| |
Living donor liver transplantation
for end-stage hepatitis C.
Sugawara Y, Kaneko J, Akamatsu N, Kishi Y, Hata S, Kokudo N, Makuuchi
M.
Artificial Organ and Transplantation Division, Department of Surgery,
Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Living donor liver transplantation is important for patients with
end-stage viral hepatitis because of the shortage of organs from
deceased donors. However, preliminary results indicate that living liver
donation might be disadvantageous for hepatitis C virus-positive
patients. Twenty-seven patients who underwent living donor liver
transplantation for hepatitis C virus cirrhosis preemptively received
antiviral therapy using interferon-alpha2b and ribavirin, which was
started an average of 32 days after the operation and continued for at
least 6 months thereafter. The serum hepatitis C virus RNA became
negative in the 8 of 16 patients with more than 1 year follow-up. The
cumulative 3-year patient survival was 85%, which was comparable to that
of hepatitis C virus negative patients (n = 93; 90%). Preemptive
antiviral therapy after transplantation may be necessary for
satisfactory results after living donor liver transplantation.
PMID: 15251363 [PubMed - in process]
Transplantation Proceedings
Volume 36, Issue 4 , May 2004, Pages 914-915
doi:10.1016/j.transproceed.2004.03.116
Copyright © 2004 Elsevier Inc. All rights reserved.
Liver transplantation: organ donor
Can the use of marginal
liver donors change recipient survival rate?
M. B. Rochaa, I. F. S. F. Boin, , a, C. A. F. Escanhoelaa and L. S.
Leonardia
a Unit of Liver Transplantation, Hospital de Clinicas, Campinas,
Brazil
Available online 10 June 2004.
Abstract
Liver transplantation as a therapeutic method for the treatment of
end-stage
liver disease is beclouded by a scarcity of organs. The aim of this
study
was to retrospectively analyze the relation between the classification
of
donors as marginal versus ideal and recipients survival after 148 of
197
orthotopic liver transplantations (OLT) performed from 1991 to 2001.
Donors
were classified as marginal if they showed the major criteria of: age
over
55 years, aspartate aminotransferase greater than 150 UI/L; serum
bilirubin
greater than 2 mg/dL, serum sodium greater 150 mEq/L, high-dose
dopamine or
any other vasoactive amine, cardiac arrest, intensive care unit (ICU)
stay
over 5 days, and moderate severe macrosteatosis. The minor criteria
for a
marginal donor were: use of dopamine below 10 g/kg/min, history of
alcoholism, drug abuse, ICU stays less than 4 days, microsteatosis of
any
degree, and mild macrosteatosis. Statistical analysis was performed
using
Cox regression analyzing and the Kaplan-Meier survival method. The
rate of
marginal donors was 61.5%. The 180 postoperative day survival was
77.0%.
Survival rates were 81.1% for recipients of marginal donor organs, and
70.7%
for ideal donor recipients (P > .05). In conclusion, the use of
marginal
liver donors is viable and safely expands the numbers of liver
transplants,
thereby diminishing the number of waiting list deaths.
Corresponding author. Address reprint requests to Ilka Boin, Rua Aldo
Oliveira Barbosa 184, , Campinas SP, CEP 13086-030; , Brazil.
Natural
history of hepatitis C following liver transplantation.
Rodriguez-Luna H, Douglas DD.
Division of Transplantation Medicine, Mayo Clinic Hospital, Phoenix,
Arizona, USA.
PURPOSE OF REVIEW: Currently, chronic hepatitis C
virus-infection-related cirrhosis is the most common indication for
liver transplantation in the USA and most parts of the world. While
the incidence of new hepatitis C virus cases has decreased, the
prevalence of infection will not peak until the year 2040. In
addition, as the duration of infection increases, the proportion of
new patients with cirrhosis will double by 2020 in an untreated
patient population. If this model is correct, the projected increase
in the need for liver transplantation secondary to chronic hepatitis C
virus infection will place an impossible burden on an already limited
supply of organs. In this article we present a comprehensive review of
post-transplant hepatitis C virus infection and address the major
challenges that face the transplant community. RECENT FINDINGS:
Hepatitis C virus infection recurs virtually in every post-transplant
patient. Typically, serum levels of hepatitis C virus RNA increase
rapidly from week 2 post-liver transplant, achieving 1-year post-liver
transplant levels that are 10-20-fold greater than the mean pre-liver
transplant levels. Progression of chronic hepatitis C virus is more
aggressive after liver transplantation with a cumulative probability
of developing graft cirrhosis estimated to reach 30% at 5 years.
