title: Prednisolone does not affect direct-acting antivirals against hepatitis C, but inhibits interferon-alpha production by plasmacytoid dendritic cells.
abstract: BACKGROUND
  Chronic hepatitis C virus (HCV) infection compromises long-term outcomes of liver transplantation. Although glucocorticosteroid-based immunosuppression is commonly used, discussion is ongoing on the effect of prednisolone (Pred) on HCV recurrence and response to antiviral therapy post transplantation. Recently, new drugs (direct-acting antivirals) have been approved for the treatment of HCV, however, it remains unknown whether their antiviral activity is affected by Pred. The aim of this study was to investigate the effects of Pred on the antiviral activity of asunaprevir (Asu), daclatasvir (Dac), ribavirin (RBV), and interferon-alpha (IFN-α), and on plasmacytoid dendritic cells (PDCs), the main IFN-α-producing immune cells.
  
  
  METHODS
  The effects of Pred and antiviral compounds were tested in both a subgenomic and infectious HCV replication model. Furthermore, effects were tested on human PDCs stimulated with a Toll-like receptor-7 ligand.
  
  
  RESULTS
  Pred did not directly affect HCV replication and did not inhibit the antiviral action of Asu, Dac, RBV, or IFN-α. Stimulated PDCs potently suppressed HCV replication. This suppression was reversed by treating PDCs with Pred. Pred significantly decreased IFN-α production by PDCs without affecting cell viability. When Asu and Dac were combined with PDCs, a significant cooperative antiviral effect was observed.
  
  
  CONCLUSIONS
  This study shows that Pred acts on the antiviral function of PDCs. Pred does not affect the antiviral action of Asu, Dac, RBV, or IFN-α. This implies that there is no contraindication to combine antiviral therapies with Pred in the post-transplantation management of HCV recurrence.
authors.affiliation: Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: P E
authors.initials: PE
authors.lastname: de Ruiter
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: P P C
authors.initials: PP
authors.lastname: Boor
authors.affiliation: Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: de Jonge
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: H J
authors.initials: HJ
authors.lastname: Metselaar
authors.affiliation: Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: H W
authors.initials: HW
authors.lastname: Tilanus
authors.affiliation: Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: J N
authors.initials: JN
authors.lastname: Ijzermans
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Kwekkeboom
authors.affiliation: Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: L J W
authors.initials: LJ
authors.lastname: van der Laan
mesh_terms: D000998:Antiviral Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D002219:Carbamates; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000187:drug effects* / Q000378:metabolism; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D016898:Interferon-alpha / Q000378:metabolism* / Q000627:therapeutic use; D007546:Isoquinolines / Q000627:therapeutic use; D016031:Liver Transplantation; D011239:Prednisolone / Q000009:adverse effects*; D011759:Pyrrolidines; D012254:Ribavirin / Q000627:therapeutic use; D013449:Sulfonamides / Q000627:therapeutic use; D014633:Valine / Q000031:analogs & derivatives
chemical_list: D000998:Antiviral Agents; D015415:Biomarkers; D002219:Carbamates; D007093:Imidazoles; D007166:Immunosuppressive Agents; D016898:Interferon-alpha; D007546:Isoquinolines; D011759:Pyrrolidines; D013449:Sulfonamides; D012254:Ribavirin; D011239:Prednisolone; D014633:Valine; C549273:daclatasvir; C571889:asunaprevir
keywords: asunaprevir; daclatasvir; hepatitis C virus; interferon-alpha; liver transplantation; ribavirin