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 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 5

Altered balance of IFN expression in liver during treatment of patients achieving SVR.

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Altered balance of IFN expression in liver during treatment of patients ...
(A) Total IFN expression decreased during treatment in all SVR patients (n = 7). qRT-PCR for individual IFNs (shown in B) was performed using 5–15 ng RNA per reaction with technical duplicates. The sum of relative gene expression values of all measured IFNs at each time point is shown for each patient who achieved SVR. (B) qRT-PCR for individual IFNs was performed using 5–15 ng RNA per reaction with technical duplicates. Shown are individual measurements with group median and interquartile range for the 7 patients with paired liver biopsies who achieved SVR. P values were determined by Wilcoxon matched-pairs signed rank test. The functional allele for IFNL4 (IFNL4-ΔG, which produces the IFN-λ4 protein; ref. 31) was shown only for the 5 patients who carried this allele. LLOD, lower limit of detection. (C) Relative ratio of individual IFNs within the total pool of measured IFNs. Median and interquartile range is shown for patients achieving SVR (n = 7). P values compare EOT vs. pretreatment (Wilcoxon signed-rank test). (D) On-treatment changes in IFN receptor mRNA expression. Data and analysis are as in B.