Approximately 10% of the patients with recurrent disease will die or
require re-transplantation within 5 years post-transplantation.
Interventions to prevent, improve, or halt the recurrence of hepatitis
C virus infection have been evaluated by multiple small studies
worldwide with similar overall rates of virological clearance of
approximately 9-30%. Current consensus recommends combination therapy
with pegylated interferon and ribavirin for those patients with
histological recurrence of hepatitis C virus infection and fibrosis of
>/=2/4. Therapy is adjusted to tolerance and rescued with granulocyte
colony-stimulating factor and erythropoietin for bone marrow
suppression. SUMMARY: The major challenges that face the transplant
community in the coming years include new strategies to meet the
growing demand for limited organ donor supplies and improvement of
treatment for those patients in whom recurrence of viral disease has
occurred. Only with improved antiviral treatments and strategies will
we make a significant impact on this problem.
PMID: 15241083 [PubMed - as supplied by publisher]
Selective digestive
decontamination reduces infection in liver transplant patients
|
| The use of selective digestive decontamination to reduce
gram-negative infections in patients undergoing liver
transplantation is of benefit, suggests a report in the latest issue
of the journal Liver Transplantation. |
| |
| The use of antimicrobials to reduce levels of aerobic
gram-negative bacteria and/or yeast in the intestinal tract and thus
prevent infections caused by these organisms is known as selective
digestive decontamination (SDD).
SDD has been proposed as a tool for preventing infection in liver
transplant patients, who are at high risk of bacterial infection
within the first month after transplantation. Such patients are
particularly susceptible to gram-negative bacteria, hence the
suggestion that SDD may be of particular value in such cases.
However, the true value of SDD has remained controversial.
Therefore, Nasia Safdar and colleagues from the University of
Wisconsin Medical School, USA, conducted a systematic review and
meta-analysis to determine whether SDD is beneficial in patients
following liver transplantation.
The researchers examined all studies that evaluated the efficacy
of SDD in liver transplant patients, as well as including randomized
trials that included liver transplant patients given SDD versus
either placebo or no treatment or minimal treatment (e.g. oral
nystatin alone) and that provided adequate data to calculate a
relative risk ratio.
The researchers found most studies showed SDD to be effective in
reducing gram-negative infection.
 |
 ...the
risk of antimicrobial resistance must be considered.  |
| Nasia Safdar , Liver
Transplantation |
They also found the non-randomized and uncontrolled trials showed
benefit with SDD in reducing overall infection.
However, the effect on overall infection was limited in the 4
randomized trials evaluated; the pooled relative risk was 0.88,
indicating no statistically significant reduction in infection with
the use of SDD.
The summary risk ratio for the association between SDD and
gram-negative infection was 0.16, indicating an 84% relative risk
reduction in the incidence of infection caused by gram-negative
bacteria in patients receiving SDD in randomized trials.
The authors conclude that the available literature supports a
beneficial effect of SDD on gram-negative infection following liver
transplantation.
They caution however, that the risk of antimicrobial resistance
must be considered and add, " Larger multicenter randomized trials
in this patient population to assess the effect of SDD in reducing
infection and mortality, while assessing the risk of antimicrobial
resistance, are needed."
|
|
|
|
Hepatitis C,
interferon, and risk of rejection after liver transplantation
|
| http://www.natap.org/ |
| |
EDITORIAL
Liver Transplantation
Volume 10, Issue 7, July 2004
Didier Samuel *Centre HÈpatobiliaire, HÙpital Paul Brousse, Villejuif,
France
Hepatitis C virus (HCV)-related end stage cirrhosis is currently the
leading indication for liver transplantation in Europe and in the United
States. HCV recurrence after transplantation is almost universal and 60
to 90% of patients will develop lesions of chronic hepatitis C on the
graft. Recent data confirm that HCV infection impairs patient and
allograft survival. The course of HCV graft disease is accelerated in
transplant recipients compared with immune-competent patients, with
reported 5-year cirrhosis rates around 10 to 20% and up to 28 to 40% in
some series. This yields excess a risk of death or retransplantation for
liver failure at 10-15 years posttransplant.
