DDW 2007: Sunday Abstracts:
Topic:
Liver Transplantation - General
2. Use of hepatitis C-infected donors in liver
transplantation: a case-control study
P. Kwo; S. Wilson; R.
S. Mangus; A. Tector; J. A. Fridell; R. Vianna; S. Liangpunsakul; V. Misra; S.
Bhardwaj
Background
Hepatitis C is the major reason for the increase in HCC
(Liver Cancer) the need for liver transplantation in the
Methods
Data was extracted from the transplant center registry, UNOS
data, and from the original on-site donor data chart. Thirty percent of all
donors met non-ECD criteria (standard donors) and were included as potential
matches for the case-control study. Each HCV-positive liver donor recipient was
matched to two standard donor recipients as matched standard donor controls
(MSDC) by: recipient age +/- 10 years, primary diagnosis, cancer stage for
those with HCC, recipient MELD +/- 5, and donor age +/- 10 years. Outcomes
included graft and patient survival at 3-months, 1-year and 2-years;
perioperative death; and, HCV recurrence by 4-month and 1-year fibrosis
(F0-F4-Metavir).
Results
The HCV-donor and matched standard donor control groups did
not differ for recipient or donor demographics or in cold and warm ischemia (decrease
in the blood supply) time. Survival results and fibrosis progression are shown
in the table. Median follow- up time was 36 months. Kaplan-Meier actuarial
survival demonstrated improved graft survival for HCV-infected donors with a
trend toward significance (p=0.10).
Conclusions
These preliminary results suggest that HCV-infected liver
transplant recipients receiving livers from HCV-infected donors may have a
slower rate of fibrosis progression at 1-year. A trend was seen in survival
advantage for those receiving HCV-donor grafts compared to standard donor
controls. The use of HCV positive donors may be considered as a first line
therapy to increase the available donor pool of organs in those undergoing
liver transplantation for HCV-related cirrhosis.
Topic:
Liver Transplantation – Recurrence
218 Recurrent Hepatitis C After Liver Transplantation: On-Treatment
Prediction Of Response To Peginterferon Alpha-2a/Ribavirin (Peg/Rbv) Therapy
I. Hanouneh; C. M.
Miller; F. Aucejo; M. Quinn; N. N. Zein
Introduction:
Despite significant progress in the treatment of hepatitis C
(HCV), sustained virologic response (SVR) in liver transplant recipients
remains suboptimal and the clinical utility of SVR predictors during therapy is
unknown.
Aim:
Our Aims were to assess efficacy of peginterferon and
ribavirin combination therapy (Peg/RBV) in liver transplant recipients and to
estimate the predictive value of rapid virological responses (RVR, week 4) and
early virological responses (EVR, week 12) in this population.
Methods:
Retrospective analysis of
prospectively collected data from all patients who were treated with Peg/RBV
using a standardized protocol [28 patients (24 genotype 1 and 4 genotypes 2/3]. According to the protocol, all
patients received 48 weeks of therapy independent of virologic response.
Intention-to-treat analysis was used to measure the primary outcome (SVR).
On-treatment predictors of response were defined as HCV RNA negative or > 2
log10 decrease from pretreatment baseline at 4 weeks (RVR) and 12 weeks (EVR).
Results:
SVR was seen in 9/28 (32%) patients. Patients infected with
genotype 2/3 were more likely to achieve SVR than patients with genotype 1 [4/4
(100%) versus 5/24 (21%) p=0.006]. The highest rate of SVR was seen in patients
with RVR (Specificity and Positive Predictive Value = 100%) while the highest
rate of treatment failure was seen in those who did not have EVR (sensitivity and Negative Predictive Value =
100%, table). The negative predictive value of RVR to identify those who
did not achieve SVR was also very high in this population (92%). EVR had low
specificity (58%) and low positive predictive value (53%) to identify those
with SVR. None of those with detectable HCV RNA at week 24 had SVR while 3/12
(25%) patients who were HCV RNA negative at week 24 did not have SVR due to
breakthrough (1 patient) or relapse (2 patients).
