Safety and efficacy of protease inhibitors to treat hepatitis C after liver transplantation: a multicenter experience

Abstract

Background & aims: Protease inhibitors (PI) with peginterferon/ribavirin have significantly improved SVR rates in HCV G1 patients. Their use to treat HCV recurrence after liver transplantation (LT) is a challenge.

Methods: This cohort study included 37 liver transplant recipients (male, 92%, age 57 ± 11 years), treated with boceprevir (n=18) or telaprevir (n=19). The indication for therapy was HCV recurrence (fibrosis stage ≥F2 (n=31, 83%) or fibrosing cholestatic hepatitis (n=6, 16%).

Results: Eighteen patients were treatment-naive, five were relapsers and fourteen were non-responders to dual therapy after LT. Twenty-two patients received cyclosporine and fifteen tacrolimus. After 12 weeks of PI therapy, a complete virological response was obtained in 89% of patients treated with boceprevir, and 58% with telaprevir (p=0.06). The end of treatment virological response rate was 72% (13/18) in the boceprevir group and 40% (4/10) in the telaprevir group (p=0.125). A sustained virological response 12 weeks after treatment discontinuation was observed in 20% (1/5) and 71% (5/7) of patients in the telaprevir and boceprevir groups, respectively (p=0.24). Treatment was discontinued in sixteen patients (treatment failures (n=11), adverse events (n=5)). Infections occurred in ten patients (27%), with three fatal outcomes (8%). The most common adverse effect was anemia (n=34, 92%), treated with erythropoietin and/or a ribavirin dose reduction; thirteen patients (35%) received red blood cell transfusions. The cyclosporine dose was reduced by 1.8 ± 1.1-fold and 3.4 ± 1.0-fold with boceprevir and telaprevir, respectively. The tacrolimus dose was reduced by 5.2 ± 1.5-fold with boceprevir and 23.8±18.2-fold with telaprevir.

Conclusions: Our results suggest that triple therapy is effective in LT recipients, particularly those experiencing a severe recurrence. The occurrence of anemia and drug-drug interactions, and the risk of infections require close monitoring.

Keywords: AFEF; ALT; AUC; BID; BOC; Boceprevir; CNI; CYP; Drug-drug interaction; EOT; EPO; EVR; Early virological response; F; FCH; French Association for the Study of the Liver; G-CSF; G1; GGT; HBV; HCC; HCV; HCV recurrence; HIV; IL; INR; IS; International Normalized Ratio; LT; Liver transplantation; M; MELD; MMF; Model for End-stage Liver Disease; NR; PCR; PI; PegIFN; Protease inhibitors; QD; RBV; RVR; SVR12; Sustained virological response; TBC; TID; TVR; Telaprevir; VB; VL; VR; alanine aminotransferase; area under the curve; boceprevir; cEVR; calcineurin inhibitors; complete early virological response; cytochrome P450; early virological response; end of treatment response rate; erythropoietin; female; fibrosing cholestatic hepatitis; gamma-glutamyl transferase; genotype 1; granulocyte colony stimulating factor; hepatitis B virus; hepatitis C virus; hepatocellular carcinoma; human immunodeficiency virus; immunosuppressive drugs; interleukin; kg; kilogram; liver transplantation; male; mycophenolate mofetil; n.a.; non-response; not available; once a day (quaque die); pegylated interferon; polymerase chain reaction; protease inhibitors; rapid virological response; ribavirin; sustained virological response 12weeks after the end of therapy; telaprevir; three times a day (ter in die); trough blood concentration; twice daily (bis in die); viral load; virological breakthrough; virological response.