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Should we treat patients with chronic
hepatitis C on the waiting list?
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Journal Of Hepatology
April 2005
Gregory T. Everson
University of Colorado School of Medicine, University of
Colorado Health Sciences Center, 4200 East 9th Avenue,
B-154, Denver, CO 80262, USA
Article Outline
- 1. The waiting list population
- 1.1. Treatment of patients with compensated cirrhosis
- 1.2. Treatment of patients with decompensated cirrhosis
- 2. Prevention of post-transplant recurrence
- 3. Management issues in treatment of decompensated
cirrhosis
- 3.1. Cytopenias
- 3.2. Growth factors
- 3.3. Dose and duration of treatment
- 3.4. Post-treatment follow-up of responders
- 4. Stabilization or improvement in liver disease
- References
Abbreviations:: SVR, sustained virological response, MELD,
Model for End-Stage Liver Disease, G-CSF, granulocyte-colony
stimulating factor, Epo, Erythropoietin, LADR, low
accelerating dose regimen, CPT, Child-Turcotte-Pugh
1. The waiting list population
The World Health Organization estimates that there are
between 170 and 200 million persons worldwide who are
infected with hepatitis C (HCV) 1. In the US, 1.7 million
individuals have had hepatitis C for over 20 years, and by
the year 2015 this number will swell to 3 million 2. If
cirrhosis develops in 12.5% of individuals infected for 20
years [3-7], there will be approximately 375,000 Americans
with hepatitis C and cirrhosis by the year 2015. Given
current estimates of 5 million infected Europeans, there
will be approximately 600,000 Europeans with hepatitis C and
cirrhosis by the year 2015.
In the early stage of cirrhosis, patients are asymptomatic,
lack clinical events, exhibit normal or only mild
abnormalities in laboratory profile, and are defined as
'compensated'. As cirrhosis progresses, symptoms develop,
laboratory tests become abnormal, the patient experiences
ascites, varices, encephalopathy, spontaneous bacterial
peritonitis, jaundice, or coagulopathy. The latter changes
comprise the definition of 'decompensation'. Estimated rates
of decompensation, development of hepatoma, and death from
liver disease are 3.6-6.0%/yr, 1.4-3.3%/yr, and 2.6-4.0%/yr,
respectively [8-12]. Cirrhotics with hepatitis C who
experience decompensation have a five year survival of only
50% 9 and are typically listed for transplantation. Despite
the need for effective therapy and the poor prognosis of
decompensated cirrhotics, there have been few studies of
antiviral therapy due to concern over side effects and
potential complications of interferon and ribavirin (Table
1). |
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Abbreviations: Ref, reference
number of citation in bibliography; EOT, end of treatment;
SVR, sustained virologic response; LTx, liver
transplantation. A total of 79 patients underwent liver
transplantation, either deceased or living donor, and 18
remained free of HCV infection post-transplant (23%).
aAlthough there were 27 patients reported, only the 20 who
received antiviral therapy are shown in this table. Seven
were excluded from treatment due to platelet count ²50,000/ƒÊl.
There is a general perception that patients with hepatitis C
on the waiting list may be too sick to be treated with
interferon-based therapy. However, examination of MELD
(Model for End-Stage Liver Disease) scores indicates that
approximately 90% of HCV patients listed at active status in
the USA have MELD scores²18. MELD score 18 corresponds to
Child-Turcotte-Pugh (CTP) score of 7-9, or bilirubin 2.5mg/dL,
INR 1.5, and creatinine 1.5mg./dL. The Consensus Development
Conference on Liver Transplantation and Hepatitis C
suggested that patients with MELD scores 18 or less could be
considered for treatment 13. In addition, the AASLD practice
guidelines state that patients referred for liver
transplantation with mild degree of hepatic compromise could
be considered for antiviral therapy, initiated at low dose,
'as long as treatment is administered by experienced
clinicians, with vigilant monitoring for adverse events' 14.
Thus, in contradistinction to popular belief, it is very
possible that the majority of patients with chronic
hepatitis C on the waiting list for liver transplantation
might be candidates for antiviral therapy.
The three main goals of treatment of patients with cirrhosis
on the waiting list are to:
1. achieve SVR 2. prevent post-transplant recurrence, and 3.
halt disease progression.
1.1. Treatment of patients with compensated cirrhosis
Published trials have included a small percentage of
patients with either advanced bridging fibrosis or cirrhosis
[15-23]. One study was restricted to patients with bridging
fibrosis or compensated cirrhosis 20. Generally, virologic
responses in cirrhotics were lower than responses in
noncirrhotics. Nonetheless, many cirrhotics did achieve both
on-treatment and sustained virologic response (SVR) (Fig.
1). The most favorable report on treatment of cirrhotics was
that of Hadziyannis et al. 23, where 48 weeks of
peginterferon alfa-2a plus ribavirin achieved an SVR of 50%
(41% in genotype 1 and 73% in genotypes 2 and3). However, it
must be emphasized that the cirrhotic patients in all of
these trials were compensated and had not experienced any
clinical complications of liver disease. |
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Fig. 1. Rates of sustained
virologic response (SVR) with interferon-based therapy in
the treatment of chronic hepatitis C in cirrhotic patients
are shown. There has been progressive rise in efficacy as
regimens have changed from short course of interferon
monotherapy to the current standard using peginterferon plus
ribavirin.
The largest experience in treatment of hepatitis C patients
with cirrhosis was the Lead-In phase of the HALT C trial of
retreatment of nonresponders with fibrosis 24. All patients
enrolled in HALT C had prior therapy with interferon or
interferon plus ribavirin. Eighty nine percent were infected
with genotype 1 and 39% had cirrhosis. Entry criteria for
HALT C permitted enrollment of patients with platelet counts
as low as 50,000/ul; but, otherwise patients were
compensated. The percentages of patients with negative HCV
RNA at treatment week 20, end-of-treatment week 48, and
post-treatment followup week 72 were 40, 37, and 23% in
noncirrhotics, but only 26, 23, and 11% for cirrhotics. In a
followup study of the entire HALT C cohort, SVR was
independently and inversely related to severity of liver
disease with lowest response in cirrhotics with
thrombocytopenia (platelet count ²125,000/ul) 25. The low
rate of virologic response in cirrhotics in HALT C may also
have been due to prior nonresponse, high proportion of
patients infected with genotype 1, and protocol driven dose
reductions in both peginterferon and ribavirin for
cytopenias. Growth factors were not used.
The results indicate that patients with compensated
cirrhosis are candidates for treatment with interferon-based
therapies. However, retreatment of cirrhotics who were prior
nonresponders is only marginally effective.
1.2. Treatment of patients with decompensated cirrhosis
We reported our experience with treating sicker patients
many of whom had a history of clinical decompensation
[26,27]. Patients were treated with the combination of
interferon alfa-2b plus ribavirin using an initially low,
but accelerating dose regimen (LADR). Eighty seven percent
had biopsy-proven cirrhosis, and 13% had bridging fibrosis.
