Department of Gastroenterology and Hepatology, University Hospital Essen, Germany.
Department of General- Visceral- and Transplantation Surgery, University Hospital Essen, Germany.
Department of Virology, University Hospital Düsseldorf, Düsseldorf, Germany.
Direct-acting antivirals (DAA) have substantially increased sustained virological response rates after liver transplantation, with improved tolerance compared to interferon-based therapy. The influence of immunosuppressive agents on the efficacy of DAAs has not been clarified.
Subgenomic HCV replicons for genotype (GT) 1b, 2b, 3a and 4a were treated with the mammalian target of rapamycin (mTOR) inhibitors everolimus and sirolimus or with the calcineurin inhibitors (CNI) cyclosporine or tacrolimus, either alone or in combination with selected DAAs. Cell proliferation-related effects were excluded with MTT assays. HCV replication activity was quantified by quantitative real-time polymerase chain reaction or luciferase assay.
Addition of either mTOR inhibitor to the DAA daclatasvir resulted in a 30% increase in antiviral activity compared to daclatasvir alone for HCV GT2a, GT3a and GT4a (all P ≤0.01). Similar results were obtained using sofosbuvir and ledipasvir. In contrast, addition of either mTOR inhibitor to daclatasvir induced a 30% reduction in antiviral activity in GT1b cells (P≤ .01 versus daclatasvir alone). Neither CNI affects the antiviral activity of the DAAs in any HCV GT.
For patients with HCV GT2a, GT3a or GT4a infection, mTOR-based immunosuppressive therapy may be beneficial, whereas CNI-based therapy may be more efficacious in GT1b patients.