Liver Transplantation – Viral Hepatitis – Saturday Nov 1: 2pm

 

Liver Transplantation – General

596. Long Term Outcomes in Non-Heart Beating Donor Grafts in Liver Transplantation for Chronic Hepatitis C: no increase in HCV recurrence or graft loss.  

A. Suddle; V. Aluvihare; P. Muiesan; M. Foxton; J. G. O'Grady; M. A. Heneghan; M. Rela; N. Heaton; K. Agarwal

 

Introduction:

Non-Heart Beating Donors (NHBD) in Liver Transplantation (LT) are utilized as a strategy to increase the donor pool. Issues surrounding graft loss and Hepatitis C virus (HCV) recurrence are of potential concern in this donor group.

 

Aim:

A retrospective study assessing long term graft outcomes and HCV recurrence in NHBD and Deceased Brain-stem Donors (DBD) in a single institution.

 

Methods:

Our NHBD program is the largest in Europe. Patients transplanted with NHBD for HCV cirrhosis were identified at our institution between 2001-2008 from our database. A contemporaneous control cohort of DBD LT for HCV cirrhosis was assembled. All patients had standardized immunosuppression and underwent protocol liver biopsy for HCV recurrence. Biliary complications were assessed by biliary imaging.

 

Results:

30 patients with HCV cirrhosis underwent LT with NHBD grafts between 2001 and 2008, out of a total of 87 NHBD performed (34.5%). A control group of 48 DBD LT for HCV were identified. The age and sex distribution of the 2 groups were similar. MELD score at time of transplant was similar in both groups (13.6 NHBD group, 12.1 DBD group, p=0.583). Donor age was similar in both groups (53.8 vs 54.5 yrs p=NS). The incidence of Acute Cellular Rejection was similar in both groups (4 in NHBD, 6 in DBD p=0.68) as were.1 patient in the NHBD group developed Primary Non function compared to none in the DBD group. 3 patients in the NHBD group developed graft failure (1 chronic rejection, 2 recurrent HCV) in the follow up period compared to 2 in the DBD group (both recurrent HCV), all were re-transplanted with satisfactory post transplant outcome. 3 patients in the NHBD group developed biliary complications compared to 5 in the DBD group (p=0.953). Protocol biopsies showed a similar degree of fibrosis in both groups (p=NS). Overall graft survival was similar in both groups (log rank, p=0.73).

 

Conclusions:

Our data suggest no significant difference in outcomes utilizing NHBD for HCV. NHBD in our experience presents a useful to expand the donor pool for HCV disease.

 

Kaplan-Meier Curves for graft survival in NHB and DBD grafts

 


Liver Transplantation – HCV Recurrence – HCV treatment

 

601. Incidence of Acute Cellular Rejection During Interferon-based Therapy for Recurrent Hepatitis C following Liver Transplantation: A Retrospective Study. 

S. A. Gonzalez; A. Waechter; M. Lee; A. Kamal; E. B. Keeffe; A. Ahmed

 

Background:

Interferon (IFN)-based therapy may be considered in patients with recurrent hepatitis C virus (HCV) following liver transplantation (LT). The potential risk of acute cellular rejection (ACR) during IFN-alfa therapy has not been clearly defined.

 

Methods:

We performed a retrospective cohort study of all patients with chronic HCV who underwent LT at our center between 1995 and 2006. All results from liver biopsies performed during the post-LT follow-up were reviewed. The presence of ACR and recurrence of HCV were defined by histopathological criteria.

 

Results:

Two hundred five patients with active HCV infection who underwent LT were included in this study; 73 patients received at least one dose of IFN-based therapy. Median post-LT follow-up was 4.0(0-12.3) years. Overall patient characteristics were as follows: median age 52, 71% male, 66% HCV genotype 1, 35% hepatocellular carcinoma, 49% alcohol abuse. Treated patients were more likely to have received IFN-alfa therapy before LT (21% vs. 11%, p=0.05). In treated patients (n=73), 58% received pegylated IFN-alfa and 21% had multiple treatment courses. Median cumulative duration of IFN therapy was 47(2-284) weeks. Overall, 473 liver biopsies were performed in 162 patients: 97% of treated patients had biopsy-proven HCV recurrence vs. 42% of untreated patients. IFN-treated patients were more likely to have immunosuppressive regimens including prednisone (81% vs. 63%, p=0.01) or tacrolimus (96% vs. 85%, p=0.02). The overall incidence of ACR was greater in IFN-treated patients (32/73, 44% vs. 38/132, 29%; p=0.03), although no difference was noted when restricting analysis to patients with biopsy-proven HCV recurrence (30/71, 42% vs. 23/56, 41%; p=NS). In IFN-treated patients with ACR, 17/32(53%) had occurrence of ACR during or following IFN-alfa therapy. Patients with IFN-associated ACR (n=17) had a longer time to ACR occurrence (p=0.02) and received a shorter cumulative duration of IFN therapy (p=0.05). In patients receiving IFN-alfa, those with ACR had overall decreased survival (p<0.01) and increased graft loss (p<0.01). Patients with IFN-associated ACR had decreased survival (p=0.03) and increased graft loss (p=0.07) compared with patients in which ACR occurred before IFN-based therapy.

 

Conclusions:

The overall incidence of ACR was increased in our patients who received IFN-based therapy; however no difference was noted in analysis restricted to those with biopsy-proven HCV recurrence. In treated patients, IFN-associated ACR may have a negative impact on graft loss and survival. Prospective studies should be performed to identify risk factors associated with ACR during IFN-based therapy.

 


Liver Transplantation – General

 

602. Outcomes of Patients with Hepatitis C Undergoing Simultaneous Liver-Kidney Transplant vs. Liver Transplant Alone.

L. B. VanWagner; J. Norvell; E. Wang; J. Levitsky

 

Background:

The number of simultaneous liver-kidney transplants (SLK) performed has been steadily increasing. Data on outcomes of HCV+ SLK compared to HCV+ liver transplant alone (LTA) recipients are limited.

 

Methods:

A case/control study comparing outcomes of all HCV+ SLK recipients (6/99-1/07) vs. transplant year-matched HCV+ LTA controls (1:1) was performed (up to 5 year data). Univariate analysis of covariates and Kaplan Meier and Cox proportional hazard models on overall survival and freedom from HCV recurrence were conducted.

 

Results:

38/142 (26.7%) SLK recipients were HCV+. At SLK: Age 53.9±8.1 yrs, 60.5% males, 10.5% HCC, Calc MELD 34.5±6.6. Controls were not different by age/gender but had significantly higher % HCC (55.2%) and lower Calc MELD (17.4±8.6) at LTA (p=0.001). Survival analysis (Fig 1) demonstrated a higher death rate in the SLK vs. LTA groups, particularly early after transplant, but not significant when controlled for Calc MELD. Univariate analysis revealed a higher percentage of SLK recipients with early (0-6 mos) infections (56.3%) compared to LTA (21.6%) (p=0.001). Other outcomes, i.e. freedom from HCV recurrence, % ≥ stage 2 fibrosis (1,2 yr), rejection, ALT/bilirubin/creatinine, were not different over time. Only 4 (10.5%) SLK patients had kidney rejection. 10 (26.3%) SLK patients treated with PEG+RBV: 2 (20%) SVR, 8 NR, 0 liver/kidney rejection.

 

Conclusions:

Our study represents the largest analysis of HCV+ SLK outcomes and demonstrates a significantly worse survival than LTA, likely due to higher MELD at transplant and having early complications (infections) unrelated to HCV. However, long term outcomes, i.e., HCV recurrence, graft and renal dysfunction, are similar to that of LTA patients. While SVR rates are low, HCV treatment in SLK recipients appears safe. Further investigation of measures to improve survival early after SLK in HCV+ recipients is needed.