It appears now that the survival at 5-10 years is impaired in HCV-positive
recipients in comparison to non-HCV recipients, due in part to the
development of liver cirrhosis and of liver failure after liver
transplantation. Given this risk, it appears important to offer
antiviral therapy to liver transplant patients who develop a recurrence
of chronic hepatitis C.
Several approaches are under evaluation: the first option is to start
the treatment just after transplantation as a preemptive therapy, the
advantage is that the viral load is low at that time; however, tolerance
of patients is poor in the immediate posttransplant period, and risk of
rejection and of sepsis are high. The second option is to treat at time
of acute hepatitis (in general during posttransplant months). The third
option is to start the treatment at time of chronic hepatitis on the
graft; in this latter situation the groups are heterogeneous, since some
patients are treated during the first posttransplant year, some much
later, with major differences both in the immunosuppressive drugs given
to these patients, and in the severity of graft hepatitis.
The type of antiviral treatment used is now mostly the combination
therapy interferon plus ribavirin. Indeed, results with interferon alone
have been disappointing in term of virologic response, several studies
using nonpegylated interferon alone have reported a sustained virologic
response rate below 10%.
The combination interferon alpha-2b plus ribavirin combination therapy
gave promising results in liver transplant patients with chronic
hepatitis C on the graft, achieving sustained virologic response rate of
20 to 35%. It is not well known if the use of pegylated interferon in
the combination therapy will further improve these results. However, the
first reported results of posttransplant treatment with pegylated
interferon plus ribavirin gave promising results, achieving sustained
virologic response in 25 to 40% of the patients.
The antiviral treatment is particularly important in the management of
these patients, since progression of fibrosis can probably be stopped
after sustained virologic response. However, there are some
controversies on the long-term outcome of the graft histology after
sustained virologic response, and some authors have described a
decreased activity grade and an absence of true improvement in the
fibrosis score at least during the first years posttreatment.
Patients with HCV reinfection of the graft after liver transplantation
differ from immune-competent patients in several ways: their viral load
is very high, and most transplant patients in Europe are infected with
genotype 1 - both factors predictive of a lower virologic response rate.
Despite the absence of certitude on the possibility of fibrosis
regression, patients with sustained virologic response have normal liver
enzymes level, a dramatic decrease of the activity score, and probably a
much better long-term outcome in comparison to the patients with ongoing
infection.
For these reasons, the antiviral treatment is now fully part of the
overall therapeutic strategy posttransplantation. The timing, the
duration of treatment, the use of pegylated interferon instead of
nonpegylated interferon, and the optimal dosage of ribavirin are still
matter of debate. It has been clearly shown that in the absence of
treatment there is no decrease of viral replication, no spontaneous
clearance of the virus, and there is a progression of liver graft
disease.
The drawbacks of the treatment are a rather disappointing virologic
efficacy and a poor tolerance. Indeed, the treatment with interferon
plus ribavirin is poorly tolerated and tolerance appears lower than in
immune-competent nontransplant patients.
One of the main complications reported in comparison to nontreated
patients is anemia; this is due to an increase toxicity of ribavirin in
these patients with frequently impaired renal function, and with an
impaired regenerative bone marrow. For this reason, it was necessary to
introduce ribavirin at lower dosage than in nontransplant patients, to
add erythropoietin administration in some patients, and to decrease the
dosage of ribavirin, reducing the efficacy of the antiviral treatment.
The other complications are similar to nontransplant patients:
leukopenia, thrombocytopenia, depression, and irritability.
The risk of rejection in transplant patients treated with interferon is
specific to transplant recipients, but remains a matter of debate. It is
well known that interferon can provoke acute or chronic rejection of the
renal allograft in renal transplant patients; there are numerous reports
of irreversible renal failure due to rejection in renal transplant
recipients treated with interferon.
Until recently, interferon was still considered as a contraindication in
renal transplant patients. The risk and severity of rejection due to
interferon in liver transplant recipients are still controversial.
