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Consensus Development Symposium Focuses on Recurrent
HCV Infection Following Liver Transplantation
By Thomas Shaw-Stiffel,
MD
Dr. Shaw-Stiffel is
Medical Director, Living Donor Liver Transplantation, Univ of Pittsburgh
Medical Center, Center for Liver Diseases,
Pittsburgh, PA.
He is also a Contributing Editor to
HIV and Hepatitis.com.
E-mail:
stiffelt@msx.dept-med.pitt.edu
 Introduction
End-stage liver disease
(cirrhosis) due to chronic hepatitis C viral (HCV) infection is now the
leading indication for orthotopic liver transplantation (OLTx) in the United
States. During the past decade, there has also been a striking rise in the
incidence of hepatocellular carcinoma (HCC) related to HCV-cirrhosis, which
has accentuated the rising number of cases awaiting OLTx.
According to the United
Network for Organ Sharing (UNOS) in Richmond, VA, of the approximately
16,000 people currently listed for OLTx, close to 8,000 have HCV-cirrhosis
with or without HCC or another complication of HCV.
To compound things
further, in almost all recipients, HCV reinfection of the new liver (termed
“recurrent HCV”) occurs within just a few weeks post-OLTx. Significant liver
injury is found in over two-thirds of cases at one year and cirrhosis
develops in about 20-30% within 5 years.
A sizeable number require
a second or even a third OLTx, but this is hard to justify given the serious
organ shortage.
With these concerns in
mind, the International Liver Transplantation Society (ILTS) recently held a
Single Topic and Consensus Development Symposium on this topic in Phoenix,
AZ, March 14-16, 2003. Hoffman LaRoche (Nutley, NJ) was a major sponsor.
The course directors were
Dr Russell Wiesner (Mayo Clinic and Foundation, Rochester, MN), Dr Michael
Sorrell (University of Nebraska, Omaha, NE) and Dr Federico Villamil (Fundaction
Favaloro Unidad, Buenos Aires, Argentina).
Key concepts from this
important meeting are highlighted below.
The
Expanding Scope of the Problem
Dr. Robert Brown
(Columbia University, New York, NY), Dr. Mitchell Shiffman (Virginia
Commonwealth University, Richmond, VA), Dr. Edward Gane (Need University,
Auckland, New Zealand) and Dr. Marina Berenguer (Hospital la Fe, Valencia,
Spain) discussed the mounting concerns with recurrent HCV post-OLTx.
Initially, recurrent HCV
did not appear to be a major problem. Retrospective studies in the mid-1990s
showed no major differences in patient or graft survival at 5 years post-OLTx
when cases with recurrent HCV were compared to those without.
Nevertheless, in most
studies, about 80% of recipients with recurrent HCV developed some degree of
“hepatitis” after 3-5 years. Protocol liver biopsies done at one year
post-transplant were shown to help predict the risk of subsequently
developing cirrhosis: <10% in cases with mild hepatitis vs >65% in
those with moderate to severe hepatitis.
However, during the past
few years, most transplant specialists have noted worse outcomes in patients
with recurrent HCV, clearly out of keeping with the results of older
studies.
These concerns were
confirmed in a recent analysis based on UNOS data from 1992-98 which
revealed significant differences at 5 years post-OLTx both in patient
survival [69.9% for HCV-positive cases vs 76.6% for non-HCV cases
(p<0.0001), RR = 1.23] as well as graft survival [56.8% vs 67.7%
(p<0.0001), respectively, RR = 1.30]. The analysis held firm even after
cases with HCC were factored in (7.3% vs 4.2%, respectively).
Similar findings have
also been seen in studies from Valencia, Spain, where close to 30% of
patients with recurrent HCV developed cirrhosis within 5 years post-OLTx.
In Valencia, the median
time to develop cirrhosis was 9-12 years post-OLTx vs 20-40 years
pre-OLTx, and the rate of fibrosis progression was 0.3 fibrosis units per
year post-OLTx vs 0.2 per year pre-OLTx.
