What determines the natural history of recurrent hepatitis C after liver transplantation?

Abstract

Hepatitis C virus (HCV) cirrhosis is the most common indication for liver transplantation in developed countries. Re-infection of liver allografts is virtually universal and occurs at reperfusion [1Berenguer M. Lopez-Labrador F.X. Wright T.L. Hepatitis C and liver transplantation.J Hepatol. 2001; 35: 666-678Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar, 2Wiesner R.H. Sorrell M. Villamil F. Report of the first international liver transplant society consensus conference on liver transplantation and hepatitis C.Liver Transpl. 2003; 9: S1-S9Crossref PubMed Scopus (402) Google Scholar]. A significant increase in viral load is typically observed following transplantation, presumably as a consequence of the administration of immunosuppressive agents for the prevention and treatment of rejection. In this setting, HCV mediated liver injury follows a more aggressive course compared to the non-immunosuppressed state, leading to recurrent disease and allograft failure in a substantial proportion of patients [1Berenguer M. Lopez-Labrador F.X. Wright T.L. Hepatitis C and liver transplantation.J Hepatol. 2001; 35: 666-678Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar, 2Wiesner R.H. Sorrell M. Villamil F. Report of the first international liver transplant society consensus conference on liver transplantation and hepatitis C.Liver Transpl. 2003; 9: S1-S9Crossref PubMed Scopus (402) Google Scholar, 3Gane E. The natural history and outcome of liver transplantation in hepatitis C virus-infected recipients.Liver Transpl. 2003; 9: S28-S34Crossref PubMed Scopus (190) Google Scholar]. While it seems evident that the immune suppressed status ‘per se’ modifies the natural history of hepatitis C in liver transplant recipients, the effect of several other factors on determining both the pattern and severity of recurrence still remains a matter of intense research. Identifying the factors, whether present prior to transplantation or developing in the post-transplant setting, that impact on the natural history of recurrent hepatitis C is of paramount importance not only to target those at high risk of severe recurrence with current imperfect and difficult-to-tolerate antiviral therapies but also to improve organ allocation and patient management. In this review, I will summarize the available data regarding risk factors associated with cholestatic hepatitis, severe chronic recurrent hepatitis and severe but delayed-onset hepatitis. I will also describe the determinants of higher mortality in this population, and those associated with clinical decompensation among recipients with established recurrent HCV-related allograft cirrhosis.1. Natural historyThree patterns of recurrence have been described with differences in clinical presentation, prognosis, pathogenesis and therapeutic strategies (Fig. 1) [1Berenguer M. Lopez-Labrador F.X. Wright T.L. Hepatitis C and liver transplantation.J Hepatol. 2001; 35: 666-678Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar, 2Wiesner R.H. Sorrell M. Villamil F. Report of the first international liver transplant society consensus conference on liver transplantation and hepatitis C.Liver Transpl. 2003; 9: S1-S9Crossref PubMed Scopus (402) Google Scholar, 3Gane E. The natural history and outcome of liver transplantation in hepatitis C virus-infected recipients.Liver Transpl. 2003; 9: S28-S34Crossref PubMed Scopus (190) Google Scholar, 4McCaughan G.W. Zekry A. Mechanisms of HCV reinfection and allograft damage after liver transplantation.J Hepatol. 2004; 40: 368-374Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar, 5Berenguer M. Ferrell L. Watson J. Prieto M. Kim M. Rayón M. et al.HCV-related fibrosis progression following liver transplantation: increase in recent years.J Hepatol. 2000; 32: 673-684Abstract Full Text Full Text PDF PubMed Scopus (688) Google Scholar, 6Berenguer M. Aguilera V. Prieto M. Carrasco D. Rayón M. San-Juan F. et al.Delayed onset of severe hepatitis C-related liver damage following liver transplantation: a matter of concern?.Liver Transpl. 