IFN IFN ‐free therapy is associated with restoration of type I IFN IFN response in HIV HIV ‐1 patients with acute HCV HCV infection who achieve SVR SVR

摘要

Summary Interferon ( IFN )‐free direct‐acting antiviral agents ( DAA s) have revolutionized chronic hepatitis C virus ( HCV ) treatment; early studies suggest excellent efficacy in acute HCV . However, changes in innate immune responses during DAA therapy for acute HCV are unknown. We studied interferon‐stimulated gene ( ISG ) expression and related cytokines/chemokines in HIV ‐infected patients with acute HCV receiving sofosbuvir plus ribavirin ( SOF + RBV ) as part of the A5327 clinical trial. ISG expression was determined from PBMC s, and circulating cytokines/chemokines were quantified from serum from study participants. The overall sustained virologic response ( SVR ) was 57%; all treatment failures were due to virologic relapse. Apart from NOS 2a , baseline ISG /chemokine/cytokine levels were similar irrespective of treatment outcome. Downregulation of ISG s was observed at treatment week four and end of treatment ( EOT ), implicating HCV in establishing elevated ISG s early during HCV infection. Levels of many of these ISG s increased at post‐treatment week 12 ( PTW 12) in relapsers only, coinciding with recurrent HCV RNA . Eleven ISG s were differentially expressed in responders vs relapsers. On‐treatment viral suppression was also associated with a reduction in IP ‐10, CXCL 11 and MIP ‐1β levels. In contrast, circulating IFN ‐α levels were significantly higher at EOT and PTW 12 in responders vs relapsers. Upregulation of peripheral ISG expression is established early in the course of HCV infection during acute HCV infection, but did not predict subsequent treatment outcome with SOF + RBV . ISG s were downregulated during therapy and increased post‐therapy in relapsers. IFN ‐α levels were higher in responders at EOT / PTW 12, suggesting that impaired type I IFN production/secretion may contribute to relapse.