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Corticosteroid-Sparing
Immunosuppression in Liver Transplantation W. Kenneth Washburn, MD
Introduction
Corticosteroids (steroids) have been the cornerstone of immunosuppressive
regimens since the inception of solid organ transplantation. The benefits of
using steroids include ease of use, low cost, and efficacy. Virtually all
transplant programs use smaller doses of steroids now compared with 10-15
years ago. The addition of newer immunosuppressive agents in the past decade
has allowed many transplant physicians to reduce dependence on steroids as
the cornerstone of immunosuppressive therapy. As the rates of acute and
chronic rejection have diminished over the past decade, more focus has been
placed on minimizing side effects and toxicities of the regimens used. The
known side effects of steroids -- including infectious risk, loss of bone
density, diabetes, hypertension, hyperlipidemia, worsening of hepatitis C
virus (HCV) infection recurrence, and growth retardation -- have led some
centers to attempt to withdraw steroids very early in the posttransplant
setting or to avoid them altogether.
Steroid Avoidance Using Tacrolimus-Based Regimens
Moench and colleagues[1] reported their experience with early
steroid reduction in liver transplant (LTX) recipients in a prospective,
randomized, double-blind, placebo-controlled trial. In this trial, patients
were randomized prior to transplantation to receive steroid or placebo
starting at day 14. All patients received tacrolimus (TAC) with target
levels of 10-15 ng/dL during the first 6 weeks postoperatively and levels of
5-10 ng/dL thereafter. Both the study and control groups received steroid
therapy from day 1-14 following LTX. After 14 days, the study patients
received placebo and the control group received steroids at a dose of
approximately 12 mg the first month in a decremental taper stopping after 6
months. All steroids and placebo were stopped 6 months following LTX. All
rejection episodes were biopsy-proven and were treated with pulse steroid
therapy for 3 days. The results showed equivalent survival of 88% for the
steroid arm and 85% for the placebo arm. The rejection rate was 48% in the
placebo group and 35% in the steroid arm, which was not statistically
significant. Recurrent rejection occurred in 25% of patients taking steroid
vs 37% of those taking placebo. Chronic rejection occurred in 2 of 56
patients on the placebo arm and none of the patients in the steroid arm.
Infection rates did not differ between the 2 arms and there was no
difference in triglyceride levels. However, there was a significantly
reduced rate of diabetes in the placebo arm, 30% vs 53%, which was
statistically significant. There was also a significant reduction in the
cholesterol level in patients not taking steroids. Early withdrawal of
steroid therapy following LTX is feasible and safe without a significantly
increased rate of acute cellular rejection in the setting of TAC monotherapy.
Studenik and colleagues[2] presented their results of a
steroid-free protocol using TAC and mycophenolate mofetil (MMF) with 1
intraoperative dose of steroid (group A, n = 20) vs a protocol of TAC + MMF
+ steroid taper (group B, n = 19) in adult LTX recipients. Both groups
received daclizumab (DAC) induction at a dose of 1 mg/kg during the
operative period. DAC was redosed based on the CD25 saturation levels within
the first 2-7 days following LTX. Graft and patient survival rates were
excellent in both groups without any significant differences. The incidence
of acute rejection in Group A was 35% vs 16% in Group B, which was not
statistically different. The incidence of hypertension was 15% in Group A vs
37% in Group B. The incidence of diabetes was 5% in Group A vs 11% in Group
B, and the incidence of cytomegalovirus infection was 20% in Group A vs 5%
in Group B. In all, 2 of 19 patients in Group B had their immunosuppression
regimen changed due to side effects, but no patients in Group A had their
regimen changed. CD25 saturation decreased from 10.8% to 3.2% 1-2 days
following LTX and was 1.9% at the time of discharge. A TAC-based
immunosuppressive regimen including 1 dose of steroid after LTX achieves
results comparable to those of regimens including long-term steroid therapy.
Soria and colleagues[3] evaluated 26 patients transplanted for
primary biliary cirrhosis (PBC) with greater than 1-year follow-up. Of
these, 16 patients had recurrent PBC by protocol liver biopsy. Maintenance
immunosuppression was CsA-based in 15 and TAC-based in 11 recipients.
Steroid withdrawal was achieved in 53% of CsA-treated patients and 91% of
TAC-treated patients (P = .04). Recurrence of PBC, as defined by
biopsy, was 73% with the TAC-based regimen and 53% with the CsA-based
regimen, and time to recurrence was significantly shorter in patients
receiving TAC. This difference may be due to the fact that many more
patients under TAC-based immunosuppression are steroid-free compared with
those under CsA-based immunosuppression. In fact, steroid withdrawal was the
only factor in multivariate analysis that was associated with recurrence.
The study authors recommended that patients receiving LTX for PBC not be
maintained on a TAC-based immunosuppressive regimen.
Steroid Avoidance Using CsA-Based Regimens
Llado and colleagues[4] examined 198 patients who where
randomized to receive basiliximab (BAS) and CsA with or without steroids in
a prospective randomized fashion. Rejection was observed in 13% of patients
receiving steroids and 18% of patients in the steroid-free arm, which was a
statistically insignificant difference. The rejection rate was higher in the
non-HCV-infected patients not receiving steroid (24% vs 10%, P =
.05). HCV recurrence was 90% by protocol biopsy at 6 months in all patient
groups. Hypertension and diabetes were more frequent in patients receiving
steroids. In this study, steroid avoidance reduced infectious and metabolic
complications.
Ganschow and colleagues[5] examined the efficacy of steroid
minimization in pediatric LTX using BAS induction therapy. They postulated
that steroids could be reduced in the pediatric LTX recipient using
induction therapy without detrimental effects. Eighty-one pediatric LTX
recipients were prospectively randomized in a multicenter study. Forty
patients in group 1 received immunosuppression with CsA + BAS + steroids
starting at a steroid dose of 60 mg/m2 and tapered over 1 year.
