Living donor liver transplantation for HCV: Will the true outcomes stand up?
Authors: Robert S. Brown
Journal: Journal of Hepatology (2012)

Living donor vs. deceased donor liver transplantation for patients with hepatitis C virus-related diseasesJournal of HepatologyVol. 57Issue 6PreviewLiving donor liver transplantation (LDLT) provides a timely alternative to deceased donor liver transplantation (DDLT) for patients with hepatitis C virus-related (HCV-related) diseases in the circumstances of severe organ dearth. However, the patient and graft outcomes, and recurrence of HCV after LDLT remain controversial. Here we sought to compare the post-transplant outcomes after LDLT and DDLT. Full-Text PDF Hepatitis C (HCV) remains the most common indication for liver transplantation. Early data suggested that patients with HCV that received a living donor liver transplantation (LDLT) had worse outcomes, including increased rates of cholestatic HCV than did recipients of dead donor liver transplantation (DDLT) [1Garcia-Retortillo M. Forns X. Llovet J.M. et al.Hepatitis C recurrence is more severe after living donor compared to cadaveric liver transplantation.Hepatology. 2004; 40: 699-707Crossref PubMed Scopus (168) Google Scholar, 2Gaglio P.J. Malireddy S. Levitt B.S. et al.Increased risk of cholestatic hepatitis C in recipients of grafts from living versus cadaveric liver donors.Liver Transpl. 2003; 9: 1028-1035Crossref PubMed Scopus (108) Google Scholar]. These early studies have attributed the increase in graft failure in LDLT recipients to more rapid HCV progression in the regenerating LDLT graft. Several in vitro studies suggest that dividing hepatocytes are more vulnerable to HCV infection. This could lead to increased levels of viremia, which is seen in cholestatic HCV, in LDLT recipients. This also may have been due to an increased rate of biliary complications or other problems seen during the learning curve of early LDLT experience. It was thought that biliary complications were synergistic in their adverse impact on HCV outcomes, but this has not been supported by subsequent data [[3]Verna E.C. De Martin E. Burra P. et al.The impact of hepatitis C and biliary complications on patient and graft survival following liver transplantation.Am J Transplant. 2009; 9: 1398-1405Crossref PubMed Scopus (18) Google Scholar]. More recent data suggests that there is no difference in recurrent HCV between recipients of DDLT and LDLT. These studies were often based on protocol biopsies, were larger, and included a later experience with LDLT. In a study of 23 LDLT recipients and 53 DDLT, protocol biopsies at 6 and 12 months were compared for inflammation and fibrosis and there was no difference in mean inflammation scores or fibrosis at any of the time points measured [[4]Shiffman M.L. Stravitz R.T. Contos M.J. et al.Histologic recurrence of chronic hepatitis C virus in patients after living donor and deceased donor liver transplantation.Liver Transpl. 2004; 10: 1248-1255Crossref PubMed Scopus (124) Google Scholar]. 21% of the recipients of DDLT suffered acute rejection compared to 14% of the LDLT recipients; this difference was not statistically significant. Graft and patient survival rates between the two groups were similar: at 48 months, 82 and 82% for DDLT patients and 76 and 79% for LDLT patients (p = n.s.). Results from this study, which looked at liver histology, do not support the idea that recurrent HCV is more prevalent among recipients of LDLT. Additional studies including those from the UNOS database and the NIH-sponsored Adult-to-Adult Living Donor Liver Transplant Cohort Study (A2ALL) have also concluded that rates of HCV recurrence are not different among recipients of LDLT [5Russo M.W. Galanko J. Beavers K. Fried M.W. Shrestha R. Patient and graft survival in hepatitis C recipients after adult living donor liver transplantation in the United States.Liver Transpl. 2004; 10: 340-346Crossref PubMed Scopus (99) Google Scholar, 6Terrault N.A. Shiffman M.L. Lok A.S. et al.Outcomes in hepatitis C virus-infected recipients of living donor vs. deceased donor liver transplantation.Liver Transpl. 2007; 13: 122-129Crossref PubMed Scopus (105) Google Scholar]. The A2ALL data on HCV comparing 181 HCV positive LDLT recipients to 94 HCV positive DDLT recipients showed similar patient survival but lower 3-year graft survival in LDLT recipients than in DDLT recipients (68% compared to 80% p = 0.04) [[6]Terrault N.A. Shiffman M.L. Lok A.S. et al.Outcomes in hepatitis C virus-infected recipients of living donor vs. deceased donor liver transplantation.Liver Transpl. 