Ribavirin with either standard or pegylated interferon to treatrecurrent hepatitis C after liver transplantationV. R. CICINNATI* ,� , S . IACOB� ,� , C . G. KLEIN* ,� , H . A. BABA§, G. C. SOTIROPOULOS� ,
P . HILGARD*, Y . ERIM– , C . E . BROELSCH� , G . GERKEN* & S. BECKEBAUM*,�
*Department of Gastroenterology and
Hepatology, University Hospital Essen,
University of Duisburg-Essen, Essen,
Germany; �Department of General,
Visceral and Transplantation Surgery,
University Hospital Essen, University
of Duisburg-Essen, Essen, Germany;
�Gastroenterology and Hepatology
Center, Fundeni Clinical Institute,
Bucharest, Romania; §Institute of
Pathology and Neuropathology, Uni-
versity Hospital Essen, University of
Duisburg-Essen, Essen, Germany;
–Department of Psychosomatic Medi-
cine and Psychotherapy, University
Hospital Essen, University of Duis-
burg-Essen, Essen, Germany
Correspondence to:
PD Dr S. Beckebaum, Interdisciplinary
Liver Transplant Unit, University
Hospital Essen, OPZ 2, Ebene A1,
Hufelandstr. 55, 45122 Essen,
Germany.
E-mail: susanne.beckebaum@uni-
due.de
Publication data
Submitted 14 January 2007
First decision 18 February 2007
Resubmitted 30 April 2007
Accepted 30 April 2007
SUMMARY
AimTo investigate the efficacy of two anti-viral protocols in hepatitis Cvirus-reinfected liver transplant recipients.
MethodsIn this prospective study, 26 liver transplant patients were treated withstandard interferon-a2b for 12 months or standard interferon-a2b for3 months followed by pegylated interferon-a2b for 9 months. Interferonwas combined with ribavirin in all patients. The histological course ofthe study population was compared with an untreated historic controlgroup (n = 38) with similar baseline characteristics.
ResultsThe sustained virological response rates in the standard interferon groupand in the pegylated interferon group were 27.3% and 26.7%, respect-ively. Only 29% of patients with sustained virological response had endof treatment histological response, whereas 47% of viral non-respondersshowed end of treatment histological response. The percentage ofpatients with histological improvement was significantly higher in thestudy population when compared to the controls. Univariate analysisindicated that hepatitis C virus genotype non-1, high baseline alanineaminotransferase, the time interval between liver transplant and inter-feron therapy and the body mass index predicted sustained virologicalresponse. In the multivariate model, baseline alanine aminotransferaseand the body mass index remained a significant predictor of sustainedvirological response.
ConclusionsBoth treatment regimens offer similar efficacy profiles. Failure to eradi-cate hepatitis C virus should not lead to treatment discontinuation ifserial liver biopsies demonstrate histological response.
Aliment Pharmacol Ther 26, 291–303
Alimentary Pharmacology & Therapeutics
ª 2007 The Authors 291
Journal compilation ª 2007 Blackwell Publishing Ltd
doi:10.1111/j.1365-2036.2007.03363.x
INTRODUCTION
Hepatitis C virus (HCV)-related cirrhosis represents the
leading indication for liver transplantation (LT) world-
wide. Recurrence of HCV infection in replicative
patients occurs during reperfusion of the allograft and
the natural course of the disease is accelerated com-
pared to the non-transplant setting.1 At least 50% of
recipients develop histological evidence of recurrent
disease within 1 year post-transplant2 and progression
to allograft cirrhosis occurs in 10–30% at 5 years of
follow-up,3 leading to increasing incidence of retrans-
plantation in HCV recipients.4 In the context of a
growing demand for LT services and shortage of
cadaveric donor organs, there are continuous efforts to
improve the outcome in HCV recipients.
Currently, available anti-viral regimens are effective
in immunocompetent patients with overall sustained
virological response (SVR) rates of approximately
55%.5–7 However, in the setting of LT, sustained
response rates are markedly lower and highly vari-
able.8 Potential factors responsible for reduced virolo-
gical response to anti-viral therapy are non-response
to interferon (IFN) and ribavirin (RBV) therapy prior to
LT, influence of immunosuppression on drug efficacy
and tolerance, predominance of genotype 1 infection,
frequent dose reduction because of cytopenia or renal
dysfunction and high rates of discontinuation. Thus,
treatment of established HCV infection in the LT set-
ting is much more challenging as in non-immune
compromised patients, and several questions such as
the onset, the modality and the duration of treatment
have yet to be answered.9 In addition, the criteria for
selecting patients for anti-viral treatment have not
been evaluated yet.
