Impact of Everolimus-Based Immunosuppression on Efficacy, Safety and Progression of Fibrosis in Hepatitis C Virus Positive De Novo Liver Transplant Recipients: 12 Months Results from H2304 Study

Abstract

Introduction: Progression of fibrosis in liver transplant recipients (LTxR) with recurrent hepatitis C virus (HCV) infection has been identified as a crucial factor influencing graft and patient survival. Everolimus (EVR) is associated with antifibrotic and antiproliferative effects in several animal models of liver fibrosis. Present study evaluated the effect of EVR on HCV-associated fibrosis progression in de novo LTxR. Methods: H2304 (NCT00622869) is a 24-month (M), multicenter, open-label study. A total of 719 de novo LTxR were randomized 1:1:1 after 30 days of run-in period with tacrolimus (TAC) ± mycophenolic acid to receive either EVR (C0 3-8ng/mL)+reduced TAC (C0 3-5ng/mL; EVR+rTAC, N=245) or EVR (C0 6-10ng/mL)+TAC withdrawal (TAC-WD; N=231) at M4 or standard TAC (C0 6-10ng/mL; TAC-C, N=243); all with steroids. Composite efficacy failure (treated BPAR, graft loss, death) and renal function (RF) were assessed at M12 in the overall study group. In the HCV+ population, fibrosis progression was evaluated using the Ishak system and change of HCV viral load from baseline [BL] to M12 was determined. Comparison of EVR+rTAC vs TAC-C is presented as enrollment into TAC-WD arm was stopped early due to a high acute rejection rate. Results: In the overall study population, composite efficacy failure was comparable in both treatment groups (6.7% EVR+rTAC vs 9.7% TAC-C; p=0.23); similar pattern was observed in the HCV subgroup (Table). Overall population showed significantly lower rate of tBPAR with EVR+rTAC vs TAC-C (2.9% vs 7.0%; p=0.03), while tBPARs were more frequent with EVR+rTAC in HCV+ patients (3.8% vs 1.3%). The EVR+rTAC group had superior RF over TAC-C (80.9 vs 70.3 mL/min/1.73 m2, p< 0.001) at M12, with similar results in HCV+ patients. Fibrosis progression ≥1 stage from BL to M12 was lower in EVR+rTAC group; however the number of biopsies was limited. Change in fibrosis from BL to M12 was comparable in both treatment groups. At BL, the mean viral load was higher for EVR+ rTAC to TAC-C (6.4 vs 5.9); the difference was maintained up to M12 (6.6 vs 6.1). Study drug discontinuations in HCV+ patients were comparable between the groups (EVR+rTAC 23.4% vs TAC-C 20.0%) and there were no differences in anti-HCV treatment use post-LTx. Safety profile in HCV+ patients was comparable to the overall study population.[Table: Month 12 data in HCV+ patients]Conclusions: This study showed comparable efficacy and superior RF with early EVR-facilitated TAC reduction compared to TAC-C in HCV+ patients reflecting the overall H2304 study results. EVR + rTAC treatment demonstrated similar patterns of HCV replication with numerically less fibrosis progression compared to TAC-C. Impact of EVR+ rTAC on fibrosis progression needs confirmation by M24 biopsy results.