Despite some reports on the possible occurrence of acute or chronic
rejection in liver transplant recipients, this complication is not
always recognized, and the role of interferon is controversial. This may
be due to several factors: the risk of rejection due to interferon is
probably lower in liver transplant recipients than in renal transplant
recipients, the liver being considered as more resistant to rejection
than the kidney. Not all patients have been biopsied in the presence of
abnormal liver enzymes during interferon, and the risk of rejection is
probably underestimated. The risk of rejection with interferon might be
dependent of the posttransplant interval and of the level of
immunosuppressive drugs.
It is unclear whether the risk of rejection due to interferon is
modified by the use of pegylated interferon or by the adjunction of
ribavirin. Pegylated interferon may theoretically increase the risk of
rejection, due to its greater efficacy, its different pharmacokinetics,
and its renal clearance, which is frequently decreased in liver
transplant patients. On the contrary, it has been suggested that the
adjunction of ribavirin might decrease the risk of rejection, since
ribavirin has immune modulatory action. This has been suggested by the
lower number of reported cases of rejection in liver transplant patients
treated with interferon plus ribavirin therapy than with interferon
alone and by a recent report of 4 cases of renal transplant patients
treated successfully for acute hepatitis C without occurrence of
rejection.
The report by Saab et al. in this issue of Liver Transplantation
highlights the risk of rejection in liver transplant patients treated
with combination pegylated or nonpegylated interferon plus ribavirin.
Five out of 41 patients experienced acute or chronic rejection episodes
during combination treatment, leading in several cases to
discontinuation of the antiviral treatment. Several points appeared from
this study: 1) the cases of rejection are well documented; 2) the risk
of rejection appeared as relatively low (4/41, 10%) but remains high if
the late period after transplantation is taken into account; 3) the
consequences of these episodes of rejection can be severe, since some
patients died or were retransplanted for chronic rejection. Most of
these patients experienced rejection at long-term posttransplantation,
at a time where the risk of rejection is usually low reinforcing the
deleterious role of interferon in these cases; 4) rejection occurs
relatively rapidly after the start of the treatment, during the first 3
months in 4 out of 5 cases.
The immunosuppressive regimen was relatively low in most patients at the
start of the treatment. In the report of Feray et al. with interferon
alone, the rate of rejection was higher (35%), mostly represented by
severe chronic rejection, and was significantly higher than pair-matched
untreated HCV liver transplant patients. In the report of Saab et al.,
patients experienced both features of acute and chronic rejection. The
mechanisms of action of interferon on rejection are not well known,
however, it seems to activate human leukocyte antigen class II
expression on biliary ducts, triggering lymphocyte infiltrate or
disappearance of interlobular biliary ducts. The fact that ribavirin may
decrease the risk of rejection of interferon has been suggested but has
not been really proven. In a randomized study with interferon plus
ribavirin, we observed 1/28 episodes of rejection in the treated group
vs. 0/24 in the nontreated group.
Why these differences in the prevalence and the severity of rejection
episodes during interferon treatment among different studies? First, the
delay when initiating the treatment after transplantation is important,
the risk of rejection being higher in the first months posttransplant.
Second, the immunosuppression dosage used at the time antiviral
treatment begins may interfere positively or negatively with the risk of
rejection. Third, the prevalence of rejection can be underestimated
particularly in nonresponding patients, the increase in liver enzymes
being considered falsely as due to hepatitis C in the absence of liver
biopsy. Fourth, the use of pegylated vs. nonpegylated interferon and the
combination with ribavirin might modify the prevalence of rejection.
Indeed, pegylated interferon might increase the risk of rejection due to
its long-lasting effect and its renal clearance in patients with
impaired renal function. Recently, a prevalence of 25% of mild rejection
episodes was reported in a series of 20 patients treated with pegylated-interferon
plus ribavirin.
In conclusion, from these reports, we can conclude that while there is a
risk of rejection during interferon-based treatment for hepatitis C
recurrence after liver transplantation, the prevalence and the severity
of rejection remains matters for debate. The risk of rejection might be
higher in patients receiving pegylated interferon, however this has not
yet be proven. The decreased risk of rejection due to the combined use
of ribavirin has been suggested, but not proven. Finally, these reports
point out the need to perform a liver biopsy before starting the
antiviral treatment, to eliminate any ongoing histological rejection, to
maintain a sufficient level of immunosuppression (which should be
balanced with the need to decrease viral replication), to closely
monitor liver tests during antiviral treatment, and to perform a liver
biopsy in case of increased liver enzymes. The risk of rejection during
interferon-based treatment should not be ruled out and should be
evaluated in further studies.