Anti-viral therapy has been applied prior to LT,
pre-emptively in the early post-operative period or
for established recurrent hepatitis C. However, pre-
transplant IFN treatment has not shown to be a con-
vincing approach because of low therapeutic benefit,
high rate of premature discontinuation and severe
side effects including the risk of infectious complica-
tions, hepatic decompensation and death.10, 11
Moreover, patients with pretransplant response to
anti-viral therapy may relapse after surgery.10 Only a
few studies have been published reporting experien-
ces with pre-emptive anti-viral therapy within the
first weeks after LT.12–15 This ‘prophylactic’ approach
though does not seem feasible in a considerable pro-
portion of patients due to initial intense immunosup-
pression, post-operative infections, cytopenia and
insufficient recovery from surgery. Another approach,
focusing on the treatment of patients with established
HCV reinfection of the allograft, seems to be the
most applicable strategy.16–18
The aim of this prospective study was to determine
the efficacy and the tolerability of two anti-viral
treatment strategies in LT recipients with established
HCV reinfection and to compare their histological
course with an untreated historic control group. In
addition, potential predictive factors for virological,
histological and biochemical response were assessed
to achieve a better selection of patients for effective
anti-viral therapy.
MATERIALS AND METHODS
Study population
Since 2001, we prospectively evaluated transplant
recipients with recurrent HCV infection in our Liver
Transplant Unit.
Patients were eligible for anti-viral therapy if they
fulfilled the following inclusion criteria: (i) positive
HCV-RNA [serum HCV-RNA levels determined by the
branched DNA signal amplification assay (Bayer
Diagnostics, Emeryville, CA, USA; limit of detection
615 IU ⁄ mL) and qualitative testing utilizing the
TMA assay (Bayer Diagnostics, limit of detection
9.6 IU ⁄ mL)]; (ii) histological evidence of recurrent HCV
infection, scored according to the Ishak-modified HAI
System using a seven-point scale for fibrosis stage
(0–6) and an 18-point scale for inflammatory activity.
Patients were excluded from the study if they presen-
ted with any of the following manifestations: white
blood counts <3000 ⁄ mm3, neutrophils <1500 ⁄ mm3,
platelet counts <80 000 ⁄ mm3, haemoglobin levels
<11 g ⁄ dL, liver cirrhosis, hepatitis B virus or human
immunodeficiency virus coinfection, other concurrent
causes of liver disease, alcohol abuse or drug depen-
dence within the previous 6 months, severe psychiatric
illness, thyroid dysfunction, severe pulmonary or
cardiovascular disease, renal impairment defined as
serum creatinine >1.5 mg ⁄ dL and ⁄ or creatinine clear-
ance <50 mL ⁄ min, current pregnancy or breastfeeding
of infants, unable ⁄ unwilling to use contraception dur-
ing the treatment and 6 months after discontinuation.
For exclusion of severe psychiatric illness, patients
were evaluated by a specialist from the Department of
Psychosomatic Medicine and Psychotherapy at the
292 V . R . C IC INNAT I et al.
ª 2007 The Authors, Aliment Pharmacol Ther 26, 291–303
Journal compilation ª 2007 Blackwell Publishing Ltd
University Hospital Essen. None of our patients
included in this study met the criteria for major
depression prior to administration of IFN. Patients
were educated about potential coping strategies that
are beneficial for IFN-related neuropsychiatric adverse
events. Patients were extensively informed about
potential IFN-induced neuropsychiatric side effects
and were educated about the possibility of antidepres-
sant therapy to allow them to play an active role in
the decision whether to start therapy. Patients were
also educated to receive, if necessary, psychotherapist
consultations.
Historic control group
Potential control individuals were obtained from a
historic database including 102 patients who were
transplanted for HCV-induced cirrhosis in our depart-
ment and had data from regular follow-up visits.
Among these recipients, 38 patients fulfilled the
selection criteria for inclusion in the historic control
group: positive HCV-RNA levels in the serum and
histological evidence of recurrent HCV infection,
available paired graft biopsies (defined as two con-
secutive liver biopsies at an interval of 12 months),
no IFN therapy after LT and lacking evidence of
hepatitis B virus or human immunodeficiency virus
coinfection or other concurrent causes of liver dis-
ease. None of the patients in the historic control
group had a history of alcohol abuse.