2003; : 1152-1158Crossref PubMed Scopus (47) Google Scholar]. The commonest response to persistent HCV infection is the evolution over time to chronic hepatitis in a similar way to what has been described in the non-transplant patient but occurring at a viral set at least one log higher. Disease progression in these patients is typically accelerated compared to that observed in the immune competent host [1Berenguer M. Lopez-Labrador F.X. Wright T.L. Hepatitis C and liver transplantation.J Hepatol. 2001; 35: 666-678Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar, 2Wiesner R.H. Sorrell M. Villamil F. Report of the first international liver transplant society consensus conference on liver transplantation and hepatitis C.Liver Transpl. 2003; 9: S1-S9Crossref PubMed Scopus (402) Google Scholar, 3Gane E. The natural history and outcome of liver transplantation in hepatitis C virus-infected recipients.Liver Transpl. 2003; 9: S28-S34Crossref PubMed Scopus (190) Google Scholar, 4McCaughan G.W. Zekry A. Mechanisms of HCV reinfection and allograft damage after liver transplantation.J Hepatol. 2004; 40: 368-374Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar, 5Berenguer M. Ferrell L. Watson J. Prieto M. Kim M. Rayón M. et al.HCV-related fibrosis progression following liver transplantation: increase in recent years.J Hepatol. 2000; 32: 673-684Abstract Full Text Full Text PDF PubMed Scopus (688) Google Scholar, 6Berenguer M. Aguilera V. Prieto M. Carrasco D. Rayón M. San-Juan F. et al.Delayed onset of severe hepatitis C-related liver damage following liver transplantation: a matter of concern?.Liver Transpl. 2003; : 1152-1158Crossref PubMed Scopus (47) Google Scholar]. Progression in patients with this pattern of recurrence may follow two distinct pathways: a linear rate of fibrosis progression [[5]Berenguer M. Ferrell L. Watson J. Prieto M. Kim M. Rayón M. et al.HCV-related fibrosis progression following liver transplantation: increase in recent years.J Hepatol. 2000; 32: 673-684Abstract Full Text Full Text PDF PubMed Scopus (688) Google Scholar] and a delayed onset of progression [[6]Berenguer M. Aguilera V. Prieto M. Carrasco D. Rayón M. San-Juan F. et al.Delayed onset of severe hepatitis C-related liver damage following liver transplantation: a matter of concern?.Liver Transpl. 2003; : 1152-1158Crossref PubMed Scopus (47) Google Scholar]. Regardless of the pathway used, the hepatitis C driven fibrosis response in the allograft leads to the development of graft cirrhosis in approximately 25% of recipients (range: 8–44%) after a follow up of 5–10 years [1Berenguer M. Lopez-Labrador F.X. Wright T.L. Hepatitis C and liver transplantation.J Hepatol. 2001; 35: 666-678Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar, 2Wiesner R.H. Sorrell M. Villamil F. Report of the first international liver transplant society consensus conference on liver transplantation and hepatitis C.Liver Transpl. 2003; 9: S1-S9Crossref PubMed Scopus (402) Google Scholar, 3Gane E. The natural history and outcome of liver transplantation in hepatitis C virus-infected recipients.Liver Transpl. 2003; 9: S28-S34Crossref PubMed Scopus (190) Google Scholar, 4McCaughan G.W. Zekry A. Mechanisms of HCV reinfection and allograft damage after liver transplantation.J Hepatol. 2004; 40: 368-374Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar, 5Berenguer M. Ferrell L. Watson J. Prieto M. Kim M. Rayón M. et al.HCV-related fibrosis progression following liver transplantation: increase in recent years.J Hepatol. 2000; 32: 673-684Abstract Full Text Full Text PDF PubMed Scopus (688) Google Scholar, 6Berenguer M. Aguilera V. Prieto M. Carrasco D. Rayón M. San-Juan F. et al.Delayed onset of severe hepatitis C-related liver damage following liver transplantation: a matter of concern?.Liver Transpl. 2003; : 1152-1158Crossref PubMed Scopus (47) Google Scholar, 7Neumann U.P. Berg T. Bahra M. Puhl G. Guckelberger O. Langrehr J.M. Neuhaus P. Long-term outcome of liver transplants for chronic hepatitis C: a 10-year follow-up.Transplantation. 2004; 77: 226-231Crossref PubMed Scopus (260) Google Scholar]. Liver damage in this setting is believed to involve host-mediated immune responses over-stimulated by the increased viral load [[4]McCaughan G.W. Zekry A. Mechanisms of HCV reinfection and allograft damage after liver transplantation.J Hepatol. 