In group 2, 41 patients received CsA + BAS and a substantially reduced dose
of steroid starting at 15 mg/m2 with similar tapering as in group
1. Within the first 2 months, biopsy-confirmed acute rejection occurred in
43% of patients in group 1 vs 27% of patients in group 2. Treatment failure,
defined as acute rejection, graft loss, or death, occurred in 50% of
patients in group 1 and 39% of patients in group 2 (P = NS). After 12
months, patient and graft survival rates were both 88% in group 1 and 95%
and 85%, respectively, in group 2. There was no difference in the
adverse-event profile between groups. CsA-based immunosuppression with BAS
induction therapy allows steroid doses to be reduced substantially while
maintaining efficacy of overall immunosuppression in pediatric LTX.
Denny and colleagues[6] retrospectively evaluated their
results of a steroid avoidance protocol. They traditionally used steroid
maintenance therapy and had recently switched to a steroid-avoidance
protocol. They retrospectively reviewed 81 consecutive adult LTX recipients
with 58 patients who received BAS and were maintained on triple
immunotherapy with CsA, MMF, and steroid vs a group that received no
steroid. This group received BAS and steroids for 5 days and was then
maintained on double therapy with CsA and MMF. The patient and graft
survival rates were comparable between groups. The rate of rejection in the
steroid-withdrawal group was 4.6% vs 10% (trend, not statistically
significant) in the steroid-maintenance group. Bacterial and viral infection
rates were similar between groups. There was no statistical difference in
the incidence of adverse events between groups. The study authors concluded
that steroid avoidance resulted in similar patient and graft survival
outcomes and that CsA immunosuppression with steroid avoidance is at least
comparable to traditional maintenance immunosuppression.
Conclusion
The data presented at this meeting, as well as previously reported
outcomes of steroid avoidance and withdrawal in LTX recipients, have
demonstrated comparable results to maintenance immunosuppressive protocols
including steroids. Some protocols utilize complete steroid avoidance and
others utilize a single dose of or rapid discontinuation of steroids. Many
protocols utilize antibody induction agents such as DAC, BAS, and
rabbit-derived antithymocyte globulin. The majority of protocols utilize a
regimen based on MMF in conjunction with either TAC or CsA. The recurrent
theme is that steroids are not entirely necessary in most LTX recipient
populations; steroid can be either avoided completely or withdrawn without
significant sequelae such as increased rate of rejection. In addition, there
appears to be a trend toward decreased incidence and exacerbation of
posttransplant diabetes mellitus. However, the long-term consequences of
steroid avoidance remain unclear. Long-term follow-up studies are not
available in LTX recipients to ascertain the benefits of steroid avoidance.
A number of studies have shown that steroids may be detrimental to the HCV-positive
LTX recipient, yet long-term studies once again are still not available to
demonstrate the benefit of avoidance in this patient population.
References
- Moench C, Grebe A, Schuchmann M, et al. FK506 monotherapy after early
steroid reduction for liver transplant recipients - A prospective
randomized double blinded placebo controlled trial. Liver Transpl.
2005;11:C-25.
- Studenik P, Mejzlik V, Stouracova M, et al. Steroid free tacrolimus
and mycophenolate mofetil based immunosuppression in liver transplant
recipients. Open label, randomised prospective study. Liver Transpl.
2005;11:C-42.
- Soria S, Perez-Lloret S, Descalzi V, et al. Immunosuppression with
tacrolimus and steroid withdrawal are associated with increased risk of
primary biliary cirrhosis. Liver Transpl. 2005;11:C-12.
- Llado L, Figueras J, Memba R, et al. Immunosuppression without
steroids in liver transplantation reduces infectious and metabolic
complications but increases rejection rates in non-HCV recipients. Liver
Transpl. 2005;11:C-16.
- Ganschow R, Melter M, Wallot M, et al. Maintained efficacy with
steroid minimization after pediatric liver transplantation with
basiliximab (Simulect[R]) induction therapy: A multicenter, randomized,
12-month trial. Liver Transpl. 2005;11:C-20.
- Denny J, Elkhammas E, Henry M, et al. Steroid avoidance in liver
transplantation. Liver Transpl. 2005;11:C-43.
http://www.medscape.com/viewarticle/510983?src=mp
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http://www.medscape.com/viewarticle/506626
August 31, 2005
Issues in Cirrhosis and
Liver Transplantation
CME
Disclosures
Tram T. Tran, MD
Introduction
Liver transplantation remains the only viable therapeutic option for
acute
and chronic liver failure. Excellent long-term outcomes have been
achieved
over the past 2 decades, with posttransplant survival rates approaching
90%
at 1 year and 60% at 5 years.[1] Unfortunately, the continued limited
availability of deceased donor organs as compared with the number of
patients currently awaiting transplantation necessitates that
gastroenterologists and hepatologists must try to effectively prevent
and
manage the common complications of cirrhosis in order to prolong
survival
until transplantation. The Model for End Stage Liver Disease (MELD)
allocation system, now in place for 3 years, has proven to be an
effective
predictor of mortality in those patients with decompensated
cirrhosis.[2]
Research presented on end-stage liver disease and transplantation during
this year's Digestive Disease Week (DDW) meeting explored new
developments
in the management of complications of chronic liver disease, such as
gastrointestinal bleeding, spontaneous bacterial peritonitis,
hepatocellular
carcinoma, MELD score utility, and posttransplant management.
Issues in Cirrhosis and Liver Transplantation
Decompensation of Cirrhosis
Because waiting times may approach months to years for some patients
awaiting liver transplant, the management of common known complications
of
cirrhosis and portal hypertension is paramount to the survival of
patients.
D'Amico and colleagues[3] reported the outcome of 494 consecutive
patients
with newly diagnosed cirrhosis at their center who were followed for
evidence of decompensation in the form of ascites, bleeding,
encephalopathy,
jaundice, or hepatocellular carcinoma. The majority of these patients
had
hepatitis C infection, and 117/494 (24%) had decompensation at the time
of
inclusion into the study. During the study period of 25 years, 63% of
those
patients who were compensated eventually developed decompensation.