In fact, the fibrosis
rate post-OLTx was 50-100% that seen at several transplant centers in the
United States (UCSF, Baylor and California-Pacific). This may relate to the
fact that older transplant donors are more often used in Spain, which has
recently been found to be a major risk factor for a poor outcome in
recurrent HCV
[See also
Advancing
Age of Liver Donors Has Powerful Effect on Survival of Transplant
Recipients]
Another concern is that
the severity of HCV recurrence appears to be worse now than it was several
years ago. In Spain, the rate of fibrosis progression during the years
1996-97 was almost 6 times that in the years 1985-89. Factors which may have
contributed to this include recipient age (p=0.05), incidence of HCC
(p=0.03), donor age (p<0.001), surgical issues (p<0.001) and those related
to immunosuppression (p<0.001).
Effects
of Immunosuppresants
Dr John Lake (University
of Minnesota, Minneapolis, MN) reviewed the role of various
immunosuppressants and their potential impact on recurrent HCV post-OLTx. In
several studies, corticosteroids have been shown to enhance the early return
of HCV RNA levels to pre-OLTx levels.
Each bolus of
corticosteroids given to prevent or treat acute cellular rejection (ACR) has
also been found to lead to a 1-log increase in viral load. However, there
are no apparent differences in the effects of cyclosporine and tacrolimus on
viral replication.
The possible beneficial
effects of mycophenylate mofitil and rapamycin remain controversial. Recent
data suggest that the IL2-receptor monoclonal antibody increases viral load
at 4-months post-OLTx.
Risk
of Disease Progression Increases
Once cirrhosis arises in
the context of OLTx, the risk of hepatic decompensation (e.g. new onset of
ascites, encephalopathy or variceal bleeding) is much higher than in non-immunosuppressed
cases (around 75% at 4 years vs only 15%, respectively). Furthermore,
patient survival is markedly decreased once hepatic decompensation occurs:
only 20% survive for 3 years vs 50% if non-immunosuppressed. If
another OLTx is required, the outcome is clearly not as favorable and some
liver transplant centers refuse to offer a second OLTx on this account.
Predicting
Outcome
The ability to predict
how a given patient will do post-OLTx with recurrent HCV remains an intense
area of research since it might then differentiate between patients who need
anti-HCV treatment vs those who don’t, thereby reducing side effects
and costs. Several speakers addressed this important topic.
Already certain factors
have been identified as playing a role, some virus-dependent and others
host-dependent, and these include HCV RNA levels pre-OLTx or early post-OLTx,
HCV genotype (genotype 1 in Europe), age of the liver donor, degree of
immunosuppression post-OLTx (especially the use of OKT3 for
steroid-resistant ACR), the presence of cytomegalovirus (CMV) infection
post-OLTx, and the failure to respond to interferon-based therapies prior to
OLTx.
Specific findings on
liver biopsy predictive of a poor outcome consist of steatosis, ballooning
degeneration, cholestasis and confluent necrosis. In addition, timing of HCV
recurrence appears crucial, since severe early (<6 months) recurrence is
ominous.
Some studies have linked
outcome to non-Caucasian recipient status and female gender. Unfortunately,
more often than not, these variables are not all that helpful in predicting
outcome in any given individual. If we could predict more severe recurrence
of HCV post-OLTx, this might prompt better strategies for interventions pre-
as well as post-OLTx.
Dr Jorge Rakela (Mayo
Clinic and Foundation, Scottsdale, AZ) discussed the potential benefits of
using anti-HCV-positive donor livers (as long as no significant fibrosis is
found on a pre-OLTx liver biopsy) in anti-HCV-positive recipients, since
recent data suggest a favorable outcome, perhaps even better than that seen
with anti-HCV-negative donors.
This may relate to the
fact that the liver used in this setting has already been infected with HCV
for many years without any significant fibrosis, suggesting a “preferential”
immunologic milieu or viral strain. Other studies have shown that the
predominant genotype (usually 1) takes over in the new graft.
Concerns with Recurrent HCV in Recipients of
Living Donor Liver Transplantation (LDLT)
Dr James Trotter
(University of Colorado Health Sciences Center, Denver, CO) then reviewed
the potential concerns with recurrent HCV in recipients of living donor
liver transplantation (LDLT). Theoretically, the smaller mass of liver in
LDLT recipients may alter the metabolic profile of immunosuppressants in
these cases. However, only a few studies have addressed this issue and small
numbers of cases were included.
