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In 20% to 30% of infected individuals, hepatitis C virus (HCV) can cause cirrhosis and hepatocellular carcinoma, for which liver transplantation is the best treatment available. HCV re-infection is universal, and hepatitis disease recurrence occurs in most cases with a 30% probability of progression to graft cirrhosis at 5 years post-transplant. The immunological response to HCV involves natural killer (NK) cells and killer cell immunoglobulin-like receptors (KIRs), which specifically recognize human leukocyte antigen (HLA) class I antigens present on target cells. The effector functions of NK cells are influenced by inhibitory KIR interaction with self-HLA class I ligands, with HLA-C being the most predominant. This study examines the roles of KIR genotypes and their HLA ligands in both HCV disease recurrence and its progression. A total of 151 patients were included in the cohort, and their clinical details were recorded. Liver biopsies were used to define the absence/presence of recurrent hepatitis, the degree of fibrosis, and the progression to cirrhosis over a 10-year period. Mismatching of KIR-HLA-C ligands between donor-recipient pairs was associated with the recurrence of hepatitis (P = 0.008). The presence of KIR2DL3 in the recipient correlated with progression to liver fibrosis (P = 0.04). The mismatching of HLA-KIR ligands favored the progression of the recurrent hepatitis to fibrosis only in the presence of KIR2DL3 (P = 0.04). These preliminary results indicate that the KIR genotype and KIR-HLA-C ligand compatibility play roles in the recurrence and progression of hepatitis C disease in liver transplant recipients., (Copyright 2009 AASLD.)

In recent years, a worsening outcome of hepatitis C virus (HCV)-positive recipients and a faster progression of recurrent disease to overt cirrhosis has been reported. Our aims were to 1) assess patient survival and development of severe recurrent disease (Ishak fibrosis score > 3) in different transplant years; and 2) model the effects of pre- and post-liver transplantation (LT) variables on the severity of recurrent disease. A multicenter retrospective analysis was conducted on 502 consecutive HCV-positive transplant recipients between January 1990 and December 2002. Protocol liver biopsies were obtained at 1, 3, 5, 7, and 10 yr post-LT in almost 90% of the patients. All 502 patients were included in the overall survival analysis, while only the 354 patients with a follow-up longer than 1 yr were considered for the analysis of predictors of disease progression. The overall Kaplan-Meier survival rates were 78.7%, 66.3%, and 58.6%, at 12, 60, and 120 months, respectively, and a trend for a better patient survival over the years emerged from all 3 centers. The cumulative probability of developing HCV-related recurrent severe fibrosis (Ishak score 4-6) in the cohort of 354 patients who survived at least 1 yr remained unchanged over the years. Multivariate analysis indicated that older donors (P = 0.0001) and female gender of recipient (P = 0.02) were the 2 major risk factors for the development of severe recurrent disease, while the adoption of antilymphocytic preparations was associated with a less aggressive course (P = 0.03). Two of these prognostic factors, donor age and recipient gender, are easily available before LT and their combination showed an important synergy, such that a female recipient not only had a much higher probability of severe recurrent disease than a male recipient but her risk increased with the increasing age of the donor, reaching almost 100% when the age of the donor was 60 or older. In conclusion, a trend for a better patient survival was observed in more recent years but the cumulative probability of developing severe recurrent disease remained unchanged. The combination of a female recipient receiving an older graft emerged as a strong risk factor for a severe recurrence.