Conclusions:
1. Peg/RBV is effective in the treatment
of post-liver transplant recurrent HCV.
2. On-treatment virologic monitoring is
highly predictive of SVR and may optimize the virologic response and minimize toxicity.
3. Given its high Positive and Negative
Predictive Values, RVR appears to be the most appropriate decision time point
for continuation of therapy.
|
|
|
Sensitivity |
Specificity |
Positive Predictive Value
|
Negative Predictive Value
|
|
RVR |
% |
83 |
100 |
100 |
92 |
|
95% CI |
35.9, 99.6 |
71.5, 100 |
47.8, 100 |
61.5, 99.8 |
|
|
EVR |
% |
100 |
58 |
53 |
100 |
|
95% CI |
66.3, 100 |
33.5, 79.7 |
27.8, 77 |
71.5, 100 |
|
|
Week 24 |
% |
100 |
75 |
77 |
100 |
|
95% CI |
66.3, 100 |
58.6, 96.4 |
42.8, 94.5 |
78.2, 100 |
Topic:
Current Treatment - Pegasys
B. Willems; S. J.
Hadziyannis; T. R. Morgan; M. Diago; P. Marcellin; D. E. Bernstein; P. J.
Pockros; A. LinM. L. Shiffman; S. Zeuzem
Background:
ACCELERATE, a large-scale (n=1469) prospective study recently
showed that, overall, peginterferon alfa-2a (40KD) plus ribavirin (RBV) for
24wks was superior to 16wks in hepatitis C virus (HCV) genotype 2/3 pts (EASL
2006:A734). In this study, two-thirds of pts achieved a rapid virologic
response (RVR; HCV-RNA <50IU/mL at wk 4). These early-responder pts had a
>80% probability of achieving an SVR with 16wks of therapy, suggesting that
this shortened treatment regimen may be a reasonable customized option for RVR
pts who cannot tolerate a full course of therapy. Conversely, pts without an
RVR had an SVR rate of only 49% with 24wks’ treatment, suggesting that these
pts may benefit from more intensive treatment regimens. To determine whether an
intensified regimen of peginterferon alfa-2a plus RBV may be beneficial in
genotype 2/3 pts without an RVR, we retrospectively examined available data
from other pivotal clinical studies.
Methods:
SVR and relapse rates following peginterferon alfa-2a
(PEGASYS®) plus RBV (COPEGUS®) were analyzed in HCV genotype 2/3 pts who did
not achieve RVR in two studies (NV15942, NV15801). In NV15942 (Hadziyannis.
Ann Int Med 2004), pts were randomized to 24 or 48wks of peginterferon alfa-2a
180µg/wk plus RBV 800 or 1000/1200mg/d. In NV15801 (Fried.
NEJM 2002), pts received 48wks of peginterferon alfa-2a plus RBV 1000/1200mg/d.
Results:
·
RVR
was achieved by a high proportion of genotype 2/3 pts (74% and 58% in NV15942
and NV15801).
·
In
pts in NV15942 who did not achieve an RVR, the lowest relapse rate and the
highest SVR rate (76%) was achieved with 48wks of peginterferon alfa-2a plus
RBV 1000/1200mg/d (Table).
·
This
compared with 61% for 48wks’ peginterferon alfa-2a plus RBV 1000/1200mg/d in
NV15801 and 49% for 24wks’ peginterferon alfa-2a plus RBV 800mg/d in
ACCELERATE.
Conclusions:
Genotype 2/3 pts who do not achieve an RVR could receive
added benefit if treated for 48wks with a higher dose of RBV
(1000/1200mg/d).These results merit further investigation in a prospective
controlled study to fully elucidate how treatment customization can benefit pts
before formal recommendations can be made.
|
NV15942 ITT analysis |
24wks |
24wks |
48wks |
48wks |
|
SVR, n/N (%)
[95% CI] |
14/21 (67) |
22/34 (65) |
20/30 (67) |
28/37 (76) |
|
Relapse rates,
n/N (%) [95% CI] |
5/19 (26) |
7/29 (24) |
3/23 (13) |
1/27 (4) |
Pts without follow-up data were
considered not to have achieved an SVR.