2004; 40: 368-374Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar]. Cholestatis hepatitis is an infrequent but extremely severe pattern of recurrence that leads in 50% of patients to graft failure within a few months of onset [1Berenguer M. Lopez-Labrador F.X. Wright T.L. Hepatitis C and liver transplantation.J Hepatol. 2001; 35: 666-678Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar, 2Wiesner R.H. Sorrell M. Villamil F. Report of the first international liver transplant society consensus conference on liver transplantation and hepatitis C.Liver Transpl. 2003; 9: S1-S9Crossref PubMed Scopus (402) Google Scholar, 3Gane E. The natural history and outcome of liver transplantation in hepatitis C virus-infected recipients.Liver Transpl. 2003; 9: S28-S34Crossref PubMed Scopus (190) Google Scholar, 4McCaughan G.W. Zekry A. Mechanisms of HCV reinfection and allograft damage after liver transplantation.J Hepatol. 2004; 40: 368-374Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar]. A cytopathic mechanism of allograft damage is thought to be involved given the concurrence of extremely high viral burdens, reduced immune response with intrahepatic non-specific Th2 cytokine response, and unusual histology characterized by little inflammation and severe centrizonal hepatocyte ballooning [[4]McCaughan G.W. Zekry A. Mechanisms of HCV reinfection and allograft damage after liver transplantation.J Hepatol. 2004; 40: 368-374Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar]. In a substantial proportion of infected recipients, progression is not apparent, at least for the first decade, and liver injury remains mild or absent despite high viral burden.There are a number of factors that potentially contribute to disease progression [1Berenguer M. Lopez-Labrador F.X. Wright T.L. Hepatitis C and liver transplantation.J Hepatol. 2001; 35: 666-678Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar, 2Wiesner R.H. Sorrell M. Villamil F. Report of the first international liver transplant society consensus conference on liver transplantation and hepatitis C.Liver Transpl. 2003; 9: S1-S9Crossref PubMed Scopus (402) Google Scholar, 3Gane E. The natural history and outcome of liver transplantation in hepatitis C virus-infected recipients.Liver Transpl. 2003; 9: S28-S34Crossref PubMed Scopus (190) Google Scholar, 4McCaughan G.W. Zekry A. Mechanisms of HCV reinfection and allograft damage after liver transplantation.J Hepatol. 2004; 40: 368-374Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar, 5Berenguer M. Ferrell L. Watson J. Prieto M. Kim M. Rayón M. et al.HCV-related fibrosis progression following liver transplantation: increase in recent years.J Hepatol. 2000; 32: 673-684Abstract Full Text Full Text PDF PubMed Scopus (688) Google Scholar, 6Berenguer M. Aguilera V. Prieto M. Carrasco D. Rayón M. San-Juan F. et al.Delayed onset of severe hepatitis C-related liver damage following liver transplantation: a matter of concern?.Liver Transpl. 2003; : 1152-1158Crossref PubMed Scopus (47) Google Scholar, 7Neumann U.P. Berg T. Bahra M. Puhl G. Guckelberger O. Langrehr J.M. Neuhaus P. Long-term outcome of liver transplants for chronic hepatitis C: a 10-year follow-up.Transplantation. 2004; 77: 226-231Crossref PubMed Scopus (260) Google Scholar, 8Charlton M. Liver biopsy, viral kinetics, and the impact of viremia on severity of hepatitis C virus recurrence.Liver Transpl. 2003; 9: S58-S62Crossref PubMed Scopus (61) Google Scholar, 9Berenguer M. Host and donor pre- and post-liver transplant risk factors impacting on HCV recurrence.Liver Transpl. 2003; 9: S44-S47Crossref PubMed Scopus (90) Google Scholar, 10Lake J.R. The role of immunosuppression in recurrence of hepatitis C.Liver Transpl. 