Background & Aims: This study extends our previously reported observations that various immunological factors are associated with the occurrence of histologically proven recurrent hepatitis C. The two specific issues investigated were to confirm the associations of MHC alleles and donor/recipient mismatch with the occurrence of recurrent hepatitis C in an independent cohort of newly transplanted patients and to look for immunologic and nonimmunologic variables affecting the severity of the recurrent disease., Methods: Two separate cohorts of consecutive patients were studied: a look-back cohort (LC) of 120 patients and a cohort for studying the disease progression (CSDP) of 190 patients. Protocol liver biopsies were obtained at least 1, 3, 5, 7, and 10 years after liver transplantation (LT)., Results: A fully mismatched donor/recipient pair at the DRB1 locus was confirmed to be associated with both the recurrence of histologic hepatitis in the LC (59% vs 23%, P = .0002) and its progression beyond stage 3 in the CSPD (71.4% vs 39.3%, P = .0003). Relevant immunologic and nonimmunologic variables were included into a multivariate Cox proportional model and three variables, namely, donor age, full HLA-DRB1 donor-recipient mismatch, and HLA B14, resulted in independent risk factors for the development of severe fibrosis., Conclusion: This study provides evidence that DRB1 donor-recipient mismatch affects both the occurrence and progression of recurrent hepatitis C disease. This information is clinically relevant as it may help to better allocate organs and to recognize patients at risk for progression so that specific interventions can be implemented.

Aims: The aim of this study was to identify predictors of both survival and tumor-free survival of a cohort of 155 patients, with hepatocellular carcinoma (HCC) and cirrhosis, who were treated by orthotopic liver transplantation (OLT)., Methods: From January 1989 to December 2002, 603 OLTs were performed in 549 patients. HCC was diagnosed in 116 patients before OLT and in 39 at histological examination of the explanted livers. Eighty-four percent of the patients met "Milan" criteria at histology. Ninety-four patients received anticancer therapies preoperatively., Results: The median follow-up was 49 months (range, 0-178). Overall, 1-, 3-, 5-, and 10-yr survival were 84%, 75%, 72%, and 62%, respectively. Survival was not affected by the patient's age or sex, etiology of liver disease, Child score at transplantation, rejection episodes, tumor number, total tumor burden, bilobar tumor, and pathologic Tumor, Nodes, Metastasis (pTNM) stages. There was no statistically significant difference in survival when patients were grouped according to the recently proposed simplified pTNM staging (5-yr survival, 80% in stage I, 69% in stage II, 50% in stage III, p= 0.3) or the United Network for Organ Sharing (UNOS) staging system for HCC. Encapsulation of the tumor and alpha-fetoprotein levels significantly affect patient survival. Five-year survival of patients with poorly differentiated (G3) HCC was significantly worse than that of patients with moderately (G2) or well-differentiated (G1) HCC (respectively, G3 44%, G2 67%, and G1 97%, p= 0.0015). Patients with micro- or macro-vascular invasion had a worse 5-yr survival than patients without vascular invasion (49%vs 77%, p= 0.04). Multivariate analysis showed that histological grade of differentiation and macroscopic vascular invasion are independent predictors of survival (HR 2.4, 95% CI 1.4-4.1, p= 0.0009 and HR 2.8, 95% CI 1.2-6.8, p= 0.022)., Conclusion: Histological grade of differentiation and macroscopic vascular invasion, as assessed on the explanted livers, are strong predictors of both survival and tumor recurrence in patients with cirrhosis who received transplants for HCC.

Hepatitis C virus (HCV) shows remarkable genetic variation in both populations and individuals, in whom it circulates as quasispecies (QS). Sequence variation within an infected host has adaptive significance and reflects the modes and intensity of selection mechanisms operating on the virus. We investigated the sequence diversity of hypervariable region 1 of HCV in liver transplant recipients and correlated it with the recurrence of hepatitis. Twenty-six patients were considered during a 2-year period; all had graft reinfection, and 14 patients developed hepatitis recurrence. Cloned sequences were obtained from sera collected before or within 1 month after orthotopic liver transplantation (OLT) and at 3 and 24 months thereafter. Sequence diversity within single sera and over consecutive samples was analyzed quantitatively by matrix comparison and phylogenetic analysis. Propagation of viral QS in the graft was markedly dependent on individual factors. Viral QS in post-OLT sera were less complex and evolved slower compared with immunocompetent subjects with chronic hepatitis. Sequence variation was greater during the first 3 months post-OLT than during the remaining period. Genetic diversity within single samples was not related to hepatitis recurrence or other clinical features. Conversely, sequence diversity over consecutive samples was reduced in patients who experienced hepatitis recurrence, in particular, in those infected with genotype 1b and with an HLA-DR mismatched graft. Selection of viral sequences was markedly impaired in liver transplant recipients and tended to be greater early after OLT. Reduced sequence turnover correlated negatively with the outcome of graft reinfection.

