Sunday Poster Sessions, October 29, 2006

Viral Hepatitis and Liver Transplantation

 

 

772. Survival and prognostic factors in a large cohort of HIV-HCV coinfected patients transplanted in a single centre. 

J. Duclos Vallée; C. Feray; M. Sebagh; E. Teicher; A. Roque-Afonso; B. Roche; D. Azoulay; R. Adam; H. Bismuth; D. Castaing; D. Vittecoq; D. Samuel View Pres.

 

Liver transplantation in HIV-HCV coinfected patients is a recent indication. We have compared in a single center, the survival and the severity of recurrent HCV after liver transplantation in HIV-HCV coinfected and HCV monoinfected patients.

 

Patients and methods.

67 patients receiving a first liver graft for HCV-related liver disease between 1999 and 2004 were included. Among them, 23 had HAART-controlled HIV infection with more than 150 CD4/mm3 before liver transplantation. All patients were monitored for HCV viral load and liver histology during the post liver transplantation course.

 

Results.

Coinfected patients were younger than monoinfected patients (43 years ± 7 vs 53 years ± 5; p<0.001) and had an higher MELD score (19.5± 8 vs 15.1±4.7, p=0.004). Two-year survivals were 74% and 92%, respectively in coinfected patients and monoinfected patients (log-rank=0.07). In multivariate cox analysis, survival was only related to MELD score. In coinfected patients, the 6-month HCV viral load was higher (6.8 ± 0.4 log vs 6.0 ± 1; p=0.03) than in monoinfected patients. Three coinfected patients and none of monoinfected patients had severe acute hepatitis C. Two-year survival with fibrosis less than F3 stage was 36 % in coinfected and 74 % in monoinfected (p<0.02). The rate of fibrosis defined by dividing Metavir F stage by the time from LT measured between the 12th and 18 th month post liver transplantation was 1.5 ± 1.4 in coinfected and 0.8 ± 0.5 in monoinfected patients. By multivariate analysis the only significant factor related to the rate of fibrosis was the HIV coinfection.

 

Conclusions.

·        Survival is poorer and the recurrence of hepatitis C seems more severe after liver transplantation in HIV-HCV coinfected patients. New effective drugs against HCV, avoidance of drug toxicity, prolonged anti-HCV therapies are mandatory to improve the results of this challenging indication of LT.

·        The results of liver transplant in HIV/HCV coinfection patients were satisfactory in terms of improved survival, since these patients had high MELD scores.  It will probably be possible to improve upon these results by reducing drug toxicity and using new anti-HCV specific inhibitors.

 


773. Can we expand the pool of organ donors? Use of livers from anti-HBc+ and/or anti-HCV+ organ donors. 

R. M. Taylor; R. Pietroski; M. Hagan; R. M. Merion; R. J. Fontana.

 

Detailed medical/social histories (PMSHx) including the Centers for Disease Control high risk behavior questionnaire (HRQ) are routinely collected by organ procurement organizations (OPOs) to help identify high risk donors. However, the relationship between the information gathered and organ utilization is unknown.

 

The aim of our study was to examine the association between PMSHx of anti-HBc+ and anti-HCV+ organ donor referrals and liver utilization in a large OPO.

 

METHODS:

Between 1/94-12/04, 283 of 2,868 (9.9%) organ donor referrals were anti-HBc+ and/or anti-HCV+. The 208 seropositive donors with complete records were analyzed.

 

RESULTS:

Donor PMSHx were provided by spouse, parent or offspring in 76%. 62 seropositive livers (30%) were utilized with a significant increase over the 11 year study period (OR=1.25 P=0.002). Amongst the 10 HRQ items, a hx of incarceration was reported in 28% but was not associated with liver utilization (P=0.09). On univariate analysis, a previous hx of hepatitis in the donor was significantly associated with non-utilization (P=0.03) while needle track markings and tattoos were not (P=0.60). Independent predictors of utilization on multivariate analysis included later referral year, fewer hospitalization days, lower bilirubin, non-anti-HCV+, and no hx of cardiovascular disease/hypertension (c-statistic=0.836).

 

CONCLUSIONS:

Over the past 11 years, utilization of livers from anti-HBc+ and anti-HCV+ donors has significantly increased. Contrary to expectations, identifiable hepatitis risk factors from the donor PMSHx and HRQ were not independently associated with liver utilization. These results suggest that collection of PMSHx and HRQ data may not be necessary to make informed decisions about utilization of seropositive livers but further study of these parameters in seronegative donors is required.