Five percent had a pretreatment platelet count of less than
50,000/mL, and 36% dropped below 50,000/mL during treatment.
Growth factors, G-CSF and erythropoeitin analogue (EPO),
were used in a minority of patients. Sixty-six percent of
patients had 1 or more complications before treatment,
including variceal hemorrhage, ascites, spontaneous
bacterial peritonitis, or encephalopathy. The mean
pretreatment CTP score was 7.1+2.0. An end-of-treatment
virologic response was achieved in 39% of patients (35 of
91), and SVR was achieved in 22% of patients (20 of 91).
Patients who had SVR prior to transplant did not recur
post-transplantation. Sixteen of the 56 nonresponders (27%)
discontinued treatment because of side effects, most
commonly fatigue and flu-like symptoms. Four patients
experienced hepatic encephalopathy, and 3 developed
infections. There were also 2 episodes of gastrointestinal
hemorrhage that occurred several weeks after treatment had
been discontinued. The 2 factors that predicted response to
treatment were the ability to achieve target dose and
duration of therapy and non-1 HCV genotype. We have extended
this initial experience to include 124 patients, 90 of whom
were either listed (N=43) or underwent transplantation
(N=47) (Submitted, unpublished data).
Data were particularly encouraging for patients with non-1
genotypes (mainly 2 and 3) where end-of-treatment response
was 79% and SVR 50% (Fig. 2). In contrast, end-of-treatment
response and SVR were 28 and 11% for patients infected with
genotype 1. On the basis of these results, the authors, the
Expert Panel of the ILTS consensus conference of liver
transplantation, and AASLD practice guidelines have
recommended consideration of patients on the waiting list
for pre-transplant antiviral therapy [13,14,27]. However,
the risk/benefit ratio of treating patients with
decompensated cirrhosis remains to be defined by randomized
controlled trials. Cirrhotic patients require close
monitoring during treatment and therapy is best administered
in liver clinics affiliated with liver transplant programs.
Centers treating this group of patients should have
extensive experience in management of advanced liver
disease, hepatitis C, and liver transplant recipients.
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Fig. 2. Virologic responses to
LADR in patients with decompensated chronic hepatitis C are
shown for genotype 1 versus non-1 (mainly 2 and 3) [26].
Both on-treatment and sustained virologic responses were
higher with genotypes 2 and 3.
2. Prevention of post-transplant recurrence
In our initial experience, 27 patients underwent liver
transplantation 26. All 19 who were HCV RNA positive prior
to transplantation recurred post-transplant. In contrast,
none of the 8 patients who were HCV RNA negative prior to
transplant recurred post-transplant. The rate of prevention
of post-transplant recurrence by pre-transplant therapy in
this cohort was 30% (8/27).
Forns and al. treated 30 patients with hepatitis C and
cirrhosis awaiting liver transplantation with an estimated
time to transplantation of 5 months or less 28. Eighty three
percent of patients were infected with genotype 1 HCV and
50% were CTP A, 43% were CTP B, and 7% were CTP C. The
severity of disease in this group of patients was very
similar to the group studied by Everson 26. Treatment was
initiated with 3MU tiw interferon alfa-2b plus 800mg/d
ribavirin but side effects were frequent and 63% required
dose reductions. Nine patients (30%) achieved on-treatment
clearance of HCV RNA from blood and 6 patients (20%)
remained free of HCV post-transplantation. An additional 43%
of nonresponders experienced a decline in viral load of ³2
log10 prior to transplantation. This experience prompted the
authors to suggest that pretransplant antiviral therapy
should be considered as one of several possible strategies
to prevent or reduce post-transplant HCV recurrence.
Thomas and al. studied 27 patients with chronic hepatitis C
(67% genotype 1) who had undergone transplantation 29. Seven
were judged to be poor candidates for interferon therapy and
were not treated prior to transplantation. Twelve of the
remaining 20 (60%) cleared HCV RNA with daily interferon
alfa-2b monotherapy for 14+2.5 months. Four patients
remained free of hepatitis C in the post-transplant period
(20%), and were free of histologic hepatitis in
post-transplant biopsies.
Crippin and al. treated 15 patients with severely
decompensated cirrhosis awaiting liver transplantation with
very low doses of interferon alfa-2b and ribavirin in 30.
The conditions of the patients in this trial were more
critical than in the studies by Everson 26, Forns 28, and
Thomas 29 with a higher mean pretreatment CTP score
(11.9+1.2). Patients in this multicenter, open-label trial
were randomized to receive interferon alfa-2b 1mIU three
times a week (n=3), interferon alfa-2b 3mIU three times a
week (n=6), or interferon alfa-2b 1mIU once daily plus
ribavirin 400mg/day (n=6). Even with low-dose interferon,
33% (5 of 15) of patients in this study experienced
on-treatment HCV-RNA clearance but no patient experienced
SVR (0%). It should be noted that the assay used to detect
HCV RNA (branched-chain DNA assay) was less sensitive than
the PCR (polymerase-chain-reaction assay) methods used in
the other trials. Adverse events occurred in 13 of 15
patients (87%), and 20 of 23 events were considered severe,
including thrombocytopenia (7), neutropenia (4), hepatic
encephalopathy (3), hypothyroidism (1), hyperbilirubinemia
(1), pancreatitis (1), staphylococcus aureus arthritis (1),
ventral hernia (1), and culture-negative empyema with death
(1). Because of the high rate of complications, the study
was terminated, and the authors cautioned physicians
regarding the hazards of antiviral therapy in patients with
decompensated HCV cirrhosis.
There were a total of 79 patients in the combined experience
who received antiviral therapy and underwent hepatic
transplantation. Eighteen of the 79 (23%) were free of
hepatitis C post-transplantation. This experience suggests
that patients with decompensated cirrhosis who are
candidates for liver transplantation or reside on the
waiting list have significantly lower rates of SVR that
patients with compensated cirrhosis (Fig. 3). Clinical
status at the time of initiation of antiviral therapy
appears to be the main limiting factor in decompensated HCV
cirrhosis because of poor tolerability to the drug regimen
[13,26-31]. Dose reductions and discontinuations will
compromise clinical efficacy in the patients with
decompensated cirrhosis as it does in patients with milder
disease. A recent analysis suggests that dose reduction may
compromise rates of SVR more in cirrhotics than
noncirrhotics 25. For these reasons, it is currently
recommended that patients with decompensated cirrhosis
should only be treated with antiviral therapy by highly
experienced clinicians 14 or in the context of a clinical
trial 32.