2007; 13: 122-129Crossref PubMed Scopus (105) Google Scholar]. However, center experience was a confounder of the relationship between donor type and outcome. Once the center had performed 20 cases, graft survival was equivalent between DDLT and LDLT. For LDLT <20, 3-year graft survival was only 55% compared to 79% and 80% for LDLT >20 and DDLT recipients, respectively. There was equivalent and excellent patient survival between LDLT >20 and DDLT as well, 91% and 87%, respectively. Unfortunately, the majority of patients studied in the retrospective arm of the A2ALL group did not have protocol liver biopsies. Of the 63 patients who were biopsied, there was no difference in total necroinflammatory or fibrosis scores between DDLT and LDLT at one-year post-transplant. As a result of this conflicting data, the role of LDLT in the management of patients with HCV has remained controversial. In an attempt to synthesize prior data and illuminate the issue, Hu et al. perform a meta-analysis of retrospective and prospective studies looking at outcomes for living donor vs. a deceased donor liver transplantation in this issue of the Journal of Hepatology. They excluded large database analyses, including the UNOS database, though the UNOS dataset was included in sensitivity analyses. They also attempt to control for the heterogeneity of patients by doing various sensitivity analyses including controlling for the presence of HCC, donor age, and the era of transplantation. Overall, they find no difference in patient survival and a trend towards a lower graft survival in LDLT recipients at early time points post-transplant, although this is not a consistent finding. Specifically, LDLT patients have lower one and three-year graft survival, but equivalent two, four, and five-year survival. The results answer some questions but leave others unclear. Particularly, where does this leave us in the controversial area of LDLT for HCV? I think it is clear that patient survival rates from the time of transplant are no better for a living donor transplantation, but they appear to be no worse. Second, there continues to be marked heterogeneity in the patients selected for LDLT and they systematically differ from those selected for DDLT leading to systematic biases that confound comparisons. For example, the rate of HCC was significantly higher in the living donor group and these patients had a worse outcome. Adjusting for these differences in the analysis phase may not completely remove potential confounding. Some of the differences in the outcomes for LDLT vs. DDLT is likely independent of the type of transplant and may reflect the fact that patients who have high risk of dying on the waiting list or increased risk of poor post-transplant outcome may pursue living donation, as it is their only option. Finally, the meta-analysis does not include the pre-transplant benefit of pursuing LDLT which has been clearly demonstrated in A2ALL and other studies [7Berg C.L. Merion R.M. Shearon T.H. et al.Liver transplant recipient survival benefit with living donation in the model for endstage liver disease allocation era.Hepatology. 2011; 54: 1313-1321Crossref PubMed Scopus (116) Google Scholar, 8Berg C.L. Gillespie B.W. Merion R.M. et al.Improvement in survival associated with adult-to-adult living donor liver transplantation.Gastroenterology. 2007; 133: 1806-1813Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar]. Given the large sample size in this meta-analysis, one would expect a consistent and statistically significant difference at all time points if a true significant difference in patient or graft survival was present. Given the number of patients included, my power calculation shows a 90% power to detect a 5–6% difference in patient and/or graft survival. The inconsisitent findings in graft survival raise questions as to whether any true difference exists. Additionally, the heterogeneity between studies and the LDLT and DDLT cohorts points to the need for more careful and detailed analyses of HCV recurrence including the analysis of serial protocol liver biopsies. This data should be forthcoming from the A2ALL study, and similar efforts in the European Registry should be undertaken. In the meantime, I think we can continue to conclude that LDLT does not offer a significant disadvantage to our patients in terms of post-transplant outcome that will counteract the clear pre-transplant benefits in terms of reducing the waiting list mortality. As better methods for viral eradication are developed pre and post-transplant, the outcome of LDLT for our HCV positive patients should increase. With these clinical improvements in HCV therapy, I expect an increase rather than a decrease in the use of LDLT as a therapeutic modality for HCV patients awaiting liver transplantation. The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.