Dynamic changes in innate immune responses during direct‐acting antiviral therapy for <scp>HCV</scp> infection

Abstract

Summary The role of the endogenous interferon ( IFN ) system has been well characterized during IFN ‐based therapy for chronic hepatitis C virus ( HCV ) infection; less is known for direct‐acting antivirals ( DAA s). In this phase 3b open‐label study, we assessed changes in IFN ‐stimulated genes ( ISG s) in non‐cirrhotic treatment‐naïve or peg IFN / RBV ‐experienced HCV ‐ GT 1a‐infected patients receiving paritaprevir/ritonavir/ombitasvir + dasabuvir + ribavirin (Pr OD + R) for 12 weeks. ISG expression was quantified from peripheral blood mononuclear cells at baseline, treatment weeks ( TW )2, TW 4, TW 8, end of treatment ( EOT ) and at post‐treatment week 12. Paired sera were used to assess IFN ‐α/ IFN ‐related chemokines/cytokines. Twenty‐five patients were enrolled. Overall sustained virologic response ( SVR )12 was 92% (no virologic failure [ VF ]) and 100% for those completing the study protocol. Two patients were excluded from the ISG analysis due to lack of post‐treatment samples. The majority of ISG s were downregulated at TW 2‐ TW 4 (nadir TW 4); however, a relative increase was observed at TW 8‐ EOT , although levels were lower than baseline. This downregulation was accompanied by increases in IFN ‐α/ IFN ‐related chemokines, a finding not observed with T H 1/2‐related cytokines. Following SVR , ISG expression returned to TW 2 levels. In conclusion, Pr OD + R for 12 weeks was well‐tolerated with no VF . Our data demonstrate dynamic alterations in innate immune profiles during highly potent IFN ‐free DAA therapy. The downregulation of ISG post‐therapy suggests reversal of the “exhausted” ISG phenotype following SVR , and the rise in ISG s and IFN ‐α/ IFN ‐responsive chemokines late during therapy suggests resetting of IFN responsiveness that may be relevant in determining duration of or immunological sequelae from DAA therapy, including HBV reactivation.