Sunday Poster Sessions, October 29, 2006

Transplant Plenary Sessions 1 and 2

 

 

1. Outcomes of patients with hepatitis B (HBV) who developed viral breakthrough or genotypic resistance to antiviral therapy while on the liver transplant (OLT) waiting list.

M. K. Osborn; A. Regev; S. Han; N. Bzowej; M. Ishitani; T. Tran; A. S. Lok.

Background/Aim:

Resistance to antiviral therapy can lead to hepatitis flares, liver failure and death. We determine if rescue therapy prevents adverse outcomes in patients (pts) with HBV who developed antiviral failure while awaiting OLT.

 

Methods:

Data for pts enrolled in the NIH HBV-OLT observational study who received antiviral therapy before OLT and had ≥6 mos follow-up on the waiting list were reviewed. Pts with HCV or HIV, fulminant HBV or retransplantation for recurrent HBV were excluded. Kaplan-Meier estimates were used to compare transplant-free survival and survival without transplant between pts who developed antiviral failure (viral breakthrough confirmed genotypic resistance) and those who did not. Cox regression models were used to determine factors associated with outcomes. Other covariates were gender, race, age at listing, laboratory values (including MELD) at listing, and hepatocellular carcinoma (HCC) at listing.

 

Results:

122 pts received antiviral therapy pre-OLT for a median of 40.4 mos (range 0.4-123) until transplant or last follow-up. Initial therapy was lamivudine (LAM) in 110 (90%) pts, adefovir (ADV) in 7 (6%) pts and other in 5 pts. Of the 44 (36.1%) pts who developed antiviral failure (30 with confirmed genotypic resistance), all received LAM as initial therapy. Rescue therapy was administered in 42 pts at a median of 5.2 mos (range 0-79.4) after antiviral failure was diagnosed. Most pts were clinically stable (median MELD 12) at the time rescue therapy was started. The most common rescue therapies were ADV monotherapy in 20 and ADV+LAM in 19 pts. After a median follow-up of 22.6 mos (range 0-99.8) from diagnosis of antiviral failure, 23/44 were alive on the OLT waiting list, 8 were withdrawn from the study (2 improved, none for worsening), and 4 died while in study (3 due to liver failure). 9 pts had OLT, 1 within 6 months of antiviral failure; none had HBV recurrence after 11.3-36.2 mos of post-OLT follow-up. Actuarial rates of transplant-free survival 1 and 5 years after listing were 97.6% and 67.5% for those with antiviral failure and 81.9% and 60.8% for those without failure (p=0.09). Actuarial rates of survival without transplant at 1 and 5 years were 97.5% and 83.3% and 91.6% and 84.9% for pts with and without antiviral failure (p=0.39). Multivariate predictors of death or transplant were high MELD score, HCC, and low albumin. Low MELD score and high albumin were predictors of survival without transplant.

 

Conclusion:

Our data suggest that antiviral failure in HBV pts on the OLT waiting list did not significantly affect survival compared to those without failure if rescue therapy was promptly initiated.

 


2. A Randomized Controlled Trial of Prophylactically Administered Peginterferon Alfa-2a Plus Ribavirin vs No Prophylaxis Following Orthotopic Liver Transplantation (OLT) for Hepatitis C: A Report of Initial Safety and Tolerability.

N. H. Bzowej; D. Nelson; J. A. Thommes; F. M. Hamzeh; M. Charlton.

Introduction:

Recurrent HCV infection following OLT is universal and can cause graft failure and death. Safety concerns, especially the risks of anemia, neutropenia and acute cellular rejection (ACR), have limited prophylactic/early treatment with pegylated interferon plus ribavirin in OLT recipients, and prophylaxis has not been investigated in a randomized controlled trial. The Phoenix study was designed to compare antiviral therapy before histological recurrence of HCV (prophylaxis arm) with antiviral therapy only at the time of histological recurrence (observation arm).This report presents preliminary safety and tolerability data in the first 60 randomized patients.

 

Methods:

Patients were randomized 10 to 26 wks after OLT. Patients in the prophylaxis arm received 135 μg peginterferon alfa-2a/wk for 4 wks, followed by 180 μg/wk for 44 wks; plus 400 mg/d ribavirin (initial dose), escalating to 1200 mg/d, for 48 wks. Patients in the observation arm were treated with the same regimen only upon histologic recurrence of HCV (HAI >3 and/or FS >2).

