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Severe fibrosis in patients with recurrent hepatitis C after liver transplantation: A French experience on 250 patients over 15 years (the Orfevre study)
Abstract
Recurrent hepatitis C after liver transplantation (LT) is associated with rapid fibrosis progression. The aim of this study was to evaluate the cumulative risk for severe fibrosis and the factors influencing it.
Two hundred and fifty LT patients were included 1 to 15years after LT. Recurrence of chronic hepatitis C on liver graft was classified according to Metavir score.
Kaplan-Meyer estimates for actuarial progression to severe fibrosis (Metavir>F3) showed a probability of 15.2% and 44.5% at 5 and 10years, respectively. Predictive factors for progression to severe fibrosis were: use of tacrolimus as main CNI, recipient age at time of biopsy<55, donor age ≥45, graft HCV re-infection<3months, biologically suspected graft re-infection and lack of response to antiviral treatment after LT. Multivariate analysis disclosed that only donor age ≥45 (hazard ratio 2.243, 95%CI 1.264-3.983, P=0.0058) and lack of response to antiviral treatment (hazard ratio 2.816, 95%CI 1.227-6.464, P=0.0146) were associated to severe fibrosis.
Our study confirms that donor age ≥45 and lack of response to antiviral treatment after LT are major predictive factors of progression of HCV recurrence on liver graft.
... Bei Patienten, die unter einer post LTx durchgeführten antiviralen Therapie eine SVR erreichten, konnte ein günstiger Einfluss auf das Patientenüberleben nachgewiesen werden [62]. Nach Einführung der interferonfreien antiviralen Therapien sollte, insbesondere bei Patienten mit Risikofaktoren für eine schnelle Fibroseprogression trotz der noch fehlenden Evidenz, eine frühzeitige Therapie in Erwägung gezogen werden [63,64]. Zeitlich kann sie nach postoperativer Stabilisierung und nach Ausschleichen der Steroide (in den meisten Fällen ca. 3 Monate post LTx) durchgeführt werden. ...
With the approval of new direct acting antiviral agents (DAA), therapeutic options for patients with chronic hepatitis C virus (HCV) infection are now generally available before and after liver transplantation (LT). Interferon-free DAA regimens are highly effective therapies and provide a good safety profile. However, the body of clinical evidence in this patient population is limited and the best treatment strategies for patients on the waiting list with (de)compensated cirrhosis and after LT are not well defined. The following recommendations for antiviral therapy in the context of LT are based on the currently available literature and clinical experience of experts in the field, and have been discussed in an expert meeting. The aim of this article is to guide clinicians in the decision making when treating patients before and after LT with DAAs.
© Georg Thieme Verlag KG Stuttgart · New York.
... Many centers carry out annual protocol biopsies to establish the severity of rHCV because of poor correlation of LFTs and HCV RNA with the degree of liver damage post liver transplantation. Nearly, 15-30 % of patients with progressive fibrosis may become cirrhotic within 5 years post liver transplantation and more than 40-45 % of them are cirrhotic in 10 years after transplantation [34]. Up to 40 % of patients with cirrhosis develop decompensated chronic liver disease within a year of diagnosis and their mortality can be over 50 % [19]. ...
Recurrent HCV infection (rHCV) of the liver allograft following transplantation is universal and is associated with poor graft and patient survival in comparison with other indications. Treatment of rHCV infection in the previous era with pegylated interferon and ribavirin was associated with low sustained virological response (SVR) due to poor tolerability, adverse events and graft rejection. Recently, directly acting antiviral drugs (DAA) have been approved for the treatment of hepatitis C infection and a number of clinical trials have been conducted across various centers in the management of rHCV infection of the graft. In this review we discuss about recent studies that have emerged on the use of NS5b polymerase inhibitor, sofosbuvir in combination with second generation protease inhibitor, simeprevir, fixed dose ledipasvir or daclatasvir with or without ribavirin in the treatment of post transplant rHCV infection.
... Transplantation with organs from donors between ages 41 and 50, 51 and 60, and > 60 years old was associated with a linear increase in the risk of graft loss. Subsequent single or multicenter studies confirmed these findings [39][40][41][42][43] . Analysis of the Spanish Registry for Liver Transplantation presented a lower graft survival in HCV-infected patients when organs were procured from donors older than 50 years [43] (Figure 4). ...
The age of liver donors has been increasing in the past several years because of a donor shortage. In the United States, 33% of donors are age 50 years or older, as are more than 50% in some European countries. The impact of donor age on liver transplantation (LT) has been analyzed in several studies with contradictory conclusions. Nevertheless, recent analyses of the largest databases demonstrate that having an older donor is a risk factor for graft failure. Donor age is included as a risk factor in the more relevant graft survival scores, such as the Donor Risk Index, donor age and Model for End-stage Liver Disease, Survival Outcomes Following Liver Transplantation, and the Balance of Risk. The use of old donors is related to an increased rate of biliary complications and hepatitis C virus-related graft failure. Although liver function does not seem to be significantly affected by age, the incidence of several liver diseases increases with age, and the capacity of the liver to manage or overcome liver diseases or external injuries decreases. In this paper, the importance of age in LT outcomes, the role of donor age as a risk factor, and the influence of aging on liver regeneration are reviewed.
Background
Our main objective was to assess the clinical outcomes obtained in a single orthotopic liver transplant (OLT) hospital with donors ≥80 years of age compared to a control group of patients subjected to OLT during the same period of time with donors who were under 65 years of age.
Methods
A prospective analysis was carried out on all the OLTs performed using liver grafts from donors in a state of brain death and with an age of ≥80 years (study group) between April 2007 and January 2015. The results of the study group (n = 36) were compared with those of a control group of patients less than 65 years of age receiving transplants with grafts.
Results
A total of 51 potential donors ≥80 years were assessed, with a total of 36 liver transplants being carried out and their results were compared with a control group of 283 patients receiving transplants. The median follow-up time of the patients in the series was 36 months (range: 24–120 months). Graft survival at 1, 2, and 3 years was 77%, 72%, and 62%, respectively, among the patients in the study group and 79%, 73%, and 65% among the patients in the control group, and there were no statistically significant differences. Patient survival at 1, 2, and 3 years was 86%, 82%, and 75%, respectively, among the patients in the study group and 82%, 76%, and 72% among the patients in the control group, also without there being any statistically significant differences.
Conclusions
There is no age limit for liver transplant donors. The use of octogenarian donors makes it possible to increase the pool of donors while providing enough safety for the recipient.
Alcoholic liver disease (ALD) is a major indication for liver transplantation (LT) but up to 20% of patients experience severe alcoholic relapse. The aims of this study were to evaluate the impact on the graft (based on histological examination) of severe alcoholic relapse and to identify predictive factors associated with recurrent alcoholic cirrhosis (RAC). From 1990 to 2010, 369 patients underwent LT for ALD at Edouard Herriot Hospital (Lyon, France) and survived more than one year. All patients who presented severe alcoholic relapse and histological follow-up were included. Liver biopsies were performed at 1, 5 and every 5 years after LT, and when clinically indicated. The median follow up after LT was 11 years (3-18). Severe alcoholic relapse was observed in 73 of the 369 patients (20%), from whom 56 patients with histological evaluation were included. RAC was diagnosed in 18 of the 56 (32%) patients included, which represent 5% of the 369 patients transplanted for ALD. The median delay between LT and RAC was 6 years (3-10) and 4.5 years (2-8) after severe alcoholic relapse. The median cumulated years of alcohol use before RAC was 3.5 years (2-7). The cumulative risk for F4 fibrosis was 15% at 3 years, 32% at 5 years and 54% at 10 years after severe alcoholic relapse. A young age at LT (≤50 years old) and an early onset of heavy drinking (within the first three years post LT) were associated with RAC. In conclusion, severe alcoholic relapse usually occurs in the first years after LT and is responsible for accelerated severe graft injury. This article is protected by copyright. All rights reserved.
A proportion of liver transplanted patients with recurrent chronic hepatitis have a sustained virological response to combination therapy with interferon plus ribavirin. However, the long term benefit of antiviral therapy with regard to hepatitis C virus (HCV) RNA clearance remains unknown in patients with HCV recurrence. This study examined the long term biochemical, virological, and histological outcome in transplanted patients with recurrent chronic hepatitis who had a sustained virological response to antiviral therapy.
Fifty four patients with recurrent hepatitis C were treated with antiviral therapy involving induction by combination therapy (interferon (IFN) plus ribavirin) for six months and maintenance ribavirin therapy for 12 months. Fourteen patients who had recurrent chronic hepatitis and sustained virological response to antiviral therapy were followed for three years after the end of antiviral therapy. Serum alanine aminotransferases were assessed every three months during the observation period. Serum hepatitis C RNA detected by polymerase chain reaction was evaluated every six months during follow up, and protocol biopsy procedures were performed routinely every year. Semiquantitative histopathological assessment of allograft hepatitis was performed using the Knodell score and HCV was also detected by polymerase chain reaction on frozen graft tissue samples.
At the end of antiviral therapy, the sustained response rate was 26%. A complete response (normal serum alanine aminotransferase level and undetectable serum HCV RNA) was achieved in 13/14 (93%) patients three years after the end of treatment. A comparison of liver histology findings before and after a mean of three years after antiviral therapy showed a clear improvement in 12/14 (86%) patients. In 5/14 (36%) patients, the last biopsy showed normal or near normal histological findings. After three years of follow up, the total Knodell score was 3.2 (range 1-8) versus 8.3 (range 5-12) before treatment (p=0.001). Graft HCV RNA was detectable before treatment in all 14 patients and was undetectable at the end of follow up in 13/14 (93%) patients tested.