Therapeutic protocol and follow-up
Patients were treated with standard IFN-a2b adminis-
tered at a dose of 2 million units (MU) daily for
12 months. After pegylated (PEG)-IFN became avail-
able, the remaining patients were treated with standard
IFN-a2b (2 MU ⁄ day) during the first 3 months fol-
lowed by PEG-IFN-a2b at a dose of 1.5 lg ⁄ kg once
weekly for the following 9 months. RBV was adminis-
tered concomitantly with IFN in both groups at a dose
of 10–12 mg ⁄ kg ⁄ days.
All patients on treatment were scheduled to have
complete blood count and liver function tests that
were assessed weekly for the first 4 weeks, then for
every 2–4 weeks and whenever required while on
treatment. RBV dose was reduced by 25–50% for
haemoglobin levels below 9.5 g ⁄ dL and was discon-
tinued if haemoglobin levels were <8 g ⁄ dL despite
erythropoietin (EPO) therapy. The IFN dose was
reduced by 25–50% for leucocyte counts between
1000 ⁄ mm3 and 1500 ⁄ mm3 and ⁄ or neutrophil counts
between 500 ⁄ mm3 and 750 ⁄ mm3 despite concomitant
granulocyte colony-stimulating factor (G-CSF) ther-
apy (administered if leucocyte count was <1700 ⁄ mL
and ⁄ or neutrophil count was <750 ⁄ mm3), and for
platelet counts <50 000 ⁄ mm3. However, IFN was dis-
continued in case of platelet counts <25 000 ⁄ mm3 or
white blood cell counts <1000 ⁄ mm3 and ⁄ or neutroph-
ils <500 ⁄ mm3.
Quantitative HCV-RNA was measured monthly
within the first 12 weeks after the onset of therapy
and thereafter every 3 months until 6 months after the
completion of therapy. All patients underwent protocol
liver biopsies 1–3 months before the onset of therapy,
6 months after the beginning of therapy, at the end of
therapy and thereafter at yearly intervals. All patients
had follow-up investigations in the post-treatment
period for at least 24 weeks.
Study end points and response assessment
The primary end point was the achievement of SVR
(negative qualitative serum HCV-RNA at week 72).
Secondary end points included end of treatment viro-
logical response (EOTVR) as defined by negative qual-
itative serum HCV-RNA assay at the end of anti-viral
therapy at week 48, end of treatment biochemical
response (EOTBR) as defined by normalization of
serum alanine aminotransferase (ALT) activity at week
48 and end of treatment histological response (EOTHR)
which was considered in the case of a decrease of two
or more points in the grading score in association with
unchanged or improved fibrosis score according to the
Ishak-modified HAI system.
Very early virological response (VEVR) and early
virological response (EVR) were defined as at least a
2 log10 drop or undetectable HCV-RNA at week 4 and
at week 12 after onset of therapy.
To identify factors associated with virological, histo-
logical and biochemical response, we merged the two
treatment groups and included the following parame-
ters in the univariate analysis.
Related to the recipient prior to anti-viral therapy
Presence of diabetes mellitus type II, gender, adminis-
tration of bolus corticosteroids for acute rejection epi-
sodes, mycophenolate mofetil or azathioprine induction
and prior prednisone therapy.
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Related to the recipient at the onset of anti-viraltherapy
Age, body mass index (BMI) ⁄ BMI ‡ 25 kg ⁄ m2, inflam-
matory activity, fibrosis score and presence of steatosis
prior to therapy, type of immunosuppression [ciclospo-
rin (CSA) or tacrolimus (TAC) monotherapy], time per-
iod between LT and start of IFN therapy, ALT,
ALT ⁄ aspartate aminotransferase (AST) ⁄ gamma gluta-
myl transferase (cGT) ⁄ alkaline phosphatase (AP) values
more than two times the upper normal limit (UNL) and
AST ⁄ ALT ratio >2.
Related to the virus
Hepatitis C virus genotype, viral load at baseline, high
level of viraemia before the onset of therapy
(>1 500 000 IU ⁄ mL).
Related to the donor
Living or deceased donor, age and gender.
Related to the anti-viral therapy
Administration of pretransplant anti-viral therapy,
type of IFN (standard IFN ⁄ PEG-IFN), a 2 log10 drop of
viraemia after 1 month ⁄ after 3 months of therapy, the
need to decrease the IFN or RBV doses and completion
of anti-viral regimen.
Safety and tolerability were assessed through monit-
oring of adverse events (e.g. influenza-like symptoms,
gastrointestinal, respiratory, neuropsychiatric side
effects) and laboratory abnormalities (anaemia, leu-
copenia ⁄ neutropenia and thrombocytopenia) at sched-
uled visits or when they were reported during the
treatment. Adverse events were graded as mild, moder-
ate or severe requiring withdrawal of therapy.