These studies found that
lower doses are required for any given drug-level target of
immunosuppression, especially during the first 3-6 months of liver
regeneration post-LDLT. The exact mechanisms underlying this effect need to
be explored. Due to poor outcomes in a few LDLT recipients with recurrent
HCV at his center, Dr Trotter advised against using LDLT in early cases of
HCV cirrhosis. Other centers have yet to confirm this.
Re-Transplantation
for Recurrent HCV?
Re-transplantation for
recurrent HCV remains a controversial area but a consensus is growing that
patients with rapidly progressive disease from recurrent HCV post-OLTx
should not be offered a second OLTx. Early predictors include a serum
creatinine above 2 and a total bilirubin above 3. This was highlighted in a
lively debate between Dr. Timothy McCashland (University of Nebraska, Omaha,
NE) and Dr. William Wall (London Health Sciences Centre, London, Ontario).
Immunologic
Mechanisms of Hepatocyte Injury in Recurrent HCV
Drs. Hugo Rosen (Oregon
Health Sciences University, Portland, OR) first reviewed the basic
immunology of HCV infection in general and Dr Geoffrey McCaughan (Royal
Prince Alfred Hospital, Sydney, Australia) later discussed the specifics of
recurrent HCV post-OLTx. During the first 3 weeks post-OLTx, despite the
fact that serum HCV RNA levels climb precipitously on their way to levels
10-20 times higher than those seen pre-Tx, no major liver injury due to HCV
is noted in the vast majority of cases. Within 1-2 months, however, most
recipients begin to show some degree of liver enzyme abnormalities directly
related to HCV recurrence.
Fibrosing
Cholestatic Hepatitis (FCH)
At one end of the
clinical spectrum is an aggressive form of recurrent HCV known as fibrosing
cholestatic hepatitis (FCH), which fortunately is seen in only about 10% of
cases. Patients with FCH develop early jaundice and rapidly progressive
fibrosis. Loss of the liver allograft often occurs within 3-6 months and
re-transplantation is invariably a failure.
Similar to the situation
with severe recurrent hepatitis B post-OLTx in which FCH was first
described, HCV itself is thought to be cytopathic in these cases, since
exceedingly high HCV RNA levels are seen (about 20 times those found pre-OLTx).
The aggressive nature of FCH suggests a more virulent type of HCV, which in
some way contributes to the poor outcome, perhaps aggravated by the use of
excessive immunosuppression to prevent or treat ACR early post-OLTx.
Host variables may also
play a role in FCH since recent studies have shown that a Th2 cytokine
profile (IL-4 and IL-10) predominates, in contrast to the situation with
pre-OLTx chronic HCV and most recurrent HCV post-OLTx in which a Th1
response predominates. Of interest, this Th2 cytokine profile is also seen
in ACR. Whether or not the severity of ACR or the number of episodes trigger
and then promote FCH remains uncertain.
05/16/03
Reference
Recurrent HCV Infection Following Orthotopic Liver Transplantation.
A Single Topic and Consensus Development Symposium. Sponsored by the
International Liver Transplantation Society (ILTS). March 14-16, 2003.
Phoenix, AZ.
© Copyright 2003 by
HIV and Hepatitis.com. All Rights Reserved.
Reproduction of articles for personal or educational use is encouraged
and does not require permission from the publisher. Permission to re-print
copyrighted articles is almost always granted, but does require written
permission from the publisher (email
publisher@HIVandHepatitis.com)
 Idiopathic Progression
to Chronic Hepatitis and Cirrhosis
At the other end of the
spectrum, about 20% of cases with recurrent HCV post-OLTx have minimal if
any acute hepatitis. Nevertheless, for unknown reasons, a substantial number
(10-20%) will progress to chronic hepatitis and cirrhosis.
Acute Lobular Hepatitis
In contrast to the first
2 scenarios discussed above, the vast majority of cases (about 70%) with
recurrent HCV post-OLTx initially develop an acute lobular hepatitis
(moderately elevated levels of liver enzymes and only slightly elevated
total bilirubin).