In patients with biochemical and virological responses induced by ribavirin and interferon, a complete response was sustained in 93% for at least three years after cessation of therapy. This long term response was associated with absence of detectable intrahepatic hepatitis C RNA and marked histological improvement.
Recently, a production system for infectious particles of hepatitis C virus (HCV) utilizing the genotype 2a JFH1 strain has been developed. This strain has a high capacity for replication in the cells. Cyclosporine (CsA) has a suppressive effect on HCV replication. In this report, we characterize the anti-HCV effect of CsA. We observe that the presence of viral structural proteins does not influence the anti-HCV activity of CsA. Among HCV strains, the replication of genotype 1b replicons was strongly suppressed by treatment with CsA. In contrast, JFH1 replication was less sensitive to CsA and its analog, NIM811. Replication of JFH1 did not require the cellular replication cofactor, cyclophilin B (CyPB). CyPB stimulated the RNA binding activity of NS5B in the genotype 1b replicon but not the genotype 2a JFH1 strain. These findings provide an insight into the mechanisms of diversity governing virus-cell interactions and in the sensitivity of these strains to antiviral agents.
The 1-year results of the tacrolimus versus microemulsified cyclosporin (TMC) study found a benefit with tacrolimus immunosuppression after primary liver transplants in adults with respect to freedom from graft loss and immunological failure. The integrity of the randomization process was preserved for a further 2 years for poststudy surveillance. The data after 3 years confirms the significant difference between tacrolimus and cyclosporin with tacrolimus less likely to meet the composite primary endpoint (log rank p = 0.01; relative risk 0.75; 95% CI 0.60-0.95; p = 0.016). However, freedom from death or retransplantation no longer achieves statistical significance (relative risk 0.79; 95% CI 0.62-1.02; p = 0.065). A total of 62.1% of patients randomized to tacrolimus were alive at 3 years with their original graft and still on their allocated study medication, as compared with only 41.6% in the cyclosporin limb (p < 0.001). No difference was detected between tacrolimus and cyclosporin in hepatitis-C-positive patients with the available data. The TMC study confirms after 3 years of follow-up the benefits of tacrolimus-based immunosuppression over cyclosporin using C(0) monitoring.
Introduction: Recurrence of hepatitis C virus (HCV) infection after orthotopic liver transplantation (OLT) is a virtually universal occurrence, and a significant proportion of patients develop chronic hepatitis and cirrhosis. The aim of this study was to evaluate the safety and efficacy of interferon (IFN)-alpha 2b plus ribavirin (RIBA) in the treatment of recurrent HCV after OLT over the long term. Material and methods: Fifteen patients with recurrent HCV infection (positive serum HCV RNA, elevated serum aminotransferases, histological activity) were started on IFN-alpha 2b (3-6 million units administered subcutaneously three times a week) plus RIBA (800-1200 mg/day) 18 +/- 5 months after OLT. HCV RNA was determined 1, 3, 6, 9, 12 and 18 months after initiation of treatment. Liver biopsy was performed before and after therapy. The patients were followed up for a mean of 33 +/- 5 months. Results: Thirteen patients (87%) were treated for at least 6 months and nine patients (60%) for 12 months. After 3 months, 11 patients (73%) were free from HCV RNA (<50 copies/ml); the virological end-of-treatment response was 67%. Five patients (33%) remained HCV RNA-negative 6 months posttreatment (sustained response (SR)). During the follow-up period, four patients (27%) died of liver failure, recurrent HCV after virological response, or HCC. The histological activity index improved significantly for both inflammatory activity and fibrosis, from 8.8 to 4.7 and from 7.3 to 4.8, respectively. In none of the patients were signs of rejection observed. Conclusion: Combination therapy with IFN and RIBA in transplanted patients with chronic hepatitis C is an effective treatment that results in a high virological SR rate. It is well tolerated and leads to an improvement in histological outcome.
Background:
The influence of immunosuppression on the response to antiviral treatment in recurrent hepatitis C is still under debate. The purpose of this study was to identify those factors that might predict sustained viral response and relapse.
Methods:
The ReViS-TC, a multicenter cohort study conducted in 14 Spanish liver centers, included data from liver transplant recipients from January 2000 to December 2006 who had recurrent hepatitis C virus and who had undergone antiviral treatment with pegylated interferon plus ribavirin. Sustained virological response (SVR) and viral relapse were evaluated. A multivariate logistic regression model was used to investigate host, donor, and therapeutic factors associated with SVR and relapse.
Results:
The analysis included 410 patients, 30% treated with cyclosporine A (CsA) and 70% with tacrolimus. SVR was achieved in 48% of patients with CsA and in 37% with tacrolimus (P=0.037), with a relapse rate of 18% and 36%, respectively (P=0.008). In the multivariate model, the administration of CsA (odds ratio [OR] 0.37, P=0.021) in conjunction with a longer antiviral treatment duration (OR 0.86, P=0.024) correlated with lower relapse rate, whereas the older age of the donor (OR 1.03, P=0.006) and the presence of genotype 1 (OR 3.45, P=0.032) were associated with a higher probability of relapse.
Conclusions:
Our results suggest that the use of CsA-based immunosuppression regimens and longer treatment duration may protect patients against viral relapse after a positive response to pegylated interferon plus ribavirin therapy. These data need to be further confirmed in clinical trials.
Background & Aims: Liver transplantation for hepatitis C virus (HCV)-related liver disease is characterized by frequent graft infection by HCV. The prognosis and risk factors for morbidity and mortality in this condition were determined. Methods: A retrospective study of 652 consecutive anti-HCV–positive patients undergoing liver transplantation between 1984 and 1995 in 15 European centers was conducted; 102 patients coinfected with hepatitis B virus (HBV) received immunoglobulin prophylaxis for antibody to hepatitis B surface antigen. Results: Overall, 5-year survival was 72%. Five-year actuarial rates of hepatitis and cirrhosis were 80% and 10%. Genotypes 1b, 1a, and 2 were detected in 214 (80%), 24 (9%), and 24 (9%) of 268 patients analyzed. The only discriminant factor for patient or graft survival was hepatocellular carcinoma as primary indication. Independent risk factors for recurrent hepatitis included the absence of HBV coinfection before transplantation (relative risk [RR], 1.7; 95% confidence interval [CI], 1.2–2.6; P = 0.005), genotype 1b (RR, 2; 95% CI, 1.3–2.9; P = 0.01), and age > 49 years (RR, 1.4; 95% CI, 1.1–1.8; P = 0.01). Conclusions: The results of transplantation for HCV-related disease are compromised by a significant risk of cirrhosis, although 5-year survival is satisfactory. Genotype 1b, age, and absence of pretransplantation coinfection by HBV are risk factors for recurrent HCV.GASTROENTEROLOGY 1999;117:619-625
Liver biopsy is used as the “gold standard” for the assessment of the stage and degree of activity in chronic hepatitis C and is of major importance in evaluating the effects of treatment. Because numerous therapeutic trials are undertaken with histological control, the reproducibility of liver biopsy interpretation appears essential. Therefore the aim of this study was to estimate intraobserver and interobserver variations in the assessment of features, classification, and numerical scoring of chronic viral hepatitis C among 10 pathologists specializing in liver diseases. These pathologists independently reviewed 30 liver biopsy specimens of viral hepatitis C and completed a histological form for each of the specimens. Five pairs of pathologists then were randomly designated. They independently reviewed the biopsy specimens and filled out a new coding form. The interobserver variation was calculated for each item among the 10 individuals and then among the five pairs with the intraclass correlation coefficient or ϰ statistics. Five features showed an almost perfect or a substantial degree of concordance among the 10 observers (i.e., cirrhosis, fibrosis, fibrosis grading of Knodell index, steatosis, portal lymphoid aggregates). The 17 other indicators showed a weaker concordance with, for instance, a moderate degree of concordance for piecemeal necrosis, disease activity, Knodell index, a fair degree of concordance for lobular necrosis, and only a slight degree of concordance for six items. Five items had a higher concordance when viewed by a pair of pathologists than when studied by only one pathologist (i.e., steatosis, periportal necrosis grading of Knodell index, lobular necrosis grading of Knodell index, centrilobular fibrosis, and ductular proliferation). Two showed a significant decrease, and the others were unchanged. This study reveals that certain features of major importance in assessing disease activity show significant observer variation. The acceptable degree of concordance of the Knodell index was related mainly to the substantial degree of concordance of the fibrosis score, whereas other numerical items displayed substantial observer variations. Simultaneous observation by two pathologists increased the reproducibility of numerical scoring and of certain viral hepatitis C lesions. A classification of chronic hepatitis C based on dissociated semiquantitative assessment of necroinflammatory lesions and fibrosis offered more reproducibility than the use of a global numerical index. (Hepatology 1994;20:15–20.)