3. Management issues in treatment of decompensated
cirrhosis
3.1. Cytopenias
Cirrhotic patients are prone to neutropenia,
thrombocytopenia, and anemia. Therapy with interferon,
especially peginterferon, and ribavirin tends to worsen or
precipitate cytopenias in this population. The benefit of
higher virologic response with peginterferon, compared to
nonpegylated interferon, may be counter-balanced by greater
risk of cytopenias. Two strategies are used to control
cytopenias: dose reduction or use of growth factors
(granulocyte-colony stimulating factor, G-CSF, and
erythropoietin analogues, EPO).
3.2. Growth factors
The value of either G-CSF or EPO in preventing complications
or enhancing virologic response is unknown. However, the
alternative strategy, dose reduction, may compromise the
primary objective of achieving the highest rate of virologic
response. Dietrich has demonstrated that use of EPO during
treatment of chronic hepatitis C with interferon plus
ribavirin can increase hemoglobin concentrations and
maintain higher doses of ribavirin 33. Although we tend to
favor use of growth factors over dose reduction, this
strategy has not been evaluated in controlled trials. To
date, there are no studies documenting the safety and
efficacy of growth factors in the treatment of decompensated
cirrhotic patients. For these reasons, use of growth factors
to control cytopenias cannot be generally recommended.
3.3. Dose and duration of treatment
The Consensus Development Conference on Liver
Transplantation and Hepatitis C and AASLD practice
guidelines suggested that a low-accelerating dose regimen of
therapy (LADR) is preferred in the treatment of this
population [13,14]. In Forns experience, use of higher
initial doses of both interferon and ribavirin resulted in
dose reductions in about two-thirds of patients 28.
Suggested starting doses for LADR are interferon alfa-2b,
1.5MU tiw, peginterferon alfa-2b, 0.5ug/kg/wk, or
peginterferon alfa-2a, 90ug/wk, plus ribavirin, 600mg/d.
Patients with creatinine clearance <50ml/min should be
started at a lower dose of ribavirin, 400mg/d. Dose
adjustments are made every two weeks. Interferon is first
increased as tolerated to achieve full dose treatment within
2-4 weeks. Then ribavirin is subsequently increased, in
increments of 200mg every two weeks, as tolerated, to
attempt to achieve a target dose of 0.8 to 1.2g/d. It must
be emphasized that full dose therapy is rarely achieved in
patients with more severe cirrhosis due to side effects and
dose-limiting cytopenias.
Complete blood count and biochemistry should be monitored
every 2 weeks, until stabilization of dose, and then monthly
thereafter. HCV-RNA should be measured every 3 months.
Patients who fail to respond at 24 weeks of treatment with
at least a 2 log drop in HCV-RNA should be dropped from
treatment. Expected duration of initial treatment, once the
patient achieves either target or maximum tolerated doses of
both interferon and ribavirin, would be 6 months for
genotypes 2 and 3, and 12 months for genotype 1, 4, 5, or 6.
Relapse rates may be higher than in noncirrhotic HCV
patients, particularly with genotype 1, due to inability to
achieve optimal doses of both interferon or ribavirin
[25-28]. Once treatment is stopped, relapse may occur. In
this case it has been our practice to consider
re-institution of antiviral therapy and continuation of
therapy up to the time of transplantation. This decision is
dependent upon the patient's virologic response, tolerance
to side effects, and the estimated time to transplantation.
3.4. Post-treatment follow-up of responders
Patients should be monitored for relapse at 1, 3, and 6
months post-treatment 13, and consideration given for
re-institution of treatment for those who relapse. Sustained
responders may stabilize and slow or cease progression of
their underlying liver disease. However, cirrhotic patients
should continue to be screened for hepatocellular carcinoma,
according to accepted guidelines, even after clearance of
HCV. Makiyama and colleagues recently described a series of
27 patients among 1197 sustained responders to antiviral
therpay who developed hepatoma, 20-90 months after
successful clearance of HCV RNA 34. Only 56% of these
patients had cirrhosis or advanced bridging; the remainder,
44%, had milder stages of fibrosis. Currently, it is our
practice to screen cirrhotic patients who have cleared HCV
RNA with alpha-fetoprotein every 6 months, and hepatic
imaging (either ultrasonography or CT) annually.
Fifty percent of patients with chronic hepatitis C and
cirrhosis have current or past histories of significant
alcohol use or abuse. Maintenance of abstinence from alcohol
must be emphasized.
4. Stabilization or improvement in liver disease
There are no published results on the efficacy of antiviral
therapy in preventing need for transplantation, reversal of
cirrhosis, or prevention of clinical decompensation in
patients on the waiting list. In contrast, emerging data in
patients with fibrosis and compensated cirrhosis suggest
that interferon or interferon plus ribavirin may inhibit
inflammation, stabilize fibrosis, prevent clinical
deterioration, and reduce risk of hepatoma.
In Heathcote's study of compensated cirrhosis, 50% of the
patients receiving 180ug/wk of pegylated interferon alfa-2a
demonstrated histologic improvement on liver biopsy 20.
Shiffman and colleagues demonstrated that patients who
either suppressed or eradicated HCV-RNA were more likely to
experience improvements in liver necroinflammation compared
to virologic nonresponders 35. An analysis of 3010 patients
treated in 4 randomized trials examined the impact of
therapy on inflammation and fibrosis 36. Necrosis and
inflammation improved in 39% of patients receiving standard
interferon for 24 weeks and in 73% of patients receiving
pegylated interferon alfa-2b plus ribavirin (P<0.001).
Sustained viral clearance halted progression of fibrosis and
reversed cirrhosis in 49% of 153 cirrhotic patients. A
2800-patient study from Japan suggested that interferon
therapy was associated with a reduced risk for hepatoma,
especially in patients who experienced SVR or sustained
biochemical response (risk ratio, 0.516 [95% confidence
interval, 0.358-0.742]; P<0.001 [37]. These results must be
interpreted with caution since there is potential for
selection bias in nonrandomized, retrospective analyses and
responses of Western and Japanese patients to antiviral
therapy may differ.
Shiffman et al. examined the effect of interferon alfa-2b
(3MU tiw for 24 months) versus no treatment on histologic
progression in 53 patients with prior nonresponse to
interferon 38. Knodell fibrosis score decreased in treated
patients from 2.5 to 1.7, and 80% had histologic
improvement. In comparison, untreated patients experienced
an increase in mean fibrosis scores from 2.2 to 2.4 and
histologic worsening in 30%. Alric treated biochemical
responders who were virologic nonresponders with maintenance
interferon and also demonstrated histologic improvement 39.
Despite these encouraging results, the 'jury is still out'
on the issue of interferon-based treatment in reversal of
cirrhosis or prevention of disease progression. Three
ongoing trials, HALT C (Hepatitis C Antiviral Long-Term
treatment to prevent Cirrhosis) 40, COPILOT (Colchicine
versus PEG-Intron Long-term trial) [41,42], and EPIC
(Efficacy of Peg Interferon in Hepatitis C), are currently
evaluating the role of maintenance therapy and may shed
further light on this subject.