 

 


Liver Transplantation – General

 

603. Evaluation of FIB-4 as a Marker of Fibrosis in HCV Infected Patients who Underwent Liver Transplantation. 

M. C. Segovia; E. R. Lyden; T. Bernard; T. M. McCashland

 

Purpose:

Evaluate a liver fibrosis index score (FIB-4) to predict stage of fibrosis in patients post liver transplant for hepatitis C (HCV).

 

Methods:

The records of all the HCV patients (283 subjects) who underwent liver transplantation between the years of 1997 and 2007 at the University of Nebraska Medical center (UNMC) were retrospectively reviewed. 219 patients were studied to see if FIB-4 score correlated with the histological (Metavir (F0-F4)) results of liver biopsies done after the transplant. A total of 669 biopsies from 219 patients were analyzed. The analysis was done utilizing all the biopsies. A mixed effects model was used to compare the FIB-4 index and fibrosis score with a fixed effect for fibrosis score and a random effect for recipient. Receiver operator curves (ROC) were used to examine the usefulness of FIB-4 as a diagnostic tool for identifying patients with severe fibrosis. Multiple comparisons were adjusted using Tukey’s method.

 

Results:

The median number of biopsies was 2 per recipient (range 1-12). The mean age at first biopsy was 52.3 years (sd=8.3 years) and 68.95% were male. The main three reasons for liver transplantation were HCV (53.42%), HCV plus alcohol (25.57%) and HCV plus hepatocellular carcinoma (12.79%). The distribution of the fibrosis score for the biopsies were as follows: 44.54%, no fibrosis; 25.56%, stage 1; 15.25%, stage 2; 11.36%, stage 3 and 3.29%, stage 4. The mean FIB-4 index differed significantly between the fibrosis score groups: The group with no fibrosis (F0) had a mean FIB-4 of 4.37 (se=0.41); stage 1 (F1), 5.71 (se= 0.52); stage 2 (F2), 6.10 (se= 0.66); stage 3 (F3), 8.56 (se=0.77) and stage 4 (F4), 12.86 (se=1.38) (F0 to F4, p<0.0001). For patients with F4 fibrosis, the FIB-4 index was significantly larger than for recipients with fibrosis scores F0 to F3 (p<0.05 for each comparison). The FIB-4 index for patients with F3 fibrosis was also significantly larger than the FIB4-index for recipients with fibrosis scores F0 and F1 (p<0.05 for each comparison). A threshold cut-point of 4.09 of the FIB-4 index maximized the sensitivity and specificity to 80 and 60%. Unfortunately, the negative and positive predictive values for this cut-point were 94% and 25% respectively.

 

Conclusions:

FIB-4 is not an accurate test for assessing individual grades of liver fibrosis in patients post liver transplant for HCV. FIB-4 was able to differentiate cirrhosis from low-grade fibrosis. Routine use of this non-invasive marker of liver fibrosis in the post liver transplant setting remains problematic.

 


Liver Transplantation – HEV

 

604. Incidence and outcomes of acute hepatitis E in a liver transplant unit. 

A. Gera; I. Coltart; M. J. Bruce; I. Carey; K. Agarwal

 

Background:

Hepatitis E (HEV) infection is rare in Western countries. Majority of cases are through acquisition in developing countries where the virus is endemic. However, increasing numbers of indigenous cases are being reported.

 

Aim:

To study the incidence, severity and outcome of acute HEV infection within a large transplant centre.

 

Method:

A retrospective case note review of all adults testing HEV IgM positive (MP diagnostic assay) between Jan 2000 and April 2008 was undertaken. HEV serology was tested on clinical suspicion in acute liver failure (ALF). A comparator group was assembled from all patients admitted with ALF secondary to other viral hepatitides (A, B and Delta) over the same time period.

 

Results:

28 adults tested HEV IgM positive: 60.7% male, mean age 34.3 years (range 19-63), mean MELD 24.92 (range 5-40). 15 (53.6%) acquired HEV in the Indian Sub-Continent, 1 in Italy, 1 in Croatia. The remainder acquired HEV in the UK, with no specific geographical location or risk factors identified. 21 had acute HEV mono-infection with no other aetiological factors. 2 were pregnant (12 and 27 weeks gestation, MELD 35 and 18 respectively). Both recovered and delivered successfully. 6 patients were biopsied: 5 consistent with an acute insult, likely viral and 1 with additional steatosis and fibrosis. 7 patients had co-existing positive HEV serology in the context of liver dysfunction with acute hepatitis A (HAV), EBV, malaria, and chronic hepatitis C infection, autoimmune hepatitis and Wilson’s disease (2 patients). 12/28 (42.9%) required ITU admission: length of stay 3-21 days (mean 9.58); mean MELD 33.83 (range 26-40). 4 (14.3%) progressed to super-urgent listing and liver transplantation (LT) due to ALF, with 2 having co-existing Wilson’s disease. Explant histology revealed severe hepatitis in 2 consistent with acute viral insult; cirrhosis and chronic hepatitis with unknown aetiology in 1; cirrhosis and probable Wilson’s in 1. All LT patients survived >3 months. 2 deaths occurred within the clinical presentation of acute HEV; 1 had acute HAV/HEV; (mortality 10.7%). In comparison 8/36 (22.2%) with ALF secondary to HBV/Delta required LT (p=NS). None with HAV (n=5) required LT. The acute HAV group were significantly older (p=0.044), had higher incidence of ITU admission (p=0.036) and higher death rate (p=0.032) than with acute HEV.

 

Conclusion:

Incidence of HEV in our cohort is low. It is rare for acute HEV infection to progress to LT. HEV may unmask co-existing liver disease. Delineation of HEV serology in conjunction with HEV RNA in the context of ALF is mandated for accurate diagnosis. Incidence and outcome of LT in HEV is comparable to acute HBV.

 


Liver Transplantation – General

606. Impact of donor age on SVR in liver transplant (LT) recipients treated with pegIFN-ribavirin. 

V. Aguilera; M. Rodriguez; M. Prieto; C. Ortiz; A. Palau; F. Gentili; R. Canada; B. Risalde; M. Berenguer

 

Introduction:

Antiviral therapy post-transplantation has a limited efficacy. There is an interest in determining factors associated with sustained virologic response (SVR).

 

Aim:

To assess whether the age of the donor has an impact on SVR in LT recipients treated with pegIFN-ribavirin.

 

Methods:

96 LT patients (74% men, median age: 56 (37-70)), 87% genotype 1a or 1b, treated with pegIFN-ribavirin (pegasys: 62%, pegintron 38%) for a median duration of 356 days (range:16-623 days), at 576 (50 days- 3978) days from LT. Baseline immunosuppression was tacrolimus in 62%. 19% were cirrhotic and 68% had advanced fibrosis at baseline. The median donor age was 48 years (range 12-78).

 

Results:

A SVR was achieved in 36 patients (37.5%). Among other variables evaluated (gender, age at treatment, donor age, Child-Pugh at transplantation, history of pretransplantation failed antiviraltherapy, time from transplantation, baseline fibrosis, viremia, laboratory tests and immunosuppression, type of pegIFN, rapid viral response –RVR-, early virologic response-EVR-, genotype, premature discontinuation, IFN or ribavirin dose reductions, use of growth factors), those associated with SVR in the univariate analysis were baseline viremia (p=.02), RVR (p=.002), EVR (.0001), premature discontinuation of therapy (p=.02), genotype distribution (p=.05), weight (p=.05) and donor age (p=.007). There was a trend for patients with advanced fibrosis and cirrhosis to achieve lower SVR (48% vs 32%, p=.09). In the multivariate analysis, only donor age (p=.009) and EVR (p=.001) remained in the model. The median donor age of non-responders was 54 (17-78) vs 44 (12-69) years in SVR (p=.007).