The time progression of allograft damage in patients with recurrent hepatitis C after orthotopic liver transplantation (OLT) is not precisely determined. The aim of this analysis is to study the progression of disease recurrence and its impact on patient and graft survival. Data for 300 patients who underwent OLT for hepatitis C were analyzed regarding the incidence of histological recurrence, risk factors, immunosuppressive regimen, rejection episodes, and survival. For patients with histological recurrence, the timing and risks for disease progression were analyzed. Data for 30 patients who underwent retransplantation were studied. Histological recurrence occurred in 40.3% of patients, 27.2% of whom progressed to bridging fibrosis or cirrhosis. Eighty-seven percent of the patients experienced recurrence of disease within 24 months of OLT. Patients with histological recurrence within 6 months of OLT had an increased risk for progression to cirrhosis compared with patients with recurrence later than 6 months (risk ratio, 2.3). Recurrence within 1 year was associated with decreased patient and graft survival rates at 1 and 5 years (65.1% and 56.4% versus 80.6% and 78.4%; P = .004 and P = .0008, respectively). Patients with histological recurrence had a greater incidence of acute cellular rejection, as well as multiple episodes of rejection, steroid-resistant rejections, and greater cumulative doses of corticosteroids. Histological recurrence after OLT for hepatitis C is common and usually occurs within 2 years of OLT. Early recurrence negatively affects patient and graft survival. Host factors impacting on recurrence need further study. A relation between the hepatitis C virus, allograft rejection, and immunosuppression exists and needs investigation.
End-stage liver disease secondary to hepatitis C virus (HCV) infection is the leading indication for liver transplantation in the United States. Recurrence of HCV infection is nearly universal. We studied the patients enrolled in the National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database to determine whether pretransplantation patient or donor variables could identify a subset of HCV-infected recipients with poor patient survival. Between April 15, 1990, and June 30, 1994, 166 HCV-infected and 509 HCV-negative patients underwent liver transplantation at the participating institutions. Median follow-up was 5.0 years for HCV-infected and 5.2 years for HCV-negative recipients. Pretransplantation donor and recipient characteristics, and patient and graft survival, were prospectively collected and compared. Cumulative patient survival for HCV-infected recipients was similar to that of recipients transplanted for chronic non–B-C hepatitis, or alcoholic and metabolic liver disease, better than that of patients transplanted for malignancy or hepatitis B (P= .02 and P= .003, respectively), and significantly worse than that of patients transplanted for cholestatic liver disease (P= .001). Recipients who had a pretransplantation HCV-RNA titer of ≥1 × 106 vEq/mL had a cumulative 5-year survival of 57% versus 84% for those with HCV-RNA titers of <1 × 106 vEq/mL (P = .0001). Patient and graft survival did not vary with recipient gender, HCV genotype, or induction immunosuppression regimen among the HCV-infected recipients. While long-term patient and graft survival following liver transplantation for end-stage liver disease secondary to HCV are generally comparable with that of most other indications, higher pretransplantation HCV-RNA titers are strongly associated with poor survival among HCV-infected recipients.
There is a paucity of good studies evaluating the impact of calcineurin inhibitors on posttransplantation outcome in hepatitis C virus (HCV)-infected liver transplant (LT) recipients.
We sought to determine whether there are differences on posttransplantation survival and histologic recurrence in HCV-LT recipients based on initial immunosuppression (IS) by conducting a prospective study comparing tacrolimus (Tac) versus cyclosporine-based IS in patients undergoing LT between 2001 and 2007. Protocol liver biopsies were performed.
Baseline characteristics (demographics, liver function at LT, genotype distribution, donor, surgery, and IS except for the type of calcineurin inhibitor) did not differ between groups. Severe disease (defined as bridging fibrosis, cirrhosis, cholestatic hepatitis, or allograft loss or death because of recurrent disease in the first year) was present in 67 of 253 (26.5%) and was equally distributed in the CsA and Tac groups (27% vs. 26%; P=0.68). Two thirds of protocol biopsies performed at 1 year showed some fibrosis without differences between CsA and Tac groups (75% vs. 70%). Advanced fibrosis (bridging fibrosis and cirrhosis) was diagnosed in 30% CsA and 24.5% Tac patients (P=NS). No differences in survival at 1 and 7 years were observed (83% and 67% vs. 78% and 64%, respectively, P=0.4). In summary, in patients undergoing LT for HCV-related liver disease, posttransplantation outcome is not related to the calcineurin inhibitor used.
Liver transplantation has rapidly advanced from an experimental therapy to a mainstream treatment option for a wide range of acute and chronic liver diseases. Indications for liver transplant have evolved to include previously contraindicated conditions such as hepatocellular carcinoma and alcohol-related liver disease. Cirrhosis from chronic hepatitis C infection remains the most common indication today. Multidisciplinary evaluation for liver transplantation is intended to confirm the patient's suitability and identify the appropriate timing of transplant, although the latter is problematic as a result of the ongoing donor organ shortage. Deceased liver donors have been increasing in number, but increasing donor age has been associated with less satisfactory posttransplant results. Living donor liver transplant is a dramatic but very infrequent procedure; risk to the living donor is of paramount concern. The main focus of deceased donor allocation has transitioned from waiting time to estimation of the likelihood of death without transplant (medical urgency), and now relies upon a laboratory-based Model for End-Stage Liver Disease (MELD) score for candidates with chronic liver disease. Those with acute liver failure are prioritized ahead of those with chronic conditions. Although not used as a direct criterion for allocation, development of the concept of transplant survival benefit, i.e., the extra years of life attributable to transplant, has facilitated better ordering of those candidates likely to have the most benefit, while restricting access to those whose lives will be extended minimally or not at all. Overall posttransplant outcomes have steadily improved, with unadjusted 5-year patient survival rates of 77% among patients transplanted with MELD score between 15 and 20, and 72% for those with MELD scores between 21 and 30.
Efficacy and long-term outcome of antiviral therapy for recurrent hepatitis C after liver transplantation is poorly defined.
This study aimed at assessing the efficacy of antiviral therapy regarding sustained hepatitis C virus (HCV) clearance, liver histology, and patient survival.
We retrospectively reviewed all 446 patients who received a liver allograft at our institution for HCV-related cirrhosis between January 1992 and December 2006. Two hundred thirty-two patients (52%) were eligible for antiviral therapy based on predefined criteria (Metavir stage > or =1 and/or grade > or =2; protocol biopsies). One hundred seventy-two patients (39%) had no contraindication for treatment, received more than or equal to 1 dose of interferon-alpha-based combination therapy, and form the basis of this analysis. Therapy was aimed for 48 weeks; median posttreatment follow-up was 68 months.
The overall sustained virological response (SVR) rate was 50% (genotype 1/4: 40%; genotype 2/3: 76%). SVR was higher on cyclosporine A (CsA) (56%) than on tacrolimus (44%, P=0.05), largely because of a lower relapse rate (6% vs. 19%, P=0.01). In multivariate analysis, genotype 2/3, CsA use, donor age, and pretreatment necroinflammatory activity were independently associated with SVR. SVR significantly improved histology and long-term survival (actuarial 5-year survival 96% vs. 69% in nonresponders, P<0.0001).
Antiviral therapy of recurrent hepatitis C after liver transplantation is able to clear HCV in half the patients, more likely on CsA than on tacrolimus, and markedly improves outcome.
We studied the role of donor and recipient age in transplantation/ischemia-reperfusion injury (TIRI) and short- and long-term graft and patient survival. Eight hundred twenty-two patients underwent deceased donor liver transplantation, with 197 donors being > or = 60 years old. We evaluated markers of reperfusion injury, graft function, and clinical outcomes as well as short- and long-term graft and patient survival. Increased donor age was associated with more severe TIRI and decreased 3- and 5-year graft survival (73% versus 85% and 72% versus 81%, P < 0.001) and patient survival (77% versus 88% and 77% versus 82%, P < 0.003). Hepatitis C virus (HCV) infection and recipient age were the only independent risk factors for graft and patient survival in patients receiving an older graft. In the HCV(+) cohort (297 patients), patients > or = 50 years old who were transplanted with an older graft versus a younger graft had significantly decreased 3- and 5-year graft survival (68% versus 83% and 64% versus 83%, P < 0.009). In contrast, HCV(+) patients < 50 years old had similar 3- and 5-year graft survival if transplanted with either a young graft or an old graft (81% versus 82% and 81% versus 82%, P = 0.9). In conclusion, recipient age and HCV status affect the graft and patient survival of older livers. Combining older grafts with older recipients should be avoided, particularly in HCV(+) patients, whereas the effects of donor age can be minimized in younger recipients.
Hepatitis C after liver transplantation leads to graft cirrhosis in up to 30% of patients within 5 years, but limited data exist regarding the clinical course of cirrhosis after transplantation. The aims of this study were to report the natural history of hepatitis C cirrhosis after liver transplantation and to identify risk factors for decompensation and survival. Hepatitis C patients underwent protocol liver biopsies yearly after liver transplantation. After cirrhosis was identified by biopsy, the outcomes of interest were the development of decompensation, death, or retransplantation for hepatitis C. Kaplan-Meier and Cox regression analysis was used to determine survival and risk factors for decompensation and mortality. Out of 502 liver transplants performed for hepatitis C, 88 patients (18%) had cirrhosis within 3.7 years. Seventy-one patients were compensated at diagnosis. The cumulative probability of decompensation 1 year after cirrhosis was 30%. A Model for End-Stage Liver disease score >or= 16 was predictive of decompensation and poor survival, whereas successful interferon treatment was found to reduce this risk (relative risk = 0.05). Once decompensation occurred, 1-year survival was 46%. In conclusion, the results confirm an accelerated natural history of hepatitis C cirrhosis after liver transplantation and demonstrate poor survival after decompensation. The Model for End-Stage Liver Disease can stratify risk for decompensation and survival, whereas successful antiviral therapy may be protective.
