focus on DAA that are approved in Switzerland today.
    Revue médicale suisse 04/2015; 11(471):902-6.
  • V. Loan Dao Thi · S.U. Emerson · T. Ahola · D. Moradpour · J. Gouttenoire ·

    Journal of Hepatology 04/2015; 62:S515. DOI:10.1016/S0168-8278(15)30741-8 · 11.34 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Infection with hepatitis E virus (HEV) of genotype 3 may result in chronic hepatitis in immunocompromised patients. Reduction of immunosuppression or treatment with ribavirin or pegylated interferon-α can result in viral clearance. However, safer and more effective treatment options are needed. Here, we demonstrate that sofosbuvir inhibits the replication of HEV genotype 3 both in subgenomic replicon systems as well as a full-length infectious clone. Moreover, the combination of sofosbuvir and ribavirin results in an additive antiviral effect. Sofosbuvir may be considered as an add-on therapy to ribavirin for the treatment of chronic hepatitis E in immunocompromised patients.
    Journal of Hepatology 04/2015; 62:S289-S290. DOI:10.1016/S0168-8278(15)30207-5 · 11.34 Impact Factor

  • Journal of Hepatology 04/2015; 62:S578. DOI:10.1016/S0168-8278(15)30886-2 · 11.34 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background : Recurrent hepatitis C virus infection after liver transplantation is associated with reduced graft and patient survival. Re-transplantation for graft failure due to recurrent hepatitis C is controversial and not performed in all centers. Case presentation : We describe a 54-year-old patient with hepatitis C virus genotype 1b infection and a null response to pegylated interferon-α and ribavirin who developed decompensated graft cirrhosis 6 years after a first liver transplantation. Treatment with sofosbuvir and ribavirin allowed for rapid negativation of serum HCV RNA and was well tolerated despite advanced liver and moderate renal dysfunction. Therapeutic drug monitoring did not reveal any clinically significant drug-drug interactions. Despite virological response, the patient remained severely decompensated and re-transplantation was performed after 46 days of undetectable serum HCV RNA. The patient is doing well 12 months after his second liver transplantation and remains free of hepatitis C virus. Conclusions : The use of directly acting antivirals may allow for successful liver re-transplantation for recipients who remain decompensated despite virological response and is likely to improve the outcome of liver re-transplantation for end-stage recurrent hepatitis C.
    BMC Gastroenterology 03/2015; 15(38). DOI:10.1186/s12876-015-0259-5 · 2.37 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hepatitis C virus (HCV) infections are the major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma worldwide. Both spontaneous and treatment-induced clearance of HCV depend on genetic variation within the interferon-lambda locus, but until now no clear causal relationship has been established. Here we demonstrate that an amino-acid substitution in the IFNλ4 protein changing a proline at position 70 to a serine (P70S) substantially alters its antiviral activity. Patients harbouring the impaired IFNλ4-S70 variant display lower interferon-stimulated gene (ISG) expression levels, better treatment response rates and better spontaneous clearance rates, compared with patients coding for the fully active IFNλ4-P70 variant. Altogether, these data provide evidence supporting a role for the active IFNλ4 protein as the driver of high hepatic ISG expression as well as the cause of poor HCV clearance.