Outcomes of acute rejection after interferon therapy in liver
transplant recipients
Sammy Saab 1 2 *, Denise Kalmaz 1, Nupoor A. Gajjar 3, Jonathan Hiatt 2,
Francisco Durazo 1 2, Steven Han 1 2, Douglas G. Farmer 2, R. Mark
Ghobrial 2, Hasan Yersiz 2, Leonard I. Goldstein 2, Charles R. Lassman
3, Ronald W. Busuttil 21Department of Medicine, Dumont-UCLA Liver
Transplant Center, Los Angeles, CA2Department of Surgery, University of
California at Los Angeles, Los Angeles, CA3Department of Pathology,
University of California at Los Angeles, Los Angeles, CA
ABSTRACT
Interferon alfa has been increasingly used against recurrent hepatitis C
(HCV) disease in post-liver transplant (LT) recipients. A serious
potential adverse effect is acute rejection. We reviewed our experience
using interferon-based therapy (interferon or pegylated interferon with
or without ribavirin) for treating recurrent HCV in LT recipients.
Forty-four LT recipients were treated with interferon for recurrent HCV.
Five of the 44 patients developed acute rejection during
interferon-based therapy. These 5 patients started treatment of 42.4 ±
33.89 months (mean ± SD) after LT.
Mean (± SD) histological activity index and fibrosis scores before
initiating antiviral therapy were 8.8 (± 1.92) and 2.6 (± 0.55),
respectively. Patients were treated for 3.3 ± 2.28 months (mean ± SD)
prior to rejection. At the time of rejection, HCV load was not
detectable in 4 of the 5 recipients. All 5 patients had tolerated
interferon therapy, and none had stopped therapy because of adverse
effects. The rejection was successfully treated in 3 patients. In 2 of
those 3 patients, cirrhosis eventually developed. In the 2 patients who
did not respond to rejection treatment, immediate graft failure
occurred, leading to re-LT in 1 patient and death from sepsis in the
other.
In conclusion, the results indicate that further studies are needed to
assess the safety of interferon in LT recipients. Interferon-based
therapy may lead to acute rejection and subsequent graft loss and should
therefore be used with caution. Treated recipients may also develop
progressive cirrhosis despite achieving a sustained virological
response.
BACKGROUND
Hepatitis C (HCV) is the leading indication for liver transplantation in
the United States. The number and proportion of individuals receiving
transplants for HCV will likely grow as the cohort infected several
decades ago start seeking medical care. Recurrent HCV viremia is
universal, with approximately 90% of individuals undergoing
transplantation for HCV having detectable virus soon after
transplantation.Histological disease is seen in 50% of recipients within
2 years. After 5 years, up to 30% of patients transplanted for HCV
develop cirrhosis.The rate of decompensation after developing cirrhosis
is approximately 42% after the first year in the posttransplant setting.
Although earlier studies demonstrated no impact of recurrent HCV on
patient survival, more studies suggest HCV may indeed negatively impact
patient and graft survival.
As in nontransplant patients and the general population, the treatment
of recurrent HCV disease after liver transplantation involves the use of
interferon, which is believed to have both antiviral and
immunomodulatory effects against HCV. However, in the posttransplant
setting, antiviral therapy has been limited by relative ineffectiveness,
poor tolerability, and adverse effects. Long-term response to
combination interferon and ribavirin in transplant recipients is
estimated to be 20% in patients treated for recurrent HCV. Efficacy is
increased when pegylated interferon is used in combination with
ribavirin, but it is still believed to be around 30%. Tolerance to
interferon therapy after transplantation also appears to be less than in
the general population, with exaggerated adverse effects including
anemia and leukopenia.
A serious complication of interferon in organ transplant recipients is
the precipitation of acute rejection and subsequent graft loss. Overall,
the majority of acute rejection episodes after liver transplantation
occur within 90 days of surgery and are seen in up to 75% of recipients,
regardless of immunosuppressant regimen. However, acute rejection after
liver transplantation in the setting of interferon therapy is not a
well-documented phenomenon. This complication has been seen in renal
transplant recipients and is believed to be due to the immunomodulatory
effects of interferon. As a result, interferon is avoided in renal
transplant recipients except in the setting of severe liver
complications secondary to HCV. The incidence of serious acute rejection
in renal transplant recipients treated with interferon ranges between 15
and 64%. Although interferon is used in liver transplant (LT) recipients
to treat recurrent HCV, few data exist on its association with acute
rejection. Feray et al. first reported chronic rejection in LT
recipients treated with interferon for recurrent HCV.
