Abstract Body

Severe hepatitis C virus (HCV) recurrence affects post-transplant survival in HCV infected patients. We describe the effect of sofosbuvir-based anti-HCV therapy on disposition of anti-calcineurin immunosuppressive drugs.

Liver transplant patients (pts) with severe HCV recurrence who signed the informed consent were included in the ANRS CO23 CUPILT cohort and their characteristics recorded. Immunosuppressive therapy backbone was either tacrolimus (TAC) or cyclosporine (CyA). They were treated according to HCV genotype with 2nd generation direct acting antivirals (DAA) including sofosbuvir (SOF) with either daclatasvir (DCV) +/- ribavirine (RBV) or simeprevir (SMV) at standard dosing. Predose blood samples were drawn before DAA initiation (D0) and at week4 (W4) after DAA initiation. Trough concentrations (Ct) of TAC or CyA at steady state were measured by quality controls validated assays (immunoassay or LC-MS/MS). Apparent clearance (Cl/F) of TAC or CyA was estimated from the ratio of the dose per intake over the trough concentration (as a surrogate of average concentration at steady state) times the time interval between 2 doses Cl/F= D/(DDt*Ct). W4/D0 geometric mean ratio (GMR) and 2-sided 90% CIs (CI90) were calculated for Cl/F and compared to the 0.80-1.25 bioequivalence range. Unless otherwise indicated, results are medians and ranges.

Twenty three pts were on TAC and 12 on CyA. Characteristics at inclusion were age 57years (43, 81), weight 72kg (45, 106) and MELD score 9 (0, 26). HCV genotypes were G1 (25 pts), G2 (2 pts) and G4 (8 pts). On the 3 pts on antiretrovirals, one was on efavirenz (EFV) and 2 on raltegravir-based regimen combined with 2 nucleoside analogs. Pt on EFV has the highest TAC Cl/F. Creatinine clearance (MDRD equation) remained unchanged at W4 compared to D0. Cl/F of TAC and CyA at D0 and W4 are shown in the table below.

Despite wide interindividual variability on TAC or CyA Cl/F, our data show that most liver transplant pts have an increased Cl/F on DAAs, statistically significant for TAC, leading to a decrease in concentrations and likely warranting an increased dosing. All these liver transplant pts should be monitored closely at the time of DAA initiation and during follow-up. These results need to be confirmed in a larger cohort of pts as well as the identification of factors explaining such drug-drug interaction.