    Nature Communications 12/2014; 5:5699. DOI:10.1038/ncomms6699 · 11.47 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The hepatitis C virus (HCV) NS3-4A protease is essential for the HCV life cycle and a prime target of antiviral treatment strategies. Protease inhibitors, however, are limited by emergence of resistance-associated amino acid variants (RAVs). The capacity to cleave and inactivate mitochondrial antiviral-signaling protein (MAVS) in the RIG-I-signaling pathway is a cardinal feature of NS3-4A, by which HCV blocks induction of interferon-(IFN)-β, thereby promoting viral persistence. Here, we aimed to investigate the impact of NS3-4A RAVs on MAVS cleavage. The impact of NS3-4A RAVs on MAVS cleavage was assessed using immunoblot analyses, luciferase reporter assays and molecular dynamics simulations to study the underlying molecular principles. IFN-β was quantified in serum of patients with different NS3-4A RAVs. We demonstrate that macrocyclic NS3-4A RAVS with substitutions at residue D168 of the protease result in an increased capacity of NS3-4A to cleave MAVS and suppress IFN-β induction compared with a comprehensive panel of RAVs and wild type HCV. Mechanistically, we show the reconstitution of a tight network of electrostatic interactions between protease and the peptide substrate that allows much stronger binding of MAVS to D168 RAVs than to the wild-type protease. Accordingly, we could show IFN-β serum levels to be lower in patients with treatment failure due to the selection of D168 variants compared to R155 RAVs. Our data constitute a proof-of-concept that the selection of RAVs against specific classes of direct antivirals can lead to the predominance of viral variants with possibly adverse pathogenic characteristics. Copyright © 2014. Published by Elsevier B.V.
    Journal of Hepatology 11/2014; 62(4). DOI:10.1016/j.jhep.2014.11.009 · 11.34 Impact Factor
  • Source

    2nd Annual Meeting of the International-Cytokine-and-Interferon-Society; 11/2014
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Membrane proteins are notoriously difficult to express in a soluble form. Here, we use wheat germ cell-free expression in the presence of various detergents to produce the non-structural proteins 2, 4B and 5A membrane proteins of the hepatitis C virus (HCV). We show that lauryl maltose neopentyl glycol (MNG-3) and dodecyl octaethylene glycol ether (C12E8) detergents can yield essentially soluble membrane proteins at detergent concentrations that do not inhibit the cell-free reaction. This finding can be explained by the low critical micelle concentration (CMC) of these detergents, which keeps the monomer concentrations low while at the same time providing the necessary excess of detergent concentration above CMC required for full target protein solubilization. We estimate that a tenfold excess of detergent micelles with respect to the protein concentration is sufficient for solubilization, a number that we propose as a guideline for detergent screening assays.
    Protein Expression and Purification 10/2014; 105. DOI:10.1016/j.pep.2014.10.003 · 1.70 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Nonstructural protein 4B (NS4B) is a key organizer of hepatitis C virus (HCV) replication complex formation. In concert with other nonstructural proteins, it induces a specific membrane rearrangement, designated as membranous web, which serves as a scaffold for the HCV replicase. The N-terminal part of NS4B comprises a predicted and a structurally resolved amphipathic α-helix, designated as AH1 and AH2, respectively. Here, we report a detailed structure-function analysis of NS4B AH1. Circular dichroism and nuclear magnetic resonance structural analyses revealed that AH1 folds into an amphipathic α-helix extending from NS4B amino acid 4 to 32, with positively charged residues flanking the helix. These residues are conserved among hepaciviruses. Mutagenesis and selection of pseudorevertants revealed an important role of these residues in RNA replication by affecting the biogenesis of double-membrane vesicles making up the membranous web. Moreover, alanine substitution of conserved acidic residues on the hydrophilic side of the helix reduced infectivity without significantly affecting RNA replication, indicating that AH1 is also involved in virus production. Selective membrane permeabilization and immunofluorescence microscopy analyses of a functional replicon harboring an epitope tag between NS4B AH1 and AH2 revealed a dual membrane topology of the N-terminal part of NS4B during HCV RNA replication. Luminal translocation was unaffected by the mutations introduced into AH1, but was abrogated by mutations introduced into AH2. In conclusion, our study reports the three-dimensional structure of AH1 from HCV NS4B, and highlights the importance of positively charged amino acid residues flanking this amphipathic α-helix in membranous web formation and RNA replication. In addition, we demonstrate that AH1 possesses a dual role in RNA replication and virus production, potentially governed by different topologies of the N-terminal part of NS4B.