Ten-year
actuarial survival for decompensated vs compensated cirrhosis was 7% vs
63%,
respectively, and cumulative survival rates at 2, 5, and 10 years for
decompensated cirrhotics were 50%, 31%, and 14%. Of patients who died,
43%
died at the time of the first decompensation.
This study highlights that although a cirrhotic patient may remain
stable
for a long period of time, once an event occurs signaling decompensation
of
liver function, referral to a transplant center should be done in a
timely
fashion, because mortality dramatically increases thereafter.
Ascites
First-line management of ascites in the cirrhotic patient entails
dietary
sodium restriction and judicious use of diuretics as tolerated by renal
function. Although still somewhat controversial, the use of transjugular
intrahepatic portosystemic shunting (TIPS) has been used in refractory
ascites that is not responsive to maximal diuretic dosages. Peritovenous
shunting is rarely performed as risks of infection and malfunction are
high.
Large-volume paracentesis is a viable option for patients intolerant or
refractory to diuretics, but should not be first line. The
pathophysiology
of TIPS seems to be a reduction in sinusoidal portal pressure resulting
in a
fall in the plasma renin activity and serum aldosterone levels, a rise
in
renal blood flow and glomerular filtration rate, and associated
naturesis
and diuresis.[4] Probability for 1-year survival without transplant in 1
cohort after TIPS was 69% compared with 52% in a non-TIPS large-volume
paracentesis group.[5] However, risks include worsened hepatic
encephalopathy, hepatic decompensation, and stent occlusion or
malfunction.
Measurement of hepatic venous pressure gradient (HVPG) has been
suggested as
a means of monitoring degree of portal hypertension for risk of
recurrent
variceal bleeding secondary to esophageal varices. Campbell and
colleagues[6] examined the measurement of HVPG after TIPS to determine
the
correlation with recurrent ascites. Fifty-two patients who had TIPS for
refractory ascites were followed for recurrent ascites. Twenty-two of 52
patients (42%) developed recurrent ascites requiring large-volume
paracentesis, and hepatic venous pressure measurements were obtained
showing
mean HVPG of 12 mmHg for patients with recurrent ascites compared with
10
mmHg in the non-recurrent group (P = .45). Sodium, MELD score, volume of
paracentesis, and percent change in HVPG after TIPS did not predict
recurrent ascites. Further detailed analysis of this patient population
may
yield other influencing factors in recurrent ascites, such as rapidity
of
diuretic withdrawal, patient dietary compliance after TIPS, and TIPS
stenosis, but etiology may be multifactorial. Additional data are
emerging
on the use of TIPS for this indication, but at this time, only the
carefully
selected patient should be considered for TIPS.
Spontaneous Bacterial Peritonitis
Spontaneous bacterial peritonitis (SBP) occurs in cirrhotic patients
with
ascites and is usually due to infection with enteric gram-negative
organisms. A high morbidity and mortality is associated with SBP, with
one
third of patients admitted for SBP dying from gastrointestinal bleeding,
liver failure, or hepatorenal syndrome[7]; renal failure develops in 30%
to
40% of these patients even with control of the infection. SBP can also
occur
more often after gastrointestinal bleeding.
During this year's DDW meeting, Planas and colleagues[8] reported the
results of a randomized multicenter controlled trial comparing oral
norfloxacin with intravenous ceftriaxone in decompensated cirrhotics for
prophylaxis after gastrointestinal bleeding. They randomized patients to
receive either norfloxacin 400 mg orally twice daily for 7 days (n = 55)
or
ceftriaxone 1 g intravenously for 7 days (n = 53). They found that the
group
receiving ceftriaxone had a lower probability of developing all
bacterial
infections than the oral norfloxacin group (11% vs 27%; P = .02). The
types
of bacterial infections included pneumonia, urinary tract infections,
and
SBP. It appeared that patients with more severe gastrointestinal
bleeding,
and those who already had been on norfloxacin prophylaxis, were at
increased
risk for acute bacterial infection.
Patients admitted for gastrointestinal bleeding are clearly at increased
risk for a host of complications, including infections. The role of
antibiotic prophylaxis in these high-risk patients has been recommended,
but
the routine use of intravenous antibiotics needs further study as the
development of more resistant bacterial strains needs to be considered.
Hepatic Encephalopathy
Portosystemic encephalopathy (PSE) is a common complication of
cirrhosis,
and can present mildly with only minimal symptoms such as memory loss,
irritability, and an altered sleep-wake cycle, or more severely with
deep
somnolence or coma. It is important that when a patient presents with
PSE
underlying risk factors be ruled out, including infections,
gastrointestinal
bleeding, and medications that may precipitate encephalopathy, such as
benzodiazepines. The mechanism underlying PSE is not clearly understood,
but
is believed to be partly due to hyperammonemia. PSE can often be
controlled
with the administration of lactulose, a nonabsorbable disaccharide that
acts
by several different mechanisms, including acidification of the gut
lumen,
leading to ammonia being converted into ammonium (NH4+), which is less
membrane-permeable. Lactulose also acts as an osmotic agent, decreasing
intestinal transit time. Other agents used in the management of PSE
include
nonabsorbable antibiotics such as neomycin, although its long-term use
may
be limited by nephrotoxicity because it has some systemic absorption and
ototoxicity.
Administration of ornithine, which is a substrate for urea, has been
explored as a treatment for PSE because it may increase the conversion
of
ammonia to urea. Mumtaz and colleagues[9] reported the results of a
randomized study assessing the benefit of intravenous L-ornithine
L-aspartate in patients with PSE. Patients admitted with PSE were
randomized
to receive either L-ornithine L-aspartate 20 g per day (n = 50)
intravenously or placebo for 4 consecutive days. Measurement of PSE
stage,
the number connection test, serum ammonia level, length of hospital
stay,
and mortality were recorded. In this study, all of the reported measures
of
PSE were improved with L-ornithine L-aspartate compared with placebo,
with
no reported change in mortality or side effects related to the drug.