Factors associated with sustained virological response (SVR) in patients treated for hepatitis C virus (HCV) recurrence after liver transplantation (LT) are unclear. Ninety-nine HCV-positive/hepatitis B surface antigen-negative patients received antiviral treatment (AVT) with interferon/peginterferon plus ribavirin for HCV recurrence after LT. Cyclosporine (CyA) or tacrolimus (TAC) was used as the main immunosuppressor in 37 (37%) and 62 (63%) patients, respectively. Twenty-five patients (25%) achieved an SVR. Twenty-seven donor-related, recipient-related, HCV-related, and immunosuppression-related variables were investigated for their association with SVR. In logistic regression analysis, donor age < 60 years (odds ratio = 4.45, 95% confidence interval = 1.39-14.19, P = 0.01), viral genotype other than 1 (odds ratio = 4.97, 95% confidence interval = 1.59-15.48, P = 0.006), and the use of CyA during treatment (odds ratio = 6.85, 95% confidence interval = 2.15-21.73, P = 0.001) were predictors of SVR. Patients treated with CyA (SVR rate: 43%) and those treated with TAC (SVR rate: 14%) were comparable for all variables, except for a shorter ischemia time and shorter timing of AVT initiation in the TAC group (P = 0.02 and P = 0.005, respectively) and a greater use of anti-CD25 antibodies, azathioprine, and mycophenolate mofetil in the CyA group (P = 0.03, P < 0.001, and P = 0.001, respectively). The rate of AVT discontinuation due to side effects was similar between groups (16% versus 8%, P = 0.3). In conclusion, the type of immunosuppression during AVT may predict SVR in patients treated for HCV recurrence after LT.
We hypothesized that antiviral efficacy [sustained virologic response (SVR)] has improved in recent years in the transplant setting. Our aim was to assess whether the efficacy of pegylated interferon (PegIFN)-ribavirin (Rbv) has improved over time. One hundred seven liver transplant patients [74% men, 55.5 years old (range: 37.5-69.5), 86% genotype 1a or 1b] were treated with PegIFN-Rbv for 355 (16-623) days at 20.1 (1.7-132.6) months after transplantation. Tacrolimus was used in 61%. Sixty-seven percent had baseline F3-F4 (cirrhosis: 20.5%). Donor age was 49 (12-78) years. SVR was achieved in 39 (36.5%) patients, with worse results achieved in recent years (2001-2003: n = 27, 46.5%; 2004: n = 23, 43.5%; 2005: n = 21, 35%; 2006 to January 2007: n = 36, 24%; P = 0.043). Variables associated with SVR in the univariate analysis included donor age, baseline viremia and cirrhosis, bilirubin levels, rapid virologic response and early virologic response (EVR), premature discontinuation of PegIFN or Rbv, and accumulated Rbv dose. In the multivariate analysis, the variables in the model were EVR [odds ratio (OR): 0.08, 95% confidence interval (CI): 0.016-0.414, P = 0.002] and donor age (OR: 1.039, 95% CI: 1.008-1.071, P = 0.01). Variables that had changed over time included donor age, baseline viremia, disease severity (cirrhosis, baseline bilirubin, and leukocyte and platelet counts), interval between transplantation and therapy, and use of growth factors. In the multivariate analysis, variables independently changing were donor age (OR: 1.041, 95% CI: 1.013-1.071, P = 0.004), duration from transplantation to antiviral therapy (OR: 1.001, 95% CI: 1.000-1.001, P = 0.013), and baseline leukocyte count (OR: 1.000, 95% CI: 1.000-1.000, P = 0.034). In conclusion, the efficacy of antiviral therapy with PegIFN-Rbv has worsened over time, at least in our center. The increase in donor age and greater proportion of patients treated at advanced stages of disease are potential causes.
More than 50% of patients with a recurrent posttransplant hepatitis C virus infection fail to respond to antiviral treatment. The aim of this study was to evaluate the interest of a long-term antiviral treatment maintained for more than 48 weeks. Seventy treated patients, with a histological follow-up > 1 year, were enrolled in this observational, retrospective study. The duration of antiviral treatment, tolerance, and occurrence of virological, biochemical, and histological responses were recorded. Thirty-two patients were nonresponders after 48 weeks of treatment. Combined antiviral therapy was maintained for >12 months in 26 and for >18 months in 21. Twelve patients had to discontinue their treatment. At 48 weeks, the rates of virological response and sustained virological response were 37% and 24.3%, respectively; at the end of the follow-up, they were 48.5% and 35.7%. Virological response was significantly associated with a higher incidence of biochemical and histological response, regardless of its time of occurrence (before or after 6 months). Even in the absence of virological response, the rate of progression of fibrosis was significantly slowed in patients treated for more than 6 months. Our results show the feasibility, safety, and efficacy of long-term antiviral therapy in nonresponder patients with a recurrent posttransplant hepatitis C virus infection.
Antiviral therapy after liver transplantation (LT) using interferon (IFN) and ribavirin (RBV) can achieve a sustained virological response (SVR) rate ranging from 20% to 45%. The aims of our study were to assess efficacy and tolerability of therapy, effect on fibrosis progression and the importance of the initial fibrosis stage to outcome. A total of 113 hepatitis C virus (HCV)-infected LT patients received 133 courses of IFN (standard, n = 29, pegylated IFN [pegIFN], n = 104) and RBV (75% genotype 1). Early virological response (EVR), end-of-treatment (EOT), and SVR were obtained in 74%, 55%, and 38%, respectively. EVR, completion of treatment, viral load before therapy, genotype non-1, and use of pegIFN were predictive of SVR, but only EVR remained in the multivariate analysis. SVR was obtained in 45% patients who received a second course of therapy. Paired biopsies at baseline, at EOT and at long-term were available in 42 patients. The mean fibrosis stage remained stable in patients with SVR and increased in patients without response. Rejection episodes were observed in 6% of patients. Tolerability of therapy decrease in patients with fibrosis stage > or =3 on baseline liver biopsy. A total of 20% of them died or were retransplanted due to liver failure as opposed to 1% of patients who had fibrosis stage <3. In conclusion, IFN and RBV achieved SVR in 38% of patients. EVR is independently associated with SVR. Fibrosis stage remained stable in patients with SVR and increased in nonresponders. Fibrosis stage > or =3 was associated with a high rate of liver failure, arguing for an early introduction of antiviral therapy.
1. Liver failure and liver cancer from chronic hepatitis C are the most common indications for liver transplantation and numbers of both are projected to double over the next 20 years. 2. Recurrent hepatitis C infection of the allograft is universal and immediate following liver transplantation and associated with accelerated progression to cirrhosis, graft loss and death. 3. Graft and patient survival is reduced in liver transplant recipients with recurrent HCV infection compared to HCV-negative recipients. 4. The natural history of chronic hepatitis C is accelerated following liver transplantation compared C, with 20% progressing to cirrhosis by 5 years. However, the rate of fibrosis progression is not uniform and may increase over time. 5. The rates of progression from cirrhosis to decompensation and from decompensation to death are also accelerated following liver transplantation. 6. Multiple host, donor and viral factors are associated with rapid fibrosis progression and HCV-related graft failure. 7. Over the last decade, graft and patient survival rates have improved following liver transplantation for non-HCV disease but not for HCV-cirrhosis. This may reflect worsening donor quality and changes in immunosuppression strategies over recent years. 8. Viral eradication by antiviral therapy prevents disease progression and improves survival. 9. The severity of recurrent hepatitis C at one year post-transplant predicts subsequent progression to cirrhosis. Annual protocol biopsies are recommended to help determine need for antiviral therapy. 10. The projected impact of recurrent hepatitis C on graft and patient survival can only be avoided by the development of safe and effective antiviral strategies which can both prevent initial graft infection and eradicate established hepatitis C recurrence.
Our aim was to assess the natural history of liver fibrosis progression in hepatitis C and the factors associated with this progression.
We recruited 2235 patients from the Observatoire de l'Hépatite C (OBSVIRC) population, the Cohorte Hépatite C Pitié-Salpétrière (DOSVIRC) population, and the original METAVIR population. All the patients had a biopsy sample compatible with chronic hepatitis C as assessed by the METAVIR scoring system (grades the stage of fibrosis on a five-point scale, F0 = no fibrosis, F4 = cirrhosis, and histological activity on a four-point scale, A0 = no activity, A3 = severe activity). No patient had received interferon treatment before the liver biopsy sample was obtained. We assessed the effect of nine factors on fibrosis progression: age at biopsy; estimated duration of infection; sex; age at infection; alcohol consumption; hepatitis C virus C (HCV) genotype; HCV viraemia; cause of infection; and histological activity grade. We defined fibrosis progression per year as the ratio between fibrosis stage in METAVIR units and the duration of infection (1 unit = one stage, 4 units = cirrhosis).
The median rate of fibrosis progression per year was 0.133 fibrosis unit (95% CI 0.125-0.143), which was similar to the estimates from previous studies (0.146 to 0.154). Three independent factors were associated with an increased rate of fibrosis progression: age at infection older than 40 years, daily alcohol consumption of 50 g or more, and male sex. There was no association between fibrosis progression and HCV genotype. The median estimated duration of infection for progression to cirrhosis was 30 years (28-32), ranging from 13 years in men infected after the age of 40 to 42 years in women who did not drink alcohol and were infected before the age of 40. Without treatment, 377 (33%) patients had an expected median time to cirrhosis of less than 20 years, and 356 (31%) will never progress to cirrhosis or will not progress for at least 50 years.
The host factors of ageing, alcohol consumption, and male sex have a stronger association with fibrosis progression than virological factors in HCV infection.