HCV RNA levels are
elevated but certainly not as high as those seen in FCH. Immunologically,
there is a non-specific/specific host inflammatory response to the rising
viral load via a robust CD4+/CD8+ response (as in cases of acute HCV in non-OLTx
naïve patients) involving the TNFa
and Fas pathways.
After 6 months, many of
these go on to show features of chronic hepatitis, which may progress slowly
but surely to cirrhosis (15-25% depending on the transplant center).
However, a sizeable number of these (perhaps as many as 50%) do not develop
progressive fibrosis, or if they do, this is mild to moderate (without
cirrhosis).
During the transition
from acute to chronic hepatitis, serum ALT and AST levels fall, along with
serum HCV RNA levels. This is thought to relate to “immune reconstitution”
and may correlate with the tapering of corticosteroids, commonly done around
this time at most transplant centers. As noted earlier, an intrahepatic Th1
cytokine response predominates. The degree of damage correlates with IFNg
and TNFa levels,
as well as CD69+ (activated T cell) expression. Greater Fas expression
corresponds with the severity of piecemeal necrosis.
Recent studies have also
assessed HCV quasi-species post-OLTx and suggest an increasing complexity
during chronic hepatitis due to significant immune pressure. All these
findings invoke immunologic mechanisms as the primary reason for the
progressive liver damage seen in chronic hepatitis due to recurrent HCV
post-OLTx, in contrast to the situation with FCH where cytopathic effects
predominate.
Role of
Immunosuppression
The role of
immunosuppression in the severity of chronic hepatitis remains
controversial. On the one hand, a higher viral load and more severe liver
injury are seen in patients on triple immuno-suppressants, whereas more
injury may be the case when corticosteroids are tapered too rapidly.
A recent study from Italy
showed that only 40% of patients on prednisone doses ³
7.7 mg per day had severe liver injury due to recurrent HCV compared to 89%
who were maintained on < 7.7 mg per day. Thus, a greater degree of
immunosuppression may lead to a loss of immune recognition of HCV which
results in extremely high serum HCV RNA levels and a major risk of FCH from
a cytopathic effect and/or underlying immunologic imbalance (Th2 cytokine
response), possibly induced by ACR and/or its treatment.
On the other hand, immune
recognition of HCV possibly triggered by the rapid withdrawal of
immunosuppression, especially in the presence of the higher HCV RNA levels
that are seen post-OLTx, may predispose to progressive fibrosis and
ultimately cirrhosis in most other cases of chronic hepatitis.
Viral Kinetics in the
Peri-Transplant Period
Dr. Michael Charlton
(Mayo Clinic and Foundation, Rochester, MN) reviewed the critical events
during HCV re-infection of the new liver post-OLTx. A recent study assessed
viral kinetics during and shortly after OLTx. Once the old liver is
removed, HCV RNA levels begin to fall precipitously reaching undetectable
levels shortly after reperfusion of the new liver.
This likely corresponds
to removal of the primary HCV reservoir (i.e. the liver itself), followed by
rapid re-infection of the new liver from an extra-hepatic source (as yet
undefined). HCV RNA levels then begin to rise rapidly. Already by 4 days
post-OLTx, viral levels have climbed to the levels seen prior to OLTx and
continue to rise until 1-4 months post-OLTx when they reach levels 10-20
times those found pre-OLTx.
At that point, HCV RNA
levels begin to fall but remain much higher than those prior to the OLTx,
except in cases of FCH where the levels continue to rise inexorably (to more
than 20 times baseline). However, in the majority of cases without FCH,
during the first 2-3 months post-OLTx, despite these markedly elevated serum
and intrahepatic HCV RNA levels, liver enzymes remain close to normal or
minimally elevated (unless ACR occurs which must be confirmed by a liver
biopsy and treated appropriately).
Then, around 1-4 months
post-LTx, there is often a marked rise in liver enzymes associated with an
“acute” hepatitis which can be confirmed histologically (and not always easy
to differentiate from ACR). At this time, HCV RNA levels begin to fall
significantly at this time. This is thought to be due to the body’s immune
response to HCV, although it is considerably blunted due to the
immunosuppressants the patient is on.