In the current study, we sought to examine the incidence and clinical
outcome of patients who developed acute rejection while on interferon
therapy.
A chart review was performed on patients who underwent liver
transplantation and were treated with interferon-based therapy for
recurrent hepatitis C at the University of California Los Angeles
Medical Center. We searched an administrative database and identified 44
recipients who received interferon, interferon and ribavirin, pegylated
interferon, and pegylated interferon and ribavirin between January 1998
and May 2003. We collected data on recipient variables: sex,
comorbidities, age at transplant, year of transplant, immunosuppressants,
duration of treatment, and hematological, biochemical and virological
results. We also collected data on treatment initiation date, date of
cessation of interferon therapy, and reason for cessation (if course not
completed), along with any interferon dose modifications made during
treatment. In addition, the immunosuppression regimen, including
corticosteroids, cyclosporine, tacrolimus, azathioprine, and
mycophenolate mofetil, was followed along with any changes made over the
course of interferon therapy. Side effects including anemia, leukopenia,
and thrombocytopenia were recorded, along with any interferon dose
modifications and/or use of growth factors such as erythropoietin and
filgrastim. Psychological adverse effects such as depression and
insomnia were also documented.
The immunosuppression regimens after LT consisted of combinations of
cyclosporine, prednisone, tacrolimus, azathioprine, and mycophenolate
mofetil. According to our protocol, patients initially received 1 gram
of intravenous methylprednisolone the day of transplantation; this was
then tapered to 20 mg/day over 1 week. Oral prednisone was subsequently
started at 20 mg/day and tapered as tolerated. Beginning in 1994, our
institution established a regimen consisting of tacrolimus for
maintenance immunosuppression. Generally, our protocol for
posttransplantation target immunosuppression levels for
tacrolimusconsists of 10 to 12 ng/mL at 1 to 3 months; 8 to 10 ng/mL at
3 to 6 months; 5 to 8 ng/mL at 6 to 12 months; and 2 to 5 ng/mL at
greater than 12 months. For cyclosporine, the target values are 250 to
300 ng/mL at 1 to 3 months; 175 to 250 ng/mL at 3 to 6 months; 100 to
175 ng/mL at 6 to 12 months; and 50 to 100 ng/mL at greater than 12
months. Immunosuppression levels were checked bimonthly to monthly, with
changes in doses made to reach target ranges. We collected
immunosuppression values before and during antiviral therapy, as well as
at the time of rejection.
The indication for performing liver biopsies in all transplant
recipients was elevated liver-associated tests found on routine lab
work. Protocol biopsies are not performed at our institution. Liver
biopsies were read with an experienced LT pathologist. The histological
activity index and fibrosis score, and the diagnosis of rejection, were
determined according to established criteria. Criteria for beginning
interferon therapy included detectable HCV RNA and a fibrosis score of 2
or more, and/or elevation of liver-associated tests at least twice the
upper limit of normal.
Histological criteria used for the diagnosis of rejection included (1)
portal inflammation composed of a mixed infiltrate (lymphocytes, plasma
cells, eosinophils, and neutrophils); (2) bile duct inflammation and
damage (lymphocytes within bile duct epithelium); and (3) venous
endotheliitis demonstrated by lymphocytes infiltrating the endothelial
and lifting up luminal endothelial cells. Rejection severity was based
on the number of portal tracts affected by the infiltrate, the degree of
damage, and the number of bile ducts damaged. There have been no changes
in the histological diagnostic criteria for rejection over the study
period.
Author Discussion
Interferon therapy is a widely accepted treatment for LT recipients with
recurrent hepatitis C. However, our study shows that interferon therapy
in this population is not without serious risks. Acute rejection
occurred in 5 of 44 patients (11.4%) treated with interferon at our
institution. Two of the 5 patients developed graft loss as a result of
steroid-resistant rejection, with 1 requiring a second LT and the other
expiring from sepsis. The remaining 3 patients responded to steroid
pulsation and/or additional immunosuppressant agents and recovered
completely from the rejection episode. However, 2 of these 3 patients
subsequently developed cirrhosis. This rapid progression of their
recurrent HCV may be related to accelerated viral replication after
intensified immunosuppressive therapy.