Immunosuppression in patients with hepatitis C virus (HCV) following orthotopic liver transplantation can lead to significant increases in serum viral loads. Our aim was to analyze the effect of a randomized study of two immunosuppressive agents (tacrolimus vs. microemulsion cyclosporine) on the outcome of HCV patients following orthotopic liver transplantation.
From December 1995 to September 1996, 50 adult patients transplanted for HCV cirrhosis were randomly assigned to receive tacrolimus (Prograf) (group 1, 25 patients) or microemulsion cyclosporine (Neoral) (group 2, 24 patients). All patients received alpha-interferon after transplantation, and the overall steroid doses were no different between the groups. Serum RNA levels were measured by signal amplification of Chiron. Biopsies were taken when transaminases were greater than 2x base line or when there was an inappropriate response to alterations in immunosuppression regimens.
There were more episodes of rejection in the Neoral group, but there were no differences in bacterial and viral infections, nor in the rate of HCV recurrence between the two groups. There were seven deaths in group 1 and eight in group 2. Overall patient and graft survival rates in the Prograf and Neoral groups at 18 months were 72 and 68% and 67 and 64%, respectively.
(a) Both immunosuppression regimens had similar HCV recurrence rates; (b) there were no differences in bacterial or opportunistic infections; and (c) patient and graft survival was similar between the two groups.
The majority of patients infected with hepatitis C virus (HCV) undergoing liver transplantation develop evidence of histologic recurrence, and multiple mechanisms are likely poised to affect long-term allograft injury. The purpose of this analysis was to study the hypothesis that histologic and biochemical features at the onset of HCV recurrence predict the long-term evolution of allograft hepatitis.
We studied 34 consecutive liver transplant recipients with evidence of histologic HCV recurrence and with a minimal histologic follow-up of 1 year (up to 6.2 years; mean: 696+/-83.2 days). Two-hundred and seventy-eight serial allograft biopsies (mean: 6.85+/-0.62 per patient, range: 4-21) were analyzed. The hepatic activity index was utilized to quantitate piecemeal necrosis, intralobular degeneration, portal inflammation, and hepatic fibrosis. The presence of hepatocyte ballooning degeneration and cholestasis was also assessed.
Although there was no significant difference with regard to initial hepatic activity index scores between patients who ultimately developed allograft cirrhosis (group 1; n=8) versus those with milder hepatitis (group 2; n=26), the finding of ballooning degeneration/cholestasis was more frequent in the former group (P=0.04). The distribution of HCV genotypes, the mean follow-up after orthotopic liver transplantation, the mean number of allograft biopsy specimens per patient, basal immunosuppression, and incidence of rejection were comparable in both groups. Patients who ultimately developed allograft cirrhosis had significantly higher initial total bilirubin at the onset of histologic recurrence and peak total bilirubin (pT. Bili, the highest value in the ensuing month). Actuarial rates of moderate-to-severe allograft hepatitis were significantly greater in patients with pT. Bili > or = 3.5 mg/dl (P=0.004). Multiple regression analysis identified pT. Bili as the only independent predictor of allograft cirrhosis.
Features at the onset of histologic HCV recurrence predict the natural history of allograft injury; specifically, marked, transient hyperbilirubinemia is associated with the subsequent development of allograft cirrhosis.
Liver transplantation for hepatitis C virus (HCV)-related liver disease is characterized by frequent graft infection by HCV. The prognosis and risk factors for morbidity and mortality in this condition were determined.
A retrospective study of 652 consecutive anti-HCV-positive patients undergoing liver transplantation between 1984 and 1995 in 15 European centers was conducted; 102 patients coinfected with hepatitis B virus (HBV) received immunoglobulin prophylaxis for antibody to hepatitis B surface antigen.
Overall, 5-year survival was 72%. Five-year actuarial rates of hepatitis and cirrhosis were 80% and 10%. Genotypes 1b, 1a, and 2 were detected in 214 (80%), 24 (9%), and 24 (9%) of 268 patients analyzed. The only discriminant factor for patient or graft survival was hepatocellular carcinoma as primary indication. Independent risk factors for recurrent hepatitis included the absence of HBV coinfection before transplantation (relative risk [RR], 1.7; 95% confidence interval [CI], 1.2-2.6; P = 0.005), genotype 1b (RR, 2; 95% CI, 1.3-2.9; P = 0.01), and age > 49 years (RR, 1.4; 95% CI, 1.1-1.8; P = 0.01).
The results of transplantation for HCV-related disease are compromised by a significant risk of cirrhosis, although 5-year survival is satisfactory. Genotype 1b, age, and absence of pretransplantation coinfection by HBV are risk factors for recurrent HCV.
Recurrence of hepatitis C virus (HCV) after orthotopic liver transplantation (OLT) remains a significant source of morbidity and mortality. Factors that reliably predict allograft injury from HCV have not been identified. Demographics, clinical data, and histopathological characteristics of recipients with and without persistently elevated serum transaminase levels (PEST) were compared. Twenty-four patients with HCV-induced end-stage liver disease who underwent OLT between October 1995 and December 1998 were entered into a longitudinal, prospective evaluation for identification of parameters associated with graft injury. Liver biopsies were performed preoperatively and between posttransplantation days 1 to 28, 29 to 60, 61 to 180, 181 to 360, and then every 6 to 12 months thereafter. Biopsy specimens were reviewed in a blinded fashion and scored for rejection, necroinflammatory activity, extent of fibrosis, and infiltrating cell type, location, and magnitude. Transplant recipients with PEST (alanine transaminase level >1.5 times normal for 3 consecutive months) and cholestatic hepatitis showed an increased viral load compared with their own preoperative values (16-fold and 256-fold, respectively). Compared with control transplant recipients, PEST was associated with macrovesicular steatosis within 28 days after OLT (P <.05) and showed an increased rate of fibrosis (P <.003) despite similar degrees of rejection and necroinflammatory activity. There was no difference in demographics or immunosuppression. Macrovesicular steatosis may be the earliest predictor of graft fibrosis. Despite similar degrees of necroinflammatory activity, transplant recipients with PEST had an increased rate of fibrosis that could be predicted on average within 6 months posttransplantation.
The effect of hepatitis C viral (HCV) infection on patient and allograft survival after orthotopic liver transplantation is controversial. Hepatitis C recurrence after transplant is inevitable, but studies to date have not found a survival difference between recipients with and without HCV.
Using data from the United Network for Organ Sharing, we performed a retrospective cohort study of 11,036 patients who underwent 11,791 liver transplants between 1992 and 1998. The hazard rates of patient and allograft survival for patients who were HCV-positive as compared with patients who were HCV-negative were assessed by proportional-hazards analysis, with adjustment for potential confounding variables, including donor, recipient, and transplant center characteristics.
Liver transplantation in HCV-positive recipients was associated with an increased rate of death (hazard ratio, 1.23; 95% confidence interval [CI], 1.12-1.35) and allograft failure (hazard ratio, 1.30; 95% CI, 1.21-1.39), as compared with transplantation in HCV-negative recipients. This reduction in survival persisted after adjusting for potential confounders. There was an interaction between HCV and sex (P < 0.001) with the effect of HCV on survival being most pronounced in female recipients (patient survival hazard ratio, 1.56; 95% CI, 1.35-1.81; allograft survival hazard ratio, 1.51; 95% CI, 1.34-1.70).
HCV infection significantly impairs patient and allograft survival after liver transplantation.
Recurrent hepatitis occurs in the majority of patients undergoing liver transplantation for hepatitis C virus (HCV) cirrhosis, with progression to cirrhosis in up to 30% after 5 years. Based on these data, a decrease in survival can be anticipated with prolonged follow-up. Furthermore, posttransplantation HCV-fibrosis progression has been shown in recent years to increase. Our aims were (1) to describe the natural history of HCV-infected recipients, particularly to determine whether survival has decreased in recent years; (2) to compare this outcome with that observed in non-HCV-infected cirrhosis controls; and (3) to determine the factors associated with disease severity and survival. Among 522 cirrhotic patients undergoing transplantation between 1991 and 2000, 283 (54%) were infected with HCV. Yearly biopsies were performed in these recipients and at 1 and 5 years in the remainder. With similar follow-up, the percentage of deaths in the HCV(+) group was significantly higher than in the HCV- group (37% vs. 22%, P <.001), and patient survival was lower (77%, 61%, 55% vs. 87%, 76%, 70% at 1, 5, and 7 years, respectively; P =.0001). Although survival has increased in the HCV- group in recent years, it has significantly decreased in HCV recipients (P <.0001). The main cause of death among the latter was decompensated graft cirrhosis (n = 23/105, 22%), whereas that of HCV- patients was infections (n = 10/52, 19%). Reasons for the recent worse outcome in HCV+ recipients include the increased donor age and stronger immunosuppression. In conclusion, patient survival is lower among HCV+ recipients than among HCV- ones and has been decreasing in recent years. The aging of donors is a major contributor to this worse outcome.
