Restoration of type I intrahepatic interferon signaling by the end of direct-acting antiviral treatment in patients with hepatitis C virus appears to facilitate HCV eradication and relapse prevention, according to findings from a clinical trial.
Of 60 patients treated with the direct-acting antiviral agent (DAA) sofosbuvir plus ribavirin (SOF/RBV), 69% achieved sustained virologic response and 31% relapsed within 12 weeks of treatment completion. A reduction of intrahepatic expression of type II and III interferons (IFNs) and their receptors in a sample of the patients with SVRs paralleled a decrease in hepatic and blood interferon-stimulating gene expression during HCV suppression – a finding that suggested that reactivation of hepatic type I IFN signaling at the end of treatment might be important for a favorable outcome.
A subsequent comparison of microarray mRNA expression profiling in unpaired liver biopsies obtained at the end of treatment showed that type I IFN expression was indeed higher in 17 patients who achieved sustained virologic response (SVR) than in 8 patients who relapsed, Dr. Eric G. Meissner of the National Institute of Allergy and Infectious Diseases, Bethesda, Md., and his colleagues reported online July 2 in the Journal of Clinical Investigation.
IFN signaling was identified as a top pathway distinguishing SVR from relapse, with lower expression of an IFN gene signature at the end of treatment in patients who relapsed, the investigators said (J. Clin. Invest. 2014 July 2 [doi: 10.1172/jci75938]).
"Our present results demonstrate for the first time that HCV clearance achieved during IFN-free treatment with the DAA regimen of SOF/RBV is accompanied by hepatic down-regulation of type II and III IFNs, their receptors, and interferon-stimulated genes (ISGs). Down-regulation of ISGs was associated with on-treatment viral suppression and occurred regardless of treatment outcome, since all patients achieved virologic suppression on therapy. However, patients who achieved SVR unexpectedly had higher intrahepatic expression of ISGs at end of treatment compared with patients who relapsed," the authors wrote.
They noted that the increase in IFNA2 expression in those who achieved SVR suggested that the higher end-of-treatment ISG expression might be driven by an enhanced type I IFN response.
This suggests a model in which aberrant expression of hepatic ISGs triggered by HCV and/or type II/III IFNs decreases early during treatment, and after prolonged viral suppression, higher activation of ISG expression at the end of treatment may be induced by type I IFNs, which in turn might promote elimination of residual virus, they suggested.
As has been recognized in other conditions involving prolonged immune stimulation, resolution of infection and inflammation can be followed by a period of relative immune suppression. HCV patients who are able to reestablish IFN homeostasis by the end of DAA treatment may be more likely to achieve SVR, while those who aren’t able to reestablish IFN homeostasis may be more prone to relapse, they noted. "The ability to mount an endogenous, intrahepatic type I IFN response could be important for achieving SVR, even with IFN-alpha–free DAA regimens," they added
The findings are important because although injectable IFN-alpha formulations have been the mainstay of HCV treatment, they are associated with significant side effects and often are ineffective; treatment is rapidly evolving to IFN-alpha–free oral regimens that consist of DAAs. DAAs have been shown in clinical trials to induce rapid and sustained viral suppression, and to have improved tolerability, compared with IFN-alpha treatments, the investigators said.
However, on-treatment viral breakthrough or relapse after DAA therapy is a common cause of treatment failure. The current findings, although limited by the small sample size, suggest that the ability to restore intrahepatic type I IFN signaling "may be biologically important for eradication of residual virus in the setting of prolonged HCV suppression with IFN-free therapy."
"Knowledge of expression variability in components of the IFN system could help determine the optimal duration of therapy for patients, especially in resource-limited settings, a concept that will be pursued in future studies. As HCV therapy evolves from IFN-based to DAA-only regimens, our study fosters a role for the host in determining favorable treatment outcomes in chronically infected patients treated with SOF/RBV," they concluded.
This study was funded by the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, the National Institutes of Health Clinical Center, and the German Research Foundation. Gilead Sciences provided sofosbuvir. Coauthor John McHutchison is an employee of Gilead. The other authors reported having no disclosures.