 

Conclusions:

Aging donors are associated with worse antiviral response with pegIFN-ribavirin.

 


Liver Transplantation – HEV

 

607. Lack of evidence for chronic Hepatitis E as a major cause of graft hepatitis in liver transplant recipients. 

S. Pischke; A. Heim; P. V. Suneetha; R. Raupach; C. P. Strassburg; M. P. Manns; H. Wedemeyer

 

Introduction:

Causes of graft hepatitis after liver transplantation are often difficult to define. Infection with the hepatitis E virus (HEV) causes a self-limited acute liver disease that usually does not become chronic. However, investigators from Southern France recently identified 14 cases of acute hepatitis E in organ transplant recipients of whom 8 patients developed a chronic course (Kamar et al., NEJM Feb 2008). This finding may be biased by the particular high prevalence of HEV in South-West France. We therefore questioned if chronic hepatitis E plays a significant role in graft hepatitis also in other countries and studied 237 liver transplant recipients including 92 patients with unclear graft hepatitis, 111 non-transplanted patients with kryptogenic liver disease and 108 healthy controls for anti-HEV antibodies.

 

Methods:

Anti-HEV antibodies were measured by an ELISA assay (Abbott). All sera from transplanted patients were tested for HEV-RNA by nested PCR irrespective of the presence or absence of anti-HEV antibodies. All anti-HEV-positive sera were tested by a second independent real-time PCR using different primer regions.

 

Results:

Antibodies against HEV were detected in a much lower frequency as reported by Kamar et al. in all groups of patients (see table). We did not find evidence of graft hepatitis due to hepatitis E in any of the 237 liver transplant recipients studied. None of 145 transplanted patients tested HEV-RNA positive in a cross-sectional study. Anti-HEV was detected in only two out of 92 patients specifically admitted for evaluation of elevated ALT levels after liver transplantation and HEV-RNA tested negative in both individuals.

 

Conclusions:

Chronic hepatitis E is a rather rare event in liver transplant recipients, at least in Northern Germany. A general screening for HEV seems not be necessary unless special risk factors for hepatitis E have been identified

 

Frequeny of anti-HEV IgG and HEV-RNA in liver transplant recipients and controls

 

Number

Anti-HEV positive
n (%)

HEV-RNA positive
n (%)

Healthy controls

108

1 (0.9)

not done*

Patients with cryptogenic liver disease

111

5 (4.5)

not done

Liver transplant recipients
group A: cross-sectional
7.7±3.6 (0.1-20.6) years post transplantation

145

6 (4.1)

0 (0)

Liver transplant recipients
Group B: elevated
ALT levels
1.9±0.91 (0.1-32.7) years post transplantation

92

2 (2.2)

0 (0)

 


Liver Transplantation – General

 

608. Donor age affects response to antiviral therapy in patients with recurrent hepatitis C following liver transplantation. 

L. Lilly; G. Therapondos; N. Selzner; G. A. Levy; E. L. Renner

 

Background:

The majority of patients undergoing liver transplant (LT) for Hepatitis C (HCV) develop histological recurrence, resulting in reduced patient and graft survival when compared with other indications. Antiviral treatment with interferon and ribavirin is less effective than in the non-transplant population, and factors that predict response to treatment, although not fully characterized, include genotype and, potentially, the calcineurin inhibitor used. While donor age is an important variable in HCV recurrence following LT, its impact on response to antiviral therapy has not been widely examined.

 

Aims:

To determine the effect of donor age on the rate of sustained virological response (SVR) in patients treated for recurrent HCV following LT in a large transplant center. Methods: All 166 consecutive LT recipients in our program who have received antiviral treatment for recurrent HCV at UHN were analyzed. Those who received more than one graft prior to treatment, those who received <3m of treatment (and do not have an evaluable viral response) and those with missing donor information were excluded from this analysis.

 

Results:

134 LT recipients were included. Mean age at transplant was 54.1y, 80% were male, 84% received deceased donor (DD) grafts, and patients were treated 3-99m following transplant. Overall mean donor age was 44.4y [10-79]; for DD 46y, and live donors 36y. HCV genotype 1 infection (70%), recipient age and gender were equally distributed across all donor age groups. Overall, 75 patients achieved SVR (56%); the remainder either relapsed following treatment cessation or had no virological response. The rate of SVR was highest at 64% when donor age was <30 (n=31), and lowest at 44% with donor age >60 (n=25; see Figure).

 

Conclusions:

In addition to influencing HCV recurrence, donor age appears to influence the likelihood that antiviral therapy will be successful.

 

 


Liver Transplantation – HCV Recurrence

 

609. A Clinical Characterization of Patients with the Cholestatic Variant of Recurrent Hepatitis C Following Liver Transplantation. 

S. K. Satapathy; S. N. Sclair; J. V. del Rio Martin; M. Fiel; T. D. Schiano

 

Backgound:

Recurrent hepatitis C post-liver transplantation (LT) is universal, and some patients may develop an extremely aggressive course. One form of severe recurrence is the cholestatic variant, which is characterized by hyperbilirubinemia and histologically by severe cholestasis accompanied by prominent pericellular and perisinusoidal fibrosis and few inflammatory infiltrates. To date, there have only been small case series examining this entity.

 

Aim:

Using specific histological criteria, we sought to systematically characterize the clinical features and outcome in cholestatic recurrent HCV.

 

Methods:

The pathology liver database was searched for terms: cholestasis, fibrosing and hepatitis and cross-referenced with the term “liver allograft”. There were 973 LT for HCV performed from 1/91-12/07. A total of 50 cases carried a provisional diagnosis of recurrent cholestatic HCV. After careful histological and clinical review, 21 patients were excluded from the final analysis (6 had concomitant bile duct problems,12 did not meet strict histological criteria, 3 for other reasons).

 

Results:

Twenty-five patients (mean age 53+/-7 yrs) were studied; 20(80%) were males; 24 (96%) had deceased donor LT with mean age of 57+/-18 yrs with 72% of these older than 50 yrs. HCC was present in 7 (28%) pre-LT. Mean time from LT to the diagnosis of cholestatic recurrent HCV was 458+/-552 days (49-2384 days); 17/25 (68%) were diagnosed within 1 yr of LT. Median HCV viral load was 6,605,000 IU/mL (12,900-40,100,000 IU/mL). Liver chemistry tests were: bilirubin mean 17.7 mg/dL (3.2-47); AST 223 IU/mL (35-615); ALT 164IU/mL, (27-323); alkaline phosphatase 264 IU/mL (46-682); GGTP 560 IU/mL (36-1277). Treatment with interferon was attempted in 11/25 (44%) patients following the diagnosis. Treatment could not be continued beyond 4 mos. in 6 patients due to severe constitutional symptoms in 3 and death in 3. Only 3 patients continued treatment up to or beyond 12 mos., never achieving SVR. Cumulative proportion of graft survival post-LT (death or re-LT regarded as graft loss) at 1, 3 and 5 yrs were 20%,7% and 7% respectively.

 

Conclusions:

The cholestatic variant of recurrent HCV is an uncommon complication seen in LT recipients and is seen almost exclusively in older deceased donor livers. In our study, 36% of biopsies initially diagnosed with cholestatic recurrent HCV were shown to have an alternative diagnosis after careful evaluation using specific histological criteria. The majority of these cases present during the first year post-LT with very high viral loads, hyperbilirubinemia a poor response to interferon-based regimen and carries an extremely poor prognosis.