In summary, antiviral therapy for patients with chronic
hepatitis C on the waiting list for liver transplantation is
evolving. Response of cirrhotics to antiviral therapy
declines with increasing severity of liver disease. HCV RNA
is rendered negative during treatment in 28% of patients
infected with genotype 1 and 79% of patients infected with
non-1 genotypes (mainly 2 and 3). However, relapse is common
and SVR is only 11% for genotype 1 and 50% for non-1
genotypes. Reasons for low SVR include high prevalence of
genotype 1 HCV, inability to achieve full doses of
interferon and ribavirin due to side effects and
dose-limiting cytopenias, and risk of complications related
to deteriorating liver function. The combined results from
three reports encompassing 79 treated patients who underwent
liver transplantation suggest that 23% [18/79] of
post-transplant recurrence of hepatitis C can be prevented
by pre-transplant antiviral therapy. Effectiveness of
pre-transplant therapy will be dictated by ability to time
therapy in relation to availability of donor organs.
Carefully controlled trials to define safety and efficacy of
antiviral therapy in decompensated cirrhosis and patients on
the waiting list are desperately needed to confirm and
extend these observations.
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30. [30]Crippin JS, McCashland T, Terrault N, Sheiner P,
Charlton MR. A pilot study of the tolerability and efficacy
of antiviral therapy in hepatitis C virus-infected patients
awaiting liver transplantation. Liver Transpl.
2002;8:350-355.
31. [31]Heathcote EJ. Treatment considerations in patients
with hepatitis C and cirrhosis. J Clin Gastroenterol.
2003;37:395-398. MEDLINE
32. [32]Fontana RJ, Everson GT, Tuteja S, Vargas HE,
Shiffman ML. Controversies in the management of hepatitis C
patiens with advanced fibrosis and cirrhosis. Clin
Gastroenterol Hepatol. 2004;2:183-197.
33. [33]Dietrich DT, Wasserman R, Brau N, Hassanein TI, Bini
EJ, Bowers PJ, et al. Once-weekly epoetin alfa improves
anemia and facilitates maintenance of ribavirin dosing in
hepatitis C virus-infected patients receiving ribavirin plus
interferon alfa. Am J Gastroenterol. 2003;98:2491-2499.
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Yoshioka K, et al.. Characteristics of patients with chronic
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K, Goodman Z, et al.. Impact of pegylated interferon alfa-2b
and ribavirin on liver fibrosis in patients with chronic
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T, Sata M, et al.. Interferon therapy reduces the risk for
hepatocellular carcinoma: national surveillance program of
cirrhotic and noncirrhotic patients with chronic hepatitis C
in Japan: IHIT study group-inhibition of
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Second Forum on Liver Transplantation:
Liver transplantation for hepatitis C: how
to control the virus?
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Journal of Hepatology (April 2005)
Pierre-Alain Clavien*email address Department of Visceral
and Transplantation Surgery, University Hospital Zurich,
Ramistrasse 100, Zurich 8091, Switzerland
This second Forum on Liver Transplantation will focus on
hepatitis C, which is the current leading indication for
transplantation in industrialized countries, with an
increasing incidence of infection worldwide. The major issue
with hepatitis C virus is its inevitable reappearance in the
graft with rapid evolution to severe recurrent forms of
liver diseases and cirrhosis in many patients. Therefore,
several strategies have been proposed to overcome this
negative pattern. Marina Berenguer presents in an excellent
review the natural history of recurrent hepatitis C after
liver transplantation. She provides compelling evidence that
no single factor can predict which patients will ultimately
progress to cirrhosis after transplantation from those with
a benign course. The main risk factors include high viral
load at the time of transplantation or early following
surgery, the infection by HCV genotype 1b, the use of older
donors, and immuno-suppression. She provides a useful survey
of the various immunosuppressive agents related to their
impact on recurrent hepatitis C after liver transplantation.
Greg Everson addresses the question whether we should treat
patients with chronic hepatitis C on the waiting list for
liver transplantation. This question remains largely open,
but is worth exploring further as pre-transplant therapies
currently prevent a fourth of recurrent hepatitis C after
surgery. However, these treatments are often poorly
tolerated in this sick population of patients awaiting a
graft. Isabelle Morard and Franco Negro look at the approach
of treating patients after transplantation. The current data
on preemptive therapy, i.e. treating patients early after
transplantation prior to apparent recurrences, has been
disappointing. The best approach rather seems to selectively
treat recipients when histological evidence of progressive
liver fibrosis or inflammation develops. Laura Llado, Jose
Castellote and Juan Figueras address the difficult issue of
re-transplanting patients with severe recurrent forms of
Hepatitis C. They propose a very conservative approach,
where redo transplantation should be limited to those with
late recurrence, stable renal function, and who have not yet
been treated fully with antiviral therapy. Finally, Yasuhiko
Sugawara and Masatoshi Makuuchi provide an excellent
discussion on the benefits vs. risks of living related liver
transplantation for hepatitis C cirrhosis. They conclude
that the earlier reported dramatically poorer outcomes using
living donor grafts may be related to the learning curve and
lack of effective antiviral therapies, and that recent data
including their own series from Tokyo suggest comparable
results in patients receiving a cadaveric and living donor
grafts. They however emphasize the need to identify
associated strategies such as preemptive therapies to
minimize the risk of severe recurrent diseases.
With this Forum the readers will gather a comprehensive
overview of our current knowledge and remaining questions on
hepatitis C related to liver transplantation, and the
challenges ahead, particularly considering the increasing
number of long term patients transplanted for hepatitis C
related liver diseases.
From now on we will also publish at the end of each Forum
letters related to the previous Forum to serve as a platform
to discuss controversial issues. Here we propose two letters
related to the article by R. Freeman on the MELD system
currently used for organ allocation in the US.
What determines the natural history of recurrent
hepatitis C after liver transplantation?
Marina Berenguer
Hospital Universitario La FE, Servicio de Medicina Digestiva,
Avda Campanar 21, Valencia 46009, Spain
Article Outline
- 1. Natural history
- 2. Which factors impact on the course of recurrent chronic
hepatitis C ?
- 2.1. Viral-related variables
- 2.1.1. Post-transplantation HCV RNA levels
- 2.1.2. Pretransplantation HCV RNA levels
- 2.1.3. HCV genotype
- 2.1.4. HCV diversity
- 3. Host-related variables
- 4. Iatrogenic variables
- 4.1. Immunosuppressive drugs
- 4.2. Antifibrotic agents
- 5. Donor-related variables
- 5.1. Age of the donor
- 5.2. Donor steatosis
- 5.3. Donor hepatic iron concentration
- 5.4. Donor immunogenetic background
- 5.5. Anti-HCV status of the donor
- 6. Surgical-related variables
- 6.1. Ischemic time
- 7. Other variables
- 7.1. Coinfection with other viruses
- 7.2. Alcohol consumption
- 8. Predictive models of outcome
- 9. Which factors determine the delayed onset of severe
hepatitis C?