2003; 9: S63-S66Crossref PubMed Scopus (110) Google Scholar]. In addition to those already known from the immune competent patient, there are unique variables in the transplant setting that further complicate the difficult interactions between the host and the virus. These variables include surgical related factors, particularly the time of ischemia and reperfusion injury and donor-related factors such as age, histocompatibility between donor and recipient, immunologic chimerism and the use of immunosuppressive medications.2. Which factors impact on the course of recurrent chronic hepatitis C ? (Fig. 1)2.1 Viral-related variablesWhile viral factors do not appear to influence outcome in the immune competent host, data in the liver transplant recipient remain controversial.2.1.1 Post-transplantation HCV RNA levelsSerum HCV RNA concentrations increase rapidly in the post-transplantation period to peak by the fourth post-operative month [[11]Garcia-Retortillo M. Forns X. Feliu A. Moitinho E. Costa J. Navasa M. et al.Hepatitis C virus kinetics during and immediately after liver transplantation.Hepatology. 2002; 35: 680-687Crossref PubMed Scopus (442) Google Scholar]. The relationship between levels of viremia and the long-term outcome of post-transplant HCV infection is contradictory. In some studies, early post-transplantation viral load has been shown to influence late post-transplantation outcome [[10]Lake J.R. The role of immunosuppression in recurrence of hepatitis C.Liver Transpl. 2003; 9: S63-S66Crossref PubMed Scopus (110) Google Scholar]. Sreekumar and colleagues found that HCV RNA at 4 months was the most sensitive (82 and 71%) and specific (61 and 62%) predictor of increased histological activity index (≥3) and increased fibrosis (≥2) at 3 years post-transplantation [[10]Lake J.R. The role of immunosuppression in recurrence of hepatitis C.Liver Transpl. 2003; 9: S63-S66Crossref PubMed Scopus (110) Google Scholar]. Interestingly, immunosuppression is likely the most important determinant of post-transplantation viremia (Table 1). In one study, differences in early kinetics could be attributed to the use or not of corticosteroids [[11]Garcia-Retortillo M. Forns X. Feliu A. Moitinho E. Costa J. Navasa M. et al.Hepatitis C virus kinetics during and immediately after liver transplantation.Hepatology. 2002; 35: 680-687Crossref PubMed Scopus (442) Google Scholar]. Following an initial decline, HCV RNA levels increased rapidly in patients receiving corticosteroids as part of the immunosuppressive regime, while they continued to decline in the first post-transplant week in those on a steroid-free immunosuppression protocol. Furthermore, prednisolone withdrawal protocols that are complete very early post-transplantation (within the first 2 weeks) seem to be associated with relatively low levels of viremia [[10]Lake J.R. The role of immunosuppression in recurrence of hepatitis C.Liver Transpl. 2003; 9: S63-S66Crossref PubMed Scopus (110) Google Scholar]. In addition, corticosteroid treatment for acute cellular rejection is associated with significant increases in viremia (4- to 100-fold increase) [[10]Lake J.R. The role of immunosuppression in recurrence of hepatitis C.Liver Transpl. 2003; 9: S63-S66Crossref PubMed Scopus (110) Google Scholar]. The effects of other immunosuppressive agents on viral replication are generally controversial or preliminary. Two studies have suggested that the addition of mycophenolate mofetil (MMF) to stable organ transplant recipients is associated with increased viral replication [[12]Zekry A. Gleeson M. Turhan S. McCaughan G.W. The effect of mycophenolate compared to azathioprine on viral load in HCV liver transplant recipients.Liver Transpl. 2004; 10: 52-58Crossref PubMed Scopus (63) Google Scholar]. The information on calcineurin inhibitors is also controversial. Watashi et al. recently showed an inhibitory effect of cyclosporine A (CyA) on HCV protein expression and replicon RNA levels, effect that was not detected with tacrolimus (Tac) [[13]Watashi K. Hijikata M. Hosaka M. Yamagi M. Shimotohno K. Cyclosporin A suppresses replication of hepatitis C virus genome in cultured hepatocytes.Hepatology. 2003; 38: 1282-1288Crossref PubMed Scopus (461) Google Scholar]. In vivo data though, have not shown differences in viral load between patients immunosuppressed with either CyA or Tac [[10]Lake J.R. The role of immunosuppression in recurrence of hepatitis C.Liver Transpl. 2003; 9: S63-S66Crossref PubMed Scopus (110) Google Scholar]. The effect of azathioprine on viral load has not been carefully evaluated, possibly due to the confounding effect of concomitant steroid use. In one study using the replicon system, azathioprine was found to inhibit HCV replication [[14]Stangl J.R. Carroll K.L. Illichmann M. Striker R. Effect of antimetabolite immunosuppressants on flaviviridae, including hepatitis C virus.Transplantation. 