Grafts and hepatitis C virus: Maximizing the benefit

One major consequence arising from the relative shortage of livers for transplantation is that rationing is necessary. The basis for rationing has been subject to much debate. Balancing the sometimes conflicting demands of utility, equity, and justice is difficult, and different health care systems have adopted different approaches to resolving the demands on the supply of organs. One key factor in all systems includes transplant benefit and maximizing the benefit from use of the organ. Recurrence of disease, whether malignant, autoimmune, or other, may reduce graft survival, and in the context of transplantation for hepatitis C virus (HCV), this may have a markedly adverse effect on survival. This is of major importance because end-stage liver disease caused by chronic HCV infection is a leading and increasing indication for liver transplantation. At time of transplantation, the graft becomes infected by circulating virus with serum HCV RNA concentrations peaking at 1-3 months with 10-100 times at 1 year than pretransplantation levels. Histological progression may be rapid, and fibrosis may advance 0.30. 8 stages per year. Disease progression is accelerated compared with the natural history in the native liver: up to 90% demonstrate histological recurrence at 1 year and cirrhosis is found in 30% at 5 years; the 1-year risk of decompensation in the presence of cirrhosis is approximately 40%. Recurrence may also manifest as rapidly progressive cholestatic hepatitis leading to graft failure in up to 5%. Overall, graft failure rates are greater than in recipients transplanted for other indications, inevitably leading to retransplantation or death, thus resulting in a less effective use of the graft, at least in terms of life-years gained. Thus, in this era of organ shortage, the challenge is to improve the outcome both by modifying known factors associated with graft failure and by developing new strategies. Potentially modifiable risk factors can be considered in 4 categories (Table 1). These include recipient factors before the transplantation, donor factors, viral factors, and posttransplantation factors. Factors associated with graft damage and graft loss have usually been identified from retrospective analyses of prospectively collected data. There are potential errors in this approach in addition to the obvious ones inherent in any retrospective analyses where protocols are not always identified or followed, changes in management occur over time, and there is often incomplete data, with relevant factors not collected. In addition, factors identified during retrospective analysis may not themselves be responsible for the rate of graft damage but may be surrogate markers for other factors. For example, over time, the age of donors has increased, mycophenolate is increasingly being used, and cyclosporin is being replaced by tacrolimus, so retrospective analyses could incorrectly identify one or another marker of graft damage even though the actual cause for the increase in graft failure is an as-yet unidentified change in viral characteristics. All hypotheses generated from these retrospective analyses need to be tested prospectively and supported by a sound mechanism.