Statistical analysis
The analysis of the study population was conducted on
an intent-to-treat basis. Continuous data were expressed
as mean � s.d. (if not otherwise indicated) and Mann–
Whitney U-test was used to compare continous varia-
bles between the IFN group and the PEG-IFN group, and
between the overall study population and the historic
control group. Kruskal–Wallis test was used to compare
between the IFN group, the PEG-IFN group and the his-
toric control group. Wilcoxon’s rank test was carried
out to compare continuous variables at the beginning
and at the end of therapy. Fisher’s exact test was used to
compare categorical data between the groups. To iden-
tify single variables associated with EOTVR, EOTHR,
EOTBR and SVR, univariate analyses were conducted by
logistic regression. Stepwise regression analyses with a
foreward variable selection were carried out to detect
factor combinations for the prediction of response to
anti-viral therapy.
All factors with a P-value of <0.05 were entered in
a stepwise logistic regression model, whereas all fac-
tors with a P-value of >0.10 were excluded from the
model. The significance of the logistic regression mod-
els was tested by using likelihood ratio of chi-squared
tests. To test the significance of each independent
variable in the stepwise logistic regressions, Wald tests
(IzI) were conducted. A two-tailed P-value of <0.05
was required for measuring statistical significance.
Statistics were performed using Intercooled STATA 9.1
(StataCorp LP, College Station, TX, USA).
RESULTS
Baseline features
From November 2001 to March 2005, 79 LT recipients
with recurrent hepatitis C infection in the allograft
were screened for eligibility criteria. A total of 46
patients did not qualify for anti-viral therapy; 17
patients were discarded due to anaemia and ⁄ or
thrombocytopenia and ⁄ or leucopoenia; three patients
showed histologically proven ductopenic rejection;
seven patients had biliary complications; one patient
revealed severe cardiovascular disease, two patients
had HBV coinfection, five were transplanted due to
concurrent causes of liver disease, four had renal fail-
ure and seven patients did not give their consent to
receive anti-viral therapy.
Furthermore, seven patients are still under anti-viral
therapy or have a follow-up period of <24 weeks and
were therefore excluded from the analysis. Thus, 26
patients were included in the present analysis.
Eleven patients (standard IFN group) were treated
with standard IFN-a2b plus RBV, the remaining 15
patients (PEG-IFN group) were treated with standard
IFN-a2b plus RBV during the first 3 months followed
by PEG-IFN-a2b plus RBV for the following 9 months.
Comparative analysis of the patients’ baseline charac-
teristics did not show statistically significant differences
between both groups (Table 1). The standard IFN and
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PEG-IFN groups consisted of patients with a mean age
of 56.4 � 5.7 years (range: 48–66) and 52.1 �6.9 years (range: 38–67). Eight of 11 patients (standard
IFN group) and 14 of 15 patients (PEG-IFN group) were
diagnosed with diabetes mellitus. Mycophenolate mofe-
til induction therapy directly after LT was administered
in the standard IFN group and PEG-IFN group in 55%
and 67%, whereas azathioprine induction therapy was
administered in four and three patients, respectively. All
patients received initial prednisone treatment for a
mean time period of 47.9 � 50.7 weeks and
40.8 � 22.4 weeks, respectively. Four vs. five patients
in the PEG-IFN group underwent previous corticosteroid
bolus therapy because of acute rejection. None of the
study patients had a history of chronic rejection. At the
onset of anti-viral therapy, immunosuppression consis-
ted of CSA monotherapy in the majority of patients,
while the remainders received TAC monotherapy. Liver
values are depicted in Table 1. Serum ALT values were
averaged more than two times than the UNL in 55% vs.
60% in the PEG-IFN group; cGT and AP were more than
two times than the UNL in three vs. two patients and in
none vs. one patient. In the standard IFN group, eight
patients were infected with genotype 1 and 3 with geno-
type 3, whereas 11 patients were infected with genotype
1, two with genotype 2, one with genotype 3 and one
with genotype 4 in the PEG-IFN group. Anti-viral ther-
apy after LT was started after a mean time period of
142 � 145 weeks (standard IFN group) and 151 �100 weeks (PEG-IFN group), respectively (P = 0.516).
Characteristics of the historic control group are
depicted in Table 1. There were no statistically signifi-
cant differences between the overall study population
(IFN group plus PEG-IFN group) and the historic con-
trol group as well as between the three distinct groups.