Unfortunately, difficulty in defining and diagnosing PSE hampers the
ability
to really assess therapeutic benefits in this setting. Attempts to use
quantifiable measures, such as serum ammonia levels, are not readily
applicable, because serum ammonia is not well correlated to severity of
encephalopathy. Additionally, this study compared L-ornithine L-aspartate
with placebo, not lactulose, which would be considered the current
standard
of care; thus, further studies are needed at this time.
Gastrointestinal Bleeding
Upper gastrointestinal bleeding (UGIB) is often the first and most
dramatic
presentation in a patient with cirrhosis. Mortality can approach 50%
with an
upper gastrointestinal bleed from esophageal or gastric varices.
Secondary
prevention of UGIB with nonselective beta-blockers (such as propranolol)
should be considered in patients with a history of upper
gastrointestinal
hemorrhage. The use of TIPS is reserved for patients with UGIB that is
not
controlled with endoscopic management, but it carries risk of worsened
encephalopathy or hepatic decompensation. The especially difficult
bleeding
patient is one with gastric varices, which are difficult to manage with
traditional variceal band ligation or injection sclerotherapy.
Seewald and colleagues[10] reported the use of tissue glue
N-butyl-2-cyanoacrylate (CA)* in 131 patients with gastric fundal UGIB.
They
used a mixture of CA and lipiodol, and restricted the amount injected to
1.0
mL into a varix at one time to reduce risk of embolism; endoscopy was
repeated at 4 days with repeat CA injection until obliteration of the
varices. Rebleeding-free rates at 1 and 3 years were 94% and 89%,
respectively. No embolism occurred in this study. This study is
promising,
and shows that in experienced hands, CA may be a "last ditch" lifesaving
option; however, with the published risk of cerebral and pulmonary
embolism,
and lack of US FDA approval, cyanoacrylate will probably not be widely
available to the clinician.
Hepatocellular Carcinoma
Hepatocellular carcinoma is an indication for liver transplantation, but
only within set criteria that have yielded good survival and
recurrence-free
survival compared with nonhepatocellular carcinoma transplant
indications.
Mazzaferro and colleagues[11] published the current standard criteria
for
liver transplant in patients with hepatocellular carcinoma, the
so-called
"Milan criteria" also adopted by the United Network for Organ Sharing
(UNOS), which are as follows: 1 lesion, not greater than 5 centimeters
in
diameter, or 3 lesions or fewer, none greater than 3 centimeters. With
these
criteria, overall 4-year survival was 75%.
Yao and colleagues[12] have recently published University of California,
San
Francisco (UCSF) guidelines proposing expansion of these criteria
(single
lesion not greater than 6.5 cm, or 2 or 3 lesions, none greater than 4.5
cm
with total tumor diameter less than 8 cm) with good outcomes. With the
risk
of tumor growth and metastasis and the current long waiting times for
transplant, treatment of lesions with bridging modalities such as
percutaneous ethanol injection, radiofrequency ablation, and
chemoembolization, have become fairly common at transplant centers. In
their
analysis of more than 3700 patients with hepatocellular carcinoma,
Johnson
and colleagues[13] found that more patients are now undergoing local
ablative therapies and transplant than previously, and fewer patients
are
having hepatic resection.
During this year's DDW meeting, Yao and colleagues[14] reported on the
impact of degree of tumor necrosis (as a marker of response to
locoregional
treatments) on tumor recurrence in 172 liver transplant recipients.
Five-year recurrence-free probability was 93% for patients with > 60%
necrosis of tumor on explant vs 83% for patients with < 60% necrosis (P
=
.027). Tumor necrosis > 60% was also associated with a significantly
better
5-year recurrence-free probability in patients exceeding the Milan
criteria
(83% vs 63%; P = .46). The study authors concluded that pretransplant
treatment of hepatocellular carcinoma that yields > 60% necrosis of the
tumor may be associated with lower risk of recurrence. This study adds
to
the growing body of evidence that preoperative locoregional treatment of
hepatocellular carcinoma, in carefully selected patients, is a viable
option
while awaiting transplantation, and may result in better short-term
(getting
the patient to transplant) and long-term (less recurrence) outcomes.
Acute Liver Failure
Acute liver failure is manifest by jaundice, coagulopathy, and
encephalopathy within 26 weeks, and carries a high mortality (> 80%)
without
transplant. The US Acute Failure Study Group led by Lorenzo Rossaro
published their study results investigating the prognostic value of the
MELD
score in 729 adult patients with acute liver failure.[15] Although they
found that a MELD score of < 30 (negative predictive value 82%) may
predict
spontaneous survival, a high MELD score did not predict poor outcome
well.
Taylor and colleagues[16] analyzed 29 patients with acute liver failure
secondary to acute hepatitis A, and reported a 45% death or transplant
rate.
Factors associated with poor outcome were sex (male), low alanine amino
transferase (ALT) and alkaline phosphatase levels, and higher serum
creatinine. The study authors then developed a 4-variable index for
predicting poor prognosis using any 2 out of 4 criteria upon admission
to
yield a positive predictive value of 86% and negative predictive value
of
93%: creatinine > 2.0 mg/dL, ALT < 2600 IU/mL, use of pressors, or
intubation. This group also reported the outcome in patients who had
acute
liver failure secondary to hepatic ischemia and as would be expected,
cardiopulmonary disease and hypotension were identified risk
factors.[17]
Mortality rate in this group was 34%, and renal function again played a
role
in prognosis. Early prediction of which patients will require
transplantation is still a difficult and elusive clinical task, and will
require further study.