    PLoS Pathogens 10/2014; 10(10):e1004501. DOI:10.1371/journal.ppat.1004501 · 7.56 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective The natural course of chronic hepatitis C varies widely. To improve the profiling of patients at risk of developing advanced liver disease, we assessed the relative contribution of factors for liver fibrosis progression in hepatitis C. Design We analysed 1461 patients with chronic hepatitis C with an estimated date of infection and at least one liver biopsy. Risk factors for accelerated fibrosis progression rate (FPR), defined as ≥0.13 Metavir fibrosis units per year, were identified by logistic regression. Examined factors included age at infection, sex, route of infection, HCV genotype, body mass index (BMI), significant alcohol drinking (≥20 g/day for ≥5 years), HIV coinfection and diabetes. In a subgroup of 575 patients, we assessed the impact of single nucleotide polymorphisms previously associated with fibrosis progression in genome-wide association studies. Results were expressed as attributable fraction (AF) of risk for accelerated FPR. Results Age at infection (AF 28.7%), sex (AF 8.2%), route of infection (AF 16.5%) and HCV genotype (AF 7.9%) contributed to accelerated FPR in the Swiss Hepatitis C Cohort Study, whereas significant alcohol drinking, anti-HIV, diabetes and BMI did not. In genotyped patients, variants at rs9380516 (TULP1), rs738409 (PNPLA3), rs4374383 (MERTK) (AF 19.2%) and rs910049 (major histocompatibility complex region) significantly added to the risk of accelerated FPR. Results were replicated in three additional independent cohorts, and a meta-analysis confirmed the role of age at infection, sex, route of infection, HCV genotype, rs738409, rs4374383 and rs910049 in accelerating FPR. Conclusions Most factors accelerating liver fibrosis progression in chronic hepatitis C are unmodifiable.
    Gut 09/2014; 64(10). DOI:10.1136/gutjnl-2014-306997 · 14.66 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background The CCR5 receptor, expressed on Th1 cells, may influence clinical outcomes of HCV infection. We explored a possible link between a CCR5 32-base deletion (CCR5delta32), resulting in the expression of a non-functioning receptor, and clinical outcomes of HCV infection. Methods CCR5 and HCV-related phenotypes were analysed in 1,290 chronically infected patients and 160 patients with spontaneous clearance. Results Carriage of the CCR5delta32 allele was observed in 11% of spontaneous clearers compared to 17% of chronically infected patients (OR = 0.59, 95% CI interval 0.35–0.99, P = 0.047). Carriage of this allele also tended to be observed more frequently among patients with liver inflammation (19%) compared to those without inflammation (15%, OR = 1.38, 95% CI interval 0.99–1.95, P = 0.06). The CCR5delta32 was not associated with sustained virological response (P = 0.6), fibrosis stage (P = 0.8), or fibrosis progression rate (P = 0.4). Conclusions The CCR5delta32 allele appears to be associated with a decreased rate of spontaneous HCV eradication, but not with hepatitis progression or response to antiviral therapy.
    PLoS ONE 09/2014; 9(9):e106424. DOI:10.1371/journal.pone.0106424 · 3.23 Impact Factor
  • Pierre Deltenre · Darius Moradpour ·
    [Show abstract] [Hide abstract]
    ABSTRACT: Hepatic encephalopathy is a neurological syndrome occurring in patients with liver failure or in those with a large porto-systemic shunt. In cirrhotic patients, the current classification comprises covert and overt encephalopathy. Diagnosis of covert encephalopathy requires sensitive tests. Lactulose and rifaximin are the two leading therapeutic options. Rifaximin is efficacious for maintaining remission from hepatic encephalopathy. Liver transplantation should be discussed in cirrhotic patients with encephalopathy.
    Revue médicale suisse 09/2014; 10(440):1612, 1614-6.