 

Results:

To date, 33 patients have been randomized to the prophylaxis arm (32 have received at least 1 dose of study medication, 1 withdrew consent) and 27 to the observation arm, and 25 patients in each arm have completed 12 study wks. Thirty patients in the prophylaxis arm (94%) and 22 in the observation arm (82%) have experienced at least 1 adverse event (AE); and 6 (19%) and 4 (15%), respectively, have experienced at least 1 serious AE. The most common treatment associated AE in the prophylaxis arm has been fatigue (18 patients, 56%). Treatment has been modified or interrupted in 17 patients in the prophylaxis arm (53%) and in 3 of 4 patients in the observation arm with HCV recurrence (75%). The frequency of peginterferon alfa-2a and/or ribavirin dose reductions due to anemia, neutropenia and thrombocytopenia in the prophylaxis arm were 37.5%, 25% and 13%, respectively. Six prophylaxis arm patients (19%) have withdrawn from study medications for AEs 1 from peginterferon alfa-2a due to rash and from ribavirin due to anemia; 1 from ribavirin only due to anemia; and 1 each from both medications due to thrombocytopenia, increased bilirubin, dehydration and neutropenia. No clinically apparent episodes of ACR have occurred.

 

Conclusion:

Although AEs are common during prophylaxis treatment for post-OLT HCV recurrence, only 19% of patients experienced AEs necessitating treatment withdrawal. During the first 12 wks, no signs of ACR have occurred in either study arm. These preliminary findings suggest that prophylaxis with peginterferon alfa-2a plus ribavirin is relatively safe and well-tolerated in OLT recipients.

 


3. Long-term Histological Effects of Preemptive Antiviral Therapy in Liver Transplant Recipients with Hepatitis C Virus (HCV) Infection.

A. Kuo; B. Lan; S. Feng; N. A. Terrault.

Introduction:

Recurrent hepatitis C virus (HCV) infection after liver transplantation leads to progressive fibrosis and is the most common cause of graft loss. Strategies to prevent histological progression are urgently needed. Preemptive antiviral therapy has not been shown to increase the rate of viral clearance post-transplantation but the impact of early antiviral therapy on fibrosis progression is unknown.

 

Aim:

We sought to determine whether preemptive antiviral therapy with interferon +/- ribavirin slows fibrosis progression.

 

Methods:

We retrospectively analyzed a prospective cohort of consecutive adult patients who underwent liver transplantation (LT) for chronic HCV at UCSF from December 1998 to June 2002 and who received preemptive antiviral therapy (begun between week 2-6 post-transplant) with standard interferon (IFN) or pegylated-interferon alfa-2b or IFN/peg-IFN plus ribavirin for 48 weeks. Fibrosis was assessed using Ludwig-Batts score (F0-F4). Biopsies were obtained approximately annually and as clinically indicated. Non-preemptive therapy patients were censored at the start of antiviral therapy for recurrent disease, as were preemptive patients who were retreated. Kaplan-Meier methods were used to assess time to fibrosis score (FS) ≥2 (scale of 4) in the preemptive vs. the non-preemptive groups. Other factors influencing fibrosis were controlled for in final multivariate models.

 

Results:

106 adult LT were performed with 85 patients meeting all inclusion criteria. A total of 46 patients received preemptive therapy with 4 (8.7%) patients achieving sustained virologic response (SVR); 39 patients did not receive preemptive therapy. Patients were predominantly male (72%) with median age 50 years (35-70), median donor age 40 (9-70), 67 (78.8%) deceased donors, and median follow-up 40 months (3.6-90.3). The median histological follow-up was 46.0 (4.1-90.3) and 32.2 (3.6-83.5) months in preemptive and non-preemptive groups. Time to FS ≥2 was not significantly different between groups (log-rank test, p=0.16; figure) and the median time to FS ≥2 was 40.5 vs. 33.4 months in the preemptive and non-preemptive groups. There was no significant difference after adjusting for recipient age, donor age or SVR. Similar results were obtained when patients achieving SVR were excluded.