2004; 77: 562-567Crossref PubMed Scopus (45) Google Scholar]. Precise data in the human model is missing. Data on interleukin-2 receptor monoclonal antibodies (IL2R) are also lacking. In one study, viral load was significantly greater at both 4 months and 1 year in patients whose induction regimen consisted of daclizumab-MMF-steroids compared to those treated with the standard combination Tac-steroids [[15]Nelson D.R. Soldevila-Pico C. Reed A. Abdelmaleck M.F. Hemming A.W. Van der Werf W.J. et al.The effect of anti-interleukin-2 receptor therapy on the course of hepatitis C recurrence after liver transplantation.Liver Transpl. 2001; 7: 1064-1070Crossref PubMed Scopus (135) Google Scholar]. Whether this differences was related to MMF, IL2R antibodies or the combination of both drugs remains unknown. The impact of other immunosuppressive agents, including sirolimus, everolimus and OKT3 is unknown.Table 1Effect of different immunosuppressive agents on viral replication and disease progressionMechanism of actionEffect on viral loadEffect on HCV-disease severity/progressionPulse steroidsGlobal anti-inflammatory and immunosuppressive actionsIncreaseNegativeMaintenance steroidsGlobal anti-inflammatory and immunosuppressive actionsIncreaseControversialCyclosporineInhibition of early T-cell signal pathways and IL-2 production and releaseControversial (no in vivo difference with tacrolimus. Viral decrease in replicon system)Evidence suggests no difference compared to tacrolimusTacrolimusSame as cyclosporine (more potent)UnknownSee CyclosporineAzathioprineInhibition of adenosine monophosphate productionDecrease in replicon systemControversialOKT3Antilymphocyte antibodiesUnknownNegativeAnti-IL2 receptor antibodiesInhibition of lymphocyte activation and clonal expansionUnknownControversialSirolimusInhibition of lymphocyte proliferation, fibrosis and fibroblast proliferationUnknownUnknownMycophenolate MofetilInhibition of inosine monophosphate dehydrogenaseIncreaseControversial (dose effect? Timing of discontinuation?)MMF+IL2 receptor antibodiesAddition of the two compound effectsIncreaseNegativeMMF, Mycophenolate Mofetil; IL, interleukin. Open table in a new tab 2.1.2 Pretransplantation HCV RNA levelsSeveral although not all studies have shown that, as described for HBV, level of viremia pre-transplantation predicts the occurrence and/or severity of recurrent hepatitis C [4McCaughan G.W. Zekry A. Mechanisms of HCV reinfection and allograft damage after liver transplantation.J Hepatol. 2004; 40: 368-374Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar, 8Charlton M. Liver biopsy, viral kinetics, and the impact of viremia on severity of hepatitis C virus recurrence.Liver Transpl. 2003; 9: S58-S62Crossref PubMed Scopus (61) Google Scholar]. In one study, recipients with increased HCV replication within the explanted liver (defined by a relative quantitative HCV negative-strand RNA:18S rRNA ratio >2.5) were found to be at increased risk for the development of post-transplant biochemical hepatitis, increased rate of allograft fibrosis and increased rate of mortality compared with recipients with relatively low replication [[8]Charlton M. Liver biopsy, viral kinetics, and the impact of viremia on severity of hepatitis C virus recurrence.Liver Transpl. 2003; 9: S58-S62Crossref PubMed Scopus (61) Google Scholar]. These results paralleled those obtained in a prior study, where increased serum genomic viral load prior to transplantation (>1 log Meq/mL) was also predictive of mortality [[8]Charlton M. Liver biopsy, viral kinetics, and the impact of viremia on severity of hepatitis C virus recurrence.Liver Transpl. 2003; 9: S58-S62Crossref PubMed Scopus (61) Google Scholar]. Interestingly, non-HCV infections and non-infectious causes, but paradoxically not HCV-induced liver damage, were the primary causes of death and/or retransplantation. The positive and negative predictive values of fast intrahepatic replication to predict mortality were 40 and 100%. If confirmed in larger series, this information could be useful in identifying HCV-infected recipients at high risk of severe outcome.2.1.3 HCV genotypeThe effect of the infecting genotype on the outcome of recurrent hepatitis C is still unclear [1Berenguer M. Lopez-Labrador F.X. Wright T.L. Hepatitis C and liver transplantation.J Hepatol. 