Direct acting anti-viral therapy improves neutrophil dysfunction in hepatitis C infection by ameliorating haemolysis

Background and Aims: Hepatitis C (HCV) is a systemic disease that not only impacts on the liver but also shows extrahepatic manifestations from earlier stages of liver dysfunction. HCV induced immune dysfunction that may lead to an increased risk of infection, is an underestimated extrahepatic manifestation. Method: A real life cohort of 85 (mean age 57 ± 11 years; 34 female) patients undergoing DAA therapy (sofosbuvir combined with ribavirin or daclatasvir or simeprevir or ledipasvir or a combination of paritaprevir/ritonavir/ombitasvir and dasabuvir) between 4/2014 and 9/2015 was studied. Neutrophil phagocytosis was analysed at baseline, at end of therapy and after 12 weeks follow-up by flow cytometry (Phagotest). Data were compared to 21 healthy controls (mean age 58 ± 7, 12 female). For ex-vivo experiments isolated neutrophils of healthy volunteers and patients were used and incubated with serum of healthy controls and/or patients. Results: Overall SVR rate was 86%, 66% had cirrhosis and 6 infections occurred during therapy. Baseline phagocytosis was significantly reduced and the number of inactive neutrophils was increased in HCV patients. Both recovered fully after DAA therapy. Type of DAA regimen did not impact on neutrophil function. Ex-vivo experiments revealed serum components above 30kDa to be responsible for neutrophil dysfunction in HCV patients and 3D gel electrophoresis pointed towards haemolysis as a potential mechanism for neutrophil dysfunction. Haptoglobin was investigated as marker of haemolysis during DAA therapy. Changes of haptoglobin levels during therapy mirrored the improvement of neutrophil function over time. Ribavirin delayed the improvement in haemolysis and neutrophil function. Conclusion: DAAs are able to rescue HCV induced neutrophil dysfunction probably by reducing haemolysis and hence oxidative stress.