 

Conclusions:

Preemptive antiviral therapy of HCV does not appear to slow fibrosis progression although a late effect cannot be excluded. However, given the low rate of virological response and lack of obvious histological benefits, this treatment strategy cannot be recommended.


4. Multicenter randomized trial in HCV-infected patients treated with peginterferon alfa-2a and ribavirin followed by ribavirin alone after liver transplantation: 18-month report.

Y. Calmus; D. Samuel; G. Pageaux; M. Messner; P. Wolf; L. Rostaing; C. Vanlemmens; Y. Le Treut; S. Dharancy; J. Gugenheim; F. Durand; M. Nau-Cransac; O. Boilot; O. Chazouillres; L. Samelson; K. Boudjema; C. Duvoux.

Aim:

The aim of this randomized, double-blind study was to determine the effect of placebo or maintenance therapy with ribavirin (RBV) monotherapy, after a year of combination therapy with peginterferon-alfa 2a (PEG-IFNα-2a) and RBV, on continued eradication of HCV after liver transplantation (LT). Here, we report the interim, pooled data from both treatment arms obtained at 18 months (6 months after the end of combination therapy).

 

Methods:

The study enrolled 101 patients with recurrent HCV and a minimum of stage 1 fibrosis (METAVIR scoring) on a liver biopsy obtained 15 years after LT. PEG-IFNα-2a and RBV were initiated at 90 g/wk and 600 mg/d, respectively, and increased to 180 g/wk and 1000 mg/d or adjusted as a function of hematological tolerance. At week 52, combination therapy was discontinued and patients were randomized to RBV alone or placebo for a further 48 weeks (blinded). 75% of patients received tacrolimus and 25% cyclosporine. Growth factor use was permitted.

 

Results:

At the end of combination therapy at 52 weeks, 61% of all patients (62/101) and 75% of those who completed 52 weeks therapy (62/83) achieved a virological response (VR; undetectable HCV-RNA). 37% of patients required erythropoietin (EPO) support and 12% G-CSF during combination therapy.

 

At 78 weeks, a VR was obtained in 39% of ITT patients (39/100) and 50%(39/77) of PP patients: 70.6% of patients with genotype 2/3 and 32.5% of those with genotype 1/4 (p=0.004). VR was numerically higher in patients receiving cyclosporine (52.2%) than those receiving tacrolimus (36.6%; p=0.2), and in patients treated >2 years post LT (46.3%) than <2 years (29.8%; p=0.09). Serious antiviral-related adverse effects were observed in 15 patients: acute rejection (2), severe cytopenia requiring antiviral therapy discontinuation (7), acute renal failure (2), ischemic cardiopathy (2), psychiatric disorders (2), and diabetes (2).

 

Conclusion:

A virological response at 18 months, after 1 years combination therapy with peginterferon alfa-2a plus ribavirin followed by 6 months ribavirin monotherapy or placebo, was achieved in 50% of patients following liver transplantation in PP analysis. Study end is planned in July, so final results will be presented at the congress.

 


5. Methylenetetrahydrofolate Reductase C677T Gene Polymorphism and Early Graft Fibrosis Progression among Liver Transplantation Recipients with Recurrent Hepatitis C.

D. Bitetto; E. Fontanini; A. Cussigh; E. Falleti; C. Fabris; E. Rossi; R. Minisini; A. Limoncini; P. Toniutto; M. Pirisi.

Introduction:

It has been suggested that the MTHFR C677T polymorphism, known to increase susceptibility to hyperhomocysteinemia, may favour fibrosis progression in immune competent patients with chronic hepatitis C by being a steatogenic factor. Aim of this study was to verify the role of recipient MTHFR polymorphism in favouring graft fibrosis progression in patients with recurrent hepatitis C after liver transplantation (OLT).

 

Methods:

We studied 60 consecutive patients (41 males), median age 56 years, who underwent OLT between 1996 and 2004 for hepatitis C and were followed-up for >1 year. Thirty-one patients underwent combination antiviral therapy for hepatitis C, started a median of 14 months after OLT and completed as scheduled by 19/31. The speed of fibrosis progression, expressed in fibrosis units per month (FU/mo), was calculated dividing the histological staging in a protocol liver biopsy by the time interval elapsed from OLT in the first year post OLT. MTHFR allelic variants were determined in peripheral blood samples by means of a PCR/restriction fragment length polymorphism procedure.