 


Liver Transplantation – Post Transplant – HCV Treatment

 

610. Outcome of Interferon (IFN)-Based Antiviral Therapy in African-Americans (AA) With Recurrent Hepatitis C Virus (HCV) Disease Following Liver Transplantation (LT). 

K. R. Krishnan; K. A. Brown; S. W. Biggins; F. Yao; J. P. Roberts; D. Moonka; N. Terrault

 

Introduction:

African Americans (AA), overrepresented among those with chronic HCV, respond less frequently to pre-transplant IFN-based antiviral therapy for HCV than Caucasian-Americans (CA). However, the question remains whether race predicts response to treatment of recurrent HCV (the leading cause of graft loss) following LT.

 

Methods:

Retrospective study of consecutive AA and CA patients undergoing LT for HCV between 1999 and 2006 at two centers, with no donor organs from executed prisoners or institutionalized persons. 89 patients (18 AA, 71 CA) received ≥1 dose of IFN-α or PegIFN-α ±Ribavirin (RBV) for recurrent HCV disease. Treatment duration was censored at 48 weeks in non-responders. Sustained virological response (SVR) was the primary outcome.

 

Results:

Treated AA and CA patients were without significant differences in median age, donor age, or percent males. IFN and RBV doses were comparable with a median (range) RBV dose of 800 mg/d (200-1200) in each group. The median treatment duration was 48 (6-307) wks for CA and 47 (6-103) wks for AA (p=0.34). Growth factors were used to maximize doses. At treatment, racial cohorts were comparable in baseline median viral load (AA 6.63, CA 6.36 log10 IU/ml, p=0.30), ALT (AA 122.5, CA 135 U/L, p=0.64), total bilirubin (AA 1.0, CA 1.0 mg/dl, p=0.96), Scheuer grade (AA 2, CA 2, p=0.87), or stage (AA 1, CA 1, p=0.60). Differences were present in genotype 1 proportion (AA 100%, CA 70%, p=0.009) and median time to treatment (AA 288, CA 406 days, p=0.016). Of those evaluable for SVR, 1/16 (6%) AA and 22/59 (37%) CA achieved SVR (p=0.016). Of those with genotype 1 HCV, 6% of AA and 22% of CA achieved SVR (p=0.26). Associated with lower SVR in univariate analyses were AA race (OR 0.112, p=0.040), genotype 1 (OR 0.105, p=0.001), and higher baseline total bilirubin (OR 0.458, p=0.050). In multivariate models, only genotype 1 achieved statistical significance (OR=0.192, 95% CI 0.052-0.709, p=0.013), with AA race associated with a lower but not statistically significant odds of SVR (OR 0.223, 95% CI 0.026-1.929, p=0.173). Five of 18 (28%) AA and 6 of 71 (8%) CA patients died (p=0.041), with 10 of 11 deaths secondary to complications of hepatic failure, with a median 22 month (1-92) follow-up after treatment initiation. One- and 3-year cumulative survival estimates following treatment initiation were 83% and 69% in AA and 95% and 94% in CA (p=0.028).

 

Conclusions:

AA rarely achieved viral clearance with antiviral therapy and, among treated patients, AA experienced significantly higher mortality than CA. This study highlights the significant challenges in management of AA with recurrent disease and the urgent need for alternative treatment strategies.

 


Liver Transplantation – HCV Recurrence

 

613. Serum Markers of Liver Fibrosis Identify Patients with Mild and Severe Hepatitis C Recurrence Six Months after Liver Transplantation. 

J. Carrion; G. Fernandez-Varo; X. Forns; W. Jiménez; M. Navasa

 

Introduction:

The presence of significant liver fibrosis (F≥2) and particularly portal hypertension (hepatic venous pressure gradient, HVPG ≥ 6mmHg) one year after liver transplantation (LT) identifies accurately patients with severe hepatitis C recurrence.

 

Aim:

The aim of this study was to explore if serum fibrosis markers are able to discriminate between slow and rapid “fibrosers” during the first year after LT.

 

Methods:

Serum levels of Hyaluronic Acid (HA), Amino-Terminal Propeptide of Type III Collagen (PIIINP) and Tissue Inhibitor of Matrix Metalloproteinase type 1 (TIMP-1) were retrospectively measured (Siemens Medical Solutions, Tarrytown, NY) in 135 HCV-infected liver transplant recipients at months 3, 6, and 12 after LT and an algorithm including the three markers (3-M-ALG) was constructed.

 

Results:

Results were correlated with the Scheuer fibrosis stage (n=135) and HVPG (n=95) one year after LT. Fibrosis stage was: F0-F1 in 85 (63%) and F≥2 in 50 (37%); HVPG was < 6 mmHg in 64 (67%) and ≥ 6 mmHg in 31 (33%). The diagnostic accuracy (AUC-ROC) of the algorithm assessed 12 months after LT was 0.78 for significant fibrosis (F≥ 2) and 0.90 for portal hypertension (HVPG ≥ 6mmHg). The figures at 3 and 6 months after transplantation were 0.67 and 0.77 for significant fibrosis (F≥ 2) and 0.75 and 0.87 for portal hypertension (HVPG ≥ 6mmHg).

 

Using the best cut-off of 3-M-ALG (<1: mild, ≥3: severe) at six months after LT we correctly identified 57% of patients with mild fibrosis (NPV: 88%) and 21% of patients with significant fibrosis (PPV: 100%). The same cut-off at six months after LT correctly identified 60% of patients with HVPG < 6 mmHg (NPV: 100%) and 33% of patients with HVPG ≥ 6 mmHg (PPV: 100%).

 

Conclusion:

Measurements of noninvasive serum markers 12 months after LT are accurate at identifying patients with severe hepatitis C recurrence. More importantly, discrimination between slow and rapid fibrosers can be performed as soon as 6 months after transplantation in a significant proportion of patients.

 


Liver Transplantation – Post Transplant – HCV treatment

 

614. Early virological response and absence of diabetes are associated with sustained virological response to hepatitis C treatment after liver transplantation in patients with cyclosporine A based immunosuppression. 

M. Hurtova; M. Fourti; N. Medjahed; D. Samuel; M. Neau-Cransac; Y. Calmus; G. Pageaux; R. Lorho; C. Vanlemmens; A. Laurent; T. Decaens; C. Duvoux

 

Introduction:

Antiviral properties of cyclosporine (CsA) might increase the chance of a sustained virological response (SVR) to HCV treatment after liver transplantation (LT).

 

Aim of the Study:

to evaluate virological response to Peg Interferon (Peg IFN) and Ribavirin (riba) based therapy of HCV recurrence in patients on CsA.

 

Patients and methods:

We retrospectively reviewed charts of 46 patients with proven recurrent HCV infection of the graft transplanted in 7 French Liver Transplant centers.

 

Inclusion criteria were: positive HCV RNA, CsA based immunosuppression, first antiviral therapy after LT and Peg IFN+riba treatment. We assessed virological response at Week 12 (EVR), Week 48 (end of treatment response, ETR), and Month 18(SVR), observed side effects, analyzed factors associated with SVR.

 

Results:

Patient Characteristics:

34 men, 12 women, median age at LT 53.5±9years. Mean post transplant pre-treatment follow-up was 55.5months (3-204), median pre-treatment viral load was 6.4log. Sixty-eight percent of patients had HCV genotype 1/4, 32% had G 2/3. Fibrosis was graded using the Metavir score: 60% of patients were F1-2, 40% were F3-F4. Sixty five percent of patients received Peg IFN alfa 2a; 35% alfa 2b; mean initial ribavirine dose was 800mg daily (400-1200). Median treatment period was 12 (4-18) months. EPO and GCSF were used in 84 % and 13% of patients, respectively. The EVR, ETR, and SVR rates were 67%, 85% and 62%. Eigty-two percent of patients with EVR achieved SVR.