2001; 35: 666-678Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar, 2Wiesner R.H. Sorrell M. Villamil F. Report of the first international liver transplant society consensus conference on liver transplantation and hepatitis C.Liver Transpl. 2003; 9: S1-S9Crossref PubMed Scopus (402) Google Scholar, 3Gane E. The natural history and outcome of liver transplantation in hepatitis C virus-infected recipients.Liver Transpl. 2003; 9: S28-S34Crossref PubMed Scopus (190) Google Scholar]. Some studies, particularly from European centers, have implicated genotype 1b in a more severe post-transplantation disease compared to non-1b genotype. Interestingly, fibrosis progression appears to be faster in centers where the prevalence of genotype 1b is very high [[5]Berenguer M. Ferrell L. Watson J. Prieto M. Kim M. Rayón M. et al.HCV-related fibrosis progression following liver transplantation: increase in recent years.J Hepatol. 2000; 32: 673-684Abstract Full Text Full Text PDF PubMed Scopus (688) Google Scholar], thus indirectly implicating this genotype in a more aggressive course of the disease. The mechanisms by which accelerated fibrogenesis is more often seen in patients infected with genotype 1b may be an increased rate of FAS-mediated hepatocellular apoptosis [[16]Di Martino V. Brenot C. Samuel D. Saurini F. Paradis V. Reynes M. et al.Influence of liver hepatitis C virus RNA and hepatitis C virus genotype on Fas-mediated apoptosis after liver transplantation for hepatitis C.Transplantation. 2000; 70: 1390-1396Crossref PubMed Scopus (35) Google Scholar]. In addition, preliminary data suggest that different strains belonging to genotype 1b may be involved in the pathogenesis of severe liver injury [17Gigou M. Roque-Alfonso A.M. Falissard B. Penin F. Dussaix E. Feray C. Genetic clustering of hepatitis C virus strains and severity of recurrent hepatitis after liver transplantation.J Virol. 2001; 75: 11292-11297Crossref PubMed Scopus (27) Google Scholar, 18Lopez-Labrador F.X. Berenguer M. Sempere A. Prieto M. Sirera R. Gonzalez-Molina A. et al.Genetic variability of hepatitis C virus NS3 protein in human leukocyte antigen-A2 liver transplant recipients with recurrent hepatitis C.Liver Transpl. 2004; 10: 217-227Crossref PubMed Scopus (21) Google Scholar].2.1.4 HCV diversityThe genetic nature and evolution of the virus have been implicated in the pathogenesis of progressive HCV disease. Results, generally inconclusive, need to be interpreted with caution due to a series of limitations in most studies, including: (i) only a limited number of clones are generally evaluated at each time point and hence, sequenced variants may not always be fully representative of the whole population of circulating quasispecies; (ii) while studies based on the hypervariable region-1, a putative target for neutralizing antibodies, are common, data using other potentially relevant regions are missing; (iii) small number of patients; (iv) different methodologies applied to assess HCV heterogeneity; (v) differences between studies in both the end-points chosen and the sequence time-points [1Berenguer M. Lopez-Labrador F.X. Wright T.L. Hepatitis C and liver transplantation.J Hepatol. 2001; 35: 666-678Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar, 4McCaughan G.W. Zekry A. Mechanisms of HCV reinfection and allograft damage after liver transplantation.J Hepatol. 2004; 40: 368-374Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar]. Notwithstanding these caveats, based on available data, several conclusions can be made regarding the evolution and effect of HCV quasispecies. First, in the early weeks following transplantation viral quasispecies becomes more homogenous than pretransplantation, likely as a result of the ‘bottleneck’ effect caused by the implantation of the new graft and the lack of selective pressure due to the strong immunosuppression [[4]McCaughan G.W. Zekry A. Mechanisms of HCV reinfection and allograft damage after liver transplantation.J Hepatol. 