 

Results:

MTHFR genotypes, in equilibrium according to Hardy-Weinberg equation (p>0.10), were: CC = 19 (32%), CT = 34 (56%) and TT = 7 (12%). The TT genotype was not associated with recipients gender or age. TT patients had more frequently, one year post OLT, either serum triglycerides >150 mg/dl (5/21 vs 2/39 p<0.05) or a triglycerides/cholesterol ratio >1.0 (5/19 vs 2/41 p<0.02). Patients with a TT genotype had more frequently a one year post OLT fibrosis progression >0.100 FU/mo (5/19 vs 2/41 p<0.02); on the contrary, the TT genotype was not associated with liver steatosis (5/37 vs 2/23 p>0.10). First year fibrosis progression >0.100 FU/mo was strongly related to donor age >45 years (13/26 vs 6/34 p<0.01). Time to event analysis in reaching an Ishak staging score >2 was performed stratifying the patients as follows: A) patients with donor age ≤45 years, B) patients with donor age >45 and C/* genotype, C) patients with donor age >45 years and TT genotype. A significant linear trend was observed, with increasing frequencies as follows: A) 7/34, B) 10/19 and C) 6/7 (p=0.0005).

 

Conclusion:

The MTHFR C677T polymorphism may play a role in influencing liver fibrosis progression in patients with recurrent hepatitis C, in conjunction with donor age, but not via steatosis promotion. Early fibrosis progression may be favoured in recipients with a TT genotype by mechanisms involving their lipid asset, since lipoprotein and lipoprotein receptors are involved in HCV protection from neutralising antibodies in the circulation and viral entry into the hepatocytes.

 


7. THE PAN-Caspase Inhibitor, IDN-6556, Attenuates Human Liver Preservation Injury.

E. S. Baskin-Bey; K. Washburn; S. Feng; T. Oltersdorf; D. Shapiro; L. Burgart; M. Garrity-Park; F. van Vilsteren; L. K. Oliver; C. B. Rosen; G. Gores.

Introduction:

Liver preservation injury remains a clinical problem in liver transplantation. Apoptosis, a form of cell death, is a critical mechanism of hepatic preservation injury. Intracellular proteases referred to as caspases, mediate apoptosis and their inhibition can block this cell death program. Recently IDN-6556, an irreversible pan-caspase inhibitor has been shown to reduce preservation injury in rodent models.

Aim:

Thus, the AIM of the current study was to assess the utility of IDN-6556 in human liver transplantation.

 

Methods:

This study was conducted as a multi-center, Phase II, randomized, placebo-controlled, double-blinded, parallel group study. Subjects were assigned to four treatment groups: Group I; n=23 (Organ storage/flush: Placebo - Recipient: Placebo); Group 2; n=23 (Organ storage/flush: 15 g/mL - Recipient: Placebo); Group 3; n=27 (Organ storage/flush: 5 g/mL - Recipient: 0.5 mg/kg); and Group 4; n=26 (Organ storage/flush: 15 g/mL - Recipient: 0.5 mg/kg) (total n=99). IDN-6556 was administered to the organ in cold storage and flush solutions and to the recipient intravenously every six hours for 24 hours after transplantation. Apoptosis was assessed by serum concentrations of the apoptosis-associated CK18Asp396 (M30) neo-epitope, TUNEL assay, and caspase 3/7 immunostaining of liver specimens. Liver injury was assessed by serum AST/ALT determinations.

 

Results:

The results represent a post hoc data analysis. Serum M30 concentrations were greater than 5-fold above normal, signifying the presence of massive apoptosis during human liver transplantation. Group 1 (placebo) was distinctly higher than groups 2, 3 or 4 during the first 24 hours after liver transplantation. TUNEL and caspase 3/7 positive cells were reduced in Group 2 from liver specimens obtained after reperfusion during transplantation, when compared to all groups. Similarly, Group 2 consistently showed a significant reduction in ALT/AST levels following transplantation, compared to all treatment groups (p<0.01). One center performed day 7 protocol liver biopsies (n=35), which permitted the assessment of delayed consequences of CI/WR injury. In these specimens, analyses of Group 2 demonstrated reduced neutrophil infiltrate; the latter being a cellular component of preservation injury. No post-operative adverse events were attributed to the treatment.