Viral Hepatitis in the Cirrhotic Patient
Treatment of hepatitis C with interferon has been relatively
contraindicated
in patients with a history of decompensated cirrhosis due to the risk of
hepatic decompensation, poor tolerability, and low success rates.
Everson
and colleagues[18] published their experience treating 102 patients with
decompensated cirrhosis (mean Child-Pugh score 7) with combination
interferon and ribavirin therapy using the low but accelerating dose
regimen
(LADR). Sustained virologic response was achieved in 22% of patients;
however, most important, those patients with sustained virologic
response
prior to transplantation did not have recurrent hepatitis C virus
infection,
which is normally universal in the posttransplant hepatitis C patient.
Kaiser and colleagues[19] investigated the role of consensus interferon*
in
Child-Pugh class A and B patients using a protocol starting at 9
micrograms
(mcg) 3-times weekly for 6 weeks, followed by 9 mcg daily, then adding
ribavirin at escalating dosages, increased as tolerated to weight-based
dosing. Low platelet counts required dose reduction in 31% of the 58
patients treated, and growth factors were used for anemia and
neutropenia.
Sustained virologic response rates were 45% overall, and were highest in
the
early (Child-Pugh class A) cirrhotic patient compared with the patients
with
Child-Pugh class B disease.
Given the difficulties of posttransplant recurrent hepatitis C, more
aggressive treatment is being attempted in the carefully selected
cirrhotic
patient -- but these patients should undergo therapy in clinical trials
or
at centers with extensive experience with treatment availability of
liver
transplantation.
Concluding Remarks
The continuing shortage of available donor organs for liver
transplantation
fuels the necessity for vigilance in the management of the patient with
cirrhosis. Prevention of infection, control of ascites, effective
endoscopic
management of gastrointestinal bleeding, treatment of viral hepatitis,
and
surveillance and treatment of hepatocellular carcinoma are all important
clinical goals.
*The US Food and Drug Administration has not approved this medication
for
this use.
References
2004 Annual Report of the U.S. Organ Procurement and Transplantation
Network
and the Scientific Registry of Transplant Recipients: Transplant Data
1999-2001. Rockville, Md: HHS/HRSA/SPB/DOT; UNOS; URREA.
Wiesner R, Edwards E, Freeman R, et al, and the United Network for Organ
Sharing Liver Disease Severity Score Committee. The model for end-stage
liver disease (MELD) and allocation of donor livers. Gastroenterology.
2003;124:91-96.
D'Amico G, Pasta L, D'Amico M, et al. Decompensation of cirrhosis: a
25-year
inception cohort study. Gastroenterology. 2005;128(suppl 2):A-A686.
[Abstract 187]
Wong F, Sniderman K, Liu P, Allidina Y, Sherman M, Blendis L.
Transjugular
intrahepatic portosystemic stent shunt: effects on hemodynamics and
sodium
homeostasis in cirrhosis and refractory ascites. Ann Intern Med.
1995;122:816-822.
Rossle M, Ochs A, Gulberg V, et al. A comparison of paracentesis and
transjugular intrahepatic portosystemic shunting in patients with
ascites. N
Engl J Med. 2000;342:1701-1707.
Campbell MS, Clark TW, Sanyal AJ, et al. Hepatic venous pressure
gradient
does not correlate with recurrent ascites after transjugular
intrahepatic
portosystemic shunting. Gastroenterology. 2005;128(suppl 2):A-687.
[Abstract
190]
Nasava M, Rodes J. Management of ascites in the patient with portal
hypertension with emphasis on spontaneous bacterial peritonitis. Semin
Gastrointest Dis, 1997;8:200-209.
Planas R, Fernandez J, Ruiz L, et al. Randomized, multicenter,
controlled
trial comparing oral norfloxacin vs intravenous ceftriaxone in the
prevention of bacterial infections in cirrhotics with severe liver
failure
and gastrointestinal bleeding. Gastroenterology. 2005;128(suppl
2):A-687.
[Abstract 191]
Mumtaz K, Abid S, Abbas Z, et al. Efficacy of infusion of L-ornithine
L-aspartate in cirrhotic patients with portosystemic encephalopathy: a
placebo controlled study. Gastroenterology. 2005;128(suppl 2):A-688.
[Abstract 192]
Seewald S, Naga M, Omar S, et al. Standardized Injection technique and
regimen minimizes complication and ensures safety of
N-butyl-2-cyanoacrylate
injection for the treatment of gastric fundal varices. Gastrointest
Endoscp.
2005;61. [Abstract 372]
Mazzaferro JW, Regalia E, Doci R, et al. Liver transplantation for the
treatment of small hepatocellular carcinomas in patients with cirrhosis.
N
Engl J Med. 1996; 34:693-699.
Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for
hepatocellular
carcinoma: expansion of the tumor size does not adversely impact
survival.
Hepatology. 2001;33:1394-1403.
Johnson EW, Jensen CC, Yeung R, et al. Population trends in use and
outcome
of surgical treatments for primary liver cancer. Gastroenterology.
2005;128
suppl 2:A-690. [Abstract 232]
Yao FY, Ferrell LD, Bass NM, et al. Liver transplantation for
hepatocellular
carcinoma: the impact of the degree of tumor necrosis from pre-operative
loco-regional therapy on recurrence. Gastroenterology. 2005;128(suppl
2):A-689. [Abstract 231]
Rossaro L, Chambers CC, Polson J, et al. Performance of MELD in
predicting
outcome in acute liver failure. Gastroenterology. 2005;128(suppl
2):[Poster
S1492]
Taylor R, Fontana R, Bass NM, et al. A novel 4 variable index is
superior to
King's College Criteria in identifying non-survivors with acute liver
failure due to hepatitis A. Gastroenterology. 2005;128(suppl 2):A-706.
[Poster S1494]
Taylor R, Fontana R, Shakil A, et al. Acute liver failure due to
ischemic
hepatitis: Natural history and predictors of outcome in a prospective,
multi-center U.S. study. Gastroenterology. 2005;128(suppl 2):A-706.