In the historic control group, the mean time period
between LT and ‘baseline’ biopsy (defined as the first
of the two consecutive graft biopsies) was comparable
with the mean time period between LT and the base-
line biopsy before onset of anti-viral therapy in the
study group (159 � 178 weeks vs. 147 � 119 weeks,
P = 0.67).
Table 1. Comparative analysis of the patients’ baseline characteristics
VariableIFN group(n = 11)
PEG-IFNgroup(n = 15) P-value
Overall studypopulation(n = 26)
Historiccontrol group(n = 38) P-value P-value**
Age at OLT (years) 56.4 � 5.7 52.1 � 6.9 0.10 53.9 � 6.7 54.8 � 10.8 0.49 0.35Recipient gender (male) 73% 93% 0.28 85% 73% 0.37 0.25Donor gender (male) 64% 73% 0.68 69% 61% 0.60 0.72Donor age (years) 37.4 � 17.1 33.7 � 14.2 0.56 35.3 � 15.3 37.0 � 14.4 0.59 0.73Pre-OLT anti-viral therapy 46% 40% 1.0 42% 34% 0.80 0.94HCV genotype 1 73% 73% 1.0 73% 76% 0.78 1.0BMI before therapy (kg ⁄ m2) 26.8 � 1.4 26.7 � 3.1 0.89 26.8 � 3.8 26.4 � 8.6 0.26 0.53HCV-RNA >1.5 · 106 IU ⁄ mLbefore therapy
64% 73% 0.49 69% 58% 0.44 0.59
Necroinflammatory score* 4.1 � 1.4 3.9 � 1.2 0.76 4.0 � 1.3 3.7 � 1.9 0.31 0.56Fibrosis score* 1.4 � 0.51 1.6 � 1.0 0.47 1.5 � 0.8 1.7 � 1.0 0.28 0.42Steatosis 46% 40% 1.0 42% 39% 1.0 0.94Baseline ALT >2 times the UNL 55% 60% 1.0 58% 50% 0.62 0.83Baseline bilirubin (mg ⁄ dL) 1.1 � 0.42 0.96 � 0.41 0.32 1.0 � 0.4 1.2 � 0.6 0.39 0.30Baseline creatinine (mg ⁄ dL) 1.2 � 0.25 1.2 � 0.19 0.68 1.2 � 0.2 1.1 � 0.5 0.43 0.14Ciclosporin ⁄ tacrolimusmonotherapy
9 ⁄ 2 11 ⁄ 4 1.0 20 ⁄ 6 27 ⁄ 11 0.78 0.92
Deceased ⁄ living donor 8 ⁄ 3 13 ⁄ 2 0.62 21 ⁄ 5 31 ⁄ 7 1.0 0.74
Values are expressed as mean � s.d. or percentages.IFN, interferon; PEG-IFN, pegylated IFN; OLT, orthotopic liver transplantation; BMI, body mass index; ALT, alanine amino-transferase.* According to the Ishak-modified HAI system; ** For comparison between the IFN group, PEG-IFN group and historic controlgroup.
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Efficacy
The virological and biochemical responses achieved in
the two treatment groups are illustrated in Figure 1.
Overall, there was no statistically significant difference
between the two treatment groups regarding the anti-
viral efficacy. The VEVR rates were observed as 45%
and 27% (P = 0.42) and the EVR rates were 73% and
53% (P = 0.43) in the standard IFN and the PEG-IFN
group, respectively. Likewise, the EOTVR rates (36%
vs. 40%) were not statistically significantly different
between the two groups. Three of four patients (stand-
ard IFN group) and four of six patients (PEG-IFN
group) who achieved EOTVR maintained viral
response. All patients with SVR were men with a mean
age of 55.4 � 6.0 years (range: 49–67) and all had
completed anti-viral therapy. The comparison between
the onset and end of anti-viral therapy revealed a
marked decrease of ALT values with normalization in
about 50% of patients in both groups. Two of three
sustained responders vs. two of four sustained
responders (PEG-IFN group) had EOTBR. Interestingly,
only one of three patients and one of four patients
with SVR had EOTHR in the standard IFN group and
PEG-IFN group, respectively. For both, the standard
IFN group and the PEG-IFN group, there was a slight
but not a significant improvement in the necroinflam-
matory activity (4.1 � 1.4 at onset of therapy vs.