 

Univariate analysis showed that patients with SVR had significantly lower rate of diabetes (73% vs 27%, p=0.01); higher EVR rate (54% vs 7%, p=0.004), lower bilirubine (16±11µmol/l vs 28±24 µmol/l, p=0.05) and alkaline phosphatase (105±57 UI/l vs 227±199 UI/l, p=0.02) levels. In addition, SVR tended to be more frequent in G 2/3 than in G 1/2 patients (78% vs 54 %, p=0.1) and to be associated to slightly lower pre-treatment viral load (5.9 vs 6.4 log, p= 0.1) Multivariate analysis showed that absence of diabetes and EVR are independently associated with SVR.

 

Conclusions:

Our study shows that Peg IFN-riba based therapy in CsA treated liver transplant patients can result in SVR rates similar to those observed in non-transplant setting. Moreover, in CsA treated patiets, diabetes significantly decreases a chance to achieve SVR.

 


Liver Transplantation – HCV Recurrence

 

615. Survival and risk factors associated with severe fibrosis in patients with recurrent hepatitis C. 

M. Donato; C. Rigamonti; F. Agnelli; E. Arosio; E. Melada; G. Rossi; M. Colombo

 

Background and Aims:

Hepatitis C recurrence (HepC-R) after liver transplantation (LT) is associated with reduced patients/graft survival. We aimed to define the survival rate and risk factors of severe fibrosis development in patients with HepC-R.

 

Methods:

From January 2000 through October 2007, 104 patients transplanted for HCV-related cirrhosis (38 with HCC) received 118 graft with 85% and 72% survival at 1 and 5 yrs, respectively. 90 HCV-RNA positive recipients with >6 months survival were investigated (median follow-up 38 months, range 7-99). Immunosuppression included steroids for 3-6 months in 88 (98%), CSA in 33 (37%) patients, FK506 in 23 (25%), CSA/FK506 plus MMF in 34 (38%). Liver biopsies were performed by protocol at 6 months and every year. Grading and staging were assessed according to Ishak score; severe fibrosis was defined as staging ≥4 (S≥4) and acute hepatitis according to histological criteria.

 

Results:

68 (76%) were males, 62 (69%) infected with genotype 1. Median recipient age at LT was 55 yrs (range 20-66), median donor age 51 yrs (range 15-78). 311 liver biopsies were available for histological study (mean 3.5/patient). 27 patients (30%) developed acute rejection and 22 (24%) experienced acute HepC-R. Overall, 22 (24%) developed S≥4 during follow-up: 11 (50%) within first year, the remaining 11 during second-fourth year. Thirty-nine patient (43%) underwent combined antiviral therapy (15 with pre-therapy S≥4). Patient survival was similar in patients who developed S≥4 with respect to those who did not (5 yr survival: 83% vs 81%); however, survival was significantly better in treated patients (N=39) or untreated ones with mild disease (N=23) compared to those with contraindications to antiviral treatment (N=28) (5 yr survival: 94% vs 89% vs 56%; p=0.001). Female gender (p=0.02; OR=3.76; 95%IC 1.18-12) and acute HepC-R (p=0.002; OR=5.72; 95%IC 1.85-17.62) were significantly associated with S≥4 development at multivariate logistic regression analysis. Cox proportional analysis showed that acute HepC-R (p=0.0002; HR=5.17; 95%CI 2.20-12.10) and >50 yrs donor age (p=0.01; HR=3.08; 95%CI 1.26-7.56) significantly increased the risk of severe fibrosis post-LT.

 

Conclusions:

Recipients of an aged liver who experienced acute HepC-R should be prioritized to receive antiviral therapy with Interferon/Ribavirin.

 


Liver Transplantation – HIV/HCV Coinfection

 

616. A Description of fibrosing cholestatic hepatitis after liver transplantation (LT) in HIV-HCV coinfected patients. 

T. Antonini; A. Roque-Afonso; M. Sebagh; B. Roche; R. Sobesky; C. Guettier; D. Samuel; J. Duclos-Vallee

 

Introduction:

Fibrosing cholestatic hepatitis (FCH) represents a severe complication after LT in HIV-HCV co-infected patients. The objective of this study was to evaluate clinical characteristics and prognosis of this complication in HIV-HCV coinfected patients.

 

Patients and Methods:

Between December 1999 and January 2008, 61 HIV-positive patients underwent LT because of end stage liver disease due to HCV, 13 of them with hepatocellular carcinoma (HCC). Among these patients, 9 (15%) developed FCH on the liver graft.

 

Results:

The median age of recipients and donors was 42.6 (38-46) and 50 (29-64) years respectively, predominantly male (78%). 7 patients received cadaveric LT while 2 received domino LT (using liver from familial amyloid polyneuropathy patients). Before LT median CD4 count was 299 cells/mm3 (603-140), HIV RNA was <12 cp/mL, HCV genotype was 1, 3a, and 4a for 6, 2 and 1 patient respectively. Immunosuppression included steroids in all patients, cyclosporine (n=4) or tacrolimus (n=5) and mycophenolate mofetil (n=5). After LT, mild (N=2) and severe (n=2) acute rejection was observed respectively, 2 patients have been treated by increasing immunosuppressive therapy and 2 by steroids bolus. The mean delay for diagnosis of FCH was 6 (1-14) months. At time of diagnosis the mean activity score (METAVIR) and the mean HCV viral load was A2 (0-3) and 7.2 (6.1-8) Log IU/mL respectively. All patient (n=9) received anti-HCV therapy with pegylated interferon and ribavirin with a mean delay of 4.5 (1-11) months from LT. 6 patients were non responders, 2 patients were relapsers after viral response (but clinical improvement was observed) and 1 patient is ongoing therapy. The mean delay for diagnosis of cirrhosis was 20 (12-36) months and 5 non responders patients died with a mean delay of 19 (4-28) months, 1 patient has been re-transplanted 52 months after the first LT. 4 patients died because of severe HCV recurrence and 1 patient died because of acute myocardial infarction.

 

Conclusion:

In our cohort of 61 liver transplanted HIV-HCV coinfected recipients FCH developed in 9 patients (15%). A severe progression and a high mortality rate (56%) were observed. Antiviral therapy should be started as early as possible to improve the outcome of this sub-group of patients.

 


Liver Transplantation – HCV Recurrence – HCV Treatment

 

617. The impact of antiviral therapy on fibrosis progression in HCV recurrence after liver transplantation (LT). 

E. De Martin; A. Gobbo; M. Senzolo; S. Boninsegna; M. Guido; M. Gambato; A. Masier; G. Germani; F. P. Russo; G. Zanus; U. Cillo; P. Burra

 

Background:

Few patients with histological HCV recurrence following LT may be selected for antiviral therapy mainly due to post-LT complications and risk of side effects. Whether antiviral therapy is worthy in terms of histological benefit is still open to debate.

 

Aim:

To asses the effect of antiviral therapy on fibrosis progression due to HCV recurrence after LT.

 

Methods:

All consecutive LT-HCV+ patients followed up at the Gastroenterology Unit undergoing Peg-IFN/Ribavirin therapy for HCV histological recurrence (Scheuer’s stage of fibrosis (S) >=1), with per protocol liver biopsies (LB) performed before and after antiviral treatment (AT), were included in this study. The fibrosis progression rate (FPR) was expressed as fibrosis unit per month (FU/mo). Patients were stratified in 3 categories based on when LB was performed: 0-24; 25-48; 49-72 months after LT, respectively, at 6-12 months after AT.