[Poster
S1495]
Everson GT, Trotter JF, Kugelmas M. Long-term outcome of patients with
chronic hepatitis C and decompensated liver disease treated with the
LADR
protocol [low-accelerating-dose-regimen]. Hepatology. 2002;36:297A
Kaiser S, Hass H, Gregor M. Treatment of chronic hepatitis C patients
with
Child A and B cirrhosis with a low ascending daily dosing regimen with
consensus interferon and ribavirin results in significant viral
eradication
rates. Gastroenterology. 2005;128(suppl 2):A-714. [Poster S1534] |
Recurrence of Hepatitis C Virus
Infection After Liver Transplantation
CME/CE
DisclosuresJohn R. Lake, MD
Introduction
Recurrence of hepatitis C infection (HCV) after liver transplantation (LTX)
is the most important posttransplant clinical problem faced by LTX surgeons
and physicians. The importance of this condition reflects 2 things. First,
HCV-induced cirrhosis represents the most common indication for LTX
throughout the world. Second, HCV recurrence occurs in the majority of
patients undergoing LTX for HCV-induced cirrhosis. Although initially
recurrent HCV disease was thought to be mild, recent results have shown that
HCV-positive recipients have the worst long-term survival compared with
patients transplanted for either hepatitis B virus-related disease or
nonviral causes of liver disease.[1]
HCV Uptake and Replication
King and Pruett[2] presented a model of cultured human
hepatocytes developed to study HCV infection, and which possibly will serve
as an in vitro model of HCV infection. Their technique uses donor tissue
that is processed in a standard way to generate isolated hepatocytes. Once
isolated, the hepatocytes are agitated to allow for spheroid formation,
because hepatocytes in a spheroid formation demonstrate improved functional
characteristics over cells in suspension. In this study, mechanisms of HCV
uptake and replication were examined. There have been a number of potential
receptors for the HCV virus identified on hepatocytes, including CD81,
scavenger receptor class B member 1 (SRB1), and low-density lipoprotein (LDL)
receptor. Antibodies against the E2 component of HCV, which are thought to
play an important role in virus uptake, were also examined to determine
whether this might inhibit virus uptake. King and Pruett[2] found
that anti-E2 antibodies did not inhibit binding and infection, but were
unable to demonstrate colocalization of the virus and the various receptors
discussed above. A particularly interesting aspect of the study was that
hepatocyte cultures produced a limited array of quasi-species compared with
what was added to the supernatant, which differed when cells from different
donors were used, implying that hepatocytes -- at least in part -- define
the specific quasi-species formed. This is a novel finding and may have
implications for our understanding of HCV entry and replication in
hepatocytes. Finally, this appears to be a promising model that may allow us
to investigate new agents that may be able to inhibit HCV replication.
HCV Complicated by Other Diseases
The application of LTX for HIV-infected patients has continued to expand.
It is clear that chronic liver disease, particularly related to HCV
infection, is a major cause of death in HIV-positive patients maintained on
antiretroviral therapy.[3] However, the outcome of HCV recurrence
in HIV-infected LTX recipients has been a contentious issue. In the non-LTX
setting, it appears that HIV coinfection is associated with more aggressive
liver disease.[4] Vallee and colleagues[5]
demonstrated that outcomes in coinfected patients were acceptable with
1-year and 2-year patient survival rates of 82% and 68%, respectively,
compared with rates of 95% and 80%, respectively, in patients only infected
with HCV. However, what was somewhat disturbing is that several deaths were
related to antiretroviral therapy toxicity. In this study, most of the
patients were maintained on nucleoside and nucleotide analogs, and
relatively few were receiving protease inhibitors. Much of the toxicity that
occurred seemed to be related to mitochondrial dysfunction that may be
associated, to a much greater degree, with the nucleoside and nucleotide
analogs. Clinicians may have to take a careful look at which antiviral
agents should be used post-LTX in recipients who are coinfected with HIV and
HCV. Research into this problem continues.
Bozorgzadeh and colleagues[6] compared outcomes of patients
transplanted with hepatocellular carcinoma (HCC) with those who had
underlying HCV disease and those who were HCV-negative. They found that the
3-year, tumor-free survival rate was lower in patients with HCV disease
(49.5%) compared with those without HCV disease (77.6%). Moreover, 6
patients in the HCV-infected group died because of metastatic HCC vs only 1
patient in the non-HCV-infected group. The study authors concluded that the
outcomes of LTX for HCC in the HCV-infected group may be poorer than in
HCV-noninfected recipients with HCC. One criticism of this study is that
more patients in the HCV-noninfected group did not have cirrhosis, and this
may in part account for some of the difference, but it does not account for
the difference in the development of metastatic disease. The study authors
argued that selection criteria for HCV-infected patients with HCC may need
to be modified.
Pharmacologic Complications and Implications
Both muromonab CD3 (Orthoclone OKT3) and corticosteroid (steroids)
treatment of rejection have been associated with worse outcomes in multiple
studies to date.[7] The novelty of the study by Sugar and
colleagues[8] is that it examined the impact of muromonab CD3 and
steroid bolus treatment of rejection in patients who received minimal
steroids for immunosuppression. In addition, the use of muromonab CD3 has
traditionally been relatively common at the University of Colorado at Denver
in other studies. The study included 166 patients transplanted for HCV-related
disease over a 10-year period, from 1992 to 2002. Patients were divided into
4 groups. Twenty-nine percent of the patients experienced no acute cellular
rejection; 27% received 1 course of steroids for acute cellular rejection.
Seventeen patients received more than 1 course of steroids for acute
cellular rejection, and 27% received muromonab CD3. When patient survival
was examined, the only group that had worse survival was the group that
received muromonab CD3. One course of steroids without muromonab CD3 had no
impact on survival, and the difference in those who received more than 1
course of steroids was not statistically significant. These findings confirm
the negative impact of muromonab CD3 on long-term outcomes in patients
transplanted for HCV disease.
