Sunday Poster Sessions, October 29, 2006
Viral Hepatitis and Liver Transplantation
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.
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 |
Liver Not Used |
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
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.
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.
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.
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.
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
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 |
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%) |
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.
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.
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.
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.
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.
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.