Summary and Introduction
Summary
In hepatitis C virus (HCV)-infected patients, it is generally assumed that the pattern of response to antiviral therapy remains unaltered after liver transplantation (LT). However, changes in the circulating HCV quasispecies and in the gene expression profiles of the graft might influence response to treatment after LT. We evaluated 22 HCV-infected patients who received antiviral treatment while awaiting LT and in whom HCV infection recurred. Eleven of these patients underwent a new antiviral treatment course. Our study analyses the early virological response to both treatment courses to assess the influence of the changes in HCV on the response to therapy. Patients were considered early virological responders (EVR) if viral load declined ≥2log10 during the first 12 weeks of therapy. The remaining individuals were considered nonresponders (NR). HCV sequences from hypervariable region 1 and nonstructural 5A (NS5A) region before both treatment regimens were compared. Of 11 patients, 8 (73%) showed identical early response to both courses of therapy (group A: five EVR-EVR, three NR-NR). Interestingly, the response changed in three patients (27%) (group B): two NR became EVR after transplantation, whereas one EVR became NR. Fixation of mutations within the NS5A occurred preferentially in group B (100%) compared with group A (37%)(P = 0.12). However, the number of fixed mutations was not significantly different between groups, suggesting that the changes in sensitivity to therapy after LT are not exclusively dependent on variations in HCV strains. In conclusion, in HCV-infected patients undergoing LT, the pattern of response to antiviral treatment may change after transplantation, and this possibility needs to be incorporated in clinical practice.
Introduction
Chronic hepatitis C virus (HCV) infection is the leading cause of cirrhosis and hepatocellular carcinoma in the western world and Japan and the main indication of liver transplantation (LT) in most programmes. Regretfully, infection of the graft with HCV is universal and hepatitis recurs in the majority of patients.[1] Progression to cirrhosis is variable, but it may reach as much as 30% of infected liver transplant recipients 5 years after transplantation.[2-4]
Currently, there are no effective strategies to prevent HCV infection of the graft. Treatment with interferon (IFN) or IFN plus ribavirin while on the waiting list[5-8] is effective (no recurrence after LT) in around 20% of patients. After LT, antiviral therapy is commonly initiated once a follow-up liver biopsy demonstrates histological damage and sustained virological response occurs in less than 30% of treated patients.[9,10] Therefore, it is not uncommon that liver transplant recipients receive several courses of antiviral treatment.
Two regions of the HCV genome have been selected for the study. The hypervariable region 1 (HVR1) within the aminoterminal part of the E2 envelope region exhibits a high degree of genetic variability and is a good target to study the changes in quasispecies composition.[11] The other analysed region is the nonstructural 5A (NS5A) which has been implicated in resistance to IFN;[12] fixation of mutations within this region could lead to changes in sensitivity to antiviral treatment.
It is generally assumed that in patients who underwent antiviral treatment before transplantation, the pattern of response is maintained after LT.[13,14] However, during LT the main source of virions (the liver) will be removed and this event might substantially modify the sensitivity of HCV to antiviral therapy. First, the composition of HCV quasispecies may change after LT and minor or newly emerged variants may have different sensitivity to IFN.[15-17] Secondly, the genetic background of the graft is singular and the antiviral IFN-dependent pathways may operate differently in the grafts from distinct donors.[18] Finally, the host is strongly immunosuppressed after LT, which is associated with an impaired response to antiviral treatment.[10,19]
The aim of this study was to analyse the early virological response to antiviral therapy in a cohort of 11 patients treated immediately before and after LT and to assess the possible influence of the changes in the circulating HCV on the response to therapy.
