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 August 1, 2014; First 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 Medicine Virology

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

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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Figure 8

No difference in IFN or receptor expression between by outcome in unpaired EOT liver biopsies.

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No difference in IFN or receptor expression between by outcome in unpair...
(A) Sum of total expression of IFNs, including IFNA2, IFNB1, IFNG, IFNL3, and IFNL4-ΔG. (B) Expression of individual IFN genes. (C) Relative expression of individual IFN genes as a percentage of total IFN expression. (D) Expression of IFN receptors. Data are from SVR (n = 16; black) and relapse (n = 8; red) patients in unpaired EOT liver biopsies. All assays were performed with technical duplicates using 2.5–5 ng RNA per reaction, with the exception of IFNA2 (25 ng). Shown are individual measurements with group median and interquartile range. Expression of IFNL1 and IFNL2 was not detected in any sample. No P values met criteria for significance (P < 0.05, Mann-Whitney test).