2004; 40: 368-374Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar]. This pattern of genetic evolution is particularly evident in patients with the fibrosing cholestatic pattern of recurrence where extremely potent immune suppression inhibits the cellular response to the virus, leading to the preferential replication of a few genetically divergent quasispecies [[4]McCaughan G.W. Zekry A. Mechanisms of HCV reinfection and allograft damage after liver transplantation.J Hepatol. 2004; 40: 368-374Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar]. Second, pre-transplantation quasispecies composition may have an effect on long-term outcome. It has been suggested that a less complex quasispecies composition prior to transplantation is associated with a more severe posttransplant HCV disease [[19]Arenas J.I. Gallegos-Orozco J.F. Laskus T. Wilkinson J. Khatib A. Fasola C. et al.Hepatitis C quasi-species dynamics predict progression of fibrosis after liver transplantation.JID. 2004; 189: 2037-2046Crossref PubMed Scopus (36) Google Scholar]. Third, genetic diversification appears to increase in patients with mild recurrence, possibly as a consequence of immune pressure in the context of immune restoration [[4]McCaughan G.W. Zekry A. Mechanisms of HCV reinfection and allograft damage after liver transplantation.J Hepatol. 2004; 40: 368-374Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar]. Finally, data regarding the impact of early post-transplant HCV quasispecies on long-term outcome are controversial [[4]McCaughan G.W. Zekry A. Mechanisms of HCV reinfection and allograft damage after liver transplantation.J Hepatol. 2004; 40: 368-374Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar].3. Host-related variablesIn the immune-competent population, the most powerful predictors of disease severity and progression are those related to the host. In the liver transplant setting, similar variables, both in the recipient and the donor, have been found to influence the outcome.Immune status. The immune system is clearly implicated in the pathogenesis of liver injury due to HCV [1Berenguer M. Lopez-Labrador F.X. Wright T.L. Hepatitis C and liver transplantation.J Hepatol. 2001; 35: 666-678Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar, 4McCaughan G.W. Zekry A. Mechanisms of HCV reinfection and allograft damage after liver transplantation.J Hepatol. 2004; 40: 368-374Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar, 10Lake J.R. The role of immunosuppression in recurrence of hepatitis C.Liver Transpl. 2003; 9: S63-S66Crossref PubMed Scopus (110) Google Scholar]. In fact, it is likely that the immunosuppressed status, typical of the transplant setting, is the most powerful determinant of post-transplantation disease progression. While this assumption comes mainly from indirect findings (Table 2), there are recent studies specifically addressing the impact of immune suppression on viral replication and disease progression (see iatrogenic variables).Table 2Influence of HLA matching on outcome of recurrent Hepatitis C after liver transplantationAuthor, year# (% 1b)Follow-up (months)Protocol biopsyHLA methodType of associationMañez 1995 [41]Mañez A. Mateo R. Tabasco J. Kusne S. Starzl T.E. Duquesnoy R.J. The influence of HLA donor-recipient compatibility of the recurrence of HBV And HCV hepatitis after liver transplantation.Transplantation. 1995; 59: 640-642Crossref PubMed Scopus (75) Google Scholar53 (–)18–24NoSerologyHLA-B matching: higher rate of chronic active hepatitisGane 1996 [42]Gane E.J. Portmann B.C. Naoumov N.V. Smith H.M. Underhill J.A. Donaldson P.T. Maertens G. Williams R. Long-term outcome of hepatitis C infection after liver transplantation.N Engl J Med. 1996; 334: 815-820Crossref PubMed Scopus (943) Google Scholar149 (29%)36YesSerology/PCRNo relationship to HLA I, IIVargas 1998 [43]Vargas H.E. Laskus T. Wang L.F. Radkowski M. Poutous A. Lee R. et al.The influence of hepatitis C virus genotypes on the outcome of liver transplantation.Liver Transpl Surg. 1998; 4: 22-27Crossref PubMed Scopus (85) Google Scholar150 (27%)29NoSerologyNo relationship to HLA I, IICotler 1998 [44]