 

 

Liver Utilized
n=62

Liver Not Used
n=146

P value

Age (years)

45.0±14.0

46.7±12.4

0.40

BMI (kg/m2)

25.3±5.4

25.5±6.0

0.89

African-American

19%

41%

0.003

Admission to donor referral (days)

1.1±1.5

2.2±3.6

0.03*

Total bili (mg/dl)

0.68±0.41

1.17±1.86

0.04*

Serum ALT (IU/L)

52±150

85±202

0.26

Anti-HBc+

73%

67%

0.44

Anti-HCV+

36%

67%

<0.001*

Known hx of hepatitis

16%

31%

0.03

Hx of blood transfusion

5%

14%

0.06

Hx of cardiovascular disease or hypertension

28%

49%

0.005*

Hx of incarceration

20%

31%

0.09

Alcohol use ever

58%

73%

0.03

Drug use ever

51%

62%

0.13

*=Significant on multivariate analysis


774. Detection of HCV antigens (HCV-Ag) in early post liver transplant (LT) graft biopsies predicts recurrent hepatitis C after 1 year post LT in patients transplanted for HCV related liver disease. 

A. Grassi; M. Susca; C. Quarneti; V. Cipriano; M. Ravaioli; A. D'Errico; C. Morelli; F. Piscaglia; G. Mazzella; P. Andreone; D. Zauli; G. Grazi; A. D. Pinna; F. B. Bianchi; G. Ballardini.

 

Background.

Early graft HCV reinfection occurs in almost all the patients transplanted for HCV-related liver disease and it is frequently associated with recurrent hepatitis C (RHC) which represents one of the main clinical problems to be faced in the post-LT setting.

 

Aim

Aim of the present study was to evaluate whether the immunohistochemical detection of liver HCV-Ag in early post-LT liver biopsies could be a useful tool in predicting RHC 1 year post LT.

 

Methods.

A liver biopsy was obtained from 44 HCV+ve patients in the presence of altered blood tests from 20 to 60 days post-LT. Histological diagnosis was: hepatitis (22), rejection (7), undefined (7, rejection grade-II/III excluded, but coexisting rejection grade-I and hepatitis patterns) or other (8). Quantitative HCV viremia at the time of biopsy was available in 28 cases. HCV-Ag were evaluated, on frozen sections, by an immunoperoxidase technique and the % of infected hepatocytes estimated. Patients were clinically evaluated 1 year post LT: 7 were dead, (3 of them, died within 6 months for non-HCV related disease and without evidence of hepatitis, were excluded from further evaluations), and 16 out of the remaining 37 patients had RHC.

 

Results.

Thirty out of 41 biopsies were +ve for HCV-Ag (71.5%), more frequently in case of hepatitis with respect to other diagnosis (95.4% vs 42.1%, p=0.00022). The % of HCV-Ag +ve hepatocytes in the early post-LT biopsy was significantly higher in patients with RHC after 1 year with respect to patients without (65% vs 1%, p=0.000016). HCV genotype 1, and gender were not statistically different in the 2 groups.

 

Univariate analysis indicated that RHC 1 year post-LT was significantly associated with serum HCV-RNA levels >4Meq/ml, a number of HCV-Ag +ve hepatocytes ≥30% and the diagnosis of hepatitis in the early phase post-LT (p=0.015, p=0.0000007, p=0.00001, respectively). Multivariate analysis identified a number of HCV-Ag +ve hepatocytes ≥30% as the only significant independent predictor for RHC 1 year post LT (p=0.002). When evaluating only the subgroup of patients with a diagnosis of hepatitis in the early biopsy, the number of HCV-Ag +ve hepatocytes was significantly higher in the 17 patients with RHC after 1 year with respect to the 5 patients without (70% vs 5%, p=0.025). Only 3 patients out of 19 (15.8%) without hepatitis in the early post-LT biopsy developed clinical hepatitis after 1 year.

 

Conclusions

HCV graft reinfection occurs early post LT and may be easily evaluated by immunohistochemistry evaluation of HCV-Ag in the liver. A high number of reinfected hepatocytes predicts, independently from early histological diagnosis, the risk of RHC 1 year post LT.

 


775. Early HCV RNA levels and “Super-recurrence” predict advanced allograft fibrosis at 1-year in patients undergoing liver transplant for HCV. 

J. G. O'Leary; N. Elias; M. Hertl; D. S. Pratt; A. B. Cosimi; R. T. Chung.

 

Recurrent HCV is a major problem after liver transplantation (LT). The factors that predict rapidly progressive allograft fibrosis are not well defined. It is not known whether preemptive use of antiviral therapy improves allograft outcomes. We performed a retrospective analysis of our experience with preemptive therapy compared to reactive therapy with peginterferon (PEG-IFN) and ribavirin (RBV) for HCV after LT. We also analyzed 1-year predictors of advanced allograft fibrosis (Metavir stage 3 or 4).

 

METHODS:

From 11/01-9/04 all LT recipients with HCV were preemptively initiated on PEG-IFN and RBV 1.5 to 6 weeks post-LT (n =33). The reactively treated group consisted of 38 patients prior to and after the preemptive era; patients were treated only if they developed HCV recurrence (ALT >3x ULN with histologic confirmation). Both groups were treated the same; the dose of PEG-IFN and RBV was escalated with G-CSF and epoetin to a goal dose of 180 mcg of PEG-IFN-a-2a or 1.5 mcg/kg of PEG-IFN-a-2b and 1000-1200 mg/day of RBV and continued for 12 months. Endpoints included advanced allograft fibrosis at 1-year and early HCV recurrence (<12 months post-LT).