3.2 � 1.6 at 12 months after start of therapy, P = 0.17
and 3.9 � 1.2 vs. 3.4 � 2.0, P = 0.37), and an increase
in the fibrosis score (1.4 � 0.51 vs. 2.1 � 0.83 and
1.6 � 1.0 vs. 2.7 � 1.5, P < 0.005 and P < 0.05). All
patients except one of each group who had EOTHR
had concomitant EOTBR. Figure 2 illustrates grading
and staging scores and histological response after
12 months of therapy.
Analysis of the histological course in thehistoric control group vs. the treatment group
For comparison of the historic control group with the
study population we merged the two treatment
groups.
In the historic control group, patients showed an
increase in the necroinflammatory score (3.7 � 1.9 vs.
4.8 � 3.4 after 12 months, P = 0.081), and a signifi-
cant increase in the fibrosis score (1.7 � 1.0 vs.
3.4 � 1.8 after 12 months, P < 0.001). To the contrary,
in the overall study population, the necroinflammatory
activity tended to improve upon anti-viral treatment
(4.0 � 1.3 vs. 3.3 � 1.8, P = 0.119). Improvement of
necroinflammatory activity occurred in 42% of study
patients vs. 11% of patients in the control group
(P = 0.006, Figure 3). Fibrosis was unchanged or
improved in 42% of treated patients vs. 21% of
patients in the control group (P = 0.096). Histological
improvement [grading score decrease (‡2 points) in
association with unchanged or improved fibrosis score,
defined as EOTHR in the study group] occurred in 27%
of treated patients vs. 5% of controls (P = 0.025).
Figure 1. Biochemical and virological response rates werenot statistically significantly different in the standardinterferon (IFN) group (n = 11) and the PEG-IFN group(n = 15), respectively (intention-to-treat analysis).
Figure 2. Improvement of necroinflammatory activityand staging score stabilization (unchanged or improvedfibrosis score according to the Ishak-modified HAI sys-tem) in the standard interferon (IFN) group and the PEG-IFN group, respectively. End of treatment histologicalresponse was detectable in 27% of patients in bothgroups.
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Safety: side effects, dose reduction andpremature withdrawal
No patient developed acute rejection during IFN ther-
apy and no patient began the anti-viral therapy within
the first 3 months post-LT. The most common side
effects during the first 12 weeks of therapy were influ-
enza-like symptoms, sleep disturbances, nausea, fati-
gue, myalgia and arthralgia. These adverse events
were not statistically significantly different between
both groups. None of our patients had to stop therapy
because of severe neuropsychiatric side effects and
none of them needed or required psychotropic medica-
tion.
The side effects between months 4 and 12 of therapy
are illustrated in Figure 4. Myalgia ⁄ arthralgia, pyrexia
and shortness of breath occurred more often in the PEG-
IFN group, whereas loss of appetite and nausea were
more often reported in the standard IFN group; these
differences, however, were not statistically significant.
Figure 3. Improvement of necroinflammatory activity andstaging score stabilization in the overall study populationand the historic control group, respectively. Histologicalimprovement was considered in those with improved nec-roinflammatory activity (decrease of ‡2 points) and con-comitant stabilization of fibrosis (unchanged or improvedstaging score).
Figure 4. The incidence andthe profile of side effectsbetween 4 and 12 months ofanti-viral therapy [standardinterferon (IFN) ⁄ RBV vs. PEG-IFN ⁄ RBV] were comparablebetween both study groups.
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During the first 3 months after onset of therapy,
anaemia (haemoglobin <13.5 g ⁄ dL) occurred in nine
and 13 patients, leucopoenia (<3000 ⁄ mm3) in eight
and 11 patients and thrombocytopenia (<80 000 ⁄ mm3)
in four and three patients in the standard IFN group
and the PEG-IFN group, respectively. In addition, dur-
ing this early study period, severe anaemia with hae-
moglobin values £10 g ⁄ dL was only detectable in two
patients (standard IFN group) and three patients (PEG-
IFN group), respectively, whereas severe leucopoenia
(<1500 ⁄ mm3) or thrombocytopenia (<50 000 ⁄ mm3)
was not detectable.