A potential strategy to prevent the progression of fibrosis in hepatitis
C patients is maintenance interferon (IFN). Three protocols in the
nontransplant setting assess the role of maintenance IFN in the prevention
of fibrosis. Kornberg and colleagues[9] studied 23 patients with
recurrent HCV infection. All patients received 12 months of standard-dose
IFN alfa-2b and reduced-dose ribavirin, followed by ongoing maintenance
treatment with the same dose. Initial therapy resulted in a virologic
response in 61% of patients and a biochemical response in 83% of patients.
The investigators also demonstrated that the grade of inflammation decreased
on average from 6.3 to 3.9, with the Knodell scoring system, whereas the
fibrosis stage remained unchanged at 1.7. After an additional 24 months of
maintenance therapy, there was further regression of the inflammation score
in the patients who were initial virologic responders, and improvement in
the stage of fibrosis was also noted. By contrast, virologic nonresponders
showed no change in inflammation score and some progression of fibrosis.
Exactly how this study should be interpreted is uncertain. Most clinicians
believe that maintenance therapy is designed for those patients who are
virologic nonresponders in the hopes that IFN, while not inducing the
virologic response, would still retard or even improve the fibrosis score.
This study suggests that virologic nonresponders will still show
progression, but whether this progression is slower than would be seen in an
untreated control group remains to be determined.
The impact of mycophenolate mofetil (MMF) on HCV recurrence is
controversial. Although most studies have suggested no significant affect, a
study by Berenguer and colleagues[10] has suggested that MMF is
associated with accelerated rates of fibrosis. A separate study suggested
that use of relatively high doses of MMF may lead to improved outcomes.[11]
Ghobrial and colleagues[12] randomized patients to receive either
a regimen of tacrolimus (TAC) and prednisone or TAC, MMF, and prednisone. In
the HCV-infected treated patients, there was no difference in patient
survival, hepatitis activity index, or fibrosis score to 1 year. The
mycophenolic acid (MPA) area under the curve (AUC) calculations were
completed at post-LTX day 90. The MPA AUC tended to be higher in patients
without significant disease recurrence, but did not correlate with reduced
HCV RNA levels. In addition, the investigators found that MPA trough levels
did not correlate with MPA AUCs. Thus, this study was interpreted as showing
that to perform adequate MMF monitoring, one must complete at least a
limited AUC. In addition, there is a great deal of inter- and
intraindividual variability post-LTX. Although in the randomized trial, MMF
did not appear to affect HCV occurrence, there was a suggestion that
maintaining higher AUCs could lead to better outcomes.
Fasola and colleagues[13] reported results from a 3-arm,
randomized, controlled trial, for which enrollment has been completed.
Patients were randomized in a 1:1:2 fashion to 3 immunosuppression regimens.
Arm 1 was TAC + prednisone; arm 2 was TAC + prednisone + MMF; and arm 3 was
TAC + MMF + steroid avoidance + 3 doses of daclizumab. At 1 year, there were
no significant differences for the various outcomes examined. Patient
survival and graft survival in arms 1, 2, and 3 were 95%, 97%, and 96%,
respectively. Acute cellular rejection rates were 16%, 9%, and 5%,
respectively, and HCV recurrence rates were 30%, 49%, and 35%, respectively
-- of which none of these differences were significant. Definitive
interpretation of this study awaits more long-term data, but the strengths
of this study are that it was done specifically to study HCV-infected
patients and includes protocol biopsies as well as protocol collection of
HCV RNA levels. We anxiously await the results of this trial.
Risk Factors for Poor Outcomes
A study of risk factors for cholestatic hepatitis and cirrhosis due to
HCV recurrence after LTX by Neumann and colleagues[14] included
232 transplants and 209 HCV-positive patients. The investigators examined
the long-term outcomes, in terms of whether patients developed severe liver
disease, defined as cirrhosis or cholestatic hepatitis, and then attempted
to identify risk factors for development of these conditions. Twenty-eight
of 81 graft losses in this population were related to HCV recurrence. Ten of
the 28 suffered from cholestatic hepatitis, and the remaining 18 developed
recurrent cirrhosis. Overall, the 10-year survival in this population was
69%. The risk factors for recurrent cirrhosis included donor age greater
than 33 years and 1 or more HLA matches. The risk factors for cholestatic
hepatitis included female donors and multiple steroid boluses. These data
are interesting because the risk factors for these 2 different poor outcomes
were different; however, the long-term outcome of their HCV-infected
recipients was excellent.
Finally, the use of re-LTX for recurrent HCV infection is one of the more
controversial topics in LTX, which has been fueled by the relatively poor
outcomes in this population.[15] However, some groups have
reported outcomes of re-LTX for recurrent HCV infection that are comparable
to outcomes of re-LTX for other post-LTX complications. McCashland and
colleagues[16] assembled a database from 8 centers to address
this topic. The strength of this analysis was the ability to include more
data to compare outcomes of retransplantation for different causes. They
studied 3 groups of patients: (1) patients retransplanted for recurrent HCV,
(2) HCV-negative patients undergoing re-LTX, and (3) HCV-positive patients
with recurrent disease but not undergoing re-LTX. Indications for non-HCV-related
re-LTX were chronic rejection, hepatic artery thrombosis, and recurrent
Budd-Chiari syndrome. One- and 3-year survival rates after re-LTX for
recurrent HCV infection were 69% and 51% as well as and 73% and 63%,
respectively, for non-HCV- re-LTX. MELD scores were not found to be
predictive of survival after re-LTX (as had been shown previously); 46% of
HCV-positive patients were evaluated for re-LTX, but only 23% were listed
for re-LTX. The most common reasons for not listing these patients were
fibrosing cholestatic hepatitis (29%) and recurrent HCV infection within 1
year (22%). Survival in patients who were not listed for re-LTX was 47% at 3
years. The study authors concluded that although the outcomes of re-LTX are
not good for any etiology, the outcomes of re-LTX for recurrent HCV
infection are comparable to outcomes for re-LTX for other indications. Also,
although other studies suggested that the MELD score may help identify
patients at risk to do particularly poorly following re-LTX, this was not
confirmed in this study. Finally, they confirmed that patients with severe
recurrent HCV infection who are not considered for re-LTX have poor
short-term outcomes.
