Endogenous intrahepatic IFNs and association with IFN-free HCV treatment outcome
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
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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Clinical Research and Public Health 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 7

Patients who relapse have lower expression of an IFN gene signature at EOT in liver.

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Patients who relapse have lower expression of an IFN gene signature at E...
(A) Top IPA canonical pathways differing between SVR and relapse patients from EOT liver biopsy microarray mRNA expression data. Ratios represent genes among the top 1% of genes differentially expressed by outcome assigned to specific pathways, relative to the total number of genes in the respective pathway. Genes with lower expression at EOT in relapse vs. SVR patients are denoted by bold font. (B) IPA upstream analysis of predicted activation state of proteins annotated as cytokines in EOT liver biopsies, comparing SVR and relapse patients. Negative activation z scores predict lower activation at EOT in patients who relapsed. Scores of >2 were considered significant. (C) qRT-PCR validation of select ISGs. qRT-PCR analysis was performed using 2.5–5 ng RNA per reaction. Expression of IRF9 and OAS1 was measured in technical duplicates (n = 16 [SVR; black]; 8 [relapse; red]), whereas other ISGs were tested as single replicates due to sample limitations (n = 12 [SVR; black]; 8 [relapse; red]). Statistical analysis was by Mann-Whitney test. Shown are individual measurements with group median and interquartile range. (D) qRT-PCR expression analysis of 46 ISGs in EOT liver biopsies from patients with SVR or relapse on SOF/RBV treatment. Median relative expression for individual ISGs was determined for the 20 patients with sufficient RNA available for analysis (n = 12 [SVR]; 8 [relapse]). For each ISG, the percent of patients in each outcome group with expression above the group median is plotted.