 

RESULTS:

Preemptive therapy did not decrease the incidence of early HCV recurrence (55% vs. 66%, p=NS), improve the 1-year incidence of advanced fibrosis (27% vs. 21%, p=NS), or increase the sustained virologic response rate to therapy compared to patients treated reactively (9.1% vs. 14.3%, p=NS). Univariate analysis of all 71 patients found that higher pre-LT HCV RNA, higher HCV RNA at 7-days post-LT, and nonresponse or inability to tolerate HCV therapy pre-LT were significantly associated with early recurrence. Univariate analysis found “super-recurrence” (ALT>3x ULN with histologic confirmation <3 months post-LT), pre-LT HCV RNA, post-LT day 7 HCV RNA, donor age, warm ischemia time, and receipt of adjuvant chemotherapy after LT for HCC were significantly associated with advanced fibrosis at 1-year post-LT. Stepwise multivariate modeling found that HCV RNA at 7-days post-LT (p=0.0006) and super-recurrence (p=0.0033) sufficed to predict advanced fibrosis at 1-year post-LT. Super-recurrence alone had an 86.7% positive predictive value and a 92.7% negative predictive value for advanced fibrosis at 1-year post-LT.

 

CONCLUSION:

1. Super-recurrence and HCV RNA levels 7-days post-LT predict advanced allograft fibrosis at 1-year. Our data will require prospective validation and long-term follow-up, but suggests these patients will require novel approaches to therapy. 2. Preemptive antiviral therapy with PEG-IFN and RBV does not improve short-term allograft or virologic outcomes compared to reactive therapy.


776. Recurrence risk score predicts cumulative increase in hepatitis c recurrence after liver transplantation. 

T. Collins; R. M. Ghobrial ; J. Hong; A. Cameron; J. Gornbein; M. Zimmerman; D. G. Farmer; H. Yersiz; S. Gordon; G. Lipshutz; R. W. Busuttil.

 

Background:

Graft reinfection with Hepatitis C (HCV) is universal following orthotopic liver transplantation (OLT). Multiple graft and recipient characteristics have been implicated in HCV recurrence after OLT. Avoidance of grafts with risk factors reduces the usable pool of organs for HCV patients. This study stratified risk factors for HCV recurrence to maximize graft utilization while minimizing risk of HCV recurrence.

 

Methods:

We retrospectively reviewed 398 adult patients with at least 5 years of follow up who underwent OLT for hepatitis C from 1990-2000 at UCLA. Risk factors for HCV recurrence included in the analysis were donor age, donor length of hospital stay, recipient age and recipient model for end stage liver disease (MELD) score. Independent risk factors for recurrence were identified by multivariate Cox proportional hazard regression analysis. Each risk factor was assigned one point to obtain a recurrence risk score for each transplant.

 

Results:

Among the 398 patients considered in the study, 19 had a recurrence risk score of 0, while 208, 135 and 36 had recurrence risk scores of 1, 2 and 3 respectively. Of all variables examined, independent risk factors for HCV recurrence were donor age ≥50 (RR 1.48), donor hospital stay >5 days (RR 1.6), recipient age ≥40 (RR 1.6) and recipient MELD score ≥27 (RR 1.51). The absolute recurrence rate per 100 person-months for patients with a recurrence risk score of 0, 1 or 2 points was 1.14, 1.25 and 1.97 respectively (p<0.01). In sharp contrast, a recurrence risk score of 3 significantly increased the recurrence rate to 5.61 (p=0.0024). In addition, there was no significant increase in mortality with recurrence risk scores of 0, 1 or 2. However, mortality risk increased 5-fold with a recurrence risk score of 3 (p=0.006).

 

Conclusion:

Accumulation of risk factors is associated with an escalation of risk for hepatitis C recurrence and mortality. Outcomes are notably worse with the presence of 3 or more risk factors. Recipient to donor graft pairings that involve a score of 2 or less may be safely used however pairings with a score of 3 should not be considered. The HCV recurrence risk score may be used in the clinical setting to match HCV recipients to donor organs with reduced hepatitis C recurrence and improved survival.

 


777. Diabetes and Immunohistochemical Staining for Oxidative Damage in Liver Tissue are Associated with Fibrosis Progression in Hepatitis C after Liver Transplantation. 

S. J. Cotler; T. Valyi-Nagy; A. Bhushan; J. Berkes; T. J. Layden; G. Guzman.

 

Recurrence of hepatitis C virus (HCV) infection is a major problem after orthotopic liver transplantation (OLT).

 

Aim

The aim of this study was to evaluate whether diabetes mellitus (DM) or evidence of oxidative damage in liver biopsy specimens was associated with HCV progression post-transplant.