 

Results:

27 patients (16 M, 11 F, mean age 54 (39-66 years), follow-up 12-95 months) underwent AT. 25 patients were genotype 1b, 1 2b and 1 2a/2c. 19 (70%) were on tacrolimus, while 8 (30%) were on cyclosporin. The mean time of starting AT since the transplant was 25 months (3-98). 15/27 (55.5%) patients withdrawn from AT due to side effects before the end of treatment (12 months). 9/27 patients (33.4%) were SVR+. Mean S was 2.11 pre-AT and 2.49 after-AT (p=0.09). In SVR+, pre-AT S was 2.11 and post-AT S was 2.33 (p=0.5), in SVR-, pre-AT S was 2.11 and post-AT was 2.57 (p=0.138). The FPR was overall 0.012: 0.009 for SVR+ and 0.016 for SVR-, respectively (p=0.74), and -0.036 at 0-24 months, 0.011 at 25-48 months and 0.048 at 49-72 months after LT (p=0.014). Stratifying patients according to both SVR+/SVR- and follow-up time after LT, FPR was -0.021, 0.004, 0.052 and -0.018, 0.011, 0.048 respectively (p=ns).

 

Conclusion:

The progression of fibrosis due to HCV recurrence following LT is seen despite the antiviral therapy, faster in the long-term compared to the early period after surgery whereas slower in patients with virological response.

 


Liver Transplantation – Live Liver Donation

 

618. Long-Term Outcome in HCV Recipients of Live Donor Liver Transplants: Histological and Clinical follow-up. 

S. K. Satapathy; T. D. Schiano; J. V. del Rio Martin; M. Fiel

 

Background:

Long-term outcome of recurrent hepatitis C after living donor liver transplant (LDLT) and its rate of fibrosis progression have not been well characterized. Initial studies suggested that HCV patients did poorly after LDLT. Biliary complications are common in this group and could contribute to fibrosis progression.

 

Aims:

We sought to determine the prevalence of histological HCV recurrence, rate of fibrosis progression and associated factors such as steatosis, biliary complications and response to interferon treatment as well as long-term graft survival in HCV recipients who underwent LDLT.

 

Methods:

Forty-six HCV recipients (mean 52±9 yrs) underwent LDLT from 1/99-2/05. All liver biopsies with both H&E and trichrome slides were assessed for all patients. Biopsies were performed only when clinically indicated. Fibrosis progression rate per year (FPR) was defined as the ratio between the fibrosis stage in Ishak units (0-6) and duration in months since LDLT.

 

Results:

Histological HCV recurrence was noted in 39(84.8%) recipients after a mean interval of 36 wks (3-221 wks). HCC was diagnosed in 25(54.3%) recipients before LDLT, 6(13%) with recurrence post-LDLT. Bile duct problems (leaks and strictures) were noted in 17(37%) recipients. Overall FPR at 1yr, 3yr and 5yr was 2.5±1.54, 1.09±0.44 and 0.76±0.42 fibrosis units/year, respectively. Patients with bile duct problems had significantly increased FPR at 1yr (3.28±1.49 vs 1.88±1.36, p=0.05). No significant difference was noted in rates of FPR in patients with and without steatohepatitis. There was a significantly increased FPR at 3yr (1.19±0.43 vs.0.67±0.00 units/yr, p=0.04) in patients with significant ductular reaction on histology at any time point. Eighteen patients [51 ± 6, M:F:12/6] received pegylated interferon therapy. EVR and ETR were noted in 9(50%) and 7(38%) patients, respectively, whereas SVR was noted only in 5(28%) patients. No significant difference was noted in overall FPR in patients who received therapy vs. those who were not treated. Cumulative proportion of long-term graft survival (death or re-transplant) at 1yr, 3 yr, 5 yr and 7 yr are 76%, 66%, 53% and 48%, respectively.

 

Conclusions:

Histological recurrent HCV in recipients of LDLT is associated with accelerated fibrosis progression during the first year, especially in those who have concurrent bile duct problems. The presence of significant ductular reaction on histology potentially may be playing a significant role in fibrosis progression in recipients with recurrent HCV.

 


Liver Transplantation – General

 

620. Short term maintenance steroids and azathioprine and absence of hepatitis flares are associated with improved patient and graft survival of HCV after Liver Transplantation. 

P. Manousou; D. N. Samonakis; E. Cholongitas; E. Xirouchakis; V. Calvaruso; V. A. Arvaniti; A. Sigalas; M. Pleguezuelo; F. Grillo; I. Giamalis; D. W. Patch; J. O'Beirne; A. P. Dhillon; A. Burroughs

 

Introduction:

Post-transplant recurrence of HCV is a universal phenomenon with a cumulative probability of developing graft cirrhosis of about 30% at 5 years.

 

Aim:

Evaluate impact of immunosuppression and other factors on survival and progression of significant fibrosis in a consecutive series of patients transplanted for HCV cirrhosis.

 

Methods:

We evaluated survival, time to reaching fibrosis Ishak stage≥4 (F4) (with time to last biopsy for all patients who did not reach this stage) and HVPG (Hepatic Venous Pressure Gradient) ≥10mmHg and analysed independently associated risk factors with Cox regression analysis. Recipient age/gender, donor age/gender, pretransplant HCC and/or concomitant alcohol, diabetes, year of transplant, genotype of HCV, initial maintenance tacrolimus (Fk) or cyclosporine A (CYA), initial maintenance steroids and azathioprine(aza), steroids and azathioprine still administered at 3 months, number of cellular rejection episodes, number of methylprednisolone boluses, use of ATG/OKT3, CMV infection and its treatment, and AHC (acute hepatitis C) defined as more than 2-fold increase of transaminases with histological changes consistent with hepatitis without diagnostic features of cellular rejection, bile duct loss, or other cause of liver injury.

 

Results:

246 transplanted patients with cadaveric donors, median age 51.6 years (21-66) and median follow-up of 51.6 months (1-216).

 

Concomitant HCC in 72 patients (29%), ALD in 38 patients (15%), ALD and HCC in 9 (4%). CYA as basic immunosuppressive agent was administered in 97 patients whereas Fk in 137. Aza was administered in 136 patients (70 discontinued).

 

AHC in 79 patients (32%). DM pre OLT in 62 patients (33 IDDM, 29 NIDDM).102 genotype 1 and 188 had ≥1 episodes of acute rejection with 151≥1 pulses of methylprednisolone. Donor mean age was 40.9 (11-73) ,139 males. There were 74 deaths:In Cox regression, variables independently associated with better survival were maintenance steroids (OR.1.4 95%CI: 1.1-1.8) and azathioprine still administered at 3 months (OR.6.018, 95% CI 0.9-3.6).

 

56 patients reached F4 or more. Cox regression revealed that absence of steroids (OR.4.8, 95%CI: 1.7-6.2) and episodes of AHC (OR4.9, 95% CI 1.2-19.2) were two factors independently associated with F4 (p=0.023). HVPG gradient was performed in 103 patients. Cox regression showed a significantly shorter time to reach HVPG≥10mmHg (n=17) in patients with AHC (OR 3.3, 95%CI:1.7-6.2) and absence of steroids(OR 4.8, 95% CI 1.2-19.2).

Conclusion:

Maintenance of steroids and use of azathioprine were associated with better survival and less severe fibrosis. Development of severe fibrosis was also related to a hepatitis flare.

 


Liver Transplantation – General

 

621. Excellent 5-year overall survival in patients with HBV-related cirrhosis undergoing liver transplantation for hepatocellular carcinoma. 

