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

Abstract

Interferon (IFN)-free direct-acting antiviral agents (DAAs) 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 PBMCs, 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 NOS2a, baseline ISG/chemokine/cytokine levels were similar irrespective of treatment outcome. Downregulation of ISGs was observed at treatment week four and end of treatment (EOT), implicating HCV in establishing elevated ISGs early during HCV infection. Levels of many of these ISGs increased at post-treatment week 12 (PTW12) in relapsers only, coinciding with recurrent HCV RNA. Eleven ISGs were differentially expressed in responders vs relapsers. On-treatment viral suppression was also associated with a reduction in IP-10, CXCL11 and MIP-1β levels. In contrast, circulating IFN-α levels were significantly higher at EOT and PTW12 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. ISGs were downregulated during therapy and increased post-therapy in relapsers. IFN-α levels were higher in responders at EOT/PTW12, suggesting that impaired type I IFN production/secretion may contribute to relapse.

Hepatitis B-related outcomes following direct-acting antiviral therapy in Taiwanese patients with chronic HBV/HCV co-infection

“…Rapid HCV clearance following DAA therapy has been shown to restore innate antiviral responses in both peripheral blood and liver, 27 particularly type 1 interferon responses and natural killer cell responses. 28,29 Restoration of innate immunity following DAA treatment may impact upon HBsAg seroclearance and may explain the dynamic changes observed in our HBV/HCVcoinfected patients. 30 miR-122 and miR-125b are important host factors in both HBV and HCV lifecycles.…”

Interferon Response in Hepatitis C Virus-Infected Hepatocytes: Issues to Consider in the Era of Direct-Acting Antivirals

“…DAA therapy also rapidly restored the activated type I IFN response in PBMCs, assessed in terms of the ISG expression level and STAT1 phosphorylation [102,108,109]. A recent study from our group demonstrated that pre-treatment ISG activation in PBMCs might be due to type I IFN activation of JAK-STAT signaling [108].…”

“…In another study, among patients with HIV-1 that had acute HCV infections, ISGs were downregulated in PBMCs during DAA therapy. After therapy, the ISG levels increased in patients that relapsed, but not in patients that achieved a SVR [109]. In patients with HCV infections, baseline ISG levels in PBMCs were affected by the IFNL4 genotype [98].…”

Interferon-free treatment for patients with chronic hepatitis C and autoimmune liver disease: higher SVR rates with special precautions for deterioration of autoimmune hepatitis

“…Restoration of immunologic responses after HCV clearance with interferon-free treatment has also been reported [ 12 – 14 ]. Hepatitis B reactivation during or after interferon-free treatment for HCV may be associated with the restoration of adaptive and innate immune responses [ 12 – 14 , 18 , 19 ]. Thus, interferon-free treatment for HCV may have an effect on hepatic immunity and activity of autoimmune liver diseases.…”

“…Immune restoration in the liver is occasionally associated with HCV infection [ 10 , 11 ]. Studies using interferon-free regimens demonstrated an immune restoration of immunologic responses after HCV clearance [ 12 – 14 ]. Thus, HCV clearance has effects on the human immunologic response.…”