Topic:
Disease Progression - General
62. Risk of Hepato-Pancreatico-Biliary Tumors
Following Hepatitis C Virus Infection: a Population-based Study on
H. B. El-Serag; E. A.
Engels; L. Henderson; O. Landgren; T. P. Giordano
Background:
Hepatitis C (HCV) may increase the risk of
hepato-pancreatico-biliary tumors, other than hepatocellular carcinoma.
Previous case-control studies in elderly Medicare recipients indicated a
possible association between HCV and intra hepatic cholangiocarcinoma (ICC).
Little is known about the association between HCV and extra hepatic
cholangiocarcinoma (ECC) or pancreatic cancer.
Methods:
We conducted a cohort study including 146,394 HCV-infected
and 572,293 HCV-uninfected users of U.S. Veterans Affairs healthcare
facilities. We used the inpatient, outpatient, and death files of the national
computerized VA administrative databases. Patients with two visits with a
diagnostic code for HCV infection from 1996-2004 were included, as were up to
four HCV-uninfected subjects for each HCV-infected subject, matched on age,
gender, and baseline visit date. Risks of ICC, ECC, pancreatic cancer, and
hepatocellular carcinoma were assessed using proportional hazards regression,
adjusting for selection factors, race, use of medical services, and potential
confounders. Chart review of 62 ECC and ICC cases indicated a high positive
predictive value for the algorithm used to identify cholangiocarcinoma (85.7%
for ICC, and 73.5% for ECC).
Results:
There were 75 cases of ECC, 37 ICC, 617 pancreatic cancer, and 1679 hepatocellular carcinoma during follow up
that started 6 months following index date. Risk for ICC was elevated with HCV
infection with (Hazard ratio (HR): 2.50 (95% CI: 1.29-4.86)). The adjusted
hazard ratios (aHR) ranged between 2.07 and 2.76 adjusting for cirrhosis,
diabetes, IBD, hepatitis B, alcoholism or alcoholic liver disease (up to 3
covariates at a time).
We found no increased risk for ECC (HR 1.05; 0.60-1.85). The
risk of pancreatic cancer was slightly elevated (HR: 1.23, 1.02-1.49), but was
attenuated when adjusting for acute or chronic pancreatitis or alcoholism (aHR
1.18; 0.97-1.42). As expected, the risk of hepatocellular carcinoma associated with
HCV was very high (HR 14.8; 13.2-15.6).
Conclusions:
·
HCV
infection confers more than two-fold elevated risk of ICC.
·
There
does not appear to be an association between HCV and ECC,
·
The
association with pancreatic cancer needs further study.
S1000. Identification of Novel Biomarker Profiles in
Hepatitis C Positive Liver Cancer Patients.
J. Petersen; K.
Kasturi; C. Elferink; M. Hassan; E. Fung; T. Yip; N. Snyder
Background:
Hepatocellular carcinoma (HCC)in
patients with HCV related cirrhosis occurs with a annual frequency of 1-8%.
Although the prognosis for patients with advanced HCC is poor, if detected
early, successful treatment by transplantation, resection, or radiofrequency
ablation is possible. Currently used biomarkers for HCC are frequently normal
or in the indeterminate range. Thus, the identification of a biomarker or a
series of biomarkers that could identify early stage HCC would be of great
interest. ProteinChip technology (SELDI-TOF) has been used as a profiling
technique to identify potential biomarkers which may represent proteins,
protease-cleavage products, or novel peptides. We used this technology to
investigate differences in the serum profile of patients with chronic HCV from
patients with HCV associated HCC.
