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Citations to this article

Endogenous intrahepatic IFNs and association with IFN-free HCV treatment outcome
Eric G. Meissner, … , Anthony S. Fauci, Shyamasundaran Kottilil
Eric G. Meissner, … , Anthony S. Fauci, Shyamasundaran Kottilil
Published July 1, 2014
Citation Information: J Clin Invest. 2014;124(8):3352-3363. https://doi.org/10.1172/JCI75938.
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Clinical Research and Public Health Virology Article has an altmetric score of 17

Endogenous intrahepatic IFNs and association with IFN-free HCV treatment outcome

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Abstract

BACKGROUND. Hepatitis C virus (HCV) infects approximately 170 million people worldwide and may lead to cirrhosis and hepatocellular carcinoma in chronically infected individuals. Treatment is rapidly evolving from IFN-α–based therapies to IFN-α–free regimens that consist of directly acting antiviral agents (DAAs), which demonstrate improved efficacy and tolerability in clinical trials. Virologic relapse after DAA therapy is a common cause of treatment failure; however, it is not clear why relapse occurs or whether certain individuals are more prone to recurrent viremia.

METHODS. We conducted a clinical trial using the DAA sofosbuvir plus ribavirin (SOF/RBV) and performed detailed mRNA expression analysis in liver and peripheral blood from patients who achieved either a sustained virologic response (SVR) or relapsed.

RESULTS. On-treatment viral clearance was accompanied by rapid downregulation of IFN-stimulated genes (ISGs) in liver and blood, regardless of treatment outcome. Analysis of paired pretreatment and end of treatment (EOT) liver biopsies from SVR patients showed that viral clearance was accompanied by decreased expression of type II and III IFNs, but unexpectedly increased expression of the type I IFN IFNA2. mRNA expression of ISGs was higher in EOT liver biopsies of patients who achieved SVR than in patients who later relapsed.

CONCLUSION. These results suggest that restoration of type I intrahepatic IFN signaling by EOT may facilitate HCV eradication and prevention of relapse upon withdrawal of SOF/RBV.

TRIAL REGISTRATION. ClinicalTrials.gov NCT01441180.

FUNDING. Intramural Programs of the National Institute of Allergy and Infectious Diseases, National Institutes of Health Clinical Center, and National Cancer Institute; German Research Foundation.

Authors

Eric G. Meissner, David Wu, Anu Osinusi, Dimitra Bon, Kimmo Virtaneva, Dan Sturdevant, Steve Porcella, Honghui Wang, Eva Herrmann, John McHutchison, Anthony F. Suffredini, Michael Polis, Stephen Hewitt, Ludmila Prokunina-Olsson, Henry Masur, Anthony S. Fauci, Shyamasundaran Kottilil

