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

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 1

Microarray mRNA expression analysis reveals downregulation of endogenous IFN signaling in liver after SOF/RBV treatment.

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Microarray mRNA expression analysis reveals downregulation of endogenous...
(A) Top canonical pathways identified by IPA as changing over the course of treatment in paired liver biopsies (n = 8). Ratios represent the number of genes identified among the top 1% of differentially expressed genes assigned to specific pathways, relative to the total number of genes in the respective pathway. The cutoff for significance of these enrichments was –logP of 1.3 (P = 0.05). Genes downregulated at EOT relative to pretreatment are shown in bold font. (B) Heatmap of genes differentially expressed after SOF/RBV treatment. The top 1% of differentially expressed genes were filtered using cutoffs of >1.2 for fold difference and unadjusted P < 0.05. Microarray expression data were used to create a hierarchical clustering of samples using a Euclidean dissimilarity measure with average linkage. Data from all 8 paired liver biopsies are shown. Red color indicates higher relative expression. Asterisks denote data from the patient who relapsed. (C) IPA upstream analysis of activation state of proteins annotated as cytokines by IPA, comparing EOT versus pretreatment activity levels. Negative z scores predict a less active state of cytokines at EOT compared with pretreatment. Scores of >2 or <–2 were considered significant.