 

Methods:

Subjects consisted of 27 OLT recipients with HCV who had liver biopsy tissue available for immunohistochemical staining and pathologic assessment. Protocol liver biopsies were obtained at 6 months after transplantation, 1 year, annually, and when indicated based on liver biochemistries. Paraffin embedded liver tissue sections were stained for 8-hydroxy-2’ deoxyguanosine (8-OHdG), which is an indicator of hydroxyl radical mediated damage to cellular RNA and nuclear and mitochondrial DNA (FASEB J 2000;14:955-67). The average percentage of 8-OHdG staining in a histologic section was categorized as 1+ (<25%), 2+ (26-50%), 3+ (51-75%), or 4+ (>75%) by two pathologists who were masked to clinical data. Liver histology was assessed for hepatitis activity index score (Am J Surg Pathol 1995;19:1409-17). Biopsies with features of rejection were excluded. Data from a total of 49 biopsies were analyzed to assess whether high 8-OHdG score (4+ vs. 1-3+) and DM were associated with higher fibrosis index (FI). FI was calculated as fibrosis score (0-4)/time post-transplant (years). In addition, survival analysis was performed, limiting analysis to one specimen per patient. Time to bridging fibrosis or cirrhosis (F3-4) was compared as a function of 8-OHdG score and DM using the log-rank test.

 

Results:

Subjects’ mean age was 54 +/- 10 years, 17/27 (63%) were male and (10/27) 37% had DM. A median of 2 (range 1-3) biopsies were evaluated per patient. Considering all 49 biopsies, FI was higher in patients with DM (p<0.001) and high 8-OHdG score (p=0.007). Moreover, high 8-OHdG was associated with DM (p=0.001). There was no significant association between high 8-OHdG score and degree of portal inflammation, piecemeal necrosis, or lobular inflammation on liver biopsy. In linear regression analysis, both high DM and 8-OHdG were independently associated with FI (p= 0.015 and p=0.016, respectively). In survival analysis considering a single biopsy specimen per patient, time to F3-4 was significantly more rapid in cases with high 8-OHdG scores (p=0.007). There was a trend toward an association between DM and time to F3-4 (p=0.142).

 

Conclusions:

In HCV post-transplant, 1) DM and oxidative damage in liver tissue were associated with fibrosis progression and 2) oxidative damage in liver tissue was associated with DM.

 


778. Sustained Viral Response Using Peg IFN alfa-2b Plus Ribavirin in Patients with Recurrent Hepatitis C after Liver Transplantation. 

R. Ghalib; C. Levine; B. Hollinger; R. Stribling; T. Box; W. Hutson; A. Post; S. Joshi; J. Weinstein; B. Husberg; A. Mejia; S. Cheng.

 

Purpose:

To identify factors predictive of viral response to 2 different dosages of PEG IFN alfa-2b plus ribavirin in the OLT patient with recurrent hepatitis C.

 

Methods:

This is a multi-center randomized clinical trial of post OLT patients with histologic recurrent HCV. All patients were started on PEG IFN alfa-2b 0.5 mcg/kg/week plus ribavirin 600 mg/day. At week 4, patients tolerating therapy increased ribavirin to 800 mg/day and according to baseline randomization either remained at 0.5 mcg/kg/wk (low dose arm) or increased to 1.5 mcg/kg/week (high dose arm). Therapy continued for 48 more weeks unless HCV RNA was positive at week 24.

 

Results:

59 patients were enrolled with 27 (46%) in the low dose arm and 32 (54%) in the high dose arm. A total of 28 (47%) completed treatment (28 in high dose vs. 5 in low dose), 20 (34%) discontinued at week 24 with nonresponse (3 in high dose vs. 17 in low dose), 1 from each group withdrew at week 24 with genotype 2/3, and 9 (15%) discontinued for adverse events (5 in high dose vs. 4 in low dose) including 2 (3%) deaths in the high dose arm.

 

The age range was 37-67 years (mean 51.4 6.0) (20 females; 39 males) with a range of 0.3-5.1 years post OLT (mean 1.6 1.2). HCV was genotype 1 in 43 patients (73%). Mean HCV RNA at baseline was 3.9 million IU/mL (range 0.04-15.6 million IU/mL). Significantly more patients achieved an SVR in the high dose arm (19/32, 59.4%) vs. low dose arm (5/27, 18.5%; p<.001). SVR was higher with a non-1 genotype (11/16, 68.8%) vs. genotype 1 (13/43, 30%; p<.009). Logistic regression for SVR identified the higher PEG IFN dose and genotype non-1 as significant variables (-2 log likelihood 64.9; model Chi-square 14.8, df=2, p< .001).