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C CarltonSmith, JA Holmes, S Naggie, A Lidofsky, GM Lauer, AY Kim, RT Chung
Journal of Viral Hepatitis 2017
Drug Treatment for Chronic Hepatitis C Infection and Cancer Risk
MA Wörns, PR Galle, S Zeuzem, P Schirmacher, M Manns, A Vogel
Deutsches Ärzteblatt international 2017
Immune responses in DAA treated chronic hepatitis C patients with and without prior RG-101 dosing
MH van der Ree, F Stelma, SB Willemse, A Brown, L Swadling, M van der Valk, MJ Sinnige, AC van Nuenen, JM de Vree, P Klenerman, E Barnes, NA Kootstra, HW Reesink
Antiviral Research 2017
Chronic hepatitis C infection–induced liver fibrogenesis is associated with M2 macrophage activation
MT Bility, K Nio, F Li, DR McGivern, SM Lemon, ER Feeney, RT Chung, L Su
Scientific Reports 2016
Successful Re-treatment of Hepatitis C Virus in Patients Coinfected With HIV Who Relapsed After 12 Weeks of Ledipasvir/Sofosbuvir: Table 1
C Cooper, S Naggie, M Saag, JC Yang, LM Stamm, H Dvory-Sobol, LL Han, PS Pang, JG McHutchison, D Dieterich, M Sulkowski
Clinical Infectious Diseases 2016
Simtuzumab treatment of advanced liver fibrosis in HIV and HCV-infected adults: results of a 6-month open-label safety trial
EG Meissner, M McLaughlin, L Matthews, AM Gharib, BJ Wood, E Levy, R Sinkus, K Virtaneva, D Sturdevant, C Martens, SF Porcella, ZD Goodman, B Kanwar, RP Myers, M Subramanian, C Hadigan, H Masur, DE Kleiner, T Heller, S Kottilil, JA Kovacs, CG Morse
Liver International 2016
Twelve-week ribavirin-free direct-acting antivirals for treatment-experienced Chinese with HCV genotype 1b infection including cirrhotic patients
D Ji, GF Chen, C Wang, YD Wang, Q Shao, B Li, J Zhao, SL You, JH Hu, JL Liu, XX Niu, J Chen, L Lu, V Wu, G Lau
Hepatology International 2016
Cellular Mechanism for Impaired Hepatitis C Virus Clearance by Interferon Associated with IFNL3 Gene Polymorphisms Relates to Intrahepatic Interferon-λ Expression
P Ferraris, PK Chandra, R Panigrahi, F Aboulnasr, S Chava, R Kurt, JM Pawlotsky, L Wilkens, P Osterlund, R Hartmann, LA Balart, T Wu, S Dash
The American Journal of Pathology 2016
Achieving sustained virologic response after interferon-free hepatitis C virus treatment correlates with hepatic interferon gene expression changes independent of cirrhosis
EG Meissner, A Kohli, K Virtaneva, D Sturdevant, C Martens, SF Porcella, JG McHutchison, H Masur, S Kottilil
Journal of Viral Hepatitis 2016
How hepatitis C patients manage the treatment process of pegylated interferon and ribavirin therapy: a qualitative study
SM Tsai, JT Kao, YF Tsai
BMC health services research 2016
Randomized Trial Evaluating the Impact of Ribavirin Mono-Therapy and Double Dosing on Viral Kinetics, Ribavirin Pharmacokinetics and Anemia in Hepatitis C Virus Genotype 1 Infection
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PloS one 2016
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BR Bang, S Elmasry, T Saito
Journal of Medical Virology 2016
DAAs Rapidly Reduce Inflammation but Increase Serum VEGF Level: A Rationale for Tumor Risk during Anti-HCV Treatment
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PloS one 2016
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Effect of sofosbuvir and ribavirin treatment on peripheral and hepatic lipid metabolism in chronic hepatitis C virus, genotype 1-infected patients: HEPATOLOGY, Vol. XX, No. X, 2014
EG Meissner, YJ Lee, A Osinusi, Z Sims, J Qin, D Sturdevant, J McHutchison, M Subramanian, M Sampson, S Naggie, K Patel, AT Remaley, H Masur, S Kottilil
Hepatology 2015
Successful Interferon-Free Therapy of Chronic Hepatitis C Virus Infection Normalizes Natural Killer Cell Function
E Serti, X Chepa-Lotrea, YJ Kim, M Keane, N Fryzek, TJ Liang, M Ghany, B Rehermann
Gastroenterology 2015
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B Rehermann
CMGH Cellular and Molecular Gastroenterology and Hepatology 2015
Dynamic Changes of Post-Translationally Modified Forms of CXCL10 and Soluble DPP4 in HCV Subjects Receiving Interferon-Free Therapy
EG Meissner, J Decalf, A Casrouge, H Masur, S Kottilil, ML Albert, D Duffy, SJ Polyak
PloS one 2015
IFN-λ Inhibits MiR-122 Transcription through a Stat3-HNF4α Inflammatory Feedback Loop in an IFN-α Resistant HCV Cell Culture System
F Aboulnasr, S Hazari, S Nayak, PK Chandra, R Panigrahi, P Ferraris, S Chava, R Kurt, K Song, A Dash, LA Balart, RF Garry, T Wu, S Dash, G Ahlenstiel
PloS one 2015
Utility of Hepatitis C Viral Load Monitoring on Direct-Acting Antiviral Therapy
S Sidharthan, A Kohli, Z Sims, A Nelson, A Osinusi, H Masur, S Kottilil
Clinical Infectious Diseases 2015
Hepatic expression levels of interferons and interferon-stimulated genes in patients with chronic hepatitis C: A phenotype–genotype correlation study
M Noureddin, Y Rotman, F Zhang, H Park, B Rehermann, E Thomas, TJ Liang
Genes and Immunity 2015
Expression of Interferon Lambda 4 Is Associated with Reduced Proliferation and Increased Cell Death in Human Hepatic Cells
OO Onabajo, P Porter-Gill, A Paquin, N Rao, L Liu, W Tang, N Brand, L Prokunina-Olsson
Journal of Interferon & Cytokine Research 2015
Differential Specificity of Interferon-alpha Inducible Gene Expression in Association with Human Immunodeficiency Virus and Hepatitis C Virus Levels and Declines in vivo
A Katsounas
Journal of AIDS & Clinical Research 2015
Ribavirin Contributes to Hepatitis C Virus Suppression by Augmenting pDC Activation and Type 1 IFN Production
Y Wang, DR McGivern, L Cheng, G Li, SM Lemon, J Niu, L Su, NJ Reszka-Blanco, W Ho
PloS one 2015
Comparison of Functional Variants in IFNL4 and IFNL3 for Association with Hepatitis C Virus Clearance
TR OBrien, RM Pfeiffer, A Paquin, KA Kuhs, S Chen, HL Bonkovsky, BR Edlin, CD Howell, GD Kirk, MH Kuniholm, TR Morgan, HD Strickler, DL Thomas, L Prokunina-Olsson
Journal of Hepatology 2015
Effect of Hepatitis C Virus Genotype 1b Core and NS5A Mutations on Response to Peginterferon Plus Ribavirin Combination Therapy
S Nakamoto, F Imazeki, M Arai, S Yasui, M Nakamura, Y Haga, R Sasaki, T Kanda, H Shirasawa, O Yokosuka
International journal of molecular sciences 2015
Activation of Type I and Type III Interferons in Chronic Hepatitis C
S Mihm
Journal of Innate Immunity 2015
Twenty-five years of type I interferon-based treatment: A critical analysis of its therapeutic use
G Antonelli, C Scagnolari, F Moschella, E Proietti
Cytokine & Growth Factor Reviews 2014

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