Chronic hepatitis C represents a major clinical problem after liver transplantation, but factors influencing the recurrent disease have not been well characterized. We analyzed the clinical records of all the patients transplanted for hepatitis C virus (HCV)-related liver disease in our Center between 1991 and 1997. Eighty consecutive HCV-positive (+) patients (60 men, ages 28 to 64) survived more than 1 month after transplantation and were followed for a median of 45 months. Diagnosis of recurrent chronic hepatitis C was made in 38 patients (47.5%), of whom 22 had moderate/severe chronic hepatitis. Decompensated cirrhosis occurred in six patients (7.5%). No difference in patient survival was found between patients with and without hepatitis C recurrence. No association was found between recurrent hepatitis C and presumed risk factors. The method of tapering off corticosteroids was significantly associated with both hepatitis C recurrence and the severity of hepatitis. In patients receiving a higher daily prednisone dose, 12 months after transplantation, the proportion of recurrent hepatitis C was 35.7% versus 66.6% (P = .02; odds ratio [OR], 3.6; 95% confidence interval (CI): 1.25 to 10.36), and among patients receiving a higher daily prednisone dose, 6 months after transplantation, the proportion of moderate/severe chronic hepatitis C was 40% versus 89% (P = .03; OR: 0.08, 95% CI: 0.008 to 0.84). Finally, prednisone dose at month six was significantly associated with disease-free survival of the liver graft. In conclusion, our results seem to indicate that in HCV-infected liver transplant recipients, a long-term treatment with corticosteroids, slowly tapered off over time, may prevent the more aggressive forms of recurrent liver disease.
Recurrent hepatitis C virus (HCV) infection is an important cause of fibrosis and cirrhosis after liver transplantation (LT), with histological recurrence developing in at least 50% of patients within the first year. The aim of this study is to assess the safety and efficacy of interferon alfa-2b plus ribavirin in treating histological recurrent HCV after LT. Since 1998, patients with HCV with significant histological recurrence (fibrosis >/= 3 and/or histological activity index >/= 5) or progressive cholestatic disease after LT were treated with interferon alfa-2b (3 million units subcutaneously three times weekly) plus ribavirin (800 to 1,000 mg/d) for 12 months. Immunosuppression was tapered to cyclosporine/FK506 monotherapy. HCV RNA was assessed at entry, week 24, end of treatment, and 6 months after therapy. The primary end point was loss of HCV RNA 6 months after therapy, whereas the secondary end point was histological response. Fifty-four patients met criteria for treatment and have completed follow-up. Patients were mainly men (71% men; mean age, 51 +/- 5 years) with genotype 1 infection (88%) and high viral load (mean HCV RNA, 38 +/- 9 mEq/mL). Dose modification was required in 72% of patients because of cytopenia or side effects. Intent-to-treat analysis showed that serum HCV RNA was undetectable in 19 patients (35%) week 24, 21 patients (38%) week 48, and 16 patients (30%) at the 6-month follow-up. Paired liver biopsy results (before and within 6 months after treatment) were available for 35 patients. Patients who achieved viral eradication had no significant progression of fibrosis after 1 year of therapy. In summary, combination therapy is a reasonable antiviral option for recurrent HCV infection for established post-LT hepatitis and appears to prevent histological progression of disease if viral eradication is successful.
Hepatitis C virus (HCV) reinfection after liver transplantation is frequent and leads to chronic hepatitis and cirrhosis. The use of antiviral therapy in this situation remains controversial. This study aimed to assess the safety and efficacy of interferon alfa-2b plus ribavirin for recurrent hepatitis C following liver transplantation.
Transplant recipients with recurrent chronic hepatitis C were randomized to receive either no treatment or therapy with interferon alfa-2b (3 MU 3 times a week) plus 1000-1200 mg/day ribavirin for 1 year. Patients were followed up for 6 months after the end of treatment. The primary end point was loss of HCV RNA 6 months after the end of treatment.
Fifty-two patients were randomized (treatment, 28; placebo, 24). Sixteen patients were withdrawn from the study; 12 (43%) were from the treated group (mainly for anemia [7 patients]) and 4 (17%) from the control group. In the treated group, serum HCV RNA was undetectable in 9 patients (32%) at the end of treatment and 6 (21.4%) at the end of the follow-up period, whereas no patient in the control group lost HCV RNA at any point (P = 0.036 at the end of follow-up). However, there was no significant histologic improvement.
The combination of interferon alfa-2b plus ribavirin induced a sustained virologic response in 21% of transplant recipients with recurrent hepatitis C. However, 43% discontinued therapy due to adverse events (primarily severe anemia). Strategies to enable treatment with lower doses of ribavirin need to be explored.
The benefit of antiviral treatment in recurrent hepatitis C after liver transplantation remains unclear. The aim of this study was to determine whether antiviral treatment improved histologic outcome in recurrent hepatitis C. All patients who were transplanted for hepatitis C from January, 1998 to December, 2000 were offered treatment with interferon alpha 2b (3 million units three times per week) and ribavirin (800 mg/d) for 1 year. All patients underwent liver biopsy before and after treatment. Virologic assay was performed at 3 months and at 1 year. Among the 33 patients, 13 managed 80% of total doses of both interferon and ribavirin. Dose reduction or discontinuation was necessary in others. In an intention to treat analysis, the overall virologic response at 3 months and 1 year was 27% and 12%, respectively. On an intention to treat basis, the overall histologic response showed little benefit. In the subgroup of patients who received full treatment, there was a trend towards benefit in regard to inflammation (per histologic activity index [HAI] score). However, the fibrosis score was comparable in both groups, and complete antiviral treatment did not improve the fibrosis score or prevent progression of fibrosis. In the posttransplant setting, it is often extremely difficult to give a full course of treatment with existing antiviral regimes. In an intention to treat analysis, the overall benefit of antiviral treatment in recurrent hepatitis C is disappointing, with little impact on the progression of fibrosis.
The European Liver Transplant Registry (ELTR) currently allows for the analysis of 44,286 liver transplantations (LTs) performed on 39,196 patients in a 13-year period. After an exponential increase, the number of LTs is plateauing due to a lack of organs. To cope with this, alternatives to cadaveric LT, such as split LT, domino LT, or living-related LT (LRLT) are being used increasingly. They now account for 11% of all procedures. One of the most important findings in the evolution of LT is the considerable improvement of results along time with, for the mean time, a one-year survival of 83%, all indications confounded. The improvement is particularly significant for cancers. This improvement is mainly represented by hepatocellular carcinoma, with a gain of 17% for 5-year survival rate from 1990 to 2000. Increasingly, older donors are used to augment the donor pool and older recipients are transplanted due to improved results and a better selection of patients. More than two thirds of deaths and three quarters of retransplantations occurred within the first year of transplantation. Retransplantation is associated with much less optimal results than first LT. One of the prominent features of recent years is the development of LRLT. LRLT is now performed by almost half of the European centers. As with split LT or domino LT, LRLT aims to provide more patients to be transplanted. Special attention is paid to reducing the risk for the donor, which is now estimated to be 0.5% mortality and 21% postoperative morbidity.
Recurrent hepatitis C infection is an important cause of progressive fibrosis, cirrhosis, and graft loss following orthotopic liver transplantation. Treatment for posttransplant recurrence of hepatitis C with interferon-based therapy is difficult but results in loss of detectable virus in up to 30% of patients. However, the durability of viral clearance and the associated histologic response in this setting is unknown. The aim of this study was to determine whether viral loss in response to antiviral therapy is durable and associated with improvement in liver histology. All liver transplant recipients who received interferon-based treatment for recurrent hepatitis C virus (HCV) at the University of Florida from 1991 to 2002 were included in this study. Patients who lost detectable HCV after treatment with interferon alone or in combination with ribavirin were followed to assess the durability of viral response and its impact on liver histology. One hundred nineteen transplant recipients were treated with interferon or combination therapy. Twenty-nine (20 men, 9 women; mean age, 54 yrs [range, 42-74 yrs]) lost detectable HCV RNA and remained virus negative for at least 6 months after discontinuing therapy (sustained viral response[SVR]). The mean follow-up after discontinuing therapy was 24.7 months (range, 6-70 mos). Our study cohort included one patient with SVR following interferon monotherapy and 28 patients with SVR following combination therapy with interferon plus ribavirin. All patients remained HCV RNA negative (assessed by polymerase chain reaction or branched-DNA assay) during follow-up of up to 5 years. Liver histology assessed 2 years after treatment showed less inflammation compared with before treatment in 50% and showed no change in 38%. By 3 to 5 years post-treatment (n = 15 recipients), inflammation was reduced in 60% and remained unchanged in 33%. Fibrosis stage at 2 years improved by > or = 1 stage in 27 %, remained unchanged in 38 %, and worsened in 35% despite viral clearance. At 3 to 5 years, the fibrosis stage had improved in 67%, remained unchanged in 13%, and worsened in 20%. Both grade of inflammation and fibrosis stage improved by 3 to 5 years posttreatment compared with baseline histology (p < 0.05). In conclusion, loss of HCV after treatment of recurrent chronic hepatitis C with interferon and ribavirin is durable, and the durability of the SVR is associated with improvement in hepatic inflammation and regression of fibrosis.
Aim of our study was to analyze fibrosis progression after liver transplantation (OLT) in hepatitis C virus (HCV)-infected patients based on protocol liver biopsies and to identify risk factors, which may play a role in the development of severe fibrosis stages.
One hundred and eighty-three liver graft recipients who had a histological follow-up evaluation of 1 year after OLT were analyzed. Overall 1039 protocol liver biopsies were performed after 1-, 3-, 5-, 7- and 10 years and staged according to the Scheuer score.
The fibrosis progression rate was not linear. The fibrosis scores were 1.2 after one, 1.7 after three, 1.9 after five, 2.1 after 7 and 2.2 after 10 years. The 39 recipients with fibrosis stages 3 or 4 in the 1-year biopsy had a significantly reduced survival rate, while fibrosis stage 0-2 indicated excellent survival. Independent risk factors for progression of fibrosis at 1 year were HCV genotype 1 and 4 (P=0.01) and donor age>33 years (P=0.01), whereas risk factors for development of cirrhosis (30/183 recipients (16%)) were donor age (P=0.002) and multiple steroid pulses (P=0.05).
