HCV: Alive and kicking in living donor liver grafts?
Authors: Xavier Forns
Journal: Hepatology (2005)

Recurrence of hepatitis C virus (HCV) infection after liver transplantation (LT) has became one of the most relevant problems faced by hepatologists today. Approximately 25% of patients undergoing LT for HCV-related end-stage liver disease will develop cirrhosis within the first 5 years following transplantation, and in rare cases, cirrhosis will develop within a few months.1, 2 These data underscore the accelerated course of HCV infection in liver transplant recipients. Regretfully, the mechanisms influencing the natural history of HCV infection after LT are not well understood. Available data indicate that the outcome of HCV recurrence may be modulated by many variables, but those related to the graft appear to be particularly relevant.3 Several studies have shown that recurrence of HCV is more severe in grafts from older than younger donors.4-6 Similarly, the presence of significant steatosis in the graft and a long cold ischemia time are also associated with a poor outcome of HCV infection after LT.3 HCV, hepatitis C virus; LT, liver transplantation; LDLT, living donor liver transplantation; DDLT, deceased donor liver transplantation; HIV, human immunodeficiency virus. Recently, several reports have suggested that recurrence of HCV infection is more severe in patients undergoing living donor liver transplantation (LDLT) compared to deceased donor liver transplantation (DDLT).1, 7 This observation is still highly controversial, as data from other studies have found similar patient and graft survival rates in both groups of patients.8, 9 The topic is extremely relevant, as LDLT has become an important strategy to expand the organ donor pool. From a theoretical point of view, grafts from a living donor would appear optimal for HCV-infected transplant recipients: young donor age, short graft cold ischemic time, and absence of significant steatosis. Other variables inherently associated with LDLT could, however, worsen the outcome of HCV infection after transplantation: increased HLA matching (if donation occurs between relatives), enhanced HCV replication during liver regeneration, and cholestasis secondary to biliary complications (which are significantly more frequent in LDLT than in DDLT). However, the real impact of such variables on the outcome of HCV recurrence remains elusive. Schiano et al. present us an intriguing hypothesis in their analysis of early HCV kinetics in a small cohort of liver transplant recipients.10 The authors found significant differences in HCV kinetics between recipients of LDLT compared to DDLT, suggesting a predominant role for the type of graft in the HCV life cycle during the first days or weeks following transplantation. The data may be helpful to understand the mechanisms associated with HCV-related liver damage, since several studies suggest a strong influence of the early course of HCV infection on its long-term outcome.1, 11, 12 The first observed difference was a significantly higher clearance of HCV following graft reperfusion in LDLT compared to DDLT. It has been previously shown that during LT and immediately following liver extraction, hepatitis C viral load decreases considerably.13 The causes of such viral load decay are: (1) lack of virus production during the anhepatic phase and the first hours that follow graft reperfusion, (2) blood loss, and (3) HCV clearance by the graft (and possibly by neutralizing antibodies) (Fig. 1). Blood loss was less pronounced in LDLT than DDLT recipients and the duration of the anhepatic phase was presumably similar between both groups. Therefore, it is possible, as suggested by the authors, that the sharper viral load decay observed in LDLT reflects a greater clearance of HCV. Differences in HCV graft clearance may be explained both by viral and host factors. Regarding viral factors, there are variations in infectivity among diverse HCV strains14 and the results of in vitro experiments suggest minor differences in the interaction of CD81 with diverse HCV glycoproteins.15 The latter has been clearly shown for human immunodeficiency virus (HIV) particles bearing envelope proteins from diverse genotypes and their diverse affinity for CD4 and chemokine co-receptors.16 However, it is unlikely that this explains the differences in viral clearance between LDLT and DDLT. The only inherent characteristic of grafts from living donors is the quality of the organ. In fact, adhesion of HCV particles to their receptors followed by viral entrance should be facilitated in a liver with intact cells. Considering the number of hepatocytes in a liver (1011) and the amount of circulating virions (108-1010), graft reperfusion should be followed by a dramatic clearance of HCV from the