In the current era of liver transplantation, graft loss due to acute
rejection is rare. Most episodes of acute rejection occur within 3
months of surgery and are responsive to steroids. In a cohort of 55 LT
recipients treated for early acute cellular rejection, there were no
deaths or retransplantation. Late acute rejection occurs after more than
180 days posttransplantation and has been reported at rates of 7 to 10%
of all transplant patients. Late acute cellular rejection tends to be
refractory to medical treatment, particularly if the indication for
transplantation was viral hepatitis. Nevertheless, graft loss or death
from late acute rejection in a series of 122 patients was still
uncommon, occurring in 14 recipients. In the present study, acute
rejection developed up to 83 months after liver transplantation, and 2
of the 5 patients who developed late acute rejection eventually
experienced graft loss leading to retransplantation in 1 and death in
the other.
Interferon has not previously been associated with an increased risk of
acute rejection in post-LT patients. Several studies have supported the
long-term efficacy and safety of interferon in this population. However,
many of the published studies included small study groups. Jain et al.
published a study of the safety and efficacy of interferon therapy. The
study included LT recipients with either hepatitis B or C. They
concluded that the risk of acute rejection was not increased by the
introduction of interferon alfa. However, the patients who received
interferon were given higher levels of prednisone during the trial than
the controls. Feray et al. showed that chronic rejection can occur in up
to 35% of patients treated with interferon.
Although the relationship between interferon therapy and acute rejection
in LT recipients has not been well documented, this association has been
well established in the renal transplant population. Interferon was
initially studied in these patients as prophylaxis against
cytomegalovirus (CMV) infection after transplantation. In a study by
Kovarik et al., there was a higher rate of rejection and a significantly
higher number of HLA-DR mismatches in the group of patients who received
interferon compared with the placebo group. The study was discontinued
because of ethical concerns over the high rate of rejection after
treatment with interferon in this population. Subsequent studies of
renal transplant patients on interferon have also shown increased rates
of steroid-resistant acute vascular rejection episodes. As a result of
this data, a recent review recommends that interferon therapy not be
used in renal transplant recipients except those with fibrosing
cholestatic hepatitis. It is unclear why renal transplant grafts appear
to be more vulnerable to rejection episodes after interferon than LT
grafts. HLA compatibility has been shown to influence the outcome of
renal transplants to a greater degree than liver transplants.
As a result of the immunomodulatory and immunostimulatory effects of
interferon, several mechanisms behind the induction of acute rejection
have been postulated. One hypothesis is that interferon alfa may enhance
the expression of HLA-DR antigens on donor hepatocytes, thus initiating
a vigorous immune response and subsequent episode of rejection. This has
been supported by in vivo studies showing that HLA-DR expression is
enhanced in response to human interferon. Alterations in class II
histocompatibility expression in transplanted tissue by interferon alfa
have also been seen in a model of heart transplantation in rats. In an
analysis of human liver grafts after transplantation, when rejection was
the reason for graft failure, bile duct epithelial cells were found to
be HLA-DR positive, as were hepatocytes in severe rejection episodes.
The bile duct epithelia of donor specificity is thought to become the
dominant class II antigenic stimulant and contribute to the vanishing
bile duct syndrome seen in rejection. Dousset et al. reported the
observation of acute vanishing bile duct syndrome in 2 of 5 patients
treated with interferon: 1 of those 2 patients required
retransplantation;the other expired. This hypothesis of enhancement in
the expression of HLA-DR antigens by interferon can also be supported by
recent evidence that pegylated interferon may be more likely to cause
rejection than traditional interferon alfa. In the present study, 4 of
the 5 patients who experienced rejection received pegylated interferon.
A possible mechanism for this increased rejection risk is related to the
extended half-life and increased serum concentration of pegylated
interferon. These properties could make it more likely to increase HLA
expression, and therefore rejection, than interferon.