 

Conclusions:

Intention to treat analysis of SVR in this post liver transplant population with recurrent hepatitis C shows that the 2 most predictive factors were dose of PEG IFN alfa-2b comparing 1.5 mcg/kg/week to 0.5 mcg/kg/week (59.4% and 18.5%, respectively) and genotype 1 vs. non-1 (30.2% and 68.8% , respectively). No significant relationship was found for gender, BMI >30 or ribavirin dose <9 mg/kg. Further investigation of predictive factors of viral response are needed in the OLT population to guide selection of appropriate treatment candidates and therapies

 


780. Impact of Extended Criteria Donor on Hepatitis C recurrence following Liver Transplantation. 

T. Murakami; A. Fahmy; D. G. John; G. R. Morgan; T. Diflo; H. Tobias; L. Petrovic; L. W. Teperman.

 

Introduction:

Hepatitis C virus (HCV) infection has become the most common indication of Liver transplantation (LT). The Extended Criteria Donor (ECD) has come to be used routinely in LT in this era of critical organ donor shortage. In this study, we examined the impact of ECD on the severity of recurrence as well as patient survival follwing LT for HCV patients.

 

Methods:

Between January 1, 2001 and December 31, 2005, 175 LT procedures (49.9% of all cases) were performed for 162 HCV recipients from 70 ECD, 64 ideal donor (ID), and 41 living donor (LD). ECD included: age>65 years, Na>170mEq, Macrosteatosis>30%, Cold ischemic time>14Hr, AST>150IU, Split liver, and Donation after cardiac death. Recurrent HCV was diagnosed by biochemical graft dysfunction with the presence of features consistent with recurrent HCV on liver biopsy. Protocol biopsies were not performed.

 

Result:

HCV recurrence were 43% (n=30) in ECD, 50% (n=32) in ID, and 46% (n=19) in LD, the incidence of recurrence and time to recurrence were not statistically different in each donor groups. The incidence of severe HCV recurrence, either grade 3-4 fibrosis, cholestatic hepatitis, and/or HCV induced graft failure, were significantly higher in ECD group (p<.05). 1 year patient survival was significantly shorter in ECD than ID and LD (66.4%:ECD, 80.1%:ID, and 87.8%:LD) (p<.05). The risk factor for HCV induced graft failure were mutifactorial ECD, early HCV recurrence, and history of methyl-prednison bolus for acute rejection.

 

Conclusion:

The outcome of LT for HCV recipient from ECD was very poor. ECD has a possibility to lead severe HCV recurrence. HCV recipient should avoid ECD if at all possible. Recipient parameters must be carefully considered prior to the use of ECD grafts.

 

Clinical characteristic of HCV recipient

 

Number

Mean age

Mean observation period

HCV re-currence

Mean time to HCV recurrence

Grade
 3-4 Fibrosis

Cholestatic Hepatitis

HCV induced Graft loss

Acute Rejection

Chronic Rejection

ECD

70

53.1

26.2 Mo

30 (43%)

7.1 Mo

10 (33%)

8 (27%)

6 (20%)

12 (17%)

2 (17%)

ID

64

54.2

26.3 Mo

32 (50%)

8.3 Mo

6 (19%)

4 (13%)

1 (3%)

16 (25%)

9 (63%)

LD

41

53.6

36.1 Mo

19 (46%)

9.5 Mo

5 (26%)

2 (11%)

2 (11%)

9 (22%)

0 (0%)

 


781. Sustained virological response to antiviral therapy for recurrent HCV post liver transplant favorably influences histological progression. 

N. Selzner; M. Guindi; N. Girgrah; P. Wong; G. Levy; L. Lilly.

 

Background:

Hepatitis C virus (HCV) recurrence following liver transplantation is universal and is an important cause of graft loss. Treatment of recurrent disease with interferon-based therapy is more complex and challenging in this setting than in non-transplant patients. Furthermore, impact of treatment response on graft histology is unknown. We have reported recently an on treatment virological response of 73% and a sustained viral response (SVR: HCVRNA negative six months post treatment cessation) of 50% in post transplant HCV patients treated with combination therapy.

 

Aim

The aim of this study is to determine whether the viral loss in response to treatment is associated with improvement in liver histology.

 

Patients & Methods:

116 post transplant patients (68% Genotype 1) with histologically-proven recurrent HCV received at least three months of combination therapy with Interferon/PEG-Interferon and Ribavirin between Jan 98 and Dec 05. To date, 46 patients have achieved an SVR. Among them, 21 patients had paired biopsies (pre- and post-treatment) available for analysis.

 

Results:

The mean follow up after discontinuation of treatment in these patients was 29 months (range, 9-53 months). When compared to the pre-treatment liver biopsy, histology at one year (n=20) demonstrated decreased activity in 50% of patients, and no change in 50% of patients. Fibrosis stage at one year improved by 1 grade in 33% of patients and remained unchanged in 52%. However, in 15% of patients, the fibrosis score increased despite persisting negative HCVRNA results. Conclusion: Sustained virological response in post transplant HCV patients treated with combination therapy is mainly associated with non progression (or regression) of the activity score and fibrosis stage and should encourage the application of these treatments in patients with post transplant HCV recurrence.