Recurrent hepatitis C is a common problem after liver transplantation that can progress to liver cirrhosis of the graft. Preliminary reports of combination treatment with interferon (IFN) and ribavirin have been promising, but long-term follow-up data are not yet available. We report our experience with 1 year of combination therapy with IFN (3 million units thrice weekly) and low-dose ribavirin (600 mg/d), followed by long-term ribavirin monotherapy in 18 patients with moderate to severe recurrent hepatitis C and a median follow-up of 32 months after the completion of combined therapy. All patients were followed up clinically and histologically at regular intervals. Overall, in an intention-to-treat analysis, 15 patients had normal alanine aminotransferase levels (biochemical end-treatment response [ETR], 83%), and 8 patients were also hepatitis C virus RNA negative in serum (virological ETR, 44%) at the end of combined treatment. At last follow-up after the completion of combined therapy (median, 32 months; range, 18 to 73 months), 13 patients were biochemical responders (biochemical long term-sustained response [LT-SR], 72%), and 5 patients also maintained viral clearance (virological LT-SR, 27%). Comparison of liver biopsy specimens before and after 12 months of combined therapy showed improvement in grading scores of at least two points in the majority of the patients (73%). Notably, a trend toward fibrotic progression was only noted in nonresponders. Regarding side effects, despite the low dose of ribavirn, almost half the patients developed hemolytic anemia requiring dose reductions. In addition, long-term ribavirin monotherapy was not associated with iron accumulation. We conclude that combined therapy with low-dose ribavirin followed by long-term ribavirin monotherapy can be recommended because it favorably modifies the natural history of recurrent hepatitis C in most patients and possibly halts histological disease progression without causing iron accumulation.

In immunocompetent patients, specific human leukocyte antigen (HLA) class II alleles have been associated with the severity of hepatitis C virus (HCV)-related disease, in particular, HLA-DRB1*11 has been found to exert a protective effect. The authors have analyzed the role of HLA class I and II alleles in determining the frequency, timing, and progression of histologically proven recurrent hepatitis C in 89 patients who underwent a liver transplant for HCV-related cirrhosis. In addition, the influence of HLA mismatch between donor and recipient, HCV genotype, and use of steroid pulses was also evaluated. Median patient follow up was 35 months (range 4-119). HLA-DRB1 typing was performed by genomic analysis in all cases. Liver biopsies were obtained routinely and at least at yearly intervals. Histologically proven recurrent hepatitis was observed in 46 patients (52%), 10 patients progressing to stage 5-6 fibrosis in most cases within 2 years after transplant. By univariate analysis, 3 variables, HLA-B14, HLA-DRB1*04, and HLA-DRB1 donor/recipient mismatch, showed a significant effect on time to recurrent hepatitis C disease. These parameters were included in a multivariate regression model along with HCV genotype, treatment with steroid pulses and DRB1*11. HLA-B14, HLA-DRB1*04, and HLA-DRB1 donor/recipient mismatch were confirmed to provide a significant and independent contribution to the risk of hepatitic disease recurrence. As for the severity of the disease, none of the 10 patients with stage 5-6 hepatitis carried the HLA-DRB1*11 allele, in line with what was observed in nontransplant subjects. Our results suggest that in posttransplant recurrent hepatitis C, immunogenetic factors are relevant in determining HCV infection outcome.