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 4

Rapid treatment-induced downregulation of endogenous IFN signaling in peripheral blood.

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Rapid treatment-induced downregulation of endogenous IFN signaling in pe...
(A) Rapid decrease of gene expression of 6 selected ISGs in PBMCs. Shown are individual measurements (n as indicated) with group median and interquartile range. A linear mixed-effects model showed a significant decrease in expression of all 6 genes over the course of treatment (P < 0.0001). (B) MX1 gene expression in blood did not correlate with baseline viral load. Data points are from patients who achieved SVR (n = 22; black) and from patients who later relapsed (n = 10; red). Statistical analysis was by nonparametric Spearman correlation (r) including all data. (C) Viral kinetic decline during treatment did not correlate with MX1 expression in PBMCs. Shown are median values with interquartile range for viral load (red) and median values with 95% confidence intervals for MX1 (black). LLOD, lower limit of detection for viral load. Data are from the 32 patients with available data. See Table 2 for statistical analysis.