Strengthening Management of HCV in Liver Transplantation

Following liver transplantation (LTx), re-infection of the graft with hepatitis C virus (HCV) occurs almost universally. Professor W. Ray Kim, from the Mayo Clinic College of Medicine, Rochester, MN, USA, presented a report on management of HCV in liver transplantation. He said that recurrent hepatitis C in a transplanted liver progressed more rapidly than that in the native liver. Cirrhosis of the transplanted liver may occur in about a third of patients with recurrent hepatitis C within 5 years of LTx. In particular, recurrent hepatitis occurring early after LTx has a poor prognosis.

Professor Kim pointed out that several factors associated with severe recurrent hepatitis C had been identified. Older donor age and administration of OKT-3 or bolus doses of corticosteroids are the strongest predictors of recurrent hepatitis C. In addition, viral load prior to LTx, CMV infection, tacrolimus (compared to cyclosporine) and steatosis of the donor liver have been proposed as predictors of recurrent hepatitis C. Initially, live donor LTx was postulated to have an adverse impact on recurrent hepatitis C. More recent data have largely dispelled such an association. Because recurrent disease, once it is established, leads to poor outcome, efforts for prevention are warranted. First, in carefully selected patients, antiviral therapy prior to LTx may achieve undetectable levels of HCV RNA. When the so-called low-accelerating dose regimen (LADR) is used, up to 80% of patients who are RNA-negative at the time of LTx may avoid reinfection of the graft. Second, if possible, older donors are best avoided for recipients with HCV. Third, in the early post-LTx phase, careful considerations in diagnosing and treating acute cellular rejection are necessary. At Mayo Clinic, steroid boluses are reserved only for patients with rejection of moderate degree or worse. Although it is at times difficult to differentiate acute rejection from recurrent hepatitis C, most experienced pathologists are able to diagnose acute rejections that require therapy. In most cases with mild acute cellular rejection, adjustment of maintenance immunosuppression may be sufficient. In contrast to intravenous boluses, avoidance or early withdrawal of oral corticosteroids as a part of maintenance immunosuppression has not been shown to be beneficial. Finally, some have advocated using antiviral therapy in a ‘pre-emptive’ fashion. In this approach, antivirals (pegylated interferon and ribavirin) are given to patients in the early post-LTx period before recurrent hepatitis C is established. To date, there is no evidence that pre-emptive antiviral therapy improves patient outcome.

He continued that antiviral therapy for established recurrent hepatitis C consisted of pegylated interferon and ribavirin. ‘Protocol’ biopsies (biopsies performed at preset interval) are frequently utilized in the decision to initiate therapy. Fibrosis of stage 2 (of 4) or higher is the most commonly used parameter in initiating therapy. However, treatment of recurrent hepatitis C is fraught with frequent needs for dose reductions and discontinuations. LTx recipients are particularly prone to adverse effects of these medications, most commonly hematologic toxicities. Use of growth factors such as erythropoietin or granulocyte colony stimulating factor is common in this setting. In addition, because of the high prevalence of renal insufficiency among LTx recipients, dose adjustment may be necessary for ribavirin. Sustained viral response (SVR) may be achieved in approximately 25% of patients. Whether the stopping rules used in non-LTx patients also apply in post-LTx patients is not well-studied, but they are often followed. In patients who fail to achieve SVR, suppressive therapy with reduced doses of pegylated interferon alone has been used, although data in its support are lacking. In patients whose recurrent hepatitis leads to graft cirrhosis and hepatic decompensation, re-transplantation may be considered. As outcome after re-LTx has been shown to be inferior to that after primary LTx, re-LTx candidates are selected carefully.

Finally, Professor Kim concluded that the most serious type of recurrent hepatitis C presented with severe cholestasis (cholestatic hepatitis C), usually early after LTx. Characteristically, these patients have extremely high viral loads. Patients may experience hepatic decompensation and display signs of portal hypertension without clear histologic evidence of cirrhosis. Although some of these patients may respond to antiviral therapy, prognosis in general is poor. Re-transplantation in this setting is highly controversial.