P. Lampertico; M. Viganň; S. Bhoori; F. Agnelli; M. Donato; M. Bongini; M. Iavarone; C. Cotsoglou; A. Russo; L. Caccamo; G. Rossi; M. Colombo; V. Mazzaferro

 

Background and Aim:

The long-term outcome of hepatitis B virus (HBV) infected patients who underwent liver transplantation (LT) because of hepatocellular carcinoma (HCC) and received nucleos(t)ide suppressive therapy, is unknown.

 

Patients and Methods:

We retrospectively reviewed all patients consecutively transplanted between January 1999 and September 2007 for HCC in HBV-related cirrhosis in two Italian LT Centers. Before LT, all patients underwent anti-HBV therapy and bridge treatment with radiofrequency and/or chemoembolization. Post-LT prophylaxis was LMV+HBIg in 49 (63%) patients, LMV+ADV+HBIg in 25 (32%) and HBIg in 4 (5%). Endpoints of the study were overall survival and HBV- and HCC-recurrence rates.

 

Results:

78 patients were followed-up for a median of 48 (2-110) months. Five patients (6%) showed HCC recurrence after a median of 15 month (3-39) while 4 patients (5%) had HBV recurrence at month 1, 3, 18, 38. Six patients (7%) died: causes of death were recurrent HCC (=2), infection (n=2), de-novo neoplasia (n=1), surgical complications (n=1). The estimated 5-yr cumulative rates of HCC and HBV recurrence, and survival were 9%, 7% and 91%. HCC recurred in 3 of 69 patients fulfilling the Milan criteria compared to 2 of 9 exceeding Milan criteria (5-year recurrence: 6% vs 35%, p<0.01). HBV recurred in 4 of 6 patients with pre-LT HBV DNA > 5 log cp/ml compared to none of the 72 with < 5 log viremia (67% vs 0%, p<0.001). The 4 recurrent patients had LMV resistance; 2 developed high HBV DNA levels and HBeAg positive chronic hepatitis, one had a fibrosing cholestatic hepatitis, one maintained undetectable HBV DNA. In patients fulfilling the Milan criteria, the estimated 5-yr cumulative rates of HCC and HBV recurrence, and survival were 6%, 7% and 92%.

 

Conclusions:

Cirrhotic patients undergoing liver transplantation for HBV-related HCC within the Milan criteria and under anti-HBV therapy had excellent overall 5-year survival with negligible rates of HCC and HBV recurrence.

 


Liver Transplantation – HCV Recurrence – HCV Treatment

 

623. Pegylated-interferon and ribavirin in liver transplant candidates and recipients with HCV cirrhosis: Systematic review and meta-analysis of prospective controlled studies. 

E. Xirouchakis; C. K. Triantos; P. Manousou; A. Sigalas; V. Calvaruso; A. Corbani; D. W. Patch; A. K. Burroughs

 

Background and Aim:

Pegylated interferon with ribavirin (Peg/R) is the most effective therapy for chronic hepatitis C (HCV) but its utility and effectiveness after liver transplantation has been difficult to assess. We evaluated efficacy, tolerability, and safety of Peg/R in liver transplant candidates and recipients with HCV cirrhosis.

 

Methods:

We searched medical databases and conference proceedings between January 1999 to January 2008 selecting randomized and non randomized studies. Primary end points meta-analytically were: 1) sustained viral response (SVR) and 2) histological response. Secondary end points were: 1) treatment discontinuation, 2) mortality and 3) rejection episodes. When a meta-analysis was appropriate the random effects model was used.

 

Results:

Peg interferons using 1-1.5mcg/Kg (alpha-2b) or 180ug (alpha-2a) combined with ribavirin 800-1200mg/day were the most effective compared to any other regimen or no therapy. In 3 pretransplant studies (n=355 pts) the median SVR for Peg/R was 19.6% (19.6%-50%). In 6 postransplant studies (n=264 pts) the median SVR for Peg/R was 41% (range 29.6% – 77.7%) and in the following metanalysis the cumulative risk difference in SVR was 0.31% (95%CI, 0.18-0.44, p<0.001). In a subgroup analysis Peg/R was significantly better in comparison with no treatment and the cumulative risk difference in SVR was 0.36% (95%CI, 0.25-0.47, p<0.001) but not in comparison to other regimens eg. Peg monotherapy or a low dose Peg/R. Histological response was not significantly better compared to no therapy or other antiviral regimens. There were no significant differences in discontinuation of therapy, acute or chronic rejection or mortality rates between optimal Peg/R versus no treatment or other regimens.

 

Conclusion:

PEG/R in full doses is effective pre and post transplant but has a low SVR rate. To date no significant histological improvement has been reported.

 


Liver Transplantation – General

 

624. Survival after Orthotopic Liver Transplantation (OLT) for HCV Cirrhosis has not improved in the Model for End-stage Liver Disease (MELD) era. 

N. S. Becker; J. M. Vierling; N. L. Sussman; R. Stribling; C. A. O'Mahony; J. A. Goss; P. K. Jalal

 

Background:

HCV cirrhosis, the most frequent indication for OLT in the U.S., has been associated with a decreased survival after OLT. Whether liver allocation during the MELD era and/or post-OLT use of newer antiviral therapies for HCV have improved outcomes after OLT for HCV cirrhosis is unclear.

 

Aim:

To compare patient and graft survivals for: 1) HCV cirrhosis patients in the pre-MELD and MELD eras and 2) patients transplanted for HCV and non-HCV indications.

 

Methods:

The UNOS database for adults (>18 yrs) undergoing OLT was used to compare patient and graft survival rates for patients transplanted in 2 eras: pre-MELD (1992-2001) and MELD (2002-2007). Patients requiring retransplantion or multi-organ transplantion were excluded. Survivals were determined using Kaplan-Meier analysis and compared using a log-rank test.

 

Results:

Of 59,605 adult OLT recipients included in the study, 25,052 (42%) had HCV. HCV significantly increased as an indication for OLT from the pre-MELD to MELD era: 40% vs. 45%, p<0.001. There was no difference in HCV patient survival between the two eras: 87% vs. 87% at yr 1 and 77% vs. 76% at yr 3. Similarly, there was no difference in HCV graft survival between the two eras: 81% vs. 82% at 1 yr and 70% for both at 3 yrs. There was a significant reduction in mortality within 30 days of OLT in the MELD era: 2.85% vs. 4.40%, p<0.001. The primary causes of mortality 30 or more days post-OLT were similar in both eras: graft failure (25%), infection (20%), malignancy (14%), multiorgan failure (14%) and cardiovascular causes (12%). Patient survival at 3 yrs was significantly decreased for HCV compared to non-HCV in both eras: pre-MELD 77% vs. 81%, p<0.001 and MELD 76% vs. 80%, p<0.001. Similarly, 3 yr graft survival was also significantly decreased in HCV compared to non-HCV in both eras (p<0.001). Patient survivals did not differ for non-HCV patients in either era.

 

Conclusions:

Neither patient nor graft survivals for HCV patients undergoing OLT have improved from the pre-MELD to MELD era. In both eras, patient and graft survival rates were significantly lower in HCV patients compared to non-HCV patients. It is imperative that all modifiable risk factors for poorer outcomes in HCV patients be identified and ameliorated to improve long-term outcomes.

 


Liver Transplantation – HCV Recurrence – HCV Treatment

 

626. PegIFN-ribavirin for recurrent hepatitis C: worse efficacy in recent years. 

M. Berenguer; V. Aguilera; C. Ortiz; M. Rodriguez; F. Gentili; A. Palau; R. Canada; B. Risalde; M. Prieto

 

Introduction:

Antiviral therapy post-transplantation has a limited efficacy. Results have however improved over time with the introduction of ribavirin and pegylation of interferon (IFN).

 

Hypothesis:

Improved efficacy (higher sustained virologic response-SVR-) in recent years as a consequence of a better management of antiviral therapy in the liver transplant (LT) setting.

