Immunosuppression for HCV following liver transplantation: enough is just enough.

I t is known that recurrence of HCV infection is universal following liver transplantation. Viral replication is thought to commence within hours of reperfusion and viral levels may reach pretransplant levels within 48 hr following liver transplantation. It is also recognized that such replication does not lead to histological evidence of liver disease for approximately 3 weeks. Somewhere between this time and the 6-month period (usually between the 2– 4 month periods) a lobular hepatitis occurs. In less than 10% of patients early recurrence can take a cholestatic form that has a very poor prognosis. Following the acute hepatitis, chronic hepatitis develops with progression to cirrhosis and graft failure at an accelerated rate compared with the nonimmunosuppressed state. There is now data that suggest that donor age is an important predictor for more rapid fibrosis progression. Serum HCV levels also predict worse outcomes while the effect of HCV genotypes is controversial. Well then, where does immunosuppression (IS) fit in and does it play a role in driving a more rapid course posttransplant? There is certainly data that corticosteroid (CS) therapy may be detrimental to HCV outcomes postliver transplant (1). CS therapy increases levels of HCV in serum and pulse CS therapy for acute rejection is associated with worse outcomes. Also patients who did not receive CS therapy in the intraoperative/early postoperative phase did not have a sudden return to pretransplant levels. These data have led to a major trend to aim for long-term CS free therapy in liver transplant patients but particularly so in HCV infected patients. However recent data from two studies caution against too rapid taper of CS therapy (2, 3). In one study patients still on 7.5 mg per day at 12 months had less severe HCV disease than those on 7.5 mg per day (2). In a recent multivariate analysis rapid tapering was associated with more fibrosis (3). Are the calcineurin inhibitors associated with worse HCV outcomes? In the RCT between tacrolimus and cyclosporin (Neoral) HCV outcomes were similar although HCV infection was not a primary outcome measurement (4). However, in one multivariate analysis of HCV outcomes posttransplant tacrolimus induction and maintenance was associated with more rapid HCV fibrosis (3). The role of mycophenolate mofetil (MMF) on HCV outcomes is also controversial (5). In the double-blind RCT that compared MMF with azathioprine the HCV outcomes were similar (6). It has been suggested however that prolonged MMF at higher doses was associated with better outcomes (discussed in 5). The article in this issue by Filipponi et al. addresses the issue of using IL2R mAbs in induction therapy with the aim of avoiding CS altogether (7). There is already an RCT comparing IL2R mAb with placebo on a background of cyclosporin and CS therapy. The outcomes in HCV recurrence were similar (8). The current study is important as it provides an immunosuppressive protocol that avoids CS in HCV infected patients. This is important as CS therapy probably leads to earlier peak in allograft viral replication and indeed this was shown in the present study. However, it should be noted that such an effect is transitory. The worst effects with CS therapy are those associated with pulse CS therapy for acute rejection. This effect is almost certainly responsible for the association of total doses of CS influencing 12-month HCV outcomes postliver transplant. In the article by Filipponi et al. several claims are made from their data that require close scrutiny. First, it seems that treated acute rejection (AR) was the same in the two groups, but biopsy proven AR was higher in the group who received CS. This is a very difficult call. The recent International Liver Transplant Society (ILTS) Consensus meeting recognized that many of the features of mild AR and HCV recurrence were shared and it was this lesion, i.e. mild AR HCV, that was almost impossible to differentiate from HCV alone (9). The second conclusion from the study was that outcomes were actually worse with quadruple therapy (IL2R CS cyclosporin azathioprine), although the rate of significant HCV histological injury was the same between groups. The ILTS Conference warned against using quadruple induction therapy in HCV patients and the Filiponni et al. article (7) provide evidence for such statements. However, the exact reasons for worse outcomes in the article seem unrelated to HCV infection itself. Despite these reservations the article remains important. First, it is a randomized control trial (RCT) of an immunosuppressive regime specifically in HCV patients. There needs to be more of them, with prospective analysis of viral loads as well as protocol biopsies with grade and stage of HCV infection as the primary endpoint. Second, it does provide a CS free protocol in HCV infected patients. It also warns us that if you use CS do not use a quadruple-based approach. Perhaps a more relevant RCT would have between two triple drug protocols, e.g., CS tacrolimus MMF versus IL2R mAb Tacro ( MMF) or between two double therapy based protocols (e.g., CS tacrolimus vs. IL2RMab tacrolimus). Where does all this leave us regarding IS therapy for HCV infected patients receiving liver transplants? At a recent ILTS Consensus conference the recommendations for immunosuppression in HCV-infected patients made a couple of clear statements (9). These included a recommendation warning against routine pulse CS as initial IS therapy to treat Address correspondence to: G. W. McCaughan, M.D., A.W. Morrow Gastroenterology and Liver Centre, Australian Liver Transplant Unit, Royal Prince Alfred Hospital, University of Sydney, Sydney, Australia. E-mail: gmccaughan@centenary.usyd. edu.au. Copyright © 2004 by Lippincott Williams & Wilkins ISSN 0041-1337/04/7810-1413 DOI: 10.1097/01.TP. 0000140976.61265. 61