783. Immunohistochemical perforin staining allows differentiation between hepatitis c recurrence and rejection post-liver transplant. 

A. Quaglia; M. Hussain; M. Henegan; B. Portmann; D. Vergani.

 

BACKGROUND:

The histological distinction between recurrent HCV infection and rejection can be problematic. We investigated whether immunohistochemical characterisation of the inflammatory infiltrate can be helpful in this respect.

 

METHODS.

One group of 10 HCV+ve patients (one liver biopsy each with clear-cut recurrent post-OLT HCV infection and one sample each of explant liver) was compared with one group of 10 patients transplanted for non-viral disease (one post-OLT liver biopsy each with clear-cut acute cellular rejection (ACR). Primary murine monoclonal antibodies directed to CD3 (pan-T-cell), CD79a (B-cell), CD4 (helper T-cell), CD8 (cytotoxic T-cell), Bcl-2 (inhibitor of apoptosis), CD56 (NK cells), Granzyme (lytic granules of CD8), Perforin (lytic granules of CD8), CD68 (macrophages), CD138 (plasmacells). Immunostaining was visualised using a polymer conjugate (Envision, Dako). Semiquantitative analysis of immunostaining was carried out to assess portal, interface and lobular cell infiltrates.

 

RESULTS:

Portal, interface and lobular infiltrates of HCV liver explants, allografts with recurrent HCV or with ACR show no significant differences in the relative proportions of CD3, CD79a, CD4, CD8, CD56, Granzyme, CD56, Bcl2 and CD138 positive cells. However, perforin antibodies labelled strongly and consistently lymphocytes at site of bile duct damage in biopsy specimens showing ACR, but was sporadic and not-associated with bile duct damage in HCV+ve samples.

 

CONCLUSION:

Immunohistochemistry for perforin may represent a useful tool in the distinction between recurrent HCV infection and rejection.

 


784. Steatosis in post transplant liver biopsies may herald recurrence of Hepatitis C genotype 3. 

M. Guindi; N. Selzner; N. Girgrah; P. Wong; L. Lilly.

 

Background:

The prevalence of steatosis in patients with chronic hepatitis C (HCV) is 55%. This is higher than the prevalence of steatosis in chronic hepatitis of other etiology and higher than expected by chance association of HCV and steatosis alone. HCV genotype 3 (HCV-3) is associated with a higher prevalence and more severe extent of steatosis. Recurrence of HCV is common post liver transplantation (OLT). The histologic features of early recurrence can be subtle and nonspecific.

 

Aim:

The literature suggests that hepatic/blood viral load is the factor associated with steatosis in HCV-3. Because of the high prevalence of steatosis in HCV-3 in the nontransplant setting, we wanted to examine the development of steatosis as the initial prevalent histologic feature of recurrent HCV-3 in the transplanted liver.

 

Methods:

We reviewed retrospectively the liver transplant database between January 1, 2000 and March 1, 2006 at our institution for patients transplanted for HCV who developed steatosis involving more than 30% of hepatocytes in their post OLT liver biopsies within the first year. Liver biopsies were done by protocol or when clinically indicated. HCV genotypes were recorded. The post transplant liver were biopsies evaluated for steatosis and necroinflammation. The intervals between OLT and development of steatosis, and development of steatosis and necroinflammatory viral effects were recorded. BMI and presence of DM were also documented.

 

Results:

183 patients were transplanted for HCV between January 2000 and March 2006: 141 HCV-1, 11 HCV-2, 25 HCV-3, and 6 HCV genotypes 4-6. 10 patients had > 30% steatosis post OLT: 7 HCV-3 (28% of all HCV-3 patients), 1 HCV-1b and 1 HCV-1a (1.4% of all HCV-1 patients), and 1 HCV-4. Steatosis ranged from 30-90%. Time interval from OLT to steatosis was 5-26 weeks (mean 13 weeks). 5 of the 10 patients have not yet developed necroinflammation. In the 5 patients that did, time interval from steatosis to necroinflammation is 0-14 weeks (mean 5.3 weeks). Follow up ranged from 3 months to 3 years. Only 2 patients had steatosis in their explants (10 and 20%; both HCV-3).

 

Conclusions:

Recurrent HCV-3 is associated with significant steatosis in the allograft. Furthermore, steatosis may be the earliest histologic feature of early HCV-3 recurrence. The mean interval to development of steatosis in post OLT biopsies from HCV-3 patients correlates with the known time of expected recurrence of HCV. This finding may help to identify a subgroup of patients at risk for more aggressive disease.

 


785. Genotype and choice of calcineurin inhibitor influence response to antiviral therapy in liver transplant recipients treated for recurrent HCV. 

N. Selzner; N. Girgrah; I. Al Adawi; P. Wong; G. Levy; B. McQuarrie; M. Cattral; P. Greig; I. McGilvray; D. Grant; L. Lilly.

 

BACKGROUND:

Combination therapy with Interferon and ribavirin is widely used in the management of recurrent HCV post liver transplant. We report our response rates and identify predictors of sustained response in a large series of patients.