- 10. Which factors determine the development of fibrosing
cholestatis hepatitis?
- 11. Which factors determine the decompensation of HCV-related
graft cirrhosis?
- 12. Histology as a means to predicting outcome
- References
Hepatitis C virus (HCV) cirrhosis is the most common
indication for liver transplantation in developed countries.
Re-infection of liver allografts is virtually universal and
occurs at reperfusion [1,2]. A significant increase in viral
load is typically observed following transplantation,
presumably as a consequence of the administration of
immunosuppressive agents for the prevention and treatment of
rejection. In this setting, HCV mediated liver injury
follows a more aggressive course compared to the non-immunosuppressed
state, leading to recurrent disease and allograft failure in
a substantial proportion of patients [1-3]. While it seems
evident that the immune suppressed status 'per se' modifies
the natural history of hepatitis C in liver transplant
recipients, the effect of several other factors on
determining both the pattern and severity of recurrence
still remains a matter of intense research. Identifying the
factors, whether present prior to transplantation or
developing in the post-transplant setting, that impact on
the natural history of recurrent hepatitis C is of paramount
importance not only to target those at high risk of severe
recurrence with current imperfect and difficult-to-tolerate
antiviral therapies but also to improve organ allocation and
patient management. In this review, I will summarize the
available data regarding risk factors associated with
cholestatic hepatitis, severe chronic recurrent hepatitis
and severe but delayed-onset hepatitis. I will also describe
the determinants of higher mortality in this population, and
those associated with clinical decompensation among
recipients with established recurrent HCV-related allograft
cirrhosis.
1. Natural history
Three patterns of recurrence have been described with
differences in clinical presentation, prognosis,
pathogenesis and therapeutic strategies [1-6]. The commonest
response to persistent HCV infection is the evolution over
time to chronic hepatitis in a similar way to what has been
described in the non-transplant patient but occurring at a
viral set at least one log higher. Disease progression in
these patients is typically accelerated compared to that
observed in the immune competent host [1-6]. Progression in
patients with this pattern of recurrence may follow two
distinct pathways: a linear rate of fibrosis progression 5
and a delayed onset of progression 6. Regardless of the
pathway used, the hepatitis C driven fibrosis response in
the allograft leads to the development of graft cirrhosis in
approximately 25% of recipients (range: 8-44%) after a
follow up of 5-10 years [1-7]. Liver damage in this
setting is believed to involve host-mediated immune
responses over-stimulated by the increased viral load 4.
Cholestatis hepatitis is an infrequent but extremely severe
pattern of recurrence that leads in 50% of patients to graft
failure within a few months of onset [1-4]. A cytopathic
mechanism of allograft damage is thought to be involved
given the concurrence of extremely high viral burdens,
reduced immune response with intrahepatic non-specific Th2
cytokine response, and unusual histology characterized by
little inflammation and severe centrizonal hepatocyte
ballooning 4. In a substantial proportion of infected
recipients, progression is not apparent, at least for the
first decade, and liver injury remains mild or absent
despite high viral burden.
There are a number of factors that potentially contribute to
disease progression [1-10]. In addition to those already
known from the immune competent patient, there are unique
variables in the transplant setting that further complicate
the difficult interactions between the host and the virus.
These variables include surgical related factors,
particularly the time of ischemia and reperfusion injury and
donor-related factors such as age, histocompatibility
between donor and recipient, immunologic chimerism and the
use of immunosuppressive medications.
2. Which factors impact on the course of recurrent
chronic hepatitis C ?
2.1. Viral-related variables
While viral factors do not appear to influence outcome in
the immune competent host, data in the liver transplant
recipient remain controversial.
2.1.1. Post-transplantation HCV RNA levels
Serum HCV RNA concentrations increase rapidly in the
post-transplantation period to peak by the fourth
post-operative month 11. The relationship between levels of
viremia and the long-term outcome of post-transplant HCV
infection is contradictory. In some studies, early
post-transplantation viral load has been shown to influence
late post-transplantation outcome 10. Sreekumar and
colleagues found that HCV RNA at 4 months was the most
sensitive (82 and 71%) and specific (61 and 62%) predictor
of increased histological activity index (³3) and increased
fibrosis (³2) at 3 years post-transplantation 10.
Interestingly, immunosuppression is likely the most
important determinant of post-transplantation viremia. In
one study, differences in early kinetics could be attributed
to the use or not of corticosteroids 11. Following an
initial decline, HCV RNA levels increased rapidly in
patients receiving corticosteroids as part of the
immunosuppressive regime, while they continued to decline in
the first post-transplant week in those on a steroid-free
immunosuppression protocol. Furthermore, prednisolone
withdrawal protocols that are complete very early
post-transplantation (within the first 2 weeks) seem to be
associated with relatively low levels of viremia 10. In
addition, corticosteroid treatment for acute cellular
rejection is associated with significant increases in
viremia (4- to 100-fold increase) 10. The effects of other
immunosuppressive agents on viral replication are generally
controversial or preliminary. Two studies have suggested
that the addition of mycophenolate mofetil (MMF) to stable
organ transplant recipients is associated with increased
viral replication 12. The information on calcineurin
inhibitors is also controversial. Watashi et al. recently
showed an inhibitory effect of cyclosporine A (CyA) on HCV
protein expression and replicon RNA levels, effect that was
not detected with tacrolimus (Tac) 13. In vivo data though,
have not shown differences in viral load between patients
immunosuppressed with either CyA or Tac 10. The effect of
azathioprine on viral load has not been carefully evaluated,
possibly due to the confounding effect of concomitant
steroid use. In one study using the replicon system,
azathioprine was found to inhibit HCV replication 14.
Precise data in the human model is missing. Data on
interleukin-2 receptor monoclonal antibodies (IL2R) are also
lacking. In one study, viral load was significantly greater
at both 4 months and 1 year in patients whose induction
regimen consisted of daclizumab-MMF-steroids compared to
those treated with the standard combination Tac-steroids 15.
Whether this differences was related to MMF, IL2R antibodies
or the combination of both drugs remains unknown. The impact
of other immunosuppressive agents, including sirolimus,
everolimus and OKT3 is unknown.
2.1.2. Pretransplantation HCV RNA levels
Several although not all studies have shown that, as
described for HBV, level of viremia pre-transplantation
predicts the occurrence and/or severity of recurrent
hepatitis C [4,8]. In one study, recipients with increased
HCV replication within the explanted liver (defined by a
relative quantitative HCV negative-strand RNA:18S rRNA ratio
>2.5) were found to be at increased risk for the development
of post-transplant biochemical hepatitis, increased rate of
allograft fibrosis and increased rate of mortality compared
with recipients with relatively low replication 8. These
results paralleled those obtained in a prior study, where
increased serum genomic viral load prior to transplantation
(>1logMeq/mL) was also predictive of mortality 8.
