IL-18, CXCL-8 and CXCL-10 plasma levels decrease in patients with chronic Hepatitis C virus infection undergoing DAA therapy

The recently approved treatment of chronic Hepatitis C virus infection (cHCV) with direct acting antivirals (DAA) leads to sustained virological response rates (SVR) of more than 90%. The elimination of the virus leads to a subsequent decline of chronic inflammation. Important inflammatory mediators are cytokines that show differential profiles in cHCV patients compared to healthy controls. Until now, the effect of successful virus elimination by DAA therapy on the cytokine milieu has not been comprehensively investigated. In this study, we therefore performed longitudinal analyses of cytokine profiles in the plasma of DAA-treated patients with cHCV.

In detail, 26 cytokines in the plasma of 37 patients with cHCV were quantified by enzyme-linked immunosorbent assay (ELISA) and cytometric bead arrays. All patients received DAA therapy (n = 22 Harvoni, n = 7 Harvoni/Ribavirin, n = 3 Viekirax/Exviera, n = 3 Viekirax/Exviera/Ribavirin, n = 2 Daklinza/Sovaldi) and achieved an SVR 12. Liver cirrhosis was present in 12 of the examined patients. Cytokine profiles were analyzed at therapy baseline (W0), during therapy (W4), at the end of therapy (EOT) and in a follow-up examination (12 – 28 weeks after end of therapy; FU). 31 healthy donors served as control group.

While most of the analyzed cytokines including the anti-inflammatory cytokines IL-10 and TGF-β remained stable, plasma levels of the pro-inflammatory cytokine IL-18 declined during treatment. This decline in IL-18 indicates extensive changes of consequent immune responses since IL-18 is an important functional regulator of innate and adaptive immunity by inducing IFN-γ production in different cell types. Furthermore, the chemokines CXCL-8 and CXCL-10 decreased until they reached levels similar to healthy donors clearly suggesting a re-orchestration of innate and adaptive immune cells with potential consequences for inflammatory processes. This assumption was further supported by the observed correlation of CXCL-8 with transaminases during DAA treatment.

In sum, we observed dynamic changes in plasma cytokine profiles of DAA-treated cHCV patients that were also linked to inflammatory parameters. These results give novel insights into the complex changes in systemic viral induced immune responses during and after chronic infection.