blood. After the anhepatic phase of LT, the viral decay slope should further increase due to massive viral clearance by the uninfected graft, at least until HCV replication starts in the new organ. However, this does not occur in all HCV-infected liver transplant recipients,17 suggesting that unidentified variables are influencing HCV clearance. Variables that may influence early hepatitis C virus (HCV) kinetics during and immediately after liver transplantation. HCV-RNA concentrations are expressed in IU/mL and depicted in the y axis in a logarithmic scale. Time is represented in the x axis, in hours. Viral load in the systemic circulation is depicted with a continuous line. P: pre-transplantation, A: anhepatic phase, R: reperfusion phase. Another interesting finding of the study by Schiano et al. was the faster increase in HCV-RNA levels in LDLT compared to DDLT during the first days following graft reperfusion. Once the virus life cycle starts in the new graft, virions are produced and viral load increases at different rates.13, 17, 18 The variables that may influence the rate of viral production are: (1) the type of immunosuppression,3, 13 (2) the presence and titer of neutralizing antibodies (high titers may decrease and/or delay HCV entrance into hepatocytes), (3) the composition of HCV quasispecies (certain strains may be better fitted than others to replicate in the new graft), (4) the functional status of the liver, and (5) liver regeneration (Fig. 1). Only the last two variables are relevant to living donor liver transplantation and may explain the discrepancies in early viral replication between LDLT and DDLT. Most likely, and due to the better preservation of hepatocytes in grafts from LD, HCV initiates its life cycle in a significantly higher number of cells in LDLT than in DDLT. This effect may be accentuated by liver regeneration, which takes place during the first weeks (and particularly the first week) following LDLT.19 In animal models, 95% of hepatocytes enter into S-phase within 48 hours of hepatectomy.20, 21 The role of liver regeneration in HCV kinetics and HCV-induced liver damage is unknown. Studies performed in animal models demonstrated enhanced herpes virus adhesion and particularly replication in hepatocytes following hepatectomy.20 Data on HCV are derived from the replicon system and indicate that replication of subgenomic HCV-RNA in Huh7 cells depends on host cell growth: HCV-RNA levels are elevated in growing cells whereas replicon copy numbers drop significantly when cells reach confluence.22 The positive association between liver regeneration and viral replication, however, has not been reproduced in other experimental models.21, 22 If we assume there are differences in early HCV kinetics in grafts from LD compared to DD, would this influence the outcome of HCV recurrence? Schiano et al. do not fully answer this question. Although the study was not aimed at analyzing clinical outcomes, the authors did not find differences in either graft or in patient survival between LLDT and DDLT. The only relevant finding was a significantly higher and persistent elevation of aminotransferases in LDLT compared to DDLT recipients, which has been found in other studies.1 The higher levels of aminotransferases may be a reflection of increased liver damage in the first group of patients. Specific forms of HCV disease recurrence (such as fibrosing cholestatic hepatitis) seem to be the result of a direct cytopathic effect of an extraordinary production of virions. Thus, increased HCV protein synthesis in grafts from living donors may interfere with the fine cross talk process between different cell types that occurs during hepatic regeneration, resulting in liver cell injury, hepatic stellate cell activation and increased fibrosis deposition.23, 24 The study published by Schiano et al. has several constraints that limit the strength of their conclusions. First, the number of individuals included in each group is very small and this is a relevant limitation taking into account the number of potential variables influencing early HCV kinetics after LT. Second, a more frequent sampling during the anhepatic phase and particularly after graft reperfusion would have allowed a more precise modeling of early HCV kinetics.25 Third, some variables that may influence HCV kinetics were not considered, such as the titer of anti-HCV neutralizing antibodies and the changes in quasispecies populations following transplantation. Finally, the study does not provide a detailed analysis of the levels of immunosuppressant drugs received by the patients. As is the case with stimulating observations, the study by Schiano et al. leaves more uncertainties than answers, but it encourages further research into an area that has relevant clinical implications.