Interestingly, non-HCV infections and non-infectious causes,
but paradoxically not HCV-induced liver damage, were the
primary causes of death and/or retransplantation. The
positive and negative predictive values of fast intrahepatic
replication to predict mortality were 40 and 100%. If
confirmed in larger series, this information could be useful
in identifying HCV-infected recipients at high risk of
severe outcome.
2.1.3. HCV genotype
The effect of the infecting genotype on the outcome of
recurrent hepatitis C is still unclear [1-3]. Some studies,
particularly from European centers, have implicated genotype
1b in a more severe post-transplantation disease compared to
non-1b genotype. Interestingly, fibrosis progression appears
to be faster in centers where the prevalence of genotype 1b
is very high 5, thus indirectly implicating this genotype in
a more aggressive course of the disease. The mechanisms by
which accelerated fibrogenesis is more often seen in
patients infected with genotype 1b may be an increased rate
of FAS-mediated hepatocellular apoptosis 16. In addition,
preliminary data suggest that different strains belonging to
genotype 1b may be involved in the pathogenesis of severe
liver injury [17,18].
2.1.4. HCV diversity
The genetic nature and evolution of the virus have been
implicated in the pathogenesis of progressive HCV disease.
Results, generally inconclusive, need to be interpreted with
caution due to a series of limitations in most studies,
including: (i) only a limited number of clones are generally
evaluated at each time point and hence, sequenced variants
may not always be fully representative of the whole
population of circulating quasispecies; (ii) while studies
based on the hypervariable region-1, a putative target for
neutralizing antibodies, are common, data using other
potentially relevant regions are missing; (iii) small number
of patients; (iv) different methodologies applied to assess
HCV heterogeneity; (v) differences between studies in both
the end-points chosen and the sequence time-points [1,4].
Notwithstanding these caveats, based on available data,
several conclusions can be made regarding the evolution and
effect of HCV quasispecies. First, in the early weeks
following transplantation viral quasispecies becomes more
homogenous than pretransplantation, likely as a result of
the 'bottleneck' effect caused by the implantation of the
new graft and the lack of selective pressure due to the
strong immunosuppression 4. This pattern of genetic
evolution is particularly evident in patients with the
fibrosing cholestatic pattern of recurrence where extremely
potent immune suppression inhibits the cellular response to
the virus, leading to the preferential replication of a few
genetically divergent quasispecies 4. Second,
pre-transplantation quasispecies composition may have an
effect on long-term outcome. It has been suggested that a
less complex quasispecies composition prior to
transplantation is associated with a more severe
posttransplant HCV disease 19. Third, genetic
diversification appears to increase in patients with mild
recurrence, possibly as a consequence of immune pressure in
the context of immune restoration 4. Finally, data regarding
the impact of early post-transplant HCV quasispecies on
long-term outcome are controversial 4.
3. Host-related variables
In the immune-competent population, the most powerful
predictors of disease severity and progression are those
related to the host. In the liver transplant setting,
similar variables, both in the recipient and the donor, have
been found to influence the outcome.
Immune status. The immune system is clearly implicated in
the pathogenesis of liver injury due to HCV [1,4,10]. In
fact, it is likely that the immunosuppressed status, typical
of the transplant setting, is the most powerful determinant
of post-transplantation disease progression. While this
assumption comes mainly from indirect findings, there are
recent studies specifically addressing the impact of immune
suppression on viral replication and disease progression
(see iatrogenic variables).
Race. In a few studies, non-Caucasians were found to have
higher rates of fibrosis progression and lower survival
[1,5]. This association deserves further analysis.
Gender. Female gender has been associated with severe
recurrent hepatitis C and low survival in some studies 9.
Reasons, which explain this association, are lacking.
Interestingly, the opposite trend is described in immune
competent patients.
Pre-transplantation disease progression. In one study, a
lack of association was observed between pre- and
post-transplantation fibrosis progression 5, suggesting that
variables present either at or post-transplantation are more
important in influencing disease progression than genetic or
viral variables unique to the individual.
4. Iatrogenic variables
4.1. Immunosuppressive drugs
Data on the effect of corticosteroids on HCV-disease
progression are controversial. Several studies have clearly
shown that the use of corticosteroid boluses to treat acute
cellular rejection is harmful to HCV infected recipients
[1-5,8-10]. Their use leads to an increased frequency of
acute hepatitis, earlier time to recurrence, higher risk of
progressing to graft cirrhosis or developing cholestatic
hepatitis and greater risk of early post-transplant
mortality. In addition, high cumulative doses of
corticosteroids have also been associated with higher risk
of severe fibrosis and mortality. While recent preliminary
data suggest that complete avoidance of corticosteroids may
be beneficial 20, the effect of early corticosteroid
withdrawal remains controversial [1-3,21,22]. Indeed, there
is some evidence that a rapid reduction in the doses of
corticosteroids, strategy proposed by several authors as a
means to improving outcome may, in fact, be harmful to HCV
infected patients and, in part, responsible for the
worsening in disease progression observed in recent years
[1-4,22]. Unfortunately, most studies addressing this
question are retrospective in nature and, hence, unable to
prove a conclusive time-frame of events. Similarly, the data
with MMF are also confusing [1-3,10,12,15,22-25]. There are
two large randomized trials that have compared MMF to
azathioprine in a maintenance immunosuppressive regimen with
no differences in outcomes 10. Similar results were obtained
in a large study comparing triple (with MMF) to double
immunosuppressive therapy in HCV-infected transplant
recipients 23. Some retrospective studies trying to define
determinants of severe outcome have however found a
correlation between the use of MMF and both a greater risk
of progressing to severe hepatitis and a reduced survival
[22,25]. In addition, data from other solid organ transplant
recipients infected with HCV also suggest that the use of
MMF is associated with increased viremia and higher risk of
developing severe liver disease, particularly cholestatic
hepatitis [1,4,12]. In contrast to these observations, one
study suggested that the effect is related to the dose used,
so that patients who receive a relatively high exposure to
MMF have improved outcomes (reduced HCV RNA levels at 3
months and decreased incidence of allograft fibrosis at 1
year) over patients who receive a lower exposure to MMF 24.
Interestingly, in this study, the incidence of fibrosis was
similar among all studied groups at 2 years. The mechanism
by which this drug may adversely affect the outcome of HCV-infected
recipients is largely speculative. In a recent study, viral
load was found to double in stable liver transplant
recipients 3 months after changing azathioprine to MMF 12.
It is hence likely that the immunosuppressive properties of
MMF outweigh the antiviral ones. The data on monoclonal
antibody induction immunosuppression are also controversial.