 

PATIENTS & METHODS:

116 patients with recurrent HCV received at least three months of combination therapy with IFN or PEG-IFN and ribavirin. Growth factors were administered as required. Enzymes, HCV-RNA and histology were followed.

 

RESULTS:

79 patients were G1, 23 were G2 or G3. 85 patients (73%) achieved an on treatment virological response (OTVR; >2-log drop/negative HCVRNA). 22 patients remain on treatment (duration 6-56m), 11 of whom have had an OTVR. Of the 94 patients who have stopped treatment, 15 await repeat HCVRNA at 6m, 11 have relapsed following ETR, 46 have had an SVR, 2 terminated treatment prematurely and relapsed, and two more died while still HCVRNA positive. 59 G1 patients (75%) had an OTVR; of these, 25 have reached SVR, 7 relapsed, 9 are ETR pending repeat RNA, and 8 remain on treatment. In the G2/3 cohort, 22/23 patients had an OTVR; of these, 13 have achieved SVR, two relapsed, two remain on treatment, and 5 await repeat RNA off treatment. 7 patients experienced rejection while on treatment. 5/116 patients have died, 4 from graft failure due to recurrent HCV, and one due to metastatic HCC.

 

CONCLUSIONS:

G2/G3 patients, with a projected SVR rate of 83% are significantly more likely than G1 patients (projected SVR 47%) to respond to antiviral therapy for recurrent HCV. The only other factor that influenced SVR rates was choice of calcineurin inhibitor, with relapse rates in patients receiving Neoral significantly lower than those on tacrolimus (8.6% vs 30%). Patient age, gender, transplant to treatment interval, pre treatment viral load, and history of treated rejection had no impact on OTVR or SVR. This information may influence decisions on timing of treatment and choice of underlying immunosuppressive regimen.

 


787. Impact of the recurrence of hepatitis C in quality of life after liver transplantation. 

D. R. Gotardo; M. D. Teixeira; M. C. Machado; E. Strauss.

 

Background:

Low titres serum autoantibodies with or without clinical significance develop in children and adult recipients of liver graft transplanted for liver diseases unrelated to autoimmune etiology. Whether this reflect anti-graft or autoimmune response influenced by calcineurin inhibitors immunosuppressive agents, is unknown. Recurrent-HCV and recurrent-free HBV transplanted patients represents two different models to study autoimmune phenomena.

 

Aim:

To study serum autoimmune reactivity in HCV and HBV recipients in relation to liver function and graft damage.

 

Material and Methods:

80 recipients were studied (55 HCV-related, all with hepatitis recurrence and 25 HBV-related, all without hepatitis recurrence). 79% males, age 51 yr, ALT levels 72 +/- 85 IU/L (nv <40 IU/L) treated with FK-506 (47%) or Cyclosporin (53%). Steroids were given for 3-6 months. All patients had a protocol liver biopsy taken 12-24 month after transplant when serum samples were collected and tested for ANA antibodies by IF on Hep 2 substrate and for serum transaminases. Serum ANA titres of 1:80 or 1:160 were considered low-titre (LT) ANA and titres > 1:160 were defined as high-titre (HT) ANA. Histological activity and fibrosis were scored according to Ishak.

 

Results:

46 patients (58%) showed serum ANA reactivity and 18 were HT-ANA (22%). Overall, serum ANA positive patients were significantly older than ANA negative cases (53 vs 49 yr, p<0.03). HT-ANA positive patients showed abnormal serum ALT levels more often respect to LT-ANA patients (32% vs 13%, p<0.05). Serum ANA and HT-ANA prevalence were similar in HCV and HBV recipients respectively (58% vs 56%; 24% vs 20%). By contrast, the two groups differed for ALT levels (90 +/- 91 vs 31 +/- 46 IU/L, p<0.0001). In both HCV+ and HBV+ recipients ANA positive and negative patients had similar histological scores and liver enzymes (HCV+ grading: 6.2 vs 6.9; staging: 2.1 vs 1.9; ALT:83 vs 99 IU/L; HBV+ grading : 2.1 vs 1.8; staging: 1.0 vs 0.8; ALT: 40 vs 22 IU/L). Only in HBV recipients, but not in HCV recipients HT-ANA positive patients showed higher ALT serum levels respect to LT-ANA or negative ANA cases (ALT: 75 vs 21 IU/L, p=0.05).

 

Conclusions:

Low titres ANA are commonly seen in older transplanted patients with both HCV and HBV. High titres ANA were significantly associated with liver disfunction in HBV/recurrence-free recipients suggesting a possible pathogenetic role of autoimmunity in determining liver injury.

 


788. Prevalence of serum antinuclear antibodies (ana) after liver transplant in HCV and HBV recipients is associated with different clinical profiles. 

