The influence of immunosuppressants on direct-acting antiviral therapy is dependent on the hepatitis C virus genotype

BackgroundDirect-acting antivirals (DAAs) 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. MethodsSubgenomic hepatitis C virus (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 (CNIs) 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. ResultsAddition of either mTOR inhibitor to the DAA daclatasvir (DAC) resulted in a 30% increase in antiviral activity compared to DAC alone for HCV GT2a, GT3a, and GT4a (all P.01). Similar results were obtained using sofosbuvir and ledipasvir. In contrast, addition of either mTOR inhibitor to DAC induced a 30% reduction in antiviral activity in GT1b cells (P.01 vs DAC alone). Neither CNI affects the antiviral activity of the DAAs in any HCV GT. ConclusionFor patients with HCV GT2a, GT3a, or GT4a infection, mTOR-based immunosuppressive therapy may be beneficial. CNI-based therapy may be more efficacious in GT1b patients, as mTOR inhibitors seem to impair antiviral efficacy of DAAs in HCV GT1b infection.