Two controlled and randomized trials have suggested no
effect on survival 10. In contrast, in a retrospective study
comparing a cohort of patients treated with IL2-receptor
antibodies in combination with MMF to a historical group of
patients treated with the standard combination Tac and
steroids, the rate of recurrence, and most specifically the
stage of fibrosis at 1 year were significantly higher in the
former than in the latter group 15. Data on calcineurin
inhibitors are less confusing. While in a few studies,
differences were found between CyA and Tac, the overall
evidence suggests that results are similar with either drug
[10,26]. There are very few studies focusing on azathioprine
with discrepant results [1,27]. A large retrospective study
based on protocol liver biopsies highlights that the
negative effect may be the abrupt and early discontinuation
of azathioprine as opposed to its use or not 22. In fact, it
is generally believed that the outcome is probably not
related with the use of a specific drug but rather with (i)
the dose and drug level achieved, reflecting overall
immunosuppression, and (ii) the way the dose of the drug is
modified. A potential hypothesis is that the substantial and
abrupt changes in immunosuppression have the greatest
adverse influence on outcomes in HCV-infected patients. A
strong initial immunosuppression might lead to an inadequate
immunologic clearance of HCV virions contributing to the
high levels of viremia typically observed in the early
period post-transplantation. Increased levels of viremia and
hence of antigenemia are associated with increased
immunologically-mediated liver injury, particularly
following 'partial immune restoration'. In this setting,
global immunosuppression, and not a single immunosuppressive
agent, would dominate the effect. This would explain why
corticosteroid boluses and OKT3 use for the treatment of
rejection are particularly harmful to HCV infected patients,
while either steroid avoidance or maintaining low levels of
corticosteroids, but not abrupt and rapid steroid
withdrawal, may be beneficial.
4.2. Antifibrotic agents
Angiotensin-II has been suggested to be a major regulator of
liver fibrogenesis and experimental data with agents
blocking its effect suggest that they may lead to a
substantial reduction in fibrosis. In one recent
retrospective study, liver transplant recipients who
received angiotensin converting-enzyme ACE inhibitors or
angiotensin-II receptor antagonists showed a reduced
development of cirrhosis compared with patients who did not
receive these drugs 28. While interesting, this observation
needs to be prospectively validated before recommending the
use of these specific anti-hypertensive agents to reduce HCV-induced
fibrosis progression.
5. Donor-related variables 5.1. Age of the donor
The age of the donor has been found to be independently
associated with disease severity, disease progression, graft
and patient survival [1-3,9,22,25,29-31]. In one series,
only 14% of the recipients who received an organ from a
donor younger than 30 developed recurrent HCV-related
cirrhosis; in contrast, 45 and 52% of those receiving the
organ from donors aged 31-59 or older than 59 developed
graft cirrhosis, respectively (P<0.0001) 29. In another
study, the median rate of fibrosis progression increased
from 0.6 units/year in patients who received organs from
donors younger than 40 years to 2.7 units/years in those
using allografts from donors older than 50 years 30. In a
recent large study in which old donor allografts (>50 years)
constituted 49% of the donor pool, severe fibrosis at 12
months was observed in 26% of old donor recipients but only
in 8% of young donor recipients 31. Differences in donor age
between centers and the changing donor profile with the
increasing use of older donors may account for the
discrepancies regarding HCV-related disease progression
post-transplantation and the observed worsening in outcomes
in recent years in some centers. This observation has
important implications for donor liver allocation, in that
older donors might be more appropriate for HCV negative
recipients in whom the adverse effects of donor age appear
to be less deleterious [29,31]. The effect of donor age
correlates with data from the immunocompetent population
where age at the time of infection is an important
determinant of fibrosis. The mechanism by which older age is
associated with an accelerated course of the disease is not
completely understood, either in immune competent or in
liver transplant recipients. Age-related immune changes in
liver response, liver steatosis, iron content, pre-existent
fibrosis, and telomeres or replicative senescence may be
some of the key factors that determine the increased
susceptibility of the older liver to HCV-related fibrosis.
5.2. Donor steatosis
Allograft steatosis may be one of the mechanisms whereby
older donors are associated with worse outcome. In one
study, macrovesicular steatosis on early liver biopsies
correlated with an increased rate of fibrosis progression 9.
More data are awaited on this important issue.
5.3. Donor hepatic iron concentration
Iron is a known pro-fibrogenic agent that plays a role as a
co-morbid factor in hepatitis C. Its concentration in the
liver increases with age. In one recent study, a graft
hepatic iron concentration >1200ug/gdw was associated with
early fibrosis progression due to recurrent hepatitis C in
female recipients 32.
5.4. Donor immunogenetic background
It is increasingly accepted that genetics play a major role
in host immune responses to infectious pathogens. Regulatory
mechanisms that control cytokine production, including
TNF-alfa, operate in part at the gene level, and in that
sense, mutations in these genes may influence the production
of cytokines. In one study, Rosen et al. evaluated the
significance of polymorphisms at positions -238 and -308 of
the TNF-alfa gene promoter (mutations associated with
susceptibility to active hepatitis after HCV exposure in
immunocompetent patients) in liver donors on the
severity/outcome of recurrent HCV. They found that time to
recurrence was shorter and the hepatic activity index
greater in those who received an organ from donors with
TNF-alfa-308 allele 33. These data suggest that a specific
donor TNF-alfa genotype, known to be associated with high
TNF-alfa production, may contribute to the accelerated graft
injury observed in liver transplant recipients with HCV
infection. If these preliminary data were confirmed and
technology allowing for fast screening were developed,
appropriate matching of donors and recipients based on
genetic information could become a means to maximize
favorable outcome. A few studies have unsuccessfully
attempted to establish a link between specific
donor/recipient HLA matches and the severity of liver
disease after transplantation [1,9] (Table 2).
5.5. Anti-HCV status of the donor
The course of HCV disease is not affected by the use of
anti-HCV (+) HCV-RNA (+) grafts. Several series have
demonstrated that HCV-infected recipients receiving these
type of grafts have a similar survival and progression of
HCV disease than those receiving uninfected grafts 34.
Strict patient information and use of organs with little or
no fibrosis and only minimal inflammation are mandatory.
6. Surgical-related variables 6.1. Ischemic time
Prolonged rewarming time during allograft implantation has
been associated with severe recurrent disease 1. In one
study, the risk of severe HCV disease at 1 year was 19 and
65% for rewarming times of 30 and 90min, respectively 35. If
these data were confirmed, special emphasis should be done
to minimize rewarming time or alternatively to provide the
donor graft with nutritional enhancement that may reduce
rewarming ischemic injury.
