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See article on page 427
Cirrhosis due to hepatitis C (HCV) is now the most common indication for liver transplantation in western Europe and the United States. Given the absence of effective prophylaxis, recurrent HCV infection is almost inevitable. Although the natural history and outcome of recurrent HCV infection are now better documented, the factors which influence the recurrence of hepatitis and its subsequent progression are still unclear.1 In fact, the variation in the consequences of liver disease associated with recurrent HCV infection suggest that several viral and host factors are important in determining clinical outcome. Despite the rapid growth in knowledge of the molecular biology of hepatitis C, our understanding of the immunopathology of chronic HCV infection is still poor. Immunosuppression may well be the single most important factor responsible for variations in clinical outcome. Evidence of its potential involvement includes a more aggressive histological picture in non-transplanted patients with congenital or acquired immunodeficiency2 ,3 as well as among liver transplant recipients who require treatment with steroid boluses for acute rejection.4 In the transplant setting, however, there are conflicting reports of the effects of adjuvant immunosuppression on the natural history of HCV recurrence.
In this issue (see page 427) Papatheoridis and collaborators present their results on the impact of different immunosuppressive regimens on longitudinal variation in HCV viraemia. This non-randomised study examined fluctuations in viraemia, including the early course of HCV infection, in a cohort of 47 HCV transplant recipients. Although the patients were not randomised to the different immunosuppressive regimens, the type of treatment was not selected on the basis of patient characteristics, but changed according to different study protocols in use at the centre over time.
The authors found that the level of HCV RNA three months after transplantation is higher in patients treated with a single drug regimen as the initial immunosuppressive therapy. However, at 12 months HCV RNA levels correlated only with duration of steroid treatment, and no significant difference was observed between patients treated with either cyclosporin or tacrolimus as monotherapy. The authors did find a strong correlation between the HCV RNA level 12 months after liver transplantation and the fibrosis score at this time. Furthermore, the extent of fibrosis was also associated with the occurrence of an acute hepatitis episode.
Despite being of potential interest, the findings from this small study are preliminary as there remain many issues requiring clarification. The impact of steroids on HCV replication following liver transplantation should be further documented. Steroids have been shown to increase the level of HCV viraemia in other studies, both in transplant and non-transplant patients. However, the exact mechanism is unknown and the data presented suggest that direct stimulation of viral replication is unlikely. In fact, the HCV RNA level did not differ after 1–2 weeks between patients treated with and without steroids and at three months it was significantly higher in patients treated without steroids. It is possible that steroid withdrawal may trigger an immunological attack with increased lysis of infected hepatocytes and subsequent release of virions into the circulation. In addition, controlled trials with a longer follow up will be required to assess the benefit of early steroid tapering after transplantation. In Europe, a large randomised, controlled trial is currently underway with a tacrolimus based regimen, including rapid steroid tapering after transplantation, to assess its effects on the recurrence of HCV one year post-transplantation. Although one group observed that a tacrolimus based regimen was associated with a significant reduction in survival in HCV transplant recipients,5 other studies failed to find a difference between the cyclosporin and tacrolimus based regimens in either the incidence or severity of recurrent hepatitis on the graft.6 ,7 In our series of 120 patients transplanted for HCV, we observed that the tacrolimus based regimen delayed recurrent hepatitis after liver transplantation but that HCV RNA levels were similar in patients treated with cyclosporin or tacrolimus. Further studies are therefore needed to establish whether tacrolimus based immunosuppression changes the natural history of HCV recurrence after liver transplantation. It may be possible to clarify the effect of tacrolimus or cyclosporin on HCV replication after transplantation using quantitative methods to measure HCV in serum and liver.
Papatheoridis and colleagues found a strong correlation between fibrosis and HCV RNA levels at 12 months. The HCV RNA level may therefore be a predictive factor of long term outcome after post-transplant HCV infection if it is confirmed that progression of fibrosis is the most important predictor of chronic hepatitis after transplantation.
It has been reported recently that severe initial recurrent hepatitis may be associated with the subsequent development of cirrhosis.8 In this study, the authors found a correlation between the extent of fibrosis at 12 months and a history of previous acute hepatitis, but not with its severity. Larger numbers of patients, longer follow up and a standard definition of severity of acute hepatitis should all contribute to a better understanding of the effect on outcome of early recurrent hepatitis after transplantation. If the occurrence of symptomatic acute hepatitis does influence the histological outcome, then early antiviral treatment may be beneficial.
In conclusion, although the cumulative five year survival of HCV positive recipients seems to be similar to that of liver transplant patients without HCV infection, the large number of patients with progressive HCV related graft damage suggests that a longer follow up period may impact negatively both on graft and patient survival. The management of hepatitis C after liver transplantation has therefore become a very important issue, as has the composition of the optimal immunosuppressive regimen.