RESUMEN
INTRODUCTION: Hepatitis C (HCV) continues to be the leading indication for liver transplantation (LT). Sustained virological response (SVR) rates to pegylated interferon (PEG-IFN) and ribavirin (RBV) therapy for recurrent HCV in Genotype 1 (G1) LT recipients have been disappointing (30-40%). Experience with triple therapy using protease inhibitors (PI) boceprevir (BOC), telaprevir (TVR) in these patients has been limited. MATERIAL AND METHODS: This national multicenter retrospective study included 76 patients (64 male, mean age 57 ± 6 years), treated for G1 HCV recurrence with either BOC (n = 41) or TVR (n = 35), who were non-responders or relapsers (n = 54), treatment naïve (n = 22) or had fibrosing cholestatic HCV (n = 3). 53 patients were on cyclosporine, 22 on tacrolimus and one patient on prednisone alone. RESULTS: On treatment virologic response was observed in 84% (64/76), 83% in BOC and 85% in TVR group. A higher week 4 response after starting triple therapy (RVR) was noted in TVR group 25/35 (81%) as compared to BOC group 26/41 (63%); p value = 0.02. The end of treatment response was 78% and 75% in BOC and TVR group, respectively. SVR 12 weeks after treatment discontinuation was observed in 59.5% (22/37); 58.3% in the BOC group and 61.5% in TVR group. Treatment was discontinued early in 23 patients (serious adverse effects n = 19, treatment failure n = 4). Infections occurred in 5 patients with 2 deaths (all in BOC). Anemia was the most common side effect (n = 55, 72%) requiring erythropoietin and RBV dose reduction. In the BOC group, cyclosporine dose reduction was 2.2 ± 1.0 fold and 8.6 ± 2.4 fold with tacrolimus. In TVR group, dose reduction was 3.0 ± 1.4 with cyclosporine and 12 ± 5.7 fold with tacrolimus. CONCLUSIONS: PI-based triple therapy appears more effective in producing HCV-RNA clearance than dual therapy. Tolerability is a serious issue and drug-drug interactions are manageable with close monitoring.
Asunto(s)
Antivirales/uso terapéutico , Enfermedad Hepática en Estado Terminal/cirugía , Hepacivirus/efectos de los fármacos , Hepatitis C Crónica/tratamiento farmacológico , Trasplante de Hígado/efectos adversos , Oligopéptidos/uso terapéutico , Prolina/análogos & derivados , Inhibidores de Proteasas/uso terapéutico , Activación Viral/efectos de los fármacos , Antivirales/efectos adversos , Canadá , Proteínas Portadoras/antagonistas & inhibidores , Proteínas Portadoras/metabolismo , Interacciones Farmacológicas , Quimioterapia Combinada , Enfermedad Hepática en Estado Terminal/virología , Femenino , Hepacivirus/enzimología , Hepacivirus/genética , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/diagnóstico , Humanos , Inmunosupresores/uso terapéutico , Péptidos y Proteínas de Señalización Intracelular , Masculino , Persona de Mediana Edad , Oligopéptidos/efectos adversos , Prolina/efectos adversos , Prolina/uso terapéutico , Inhibidores de Proteasas/efectos adversos , ARN Viral/sangre , Recurrencia , Estudios Retrospectivos , Factores de Tiempo , Resultado del Tratamiento , Carga Viral , Proteínas no Estructurales Virales/antagonistas & inhibidores , Proteínas no Estructurales Virales/metabolismoRESUMEN
The transition from regular use of cyclosporine to the newer calcineurin-inhibitors, such as tacrolimus, has been suggested as a contributing factor to the "era effect" of worsening outcomes of post-transplant HCV recurrence. This retrospective medical chart review of 458 patients was undertaken to evaluate the role of immunosuppressant choice (cyclosporine vs. tacrolimus) in determining virologic response and clinical outcomes of post-liver transplant HCV infection recurrence. Our results showed that patients undergoing interferon-based treatment taking cyclosporine have significantly better odds (OR: 2.59, P = 0.043) of presenting a sustained viral response (66.7%) compared to tacrolimus (52.8%). This did not result in a significant effect on post-liver transplantation clinical events including HCV-related deaths, graft loss, fibrosing cholestatic hepatitis, hepatocellular carcinoma or graft rejection. Other variables, which showed a significant relationship with the achievement of sustained viral response included donor age (OR 0.96, P = 0.001) and HCV genotype 1 infection (OR 0.05, P < 0.001). The observed significant increase in the odds of acute/hyperacute (OR 6.49, P = 0.001) and chronic rejection (OR 10.45, P < 0.001) in the cyclosporine to tacrolimus switch group, accompanied by an increase in the odds of HCV-related death (OR 2.30, P < 0.047) compared to tacrolimus merits further study. A significant increase (P < 0.044) in new-onset diabetes mellitus with tacrolimus (28.3%) compared to cyclosporine (18.7%) was also observed. Pre-transplant diabetes mellitus was associated with a significantly increased likelihood of graft fibrosis (HR 1.95, P = 0.003).