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Background Treatment with direct acting antivirals (DAAs) in patients with chronic hepatitis C infection leads to partial restoration of soluble inflammatory mediators (SIMs). In contrast, we hypothesized that early DAA treatment of acute hepatitis C with DAAs may normalize most SIMs. Methods In this study, we made use of a unique cohort of acute symptomatic hepatitis C who cleared HCV with a 6-week course of ledipasvir/sofosbuvir. Plasma samples were used for proximity extension assay (PEA) measuring 92 proteins. Results Profound SIM alterations were observed in acute HCV patients, with marked upregulation of IL-6 and CXCL10 while certain mediators were down-regulated (e.g. MCP-4, IL-7). During treatment and follow-up, the majority of SIMs decreased but not all normalized (e.g. CDCP1, IL-18). Of note, SIMs that were down-regulated before DAA treatment remained suppressed while others that were initially unchanged, declined to lower values during treatment and follow-up (e.g.CD244). Conclusions Acute hepatitis C was associated with marked changes in the soluble inflammatory milieu as compared to both chronic hepatitis patients and healthy controls. Whereas early DAA treatment partly normalized this altered signature, long-lasting imprints of HCV remained. Thus, acute HCV-induced changes in the immune system may persist even after a short duration of viremia.

Overall, our data indicate that while SIMs are significantly up-regulated, NK- and T-cells are less-activated in patients with neuropsychiatric symptoms accompanying chronic inflammatory liver diseases compared to patients without these symptoms. Moreover, HCV patients showed a unique pattern of immune alterations as compared to patients with HBV, autoimmune hepatitis and primary biliary cirrhosis. These findings hint towards potential mechanisms explaining these symptoms in patients with chronic liver diseases.

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List of abbreviations: HCV (hepatitis C virus), LT (Liver transplantation), SVR (sustained virologic response), PBMC (peripheral blood mononuclear cells), DC (dendritic cells), CD (cluster differentiation), CNI (Calcineurin inhibitor), MAIT (mucosal associated invariant T cell), IFN (interferon), IL (Interleukin), DAA (direct acting antivirals), TS (therapy start), FU (follow-up), ALT (alanine aminotransferase). AST (Aspartate aminotransferase), ARFI (Acoustic radiation force impulse), HCV+LT (transplanted patients with HCV recurrence), Non-HCV LT (transplanted patients without persistent HCV infection), SVR-LT (liver transplanted patients that cleared HCV upon therapy).

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