Type of surgery: cadaveric vs donor related liver surgery:
(This will be discussed by Sugawara and Makuuchi in the
current Forum)
7. Other variables
7.1. Coinfection with other viruses
Patients who develop cytomegalovirus (CMV) infection
following transplantation may be at increased risk of severe
HCV recurrence [1,9,25]. The reasons for a positive
association between CMV and HCV-disease are unknown but
likely relate to induction of immune-deficiencies, release
of tumor necrosis factor by CMV or the existence of
cross-reactive immunological responses. Coinfection with HBV
may influence histologic disease severity but results are
conflicting [1,9,36]. In one study, coinfected patients
appeared to have milder histological course than patients
infected only with HCV 36. Although viral interactions could
explain this phenomenon, the passive transmission of
protective antibodies against HCV in coinfected patients
receiving HBIg during the pre-HCV era is a more likely
explanation.
7.2. Alcohol consumption
A substantial proportion of patients have end-stage liver
disease caused by both alcohol and chronic HCV infection. In
fact, liver disease appears to be more severe and
accelerated in patients with alcoholism and chronic HCV
infection compared with those with HCV who have never abused
alcohol. One may also hypothesized that given this synergism
in the immune competent population patient, the
post-transplant outcome may be worse in patients with both
aetiologies as compared to those transplanted for only one
of the two. Data on this issue are surprisingly limited.
None of the studies, which have looked at predictive
variables of worse histological and/or clinical outcome have
found that a history of significant alcohol consumption
pre-transplantation was associated with a more aggressive
disease following transplantation [1,9]. Preliminary data
from our centre suggest that patients with mixed aetiologies
have a histological outcome post-transplantation that is
worse than that seen in patients undergoing transplantation
for HCV alone; based on protocol liver biopsies, only 25% of
patients transplanted for mixed aetiologies had normal or
minimally abnormal liver biopsies after a prolonged
follow-up compared to 59% in the HCV (+) group 37. More data
are needed to address this question.
8. Predictive models of outcome
Although several attempts have been made to identify
predictors of severe HCV recurrence, none have provided
satisfactory explanation to the variation among individuals
or groups in the outcome of recurrent HCV. A second step has
been to create models that may more accurately predict
outcome than single variables. Validation of these models is
however required before they can be generalized. 9. Which
factors determine the delayed onset of severe hepatitis C?
return to Article Outline
Delayed hepatitis C-related severe liver damage occurs in
approximately one third of recipients with initial benign
recurrence, defined as stable histology (F 0 or 1) during
the first 3 years post-transplantation 6. In these cases,
progression to severe disease is not linear and the patients
develop a sudden acceleration in fibrosis following an
initial period of stabilization. The presence of some degree
of fibrosis at baseline, and even more, the combination of
some fibrosis and elevated liver enzymes at 3 years
post-transplantation, appears to predict this sudden change
in progression with 70% of the patients with these
predictive factors developing this acceleration as opposed
to 5% of those without these factors 6. Other variables
previously implicated in the progression of recurrent
hepatitis C, including demographics, non-alcoholic
steatohepatitisÑvariables (diabetes, hyperlipidemia,
obesity), and the use of specific drugs (renin-angiotensin
inhibitors, ursodeoxicolic acid) were not found to be
associated with outcome.
10. Which factors determine the development of fibrosing
cholestatis hepatitis?
Fibrosing cholestatic hepatitis typically develops in the
context of profound immunosuppression [1-4]. While there are
few studies focusing on specific risk factors associated
with this pattern of recurrence, the highest rates of severe
cholestatic hepatitis have been reported in patients treated
with high levels of Tac (trough levels of approximately
15ng/dl) or CyA (trough levels around 300-400ng/dl), and in
those receiving multiple pulses of methyl-prednisolone
and/or OKT3 [1,4,9].
11. Which factors determine the decompensation of HCV-related
graft cirrhosis?
There is only one published study that has defined the
natural history of HCV-related graft cirrhosis, including
predictors of clinical decompensation 38. Thirty-nine
patients with clinically compensated graft cirrhosis were
evaluated; 46% developed at least one episode of
decompensation at a mean of 8 months. The cumulative
probability of decompensation was 8, 17, and 42% at 1, 6 and
12 months, respectively. The most frequent event was ascites.
Patient survival rates dropped once decompensation developed
(93, 61, and 41% at 1, 6 and 12 months, respectively).
Variables associated with decompensation included a high
Child-Pugh score (>A) and low albumin level (<3.5mg/dl) at
diagnosis of graft cirrhosis, and a short interval between
transplantation and the development of cirrhosis.
12. Histology as a means to predicting outcome
Most determinants of severe disease are pathogenically
implicated in the outcome of recurrent hepatitis C. There
are additional parameters that, while not directly
implicated, may however help the clinician in early
recognizing the patient at risk of accelerated progression.
Several studies have shown an association between the early
timing of recurrence (within 6 months) [1-3,39] and some
histological findings (significant steatosis, ballooning
degeneration, cholestasis, and confluent necrosis) 1 and
subsequent disease progression. The activity observed in the
first-year liver biopsy was found in two studies to be
strongly associated with the subsequent risk of developing
cirrhosis, with only 3-10% of those with mild hepatitis
developing cirrhosis compared to 30-60% in those with
moderate to severe activity 1. The hepatic activity index
seen either on protocol biopsies at 4 months (hepatic
activity index >3) or at histological recurrence (³9) has
been shown to correlate with rapid progression of fibrosis
[8,9,39].
In conclusion, pre-transplant or early post-transplant
recognition of patients with high risk of severe outcome
post-transplantation is desirable since these patients can
be targeted for early intervention. It is likely that it is
the interplay between the immune system and the virus,
modulated by both the immunogenetic background, such as the
HLA system, and the quality of the graft that shapes the
outcome post-transplantation. While many studies have
described positive and negative associations, no single
factor is capable of accurately differentiating which
patients will ultimately progress to cirrhosis from those
with a more benign process. The combination of several of
these factors may however be used to define the patient at
high risk of severe recurrence. Based on the available data,
the major determinants of accelerated allograft fibrosis
include high viral load at transplantation (>1Meq/mL) and/or
early following transplantation (>10Meq/mL at 4 months), the
infection by HCV genotype 1b, the use of grafts from donors
older than 50 years, a net state of immunosuppression
generally but not always in the context of rejection
therapy, and the abrupt changes in immune suppression. In
addition, histology may help in predicting subsequent
fibrosis progression. Allocation of young donors to HCV-infected
recipients, pre-transplantation antiviral therapy and
avoidance of events that lead to immune evasion,
particularly a rationale use of immunosuppression and
adequate prophylaxis of CMV infection, are potential
strategies to improve the outcome in HCV-infected patients.
Their real efficacy though needs to be proved by prospective
well-designed trials.
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CrossRef Abbreviations: CMV, cytomegalovirus, CyA,
cyclosporine A neural, HBV, hepatitis B virus, HBIg,
hepatitis B immune globulins, HCV, Hepatitis C virus, IL2R,
interleukin-2 receptor monoclonal antibodies, OLT,
Orthotopic Liver transplantation, LDLT, living donor liver
transplantation, MMF, mycophenolate mofetil, TNF, tumor
necrosis factor, Tac, tacrolimus
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