M. F. Donato; E. Arosio; V. Monti; F. Agnelli; C. Rigamonti; M. Berra; M. Colombo.

 

Background:

Low titres serum autoantibodies with or without clinical significance develop in children and adult recipients of liver graft transplanted for liver diseases unrelated to autoimmune etiology. Whether this reflect anti-graft or autoimmune response influenced by calcineurin inhibitors immunosuppressive agents, is unknown. Recurrent-HCV and recurrent-free HBV transplanted patients represents two different models to study autoimmune phenomena.

 

Aim:

To study serum autoimmune reactivity in HCV and HBV recipients in relation to liver function and graft damage.

 

Material and Methods:

80 recipients were studied (55 HCV-related, all with hepatitis recurrence and 25 HBV-related, all without hepatitis recurrence). 79% males, age 51 yr, ALT levels 72 +/- 85 IU/L (nv <40 IU/L) treated with FK-506 (47%) or Cyclosporin (53%). Steroids were given for 3-6 months. All patients had a protocol liver biopsy taken 12-24 month after transplant when serum samples were collected and tested for ANA antibodies by IF on Hep 2 substrate and for serum transaminases. Serum ANA titres of 1:80 or 1:160 were considered low-titre (LT) ANA and titres > 1:160 were defined as high-titre (HT) ANA. Histological activity and fibrosis were scored according to Ishak.

 

Results:

46 patients (58%) showed serum ANA reactivity and 18 were HT-ANA (22%). Overall, serum ANA positive patients were significantly older than ANA negative cases (53 vs 49 yr, p<0.03). HT-ANA positive patients showed abnormal serum ALT levels more often respect to LT-ANA patients (32% vs 13%, p<0.05). Serum ANA and HT-ANA prevalence were similar in HCV and HBV recipients respectively (58% vs 56%; 24% vs 20%). By contrast, the two groups differed for ALT levels (90 +/- 91 vs 31 +/- 46 IU/L, p<0.0001). In both HCV+ and HBV+ recipients ANA positive and negative patients had similar histological scores and liver enzymes (HCV+ grading: 6.2 vs 6.9; staging: 2.1 vs 1.9; ALT:83 vs 99 IU/L; HBV+ grading : 2.1 vs 1.8; staging: 1.0 vs 0.8; ALT: 40 vs 22 IU/L). Only in HBV recipients, but not in HCV recipients HT-ANA positive patients showed higher ALT serum levels respect to LT-ANA or negative ANA cases (ALT: 75 vs 21 IU/L, p=0.05).

 

Conclusions:

Low titres ANA are commonly seen in older transplanted patients with both HCV and HBV. High titres ANA were significantly associated with liver disfunction in HBV/recurrence-free recipients suggesting a possible pathogenetic role of autoimmunity in determining liver injury.


789. Adherence to the 80/80/80 rule in treatment of HCV recurrence after OLT is strongly associated with sustained virologic response (SVR). 

K. Chacko; N. Sussman; J. M. Vierling; J. Goss; N. R. Barshes; R. Stribling; C. O'Mahony.

 

Recurrent HCV infection after liver transplantation (LT) is universal, and 20% rapidly progress to cirrhosis and decompensation within 4-7 years. An ideal antiviral treatment regimen has not been identified, but a sustained virological response (SVR)can occur with combination interferon and ribavirin therapy. Adherence, defined as achieving 80% of desired dosing for >80% of the desired duration (80/80/80 rule), was associated with SVR in analyses of immunocompetent patients treated for HCV infection. have an significantly higher rate of sustained virological response .

 

Objective:

To investigate the relationship of adherence to the 80/80/80 rule and the achievement of SVR in adult LT recipients..

 

Methods:

Twenty six patients with recurrence of HCV infection after liver transplantation (determined by histological evidence on liver biopsy, elevated ALT, and positive HCV RNA in the serum) were treated with weight based peg-IFN and 800mg of ribavirin for a period of 48 weeks. Therapy was analyzed based on the achievement of SVR in relation to the duration and dosage of treatment. Group comparisons for categorical and continuous variables were performed using Chi-square and the Mann-Whitney U-test, respectively. Multivariate analysis was performed with logistic regression. A p-value of <0.05 was considered statistically-significant.

 

Results:

26 patients met inclusion criteria. 12 (46%) met the 80/80/80 rule and 14 (54%) did not. The two groups did not differ with respect to gender, age, histological grade, or MELD score. In the 80/80/80 group, 6 patients (50%) attained SVR and 6 patients (50%) did not. In the suboptimally treated group, 3 patients (21%) attained SVR and 11 (79%) did not (p=0.13). Multivariate analysis showed that, after adjusting for demographic and clinical characteristics, achieving 80/80/80 was highly associated with achievement of SVR (odds ratio 16.9, p=0.04). Furthermore, duration of treatment >80% was more important than achieving >80% dosing of either drug.

 

Conclusion:

Adherence to the 80/80/80 recommendation is highly associated with the achievement of SVR in adults with recurrent HCV infection after LT. Optimal dosing is not associated with an increased frequency of adverse effects.