References
- Lake JR, Shorr JS, Steffen BJ, et al. Differential effects of donor
age in liver transplant recipients infected with hepatitis B, hepatitis C
and without viral hepatitis. Am J Transplant. 2005;5:549-557.
Abstract
- King C, Pruett TL. Primary human hepatocytes and the role in modeling
HCV infection. Liver Transpl. 2005;11:C-2.
- Gebo KA, Diener-West M, Moore RD. Hospitalization rates differ by
hepatitis C satus in an urban HIV cohort. J Acquir Immune Defic Syndr.
2003;34:165-173.
Abstract
- Dove LM, Alonzo J, Wright TL. Clinicopathological conference:
hepatitis C in a patient with human immunodeficiency virus infection.
Hepatology. 2000;32:147-152.
Abstract
- Vallee J-CD, Feray C, Afonso AMR, et al. Recurrence of hepatitis C
virus is more severe in liver transplanted HIV-HCV co-infected patients
than in HCV mono-infected patients. Liver Transpl. 2005;11:C-2.
- Bozorgzadeh A, Lansing K, Younan D, et al. Survival and outcomes in
hepatitis C infected liver transplant recipients with hepatocellular
carcinoma. Liver Transpl. 2005;11:C-3.
- Charlton M, Seaberg E. Impact of immunosuppression and acute rejection
on recurrence of hepatitis C: results of the National Institute of
Diabetes and Digestive and Kidney Diseases Liver Transplantation Database.
Liver Transpl Surg. 1999;5(suppl1):S107-S114.
- Sugar J, Forman L, Trotter JF. Impact of OKT3 and corticoidsteroids on
patient survival in hepatitis C infected liver transplant recipients
receiving steroid sparing immunosuppression. Liver Transpl. 2005;11:C-3.
- Kornberg A, Katharine T, Bernadette K, et al. Antiviral maintenance
with interferon and ribavirin in liver transplant patients with recurrent
hepatitis C: impact on fibrosis progression and long-term survival. Liver
Transpl. 2005;11:C-3.
- Berenguer M, Lopez-Labrador FX, Wright TL. Hepatitis C and liver
transplantation. J Hepatol. 2001;35:666-678.
Abstract
- Fasola CG, Netto GJ, Jennings LW, et al. Recurrence of hepatitis C in
liver transplant recipients treated with mycophenolate mofetil. Transplant
Proc. 2002;34:1563-1564.
Abstract
- Ghobrial RM, Holt CD, Sievers TM, et al. Mycophenolate mofetil
pharmacokinetics and the effect on hepatitis C recurrence in liver
transplantation. Liver Transpl. 2005;11:C-4.
- Fasola C, Heffron TG, Sher L, et al. Multi-center randomized hepatitis
C (HCV) three trial post-liver transplantation: a one year follow-up
report. Liver Transpl. 2005;11:C-4.
- Neumann UP, Bahra M, Puhl G, et al. Risk factors for cholestatic
hepatitis and cirrhosis due to recurrent hepatitis C after liver
transplantation. Liver Transpl. 2005;11:C-4.
- Pelletier SJ, Schaubel DE, Punch JD, Wolfe RA, Port FK, Merion RM.
Hepatitis C is a risk factor for death after liver retransplantation.
Liver Transpl. 2005;11:434-440.
Abstract
- McCashland T, Lyden E, Adams L, et al. Is re-transplantation for HCV a
bad idea: the results of a US multi-center regional study. Liver Transpl.
2005;11:C-35.
Hepatic Iron Overload Reduces
Survival After Liver Transplant
NEW YORK (Reuters Health) Aug 26 - In patients who have undergone
liver transplantation, hereditary hemochromatosis associated with HFE gene
mutations or other causes of hepatic iron overload are associated with
reduced survival, investigators in the US report.
Previous studies linking hepatic iron overload with poor outcome after
liver transplantation were conducted before HFE gene testing was available,
Dr. Kris V. Kowdley and his colleagues note in their report in the August
issue of the journal Gastroenterology.
Dr. Kowdley, from the University of Washington in Seattle, and his team
therefore performed HFE genotyping on preserved specimens of 260 patients
who underwent liver transplantation prior to 1996 at one of 12 liver
transplantation centers. All the patients had been diagnosed with
hemochromatosis or hepatic iron overload.
HFE-associated hemochromatosis was defined as homozygosity for the C282Y
mutation (n = 14) or compound heterozygosity for the C282Y/H63D mutation (n
= 11). One- and 5-year posttransplantation survival was 64% and 34% in this
group.
In contrast, among patients with other HFE mutations (C282Y or H63D
heterozygotes or H63D homozygotes) or who were wildtype, the 1- and 3-year
survival was 80% and 64%. The adjusted hazard ratio for death comparing HH
with non-HH patients in this cohort was 2.6.
Compared with the general population of liver transplant patients at
those institutions prior to 1996 (n = 5493), those without HFE-associated
hemochromatosis but with iron overload still had reduced survival (5-year
survival 63% versus 72%).
Thus, the authors comment, "hepatic iron overload may diminish survival
postliver transplantation even among patients without HFE-associated
hemochromatosis when compared with patients without hepatic iron overload."
They add: "We believe our findings warrant additional research to improve
methods for identification of hepatic iron overload prior to liver
transplantation, to characterize better the causes of increased mortality in
patients with HFE-associated hemochromatosis and to examine the feasibility
and efficacy of iron depletion prior to liver transplantation in patients
with hepatic iron overload."
Gastroenterology 2005;129:494-503.
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