 

Conclusion:

IDN-6556 when administered in cold storage and flush solutions appears promising as a therapeutic agent to minimize CI/WR injury in human liver transplantation. Larger studies are required to determine its actual benefit.

 


9. Liver Transplantation for Hepatocellular Carcinoma: A 5-year Prospective Study Validating Expanded Criteria Applied to Pre-operative Imaging.

F. Y. Yao; L. Xiao; N. M. Bass; R. K. Kerlan; N. L. Ascher; J. P. Roberts.

Background:

We have previously reported that modest expansion of conventional criteria for orthotopic liver transplantation (OLT) based on explant pathology in patients with hepatocellular carcinoma (HCC) did not adversely impact survival (UCSF criteria - 1 lesion within 6.5 cm or 2 to 3 lesions none exceeding 4.5 cm with total tumor diameter up to 8 cm). In the present study, we attempted to validate the UCSF criteria according to pre-transplant imaging with 5-year follow-up.

 

Methods:

Between January 2001 and January 2006, we have prospectively applied the UCSF criteria for OLT based on pre-operative radiologic staging in 138 patients. Staging within 3 months prior to OLT revealed T1 HCC (1 lesion <2 cm) in 8 patients, T2 (1 lesion 2 to 5 cm, or 2 to 3 lesions none exceeding 3 cm) in 98 patients, and T3A (exceeding T2 but meeting UCSF criteria) in 32 patients. Ninety-eight patients (70% for T1/T2 and 75% for T3A) received elective pre-operative loco-regional therapies.

 

Results:

The median follow-up was 24 months (range 1-64 months), with a minimal follow-up of 6 months among survivors. The 1- and 5- year Kaplan-Meier recurrence-free probabilities were 95% and 91%, respectively. The 1- and 5-year probabilities for survival without recurrence were 91% and 80%, respectively. The 106 patients with radiologic T1 or T2 HCC had 1- and 5- year recurrence-free probabilities of 96% and 90%, respectively, versus 93% at both 1 and 5 years for the 32 patients with radiologic T3A stage (p=0.82). The 22 patients with explant pathologic HCC stage >T3A had 1- and 5- year recurrence-free probabilities of 79% and 61%, respectively, versus 98% and 97%, respectively, for the 116 patients with pathologic HCC stage within T3A (p<0.0001). Predictors of HCC recurrence in univariate analysis included pathologic stage >T3A (HR 16.4, p=0.0005), micro-vascular invasion (HR 16.9, P<0.0001) and alpha-fetoprotein >1000 ng/mL (HR 7.8, P=0.003). Explant tumor necrosis >60% was associated with a significantly lower risk for HCC recurrence (HR 0.11, P=0.035). Radiologic T3A stage (versus T1+T2), poorly differentiated histologic grade and LDLT were not predictive of HCC recurrence. Tumor under-staging was observed in 20.8% with T1 or T2 HCC, and 28.1% with T3A HCC (p=0.64). Among them, HCC recurrence was found in 5 of 22 patients (22.7%) under-staged as T1 or T2 and 2 of 9 patients (22.2%) underestimated as T3A.

 

Conclusion:

Our results validate the ability of the UCSF criteria to discriminate prognosis for HCC after OLT, and to serve as selection criteria based on radiologic tumor staging, without resulting in a significantly higher risk for tumor under-staging or recurrence.


10. Outcomes of adult living donor vs. deceased donor liver transplantation from the time of listing.

S. A. Shah; G. A. Levy; I. D. McGilvray; R. Smith; L. D. Adcock; N. Girgrah; L. B. Lilly; P. D. Greig; M. S. Cattral; D. R. Grant.

Introduction:

Right lobe living donor liver transplantation (RLDLT) has not been adopted as a fully accepted therapy for patients with end-stage liver failure (ESLD) in the western hemisphere because of concerns about donor safety and potentially inferior recipient outcomes.