If immunosuppression has
been particularly strong (to treat ACR), especially with single or repeated
doses of corticosteroids or OKT3 (a potent immuno-modulator), viral
replication can be quite high and the patient is then at significant risk to
develop FCH. Certain host genetic factors such as cytokine response (e.g.
TNF-a), liver
steatosis, or body mass index may also contribute.
Fortunately, in most
cases, viral levels fall at this point as do liver enzymes, and the patient
develops chronic hepatitis, usually starting at 6 months post-LTx and
continuing indefinitely.
Treatment Strategies
Several speakers reviewed
the current status of anti-HCV treatment in the OLTx setting. Ideally, most
agreed that it would be best to try to clear HCV prior to OLTx in order to
minimize the risks associated with treatment of recurrent HCV in the
immunosuppressed host.
Unfortunately, it remains
very difficult to treat patients awaiting OLTx due to the low blood counts
commonly seen in these cases related to hypersplenism and GI bleeding. Dr.
Greg Everson (University of Colorado Health Sciences Center, Denver, CO)
reviewed the experience at his center using a low- accelerating-dose regimen
(LADR) with standard interferon-a
(IFNa) and
ribavirin (RBV). He noted that over 20 patients have been treated and
several have cleared HCV prior to OLTx. Most have not relapsed post-OLTx,
including 2 living donor recipients. Dr. Everson also confirmed that he is
now using low-dose pegylated (PEG)-IFNa
plus RBV with considerable initial success.
Other speakers including
Dr.John Vierling (Cedars-Sinai Medical Center, Los Angeles, CA), Dr. Norah
Terrault (UCSF, San Francisco, CA), Dr. James Neuberger (Queen Elizabeth
Hospital, Birmingham, UK) and Dr. Theresa Wright (VAMC, San Francisco, CA)
went on to discuss the problems encountered when treating recurrent HCV.
Ribavirin-related
Toxicity
They all agreed that the
situation is considerably more difficult since anti-HCV treatment is poorly
tolerated post-OLTx for a variety of reasons. For one, the kinetics of RBV
are impacted by the higher frequency of renal impairment post-OLTx.
A recent study from the
University of Pittsburgh correlated the degreee of hemolysis from RBV with
creatinine clearance in this population. Although the use of growth factors
such as granulocyte colony stimulating factor (G-CSF) and epoietin to
increase cell counts is often helpful, combination therapy with standard IFN
and RBV has led to sustained virologic response (SVR) rates of only 5-25%
post-OLTx compared to 30-40% in ideal non-cirrhotic pre-OLTx patients.
Peginterferon Plus
Ribavirin
The recent introduction
of the longer-acting PEG-IFNs in combination with RBV should help improve
SVR closer to 40% post-OLTx. Preliminary data show promise using PEG-IFN
alfa-2a (Pegasys) plus
ribavirin.
However, when best to
intervene remains uncertain. Some experts treat “pre-emptively” (within 3
months post-OLTx) before significant HCV recurrence occurs. However, most
experts recommended waiting to confirm significant histologic damage due to
chronic hepatitis or at least some degree of progression in fibrosis before
committing the patient to potentially toxic anti-HCV treatment.
Several trials are
currently addressing these issues, including the role of PEG-IFN monotherapy
vs PEG-IFN plus RBV. The results of these trials are eagerly awaited.
Dr. Gary Davis concluded
the meeting with an overview of anti-HCV immunoglobulin (HCIG), BILN (a NS3
HCV protease which despite early promise has shown cardiotoxicity) and other
innovative agents in the management of recurrent HCV.
05/16/03
Reference
Recurrent HCV Infection Following Orthotopic Liver Transplantation.
A Single Topic and Consensus Development Symposium. Sponsored by the
International Liver Transplantation Society (ILTS). March 14-16, 2003.
Phoenix, AZ.
© Copyright 2003
by HIV and Hepatitis.com. All Rights Reserved.
Reproduction of articles for personal or educational use is encouraged
and does not require permission from the publisher. Permission to re-print
copyrighted articles is almost always granted, but does require written
permission from the publisher (email
publisher@HIVandHepatitis.com)
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