These data provide information on the course of recurrent hepatitis C and may be helpful to individualize the treatment of transplanted patients.
In HCV cirrhotic patients after liver transplantation, survival and recurrence of HCV appears to be worsening in recent years. Donor age has been suggested as a cause. However, it is not clear if early and/or late mortality is affected and whether donor age is a key factor, as opposed to changes in immunosuppression. The aim of this study was to assess impact of donor age and other factors with respect to the severity of HCV recurrence posttransplant. A consecutive series of 193 HCV cirrhotic patients were transplanted with cadaveric donors, median age 41.5 years (13-73) and median follow-up of 38 months (1-155). Donor age and other factors were examined in a univariate/multivariate model for early/late survival, as well as fibrosis (grade 4 or more, Ishak score) with regular biopsies, 370 in total, from 1 year onwards. Results of the study indicated that donor age influenced only short-term (3 months) survival, with no significant effect on survival after 3 months. Known HCC independently adversely affected survival, as did the absence of maintenance azathioprine. Severe fibrosis (stage > or = 4) in 51 patients was related to neither donor age nor year of transplantation, but it was independently associated with combined biochemical/histological hepatitis flare (OR 2.9, 95% CI 1.76-4.9) whereas maintenance steroids were protective (OR 0.4, 95% CI 0.23-0.83). In conclusion, in this cohort donor age did not influence late mortality in HCV transplanted cirrhotic patients or development of severe fibrosis, which was related to absence of maintenance steroids and a hepatitis flare. Maintenance azathioprine gave survival advantage.
Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis in the absence of a history of significant alcohol use or other known liver disease. Nonalcoholic steatohepatitis (NASH) is the progressive form of NAFLD. The Pathology Committee of the NASH Clinical Research Network designed and validated a histological feature scoring system that addresses the full spectrum of lesions of NAFLD and proposed a NAFLD activity score (NAS) for use in clinical trials. The scoring system comprised 14 histological features, 4 of which were evaluated semi-quantitatively: steatosis (0-3), lobular inflammation (0-2), hepatocellular ballooning (0-2), and fibrosis (0-4). Another nine features were recorded as present or absent. An anonymized study set of 50 cases (32 from adult hepatology services, 18 from pediatric hepatology services) was assembled, coded, and circulated. For the validation study, agreement on scoring and a diagnostic categorization ("NASH," "borderline," or "not NASH") were evaluated by using weighted kappa statistics. Inter-rater agreement on adult cases was: 0.84 for fibrosis, 0.79 for steatosis, 0.56 for injury, and 0.45 for lobular inflammation. Agreement on diagnostic category was 0.61. Using multiple logistic regression, five features were independently associated with the diagnosis of NASH in adult biopsies: steatosis (P = .009), hepatocellular ballooning (P = .0001), lobular inflammation (P = .0001), fibrosis (P = .0001), and the absence of lipogranulomas (P = .001). The proposed NAS is the unweighted sum of steatosis, lobular inflammation, and hepatocellular ballooning scores. In conclusion, we present a strong scoring system and NAS for NAFLD and NASH with reasonable inter-rater reproducibility that should be useful for studies of both adults and children with any degree of NAFLD. NAS of > or =5 correlated with a diagnosis of NASH, and biopsies with scores of less than 3 were diagnosed as "not NASH."
Recurrence of hepatitis C virus (HCV) infection after orthotopic liver transplantation (OLT) is a virtually universal occurrence, and a significant proportion of patients develop chronic hepatitis and cirrhosis. The aim of this study was to evaluate the safety and efficacy of interferon (IFN)-alpha2b plus ribavirin (RIBA) in the treatment of recurrent HCV after OLT over the long term.
Fifteen patients with recurrent HCV infection (positive serum HCV RNA, elevated serum aminotransferases, histological activity) were started on IFN-alpha2b (3-6 million units administered subcutaneously three times a week) plus RIBA (800-1200 mg/day) 18+/-5 months after OLT. HCV RNA was determined 1, 3, 6, 9, 12 and 18 months after initiation of treatment. Liver biopsy was performed before and after therapy. The patients were followed up for a mean of 33+/-5 months.
Thirteen patients (87%) were treated for at least 6 months and nine patients (60%) for 12 months. After 3 months, 11 patients (73%) were free from HCV RNA (<50 copies/ml); the virological end-of-treatment response was 67%. Five patients (33%) remained HCV RNA-negative 6 months posttreatment (sustained response (SR)). During the follow-up period, four patients (27%) died of liver failure, recurrent HCV after virological response, or HCC. The histological activity index improved significantly for both inflammatory activity and fibrosis, from 8.8 to 4.7 and from 7.3 to 4.8, respectively. In none of the patients were signs of rejection observed.
Combination therapy with IFN and RIBA in transplanted patients with chronic hepatitis C is an effective treatment that results in a high virological SR rate. It is well tolerated and leads to an improvement in histological outcome.
Cyclosporine is an immunosuppressive agent widely used in the management of liver transplant recipients. Cyclosporine has been shown to have antiviral activities against HIV, herpes simplex, and vaccinia viruses. The aim of this study was to determine the effect of Cyclosporine in viral clearance in the liver transplant recipients during therapy with combination of interferon and ribavirin, and to determine the anti-viral potential of Cyclosporine in vitro. Immunosuppression consisted of either Cyclosporine or Tacrolimus-based therapy. Both groups received therapy with interferon and ribavirin for 48 weeks when evidence of progressive histologic disease was determined. We found that subjects on Cyclosporine-based immunosuppression (n = 56) had a higher sustained virological response of 46% compared to 27% in the patients on Tacrolimus-based therapy (n = 59, P = 0.03). In vitro studies were performed to evaluate the antiviral effect of Cyclosporine in the replicon system. These studies showed that Cyclosporine inhibits hepatitis C viral replication in a dose-dependent manner. Combination of Cyclosporine with interferon showed additive effect, and its function is independent of interferon signaling pathways. In conclusion, Cyclosporine may offer an advantage to Tacrolimus in those patients undergoing interferon-based therapy and should be studied in a prospective randomized trial.
There are unresolved issues regarding sustained virological response (SVR), tolerance and risk of rejection following antiviral therapy in liver transplantation (LT). The aim of our study was to determine efficacy, rejection risk and factors associated with SVR. HCV-infected LT patients with at least 6 months of follow-up following end-of-therapy (EOT) received combination therapy of ribavirin (Rbvr) + standard (n = 31)/pegIFN (n = 36) between 1999 and 2004 (95% genotype 1). An EOT and SVR was obtained in 46% and 33%, respectively. Type of antiviral therapy, use of erythropoietin, compliance, and early virologic response (EVR) were predictive of SVR, but only the latter remained in the multivariate analysis. Premature discontinuation, not impacted by the use of erythropoietin or GCSF, occurred in 40% patients. None of the variables predicted rejection (acute n = 2, chronic n = 4). A SVR occurred in 3/4 patients with chronic rejection. In conclusion, the efficacy of pegIFN-Rbvr is similar to the non-transplant population. An EVR at 3 months is useful to predict lack of response. The type of calcineurin inhibitor and history of prior non-response to IFN before LT do not influence the outcome of therapy. Severe rejection may lead to graft loss, a complication difficult to predict.
Recurrent hepatitis C virus (HCV) after liver transplantation (OLT) is a major cause of graft loss in HCV-positive patients. In this study, we evaluated the efficacy and safety of pegylated interferon alfa-2b (peginterferon) and ribavirin treatment for recurrent HCV after OLT and analyzed the influence of antiviral treatment on the histological course of recurrent hepatitis.
Twenty-five patients with recurrent HCV (genotype 1 n=20 and 2-4 n=5) received peginterferon (1 mg/kg/weekly) and ribavirin (600 mg) for 48 weeks. Viral load prior to treatment was below 1,000,000 (IU/ml) in 11 of 25 patients. Sustained antiviral response was defined as undetectable HCV-RNA in serum 6 months after stopping of therapy. All patients underwent liver biopsy prior to treatment and after 72 weeks.
Seventeen of 25 patients became HCV-RNA-negative after treatment (68%). Sustained virologic response (SVR) was achieved in 9/25 (36%) patients. Liver specimen showed increase of fibrosis from 1.7 to 2.0 within 72 weeks. Side effects like neutropenia (60%) and anemia (36%) were treated with G-CSF, erythropoietin, and dose reduction of peginterferon and ribavirin.
The use of peginterferon is safe and effective in patients with recurrent HCV. Treatment of side effects, especially neutropenia or anemia, helped to maintain antiviral therapy. Despite a viral response of 68% during treatment, the patients showed further progress of recurrent hepatitis in liver specimen.