 

Aim:

To assess whether the efficacy of pegIFN-ribavirin has improved over time.

 

Methods:

96 LT patients (74% men, median age: 56 (37-70)), 87% genotype 1a or 1b, treated with pegIFN-ribavirin (pegasys: 62%, pegintron 38%) for a median duration of 356 days (range:16-623 days), at 576 (50 days- 3978) days from LT. Baseline immunosuppression was tacrolimus in 62%. 19% were cirrhotic and 68% had advanced fibrosis at baseline. The median donor age was 48 years (range 12-78).

 

Results:

A SVR was achieved in 36 patients (37.5%), with a trend for worse results achieved in recent years (2001-2003: n=28, SVR:46.5%; 2004: n=23,SVR:43.5%; 2005: n=20, SVR:35%; 2006: n=25, SVR=24%; p=.078). Variables associated with SVR in the univariate analysis included baseline viremia (p=.02), RVR (p=.002), EVR (.0001), premature discontinuation of therapy (p=.02), genotype distribution (p=.05), weight (p=.05) and donor age (p=.007). There was a trend for patients with advanced fibrosis and cirrhosis to achieve lower SVR (48% vs 32%, p=.09). In the multivariate analysis, only donor age (p=.009) and EVR (p=.001) remained in the model. When we compared the different cohorts, the only variables changing substantially over time were donor age (p=.04), use of erythropoietin (p=.01) and neupogen (p=.01), and bilirrubin levels (p=.02). There was a trend for more cirrhotic being treated in recent years (p=.09), increased baseline viremia (p=.06), longer duration from transplantation to treatment initiation (p=.06). The remainder variables analysed (gender, age, history of prior preLT failed antiviral therapy, presence of renal insufficiency or diabetes at treatment initiation, type of pegIFN, baseline immunosuppression, baseline activity, genotype distribution, premature discontinuation or dose reductions) did not change over time.

 

Conclusions:

The efficacy of antiviral therapy with pegIFN-ribavirin has worsened over time, at least in our center. The increase in donor age and a greater proportion of cirrhotics may be potential causes. Further analysis is underway to understand the reasons for this negative trend.

 


Liver Transplantation – HCV Recurrence

 

627. Severe HCV infection recurence on the liver graft of patient transplanted for HCV related cirrhosis : Is retransplantation feasible? 

R. Sobesky; P. Carrier; B. Roche; T. Antonini; M. Sebagh; A. Roque-Afonso; C. Guettier; F. Saliba; P. Ichai; D. Azoulay; R. Adam; D. X. Castaing; D. Samuel; J. Duclos-Vallee

 

Background:

HCV-related cirrhosis is one of the most common indications for liver transplantation (LT). However, almost all patients have post-LT recurrence, with a significantly negative outcome on long term graft and patient survival. The natural history of HCV liver graft infection is faster than in immunocompetent patients and the question of the retransplantation (reLT) is discussed.

 

Aim:

To study the outcome of HCV infected patients retransplanted for severe recurrence of HCV infection on the liver graft.

 

Methods:

An indication of reLT was proposed in 28 patients with a mean age of 45 (± 8) years in a monocentric population of 504 HCV infected patients transplanted for end stage liver cirrhosis or hepatocellular carcinoma. The indication of reLT was proposed in 11 patients for surgical complication (primary non function or hepatic artery thrombosis), in 11 patients for severe complications of HCV related liver graft infection and in 6 patients because of chronic rejection or alloimmune hepatitis.

 

Results:

Among the 11 patients transplanted for severe HCV reinfection on the liver graft, the mean interval between the 2 LT was 92 (± 62) months. The mean MELD score before reLT was 22.5 (± 6.2). Three patients had renal insufficiency related to calcineurin inhibitors and had a combined kidney and liver transplantation. Four of the 11 patients deceased after reLT, three within 10 months because of infectious complications after a prolonged stay in intensive care unit. One of the 4 patients who had combined kidney and liver transplantation died because of a septic shock 6 months after reLT. One patient died 2 years after reLT because of severe HCV recurrence on the liver graft with severe hepatic insufficiency and renal failure. Survival after reLT was 7/11 (63%) at 1 year, 5/9 (55%) at 2 years and 3/7 (42%) at 5 years respectively. A severe liver fibrosis progression (upper 1 point of Metavir unit per year) was observed in 20% of patients after reLT while it was observed in 36% of patients after the first LT.

 

Conclusion:

In this study, liver fibrosis progression was not more severe after reLT than after the first LT. A combined kidney transplantation was performed in 27% of the cases of reLT.

 

The survival of patients retransplanted for severe HCV recurrence on the liver graft was at 63% at 1 year and 42% at 5 years.

 


Liver Transplantation – General

 

628. Incidence and Prognostic Significance of Immune Markers in Patients with HCV Undergoing Liver Transplantation. 

C. Aloman; M. Fiel; C. Chang; S. N. Sclair; P. Grewal; L. U. Liu; K. Iyer; G. Rodriguez-Laiz; M. L. Sturdevant; J. V. del Rio Martin; T. D. Schiano

 

Background:

Patients with liver cirrhosis have an increased incidence of immune abnormalities represented by (+)rheumatoid factor(RF) but also by non-organ specific autoantibodies. The prognostic significance of these markers regarding the development of allograft dysfunction is unknown.

 

Aim:

To evaluate the incidence of immune abnormalities in patients undergoing liver transplantation (LT) and correlate their presence with abnormal liver chemistry tests 3 months post-LT and histological severity of recurrent HCV.

 

Methods:

Cirrhotic patients undergoing LT at The Mount Sinai Hospital between 10/07 and 4/08 were studied. Patients with autoimmune hepatitis were excluded. All patients had an immune panel drawn right before LT, consisting of RF, IgA, IgG, IgM, ASCA (IgG and IgA), ANCA, ANA, SMA, LKM-1, anti-liver cytosol-1(LC-1), and soluble liver antigen (SLA) antibodies. The level of AST, ALT, alkaline phosphatase, bilirubin and GGTP 3 months after LT were assessed. Liver biopsy at any time post-LT were reviewed by a liver pathologist. Graft dysfunction was defined by the presence of at least two abnormal liver chemistry tests (at least >1.5X upper limit of normal) and/or histological evidence of HCV recurrence. Severe HCV was defined as the cholestatic variant or >/= grade 3 necroinflammatory activity on the initial biopsy documenting recurrence. Data processing and analysis were performed with SPSS software.

 

Results:

We evaluated 45 patients, average age 56; 73% had HCV infection. Both HCV and non-HCV patients had increased prevalence of immune abnormalities before LT-See Table(*p<.05). Only one case (+) for LKM-1 and LC-1 were detected. Graft dysfunction defined by abnormal laboratory tests at 3 months does not correlate with the presence of Ig abnormalities, RF or autoantibodies before LT. Severe recurrent HCV correlated with a high titer RF (>100 IU/ml) pre-LT.

 

Conclusion:

The presence of immunological abnormalities before LT may be helpful in determining the development of graft dysfunction or recurrent HCV in the first 3 months after liver transplantation. Rheumatoid factor before LT predicts the severity of HCV recurrence. Further prospective studies are necessary to define better patterns of association.

 

HCV vs Non-HCV

(+)RF, ns

96 vs 78%

IgG>2200 mg/dL, ns

42 vs 35%

IgA>400 mg/dL, ns

67 vs 64%

IgM>300 mg/dL, ns

29 vs 36%

(+)SMA,*

29 vs 0%

(+)ASCA IgG, *

61 vs 14%

(+)ASCA IgA,ns

58 vs 42%

(+)ANA,*

22 vs 14%