 

Methods:

An analysis of outcomes from the time of listing for all adult patients who were listed for liver transplantation from 2000-2006 at our center was performed. Populations were compared using descriptive statistics, chi-square tests, and log rank analysis of Kaplan-Meier survival curves.

 

Results:

From 04/2000 to 04/2006, 1091 patients were listed for liver transplantation. 154 patients (Group 1; 14%) had suitable live donors and underwent RLDLT. No patient were removed from the waiting list or died with a suitable live donor available. There were no live donor deaths and no donor suffered any permanent disability. Of the remaining patients (Group 2; n=937), 350 underwent DDLT; 299 died or dropped off the waiting list; and 288 were still waiting at the time of this analysis. Recipient age, diagnosis, and hospital status, were not different between the two groups. Group 1 had shorter mean waiting times (6.0 vs. 9.4 months; p<0.001). Groups 1 and 2 had similar medical MELD scores at the time of listing (14.7 vs. 15.8; p = 0.142). Medical MELD scores at the time of transplant were significantly different between RLDLT and DDLT (15.4 vs. 19.5;p = 0.002) Patients in Group 1 had a significant survival advantage with RLDLT from the time of listing (Figure 1; p<0.001). From 2000-2006, ninety-day, 1-year and 5-year patient survival after transplantation were equivalent (RLDLT: 99%, 91%, 80% vs. DDLT: 97%, 93%, 81%; p=0.764).

 

Conclusions:

To our knowledge, this is the first report to document a survival advantage at time of listing for RLDLT over DDLT. With experience, survival after RLDLT is comparable to survival after DDLT.

 


11. Use of a Computerized Assessment to Measure Patient Competency to Provide Informed Consent for Living Liver Donation: Findings from the Adult to Adult Living Donor Liver Transplantation Cohort Study (A2ALL).

T. L. Pruett; J. R. Freeman; P. S. Appelbaum; B. W. Gillespie; D. R. Armstrong; J. C. Emond; R. M. Weinrieb; D. C. Nixon; S. and the A2ALL.

Background:

Competence to consent to living organ donation is typically assessed via subjective interview techniques that lack empirical reliability and validity. This study assessed the reliability and preliminary validity of a video version of the MacArthur competence measure (MacCAT-CR) designed to: 1) standardize educational information to aid informed decisions by potential living liver donors, and 2) capture audiovisual data via computer interface that can be reliably rated to assess competency to consent to living liver donation.

 

Method:

Twenty-six potential donors at six A2ALL sites viewed an educational video created to provide information on the risks and benefits of live liver donation. They then completed the on-line MacCAT questionnaire, filmed for later review. The video MacCAT assesses four domains: Understanding the process, risks, and benefits; Appreciating the personal impact; Expressing a decision; and Reasoning for the decision, for 36 total points. The video recordings were rated by two coders using pre-agreed, structured, scoring criteria. Recordings were given 0, 1, or 2 points based on the completeness of responses. Interrater reliability and group means on the four domains were examined.

 

Results:

Mean total scores did not differ between coders (28.8 vs. 29.1, p=0.212) and there was high interrater consistency for total scores with a Spearman correlation coefficient of 0.96 (p<0.001), suggesting interrater agreement. Participants showed solid Understanding (mean 17.4; SD 3.1; 79% of maximum 22 points), Appreciation (mean 4.9; SD 1.0; 82% of maximum 6 points), Expressing a decision (mean 3.7; SD 0.6; 93% of maximum 4 points), and Reasoning (mean 3.0; SD 0.8; 75% of maximum 4 points). Results were conservative, as 3 missing items were scored as zero.

 

Conclusions:

Independent raters coded audiovisual data with high agreement, suggesting the video MacCAT is a reliable tool to assess competency. Participants showed solid Understanding, Appreciation, Expression of a choice, and Reasoning of choice regarding liver donation. Also, in contrast to the traditional interviewer-administered MacCAT-CR, there were no opportunities to query vague or incomplete responses, or re-disclose information, which would enhance performance, particularly on Understanding and Reasoning. Based on these early results, the MacCAT-CR appears to provide portable and reliable assessment of competency for living liver donation, with the caveat that it does not formally assess for coercion or motive. Future work will include establishing criteria for acceptable competency and mechanisms for feedback to the transplant sites for follow up.