  • Haithem Chtioui · Thierry Buclin · Darius Moradpour ·
    [Show abstract] [Hide abstract]
    ABSTRACT: Progress in the understanding of the hepatitis C virus life cycle allowed the development of new, very promising antiviral therapies. Although these new drugs have a favourable profile in terms of efficacy, tolerance and interaction potential, their prescription in the setting of comedication and impaired renal or hepatic function remains a challenge. Here, we provide a summary of pharmacological considerations, focusing on sofosbuvir, simeprevir and daclatasvir. A better understanding of their metabolic pathways and transporters may help the prescriber to identify and manage drug interactions especially in patients under immunosuppressive or anti-HIV therapy. Recommendations for the prescription of these drugs in specific situations are also discussed.
    Revue médicale suisse 09/2014; 10(440):1600-4, 1606.
  • Tobias Boettler · Darius Moradpour · Robert Thimme · Fabien Zoulim ·
    [Show abstract] [Hide abstract]
    ABSTRACT: The EASL Monothematic Conference on Translational Research in Viral Hepatitis brought together a group of leading scientists and clinicians working on both, basic and clinical aspects of viral hepatitis, thereby building bridges from bench to bedside. This report recapitulates the presentations and discussions at the conference held in Lyon, France on November 29-30, 2013. In recent years, great advances have been made in the field of viral hepatitis, particularly in hepatitis C virus (HCV) infection. The identification of IL28B genetic polymorphisms as a major determinant for spontaneous and treatment-induced HCV clearance was a seminal discovery. Currently, hepatologists are at the doorstep of even greater advances, with the advent of a wealth of directly acting antivirals (DAAs) against HCV. Indeed, promising results have accumulated over the last months and few years, showing sustained virological response (SVR) rates of up to 100% with interferon-free DAA combination therapies. Thus, less than 25 years after its identification, HCV infection may soon be curable in the vast majority of patients, highlighting the great success of HCV research over the last decades. However, viral hepatitis and its clinical complications such as liver cirrhosis and hepatocellular carcinoma (HCC) remain major global challenges. New therapeutic strategies to tackle hepatitis B virus (HBV) and hepatitis D virus (HDV) infection are needed, as current therapies have undeniable limitations. Nucleoside/nucleotide analogues (NUC) can efficiently control HBV replication and reduce or even reverse liver damage. However, these drugs have to be given for indefinite periods in most patients to maintain virological and biochemical responses. Although sustained responses off treatment can be achieved by treatment with (pegylated) interferon-α, only about 10-30% of patients effectively resolve chronic hepatitis B. It was the goal of this conference to review the progress made over the last years in chronic viral hepatitis research and to identify key questions that need to be addressed in order to close the gap between basic and clinical research and to develop novel preventive and treatment approaches for this most common cause of liver cirrhosis and HCC.
    Journal of Hepatology 09/2014; 61(3). DOI:10.1016/j.jhep.2014.05.016 · 11.34 Impact Factor

Publication Stats

11k Citations
1,388.47 Total Impact Points


  • 2008-2015
    • University of Lausanne
      • Institute of Microbiology
      Lausanne, Vaud, Switzerland
  • 2005-2014
    • University Hospital of Lausanne
      • • Institute of Microbiology (IMUL)
      • • Service de gastro-entérologie et d'hépatologie
      Lausanne, Vaud, Switzerland
  • 1998-2012
    • University of Freiburg
      • Department of Internal Medicine
      Freiburg, Baden-Württemberg, Germany
  • 2003-2011
    • Heidelberg University
      Heidelburg, Baden-Württemberg, Germany
    • Istituto Nazionale per le Malattie Infettive "L.Spallanzani"
      Roma, Latium, Italy
    • Universitätsspital Basel
      Bâle, Basel-City, Switzerland
  • 2010
    • University of Tours
      Tours, Centre, France
  • 2009
    • University of Lyon
      Lyons, Rhône-Alpes, France
  • 2000
    • Heinrich Pette Institute – Leibniz Institute for Experimental Virology
      Hamburg, Hamburg, Germany
  • 1994-1999
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States
  • 1993-1997
    • Massachusetts General Hospital
      • Molecular Biology Laboratory
      Boston, Massachusetts, United States