The haematological side effects between 4 and
12 months of anti-viral therapy encountered in both
study groups are depicted in Table 2. There was a signi-
ficant difference between the baseline values of blood
counts and values at the end of therapy in the standard
IFN group and the PEG-IFN group, respectively [haemo-
globin: 13.7 � 1.4 g ⁄ dL vs. 12.1 � 1.7 g ⁄ dL (P < 0.05)
and 14.4 � 1.3 g ⁄ dL vs. 11.6 � 1.2 g ⁄ dL (P < 0.001);
leucocytes: 4.7 � 1.2 ⁄ nL vs. 3.7 � 1.8 ⁄ nL (P < 0.05)
and 3.5 � 0.73 ⁄ nL vs. 2.9 � 0.17 ⁄ nL (P < 0.05), throm-
bocytes: 146 � 78.4 ⁄ nL vs. 126 � 76.8 ⁄ nL (P < 0.01)
and 168 � 52.1 ⁄ nL vs. 131 � 43.8 ⁄ nL (P < 0.01)]. The
incidence of IFN and RBV dose reduction was not statis-
tically significantly different between both groups. Dur-
ing the first 3 months, IFN was reduced to 25–50% in
five (standard IFN group) and four (PEG-IFN group)
patients, respectively (P = 0.42). During the following
9 months, reduced standard IFN and PEG-IFN were
administered in five and six patients (P = 1.00) and
RBV dose reduction (by 25–50%) was necessary in four
and five patients, respectively (P = 1.00). Discontinu-
ation of therapy was necessary in eight of 26 patients
(31%). The causes of treatment discontinuation were:
severe side effects [nausea and extensive weight loss
(n = 2), fatigue and shortness of breath (n = 2), depres-
sion (n = 1), confusion (n = 1), severe accentuation of
the psoriasis cutaneous lesions (n = 1)] and emigration
to the US (n = 1).
Predictive factors for anti-viral response
Univariate analysis showed a positive correlation
between SVR and HCV genotype non-1 and the pres-
ence of high ALT value (Table 3). The time period
between LT and the onset of anti-viral therapy was
negatively correlated with SVR. Analysing predictive
factors for response at the end of treatment, we found
a positive correlation between EOTVR and high base-
line ALT value, decrease of viral load ‡2 log at
1 month and presence of genotype non-1. Fifteen
patients had a BMI ‡25 kg ⁄ m2; the highest BMI value
was 34.7 kg ⁄ m2. The BMI value at baseline was a neg-
ative predictor for EOTHR. ALT >2 times the UNL was
associated with EOTBR, whereas previous bolus corti-
costeroid therapy and BMI ‡25 kg ⁄ m2 were negatively
correlated with biochemical response.
By the multivariate logistic regression analysis, a
high ALT value was identified as predictive of SVR
(Table 4). Furthermore, overweight (BMI ‡25 kg ⁄ m2)
was negatively associated with EOTBR, whereas an
elevated ALT value (more than two times the UNL)
positively predicted EOTVR. Histological response
upon the end of treatment was negatively associated
with BMI.
From those patients who had anti-viral therapy prior
to LT (n = 11), only one had completed pretransplant
anti-viral therapy with EOTVR but early relapse. In
our study, this patient had VEVR and EVR under
Table 2. Haematological sideeffects between 4 and12 months of anti-viraltherapy
VariableStandard IFN[n = 11; % (n)]
PEG-IFN[n = 15; % (n)] P-value
Anaemia (haemoglobin <13.5 g ⁄ dL) 81.8 (9) 100 (15) 0.17Haemoglobin 8–10 g ⁄ dL 36.4 (4) 33.3 (5) 1.0Repeated (>3·) erythropoietin use 36.4 (4) 33.3 (5) 1.0Leucocytes 1500–3000 ⁄ mm3 81.8 (9) 86.7 (13) 1.0Leucocytes <1500 ⁄ mm3 9.1 (1) 0.0 (0) 0.42Neutrophils <750 ⁄ mm3 9.1 (1) 20 (3) 0.61Repeated (>3·) G-CSF use 9.1 (1) 20 (3) 0.61Thrombocytes 50 000–80 000 ⁄ mm3 54.5 (6) 26.7 (4) 0.23Thrombocytes <50 000 ⁄ mm3 18.2 (2) 6.7 (1) 0.56
IFN, interferon; PEG-IFN, pegylated IFN; G-CSF, granulocyte colony-stimulating factor.
298 V . R . C IC INNAT I et al.
ª 2007 The Authors, Aliment Pharmacol Ther 26, 291–303
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IFN ⁄ RBV treatment, but decided to stop therapy
because of adverse events. All the other patients were
withdrawn from preoperative anti-viral drugs because
of non-response. By univariate analysis, we did not
find any correlation between SVR and anti-viral ther-
apy prior to LT.