Materials and Methods:
With IRB approval we analyzed serum samples from 60 HCV
positive patients, 30 with confirmed HCC and 30 with various stages of fibrosis
(6 each with F0, F1, F2, F3, and F4) without evidence of liver cancer. The
samples were prefractionated using Equalizer® bead protein biomarker discovery
technology and SELDI ProteinChip® array profiling. The fractions were analyzed
on the PCS 4000 time of flight mass spectrometer using CM10, IMAC (pretreated
with Cu), and Q10 chips. Pooled normal human plasma was analyzed concurrently
as controls and to establish criteria for peak magnitude significance. Data of
the proteomic spectra was analyzed by Ciphergen Express Data Manager software
with Pattern Track and Two-way Hierarchical Clustering algorithm.
Results:
We were able to identify 91 peaks of <50 KDa that were
significantly correlated (p<0.05) with the presence of HCC. These peaks were
then analyzed using logistic regression (Insightful Miner v 3.0, Insightful
Corporation Seattle, WA, USA). In this manner we were able to identify 7 peaks
of < 20 KDa that allowed the separation of precancerous HCV-positive
patients from HCV-positive HCC patients. Additional analysis of the profile
revealed that the magnitude of these peaks was greater in the HCV positive patients
without evidence of HCC. The average peak height average for HCV patients
ranged from 2.17 – 17 times greater than that found for the HCC patients. Using
these peaks the sensitivity and specificity for detection of HCC was 100%.
Conclusion:
We were able to identify 7 peaks of <20 KDa that allowed us to separate patients with HCC from HCV positive patients without evidence of HCC. Additional work to identify these putative biomarkers along with the development of assays will be necessary to evaluate their usefulness in the early detection of HCC.
S1004. A Comparison of Alphafetoprotein, AFP-L3% and
Des-Gamma Carboxyprothrombin in Patients with Chronic Hepatitis, Cirrhosis and
Hepatocellular Carcinoma.
F. A. Durazo; M. J.
Tong; L. M. Blatt; W. G. Corey; J. Lin; S. Han; S. Saab; R. W. Busuttil
Background:
Hepatocellular carcinoma (HCC) is a common complication in
patients with cirrhosis of the liver. Detection of HCC at an early stage is
critical for a good clinical outcome. Surveillance of patients at risk to
develop HCC is crucial.
Aims:
a) compare the accuracy of
alphafetoprotein (AFP), AFP-L3% and des-gamma carboxyprothrombin (DCP) in the
diagnosis of HCC in patients with chronic viral hepatitis and with cirrhosis;
b) define the level of each tumor marker with
the best sensitivity, specificity, and positive predictive value (PPV) for the
diagnosis of HCC.
Methods:
243 patients with either chronic hepatitis B (HBV) or chronic
hepatitis C (HCV) were included in the study. Forty eight had stage I-III
fibrosis on liver biopsy, 49 had cirrhosis and 146 had HCC.
Results:
Levels of AFP, AFP-L3% and DCP were significantly higher in
patients with HCC than in patients with chronic hepatitis or cirrhosis
(p=<.0001). ROC curves indicated that the cut-off value with the best
sensitivity and specificity for each test was ≥25 ng/mL for AFP, ≥10%
for AFP L3% and ≥84 mAU/mL for DCP. The sensitivity, specificity and PPV
of AFP was 69%, 87% and 69.8%, of AFP-L3% 56%, 90% and 56.1% and of DCP 87%,
85% and 86.8% respectively. In contrast to AFP and AFP-L3%, DCP levels were
below the ROC cut-off in all patients without HCC. No advantage was observed
when combining two or three of the tumor markers.
Conclusion:
DCP was superior to AFP and AFP-L3% in differentiating
patients with HCC from chronic viral hepatitis and from cirrhosis, and it
should replace AFP as a tumor marker for HCC. The clinical utility of AFP-L3%
is more as a confirmatory test when AFP is elevated.
AFP, AFP-L3% and DCP for the Diagnosis of Hepatocellular Carcinoma
|
|
Sensitivity |
Specificity |
PPV |
NPV |
|
AFP |
69% |
87% |
69.8% |
65.6% |
|
AFP-L3% |
56% |
90% |
56.1% |
57.6% |
|
|