Elisavet Serti1,2, Heiyoung Park1,2, Meghan Keane1,2, Ashley C O'Keefe1,2, Elenita Rivera2, T Jake Liang2, Marc Ghany2, Barbara Rehermann1,2. 1. Immunology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, Maryland, USA. 2. Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, Maryland, USA.
Abstract
OBJECTIVE: Chronic HCV infection is characterised by innate immune activation with increased interferon-stimulated genes (ISG) expression and by an altered phenotype of interferon-responsive natural killer (NK) cells. Here, we asked whether a rapid reduction in viremia by daclatasvir (DCV) and asunaprevir (ASV) improves the response to pegylated interferon (PegIFN) in patients who had previously failed a standard course of PegIFN/ribavirin (RBV) therapy. DESIGN: Twenty-two HCV-infected non-responders to previous PegIFN/RBV therapy were studied for IFN-responsiveness of NK cells during quadruple (QUAD) therapy with DCV, ASV, PegIFN and RBV. A direct comparison of early NK cell responses in PegIFN/RBV therapy and QUAD therapy was performed for seven patients using paired cryopreserved peripheral blood mononuclear cells (PBMC) from both treatment courses. As a validation cohort, nine DCV/ASV-treated patients were studied for their NK cell response to in vitro stimulation with IFNα. RESULTS: The 24 h virological response to QUAD therapy correlated with an increase in signal transducer and activator of transcription 1 (STAT1), phosphorylated STAT1 (pSTAT1) and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) expression in NK cells, and the STAT1/pSTAT1/TRAIL induction was greater during QUAD therapy than during previous PegIFN/RBV therapy. Successful QUAD therapy as well as successful IFN-free DCV/ASV regimen resulted in an improved functional NK cell response (degranulation and TRAIL expression) to in vitro stimulation with IFNα. CONCLUSIONS: IFN-responsiveness can be improved by inhibiting HCV replication and reducing the HCV-induced activation of the innate immune response. This may provide a rationale for clinical trials of a brief period of direct acting antiviral therapy followed by PegIFN/RBV therapy to reduce the overall treatment costs in low-income and middle-income countries. TRIAL REGISTRATION NUMBERS: NCT01888900 and NCT00718172. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
OBJECTIVE:Chronic HCV infection is characterised by innate immune activation with increased interferon-stimulated genes (ISG) expression and by an altered phenotype of interferon-responsive natural killer (NK) cells. Here, we asked whether a rapid reduction in viremia by daclatasvir (DCV) and asunaprevir (ASV) improves the response to pegylated interferon (PegIFN) in patients who had previously failed a standard course of PegIFN/ribavirin (RBV) therapy. DESIGN: Twenty-two HCV-infected non-responders to previous PegIFN/RBV therapy were studied for IFN-responsiveness of NK cells during quadruple (QUAD) therapy with DCV, ASV, PegIFN and RBV. A direct comparison of early NK cell responses in PegIFN/RBV therapy and QUAD therapy was performed for seven patients using paired cryopreserved peripheral blood mononuclear cells (PBMC) from both treatment courses. As a validation cohort, nine DCV/ASV-treated patients were studied for their NK cell response to in vitro stimulation with IFNα. RESULTS: The 24 h virological response to QUAD therapy correlated with an increase in signal transducer and activator of transcription 1 (STAT1), phosphorylated STAT1 (pSTAT1) and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) expression in NK cells, and the STAT1/pSTAT1/TRAIL induction was greater during QUAD therapy than during previous PegIFN/RBV therapy. Successful QUAD therapy as well as successful IFN-free DCV/ASV regimen resulted in an improved functional NK cell response (degranulation and TRAIL expression) to in vitro stimulation with IFNα. CONCLUSIONS:IFN-responsiveness can be improved by inhibiting HCV replication and reducing the HCV-induced activation of the innate immune response. This may provide a rationale for clinical trials of a brief period of direct acting antiviral therapy followed by PegIFN/RBV therapy to reduce the overall treatment costs in low-income and middle-income countries. TRIAL REGISTRATION NUMBERS: NCT01888900 and NCT00718172. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
Entities:
Keywords:
HEPATITIS C; IMMUNE RESPONSE; IMMUNOLOGY; IMMUNOLOGY IN HEPATOLOGY
Authors: Kerstin A Stegmann; Niklas K Björkström; Heike Veber; Sandra Ciesek; Peggy Riese; Johannes Wiegand; Johannes Hadem; Pothakamuri V Suneetha; Jerzy Jaroszewicz; Chun Wang; Verena Schlaphoff; Paraskevi Fytili; Markus Cornberg; Michael P Manns; Robert Geffers; Thomas Pietschmann; Carlos A Guzmán; Hans-Gustaf Ljunggren; Heiner Wedemeyer Journal: Gastroenterology Date: 2010-02-02 Impact factor: 22.682
Authors: Michael T Dill; Zuzanna Makowska; Gaia Trincucci; Andreas J Gruber; Julia E Vogt; Magdalena Filipowicz; Diego Calabrese; Ilona Krol; Daryl T Lau; Luigi Terracciano; Erik van Nimwegen; Volker Roth; Markus H Heim Journal: J Clin Invest Date: 2014-02-24 Impact factor: 14.808
Authors: Magdalena Rogalska-Taranta; Antoaneta A Markova; Andrzej Taranta; Sebastian Lunemann; Verena Schlaphoff; Robert Flisiak; Michael P Manns; Markus Cornberg; Anke R M Kraft; Heiner Wedemeyer Journal: J Leukoc Biol Date: 2015-06-01 Impact factor: 4.962
Authors: Dongliang Ge; Jacques Fellay; Alexander J Thompson; Jason S Simon; Kevin V Shianna; Thomas J Urban; Erin L Heinzen; Ping Qiu; Arthur H Bertelsen; Andrew J Muir; Mark Sulkowski; John G McHutchison; David B Goldstein Journal: Nature Date: 2009-08-16 Impact factor: 49.962
Authors: Golo Ahlenstiel; Rachel H Titerence; Christopher Koh; Birgit Edlich; Jordan J Feld; Yaron Rotman; Marc G Ghany; Jay H Hoofnagle; T Jake Liang; Theo Heller; Barbara Rehermann Journal: Gastroenterology Date: 2009-09-10 Impact factor: 22.682
Authors: Femke Stelma; Meike H van der Ree; Marjan J Sinnige; Anthony Brown; Leo Swadling; J Marleen L de Vree; Sophie B Willemse; Marc van der Valk; Paul Grint; Steven Neben; Paul Klenerman; Eleanor Barnes; Neeltje A Kootstra; Hendrik W Reesink Journal: Hepatology Date: 2017-06-07 Impact factor: 17.298