Hepatitis C recurrence after liver transplantation (LT) is universal, and frequently leads to cirrhosis and death. The aim of our study was to assess the efficacy and safety of 48-weeks of full-dose peg-interferon-alpha-2a (n = 4) or alpha-2b (n = 51) plus ribavirin (>11 mg/kg/day) in a multicentric cohort of 55 patients > or =12 months after LT. All subjects had histologically proven HCV recurrence, excluding severe cholestatic recurrence. Mean age was 54.3 +/- 9.7, 77% male, 90.9% genotype 1, 32.7% cirrhotics. All but 5 patients received monotherapy with tacrolimus (54.5%), cyclosporine (30.7%) or mycophenolate mofetil (5.5%). The rates of end-of-treatment response and sustained virological response (SVR) were 66.7% and 43.6%, respectively. Low baseline HCV-RNA (p = 0.005) and a length from LT to therapy between 2-4 years (p = 0.011) were predictors of SVR. The lack of achieving a viral load decrease > or =1-log10 at week 4 and/or 2-log10 at week 12 was 100% predictive of failure. The most frequent side effects were neutropenia (76,4%), anemia (60%) and infectious complications (30.9%). Toxicity led to peg-interferon withdrawal in 16 (29%) subjects. In 15 patients with post-treatment biopsy, the histological activity index was significantly improved (p = 0.006), whereas fibrosis did not change (p = 0.14). Three patients died (cholangitis, hepatic artery thrombosis and lung cancer). In conclusion, HCV therapy after LT was very effective, although it led to a significant rate of toxicity.
The LIS2T study was an open-label, multicenter study in which recipients of a primary liver transplant were randomized to cyclosporine microemulsion (CsA-ME) (Neoral) (n = 250) (monitoring of blood concentration at 2 hours postdose) C2 or tacrolimus (n = 245) (monitoring of trough drug blood level [predose]) C0 to compare efficacy and safety at 3 and 6 months and to evaluate patient status at 12 months. All patients received steroids with or without azathioprine. At 12 months, 85% of CsA-ME patients and 86% of tacrolimus patients survived with a functioning graft (P not significant). Efficacy was similar in deceased- and living-donor recipients. Significantly fewer hepatitis C-positive patients died or lost their graft by 12 months with CsA-ME (5/88, 6%) than with tacrolimus (14/85, 16%) (P < 0.03). Recurrence of hepatitis C virus in liver grafts was similar in each group. Based on biopsies driven by clinical events, the mean time to histological diagnosis of hepatitis C virus recurrence was significantly longer with CsA-ME (100 +/- 50 days) than with tacrolimus (70 +/- 40 days) (P < 0.05). Median serum creatinine at 12 months was 106 mumol/L with CsA-ME and with tacrolimus. More patients who were nondiabetic at baseline received antihyperglycemic therapy in the tacrolimus group at 12 months (13% vs. 5%, P < 0.01). Of patients who were diabetic at baseline, more tacrolimus-treated individuals required anti-diabetic treatment at 12 months (70% vs. 49%, P = 0.02). Treatment for de novo or preexisting hypertension or hyperlipidemia was similar in both groups. In conclusion, the efficacy of CsA-ME monitored by blood concentration at 2 hours postdose and tacrolimus in liver transplant patients is equivalent to 12 months, and renal function is similar. More patients required antidiabetic therapy with tacrolimus regardless of diabetic status at baseline.
Mammalian target of rapamycin (mTOR) signalling is central in the activation of hepatic stellate cells (HSCs), the key source of extracellular matrix (ECM) in fibrotic liver. We tested the therapeutic potential of the mTOR inhibitor rapamycin in advanced cirrhosis.
Cirrhosis was induced by bile duct-ligation (BDL) or thioacetamide injections (TAA). Rats received oral rapamycin (0.5 mg/kg/day) for either 14 or 28 days. Untreated BDL and TAA-rats served as controls. Liver function was quantified by aminopyrine breath test. ECM and ECM-producing cells were quantified by morphometry. MMP-2 activity was measured by zymography. mRNA expression of procollagen-alpha1, transforming growth factor-beta1 (TGF-beta1) and beta2 was quantified by RT-PCR.
Fourteen days of rapamycin improved liver function. Accumulation of ECM was decreased together with numbers of activated HSCs and MMP-2 activity in both animal models. TGF-beta1 mRNA was downregulated in TAA, TGF-beta2 mRNA was downregulated in BDL. 28 days of rapamycin treatment entailed a survival advantage of long-term treated BDL-rats.
Low-dose rapamycin treatment is effectively antifibrotic and attenuates disease progression in advanced fibrosis. Our results warrant the clinical evaluation of rapamycin as an antifibrotic drug.
Choice of calcineurin inhibitor may be a contributing factor to deteriorating patient and graft survival following liver transplantation for hepatitis C virus (HCV). In our multicenter, open-label LIS2T study, de novo liver transplant patients stratified by HCV status were randomized to cyclosporine or tacrolimus. Follow-up data were obtained in an observational study of 95 patients. Mean follow-up was 34 and 37 months, respectively, for cyclosporine-treated (n = 47) and tacrolimus-treated (n = 48) patients. In patients not receiving antiviral therapy, 22 of 31 given cyclosporine (72%) and 24 of 29 given tacrolimus (83%) had biochemical recurrence of HCV. In 68 patients with at least one biopsy, histological evidence of HCV-related hepatitis was present in 27 of 31 (87%) cyclosporine-treated patients and 37 of 37 (100%) tacrolimus-treated patients (P = .02, chi-square test). Three-year actuarial risk of fibrosis stage 2 was 66% with cyclosporine and 90% with tacrolimus; for fibrosis stage 3 or 4 it was 46% and 80%, respectively. Three graft losses were attributed to HCV recurrence in cyclosporine-treated patients and six in tacrolimus-treated patients. Tacrolimus may be associated with increased risk of histological HCV disease recurrence compared to cyclosporine.
Treatment of recurrent hepatitis C in liver transplant is controversial. The aim of our study was to evaluate the clinical and histological efficacy of pegylated interferon alpha 2b (PEG-IFN) and ribavirin therapy of recurrent hepatitis C after liver transplantation (LT). We prospectively included 47 liver transplant patients with: 1) a positive test for hepatitis C virus (HCV)-ribonucleic acid (RNA) in serum; 2) alanine aminotransferase (ALT) >45 UI/mL; and 3) a liver biopsy showing chronic hepatitis without rejection in the previous 2 months. Patients received PEG-IFN (1.5 microg/kg/week) and ribavirin (800-1,000 mg/day) for 12 months. Follow-up was based on biochemical (ALT), virological (RNA-HCV), and histological (liver biopsy) examinations. Follow-up lasted a minimum of 6 months after the end of antiviral therapy. Sustained virological response (SVR) was achieved in 23% of the patients. A total of 33 (70%) patients had normalized ALT levels at the end of therapy. Inflammatory portal and lobular score declined significantly in patients with SVR (P < 0.05) but not in nonresponder patients. Fibrosis did not change significantly in either group. SVR was significantly associated with low gamma-glutamyltransferase GGT (P = 0.04) and HCV-RNA levels (P = 0.03), a virological response at 12 weeks (P = 0.002) and patient's compliance (P = 0.04). Ten (21%) patients were withdrawn prematurely due to adverse effects. In conclusion, Therapy with PEG-IFN and ribavirin achieved SVR and a significant histological improvement in 23% of liver transplant recipients with chronic hepatitis C. Toxicity is an important drawback of this therapy.
HCV infection recurs almost in all HCV-positive patients receiving liver transplantation and carries a poor prognosis. Aim of this study was to analyze efficacy and effect on survival of antiviral therapy in this clinical setting.
Pegylated-interferon alpha-2b and ribavirin were administered at a dose of 1 microg/kg of bwt weekly and 600-800 mg/day. Planned duration of treatment was 24 or 48 weeks according to HCV genotype. Patients who failed to respond at week 24 were considered as non-responders.
61 patients were enrolled. According to intention-to-treat analysis, 44 (72%) patients were considered as treatment failure (31 non-responders, 4 relapsers, 9 dropout). Sustained virological response was achieved in 17 cases (28%). Genotype 2, higher doses of antivirals and absence of histological cirrhosis were predictors of sustained virological response. In the follow up, patients with sustained virological response had a significantly lower mortality compared to patients with treatment failure (chi2=6.9; P<0.01).
Response rate to antiviral therapy in HCV reinfection after liver transplantation is higher if a full dose of antiviral drugs is administered and if treatment starts before histological cirrhosis has developed. Sustained virological response improves patient survival.
Recurrent hepatitis C after liver transplantation (LT) is a major problem, since up to 30% of patients develop cirrhosis only 5 years after LT in the absence of antiviral therapy. The aim of this study was to examine the rate of progression of fibrosis and its associated risk factors in patients submitted to an early antiviral treatment post-LT. Included in the study were 105 patients submitted to LT between September 1990 and December 2004, 70 of whom were treated with interferon and/or ribavirin. A total of 939 liver biopsies were studied. The median fibrosis stage was 0.8 after 1 year post-LT, 1.1 after 3 years, 1.3 after 5 years, and 1.5 after 10 years. LT recipients with fibrosis >2 (13% at 10 years) had a significantly reduced survival rate (63% vs. 87% at 10 years, P = 0.03). Univariate analysis disclosed that recipient male gender, antiviral therapy before LT, LT after 1998, induction immunosuppressive regimen including tacrolimus, induction immunosuppressive regimen including mycophenolate (or without azathioprine), and short duration of prednisolone (<12 months) were significantly associated with progression of fibrosis. In a multivariate analysis, recipient male gender (P = 0.04), antiviral treatment before LT (P = 0.001), and initial immunosuppressive regimen without azathioprine (P = 0.03) were associated with progression of fibrosis. In conclusion, our study has documented that fibrosis progression is not linear over time and that occurrence of severe fibrosis is related to previously described factors related to immunosuppressive regimen or donor age and also to a past history of pre-LT antiviral therapy.