Another proposed mechanism for the increased risk of
interferon-associated acute rejection may be decreased levels of
immunosuppressants as a result of HCV clearance during antiviral
therapy. It is suggested that antiviral therapy improves hepatocyte
microsomal function, which leads to decreased immunosuppression levels.
However, in our study, only 1 patient who developed rejection had a
decreased mean immunosuppression level while on interferon. In addition,
3 patients who did not develop acute rejection had immunosuppression
levels below our recommended protocol while on antiviral therapy.
Decreased immunosuppression levels may be important; however, other
factors are likely required for the development of acute rejection.
Although the exact mechanism is unknown, interferon is believed to lead
to HCV clearance by inhibiting viral replication and enhancing the
immune response against the hepatitis virus. The use of an
immunomodulator such as interferon with immunosuppressants such as
cyclosporine, tacrolimus, and prednisone raises concerns about possible
interactions. These medications appear to inhibit T-cell activation and
may inhibit interferon production. This has been suggested by the
observation of low levels of circulating interferon alfa in renal
transplant recipients on immunosuppressant therapy. These studies raise
concerns about the use of interferon in a transplant and
immunosuppressed population. The effects of the additional use of growth
factors such as filgrastim to improve tolerance of interferon therapy
and avoid leukopenia also have yet to be studied. In addition, the
possible protective effect of ribavirin against acute rejection as an
adjunct to interferon remains to be explored. In the present study, 2 of
three patients treated with pegylated interferon monotherapy experienced
acute rejection. Early studies have suggested that ribavirin may have
immunosuppressive effects. Ribavirin may therefore provide additional
immunosuppressive qualities that provide protection from rejection in
addition to its role in antiviral therapy.
Another important consequence of acute rejection after treatment with
interferon observed in our study, aside from graft loss from resistant
rejection, is the acceleration of the course of recurrent hepatitis C.
Two patients who responded to increased immunosuppression and recovered
from rejection subsequently experienced progressive cirrhosis and graft
failure. With intensive immunosuppression, liver disease progression may
be accelerated. Therefore, the impact of treatment with interferon on
graft survival after achieving serum virological response remains to be
studied.
Also observed in our study were the features of mild acute rejection in
the biopsies of 3 of the study patients prior to the initiation of
interferon therapy. Two of these patients subsequently experienced graft
failure after developing acute rejection while on interferon therapy.
Distinguishing between graft hepatitis and acute cellular rejection can
be difficult because the histological features of the 2 conditions can
overlap. For example, portal infiltrate can be found in both rejection
and recurrent HCV. However, in the setting of elevated quantitative HCV
RNA levels and significant biopsy-proven elements of recurrent HCV after
more than 7 months posttransplantation, the decision was made to treat
with antiviral therapy. Gottschlich et al. suggest that quantitative HCV
RNA levels can be useful in distinguishing between recurrent HCV and
rejection. After treatment with interferon, the biopsy results of the 2
patients became diagnostic of acute rejection and interferon was
discontinued. Therefore, it is difficult to determine whether or not
interferon accelerated the process of acute rejection in these patients.
However, while some histological features of recurrent hepatitis and
rejection may overlap, it should be noted that definitive evidence for
acute rejection, such as endotheliitis, was not seen prior to interferon
therapy in any of the patients.
Limitations of our study include the lack of protocol biopsies
accounting for possible unrecognized mild rejection and the
retrospective nature of the analysis. An additional limitation is that
the rejection associated with clearance of HCV infection may have been
unrelated to interferon therapy. Indeed, Doughty et al. reported on a
single patient who cleared the infection after being treated for
rejection. However, in a series of over 500 recipients of transplants
for HCV in our institution, spontaneous HCV clearance was not observed.
Despite these limitations, our experience would argue that interferon
therapy is not without risks. Because the exact mechanism of action of
interferon in inducing liver allograft rejection remains obscure,
prospective trials are needed in order to better assess the safety of
such therapy in an immunosuppressed population.
In conclusion, with recurrent HCV becoming increasingly common in the
transplant community, there will be a greater need to find safe and
effective antiviral therapy. The risk of acute rejection and subsequent
graft loss and the risk of accelerated recurrent HCV with subsequent
cirrhosis in LT patients on interferon should be weighed heavily in
choosing treatment for recurrent HCV, which itself can cause allograft
failure if untreated. Treating physicians should therefore be aware of
the risks and monitor patients accordingly.
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