DISCUSSION
Hepatitis C virus patients show accelerated rates of cir-
rhosis and graft loss from recurrent hepatitis C in the
medium- and long-term after LT.1, 19, 20 Although an
increasing number of transplant centres use anti-viral
regimens, treatment is not standardized and is often
associated with low response rates because of insuffi-
cient dosing and patient’s intolerance. Quantitative
analysis of published data suggest that approximately
24% of HCV transplant recipients treated with stand-
ard IFN ⁄ RBV and 27% of patients with PEG-IFN ⁄ RBV
obtain SVR.21 In a recently published study by Fern-
andez et al. 23% of patients administered PEG-
IFN ⁄ RBV achieved SVR.22 So far, the therapeutic
advantage of PEG-IFN is uncertain in the transplant
setting, because studies comparing standard IFN head-
to-head to PEG-IFN are limited.16, 23
This study has focused on the efficacy, the safety
and potential predictive factors of response to anti-
viral therapy in patients with HCV recurence after LT.
In contrast to previous studies referring to a thrice
weekly dosing of standard IFN, we chose to administer
standard IFN daily to obtain a more favourable phar-
macokinetic profile. Moreover, in the PEG-IFN group,
the initial treatment during the first 3 months was per-
formed with standard IFN for safety reasons and even-
tually faster dose adjustment in case of adverse effects.
However, this approach limits the direct comparison of
the efficacy of standard IFN vs. PEG-IFN therapy.
During the early treatment period, we found that the
percentage of patients with at least a 2 log10 decrease
of viral load was similar in both groups. Likewise, the
EOTVR (36% vs. 40%) and SVR (27% vs. 27%) were
not statistically significantly different in the standard
IFN group and the PEG-IFN group, respectively, and
sustained response rates are similar to those reported
in the literature.8, 23
The most important determinant of prognosis is the
impact of anti-viral treatment on fibrosis. We com-
pared the histological course of the study population
with an untreated historic control group. We found
that the percentage of patients with histological
Table 4. Relation between EOTVR, EOTBR, EOTHR, SVRand baseline characteristics by multivariate analysis (onlysignificant variables shown)
Variables Odds ratio P > IzI
95%confidencelimits P > v2
EOTVRALT >2· UNL 15 0.021 1.5–149 0.0054
EOTBRBMI ‡25 kg ⁄ m2 0.08 0.010 0.01–0.55 0.0042
EOTHRBMI 0.6 0.048 0.4–1.0 0.0075
SVRALT 1.8 0.028 1.1–3.0 0.0037
EOTVR, end of treatment virological response; ALT, alanineaminotransferase; EOTBR, end of treatment biochemicalresponse; BMI, body mass index; EOTHR, end of treatmenthistological response; SVR, sustained virological response.
Table 3. Relation between EOTVR, EOTBR, EOTHR, SVRand patients’ characteristics by univariate analysis (onlysignificant variables shown)
Variables v2 P > v2Oddsratio
95%confidencelimits
EOTVRALT >2· UNL 7.8 0.0054 15 1.5–149ALT 7.6 0.0057 1.7 1.1–2.8Decrease of viral load‡2 log at month 1
4.6 0.0313 6.5 1.1–38.6
Genotype non-1 4.4 0.0366 7.0 1.0–48.3EOTBR
BMI ‡25 kg ⁄ m2 8.2 0.0042 0.08 0.01–0.55ALT >2· UNL 4.1 0.0440 5.3 0.97–29.3Previous boluscorticosteroid therapy
3.9 0.0470 0.19 0.04–1.0
EOTHRBMI 7.2 0.0075 0.62 0.39–1.0
SVRALT 8.5 0.0037 1.8 1.1–3.0Genotype non-1 4.2 0.0415 7.1 1.0–49.5Time period betweenOLT and start of IFNtherapy
5.6 0.0177 0.99 0.99–1.0
EOTVR, end of treatment virological response; ALT, alanineaminotransferase; EOTBR, end of treatment biochemicalresponse; BMI, body mass index; UNL, upper normal limit;EOTHR, end of treatment histological response; SVR, sus-tained virological response; IFN, interferon.
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improvement within 12 months was significantly
higher in the study population when compared to the
untreated controls.
As in the non-transplant setting, clinical and histo-
logical improvement may occur even when viral clear-
ance is not achieved. On the other hand, even in the
presence of SVR, necroinflammation may persist and
fibrosis may remain unchanged or worsen in a sub-
group of patients. A recently published study inclu-
ding 29 patients achieving SVR reported progression
of fibrosis in one-third of patients at 2 years.24 In
another study, sustained responders had a significant
improvement in their liver inflammatory activity score,
but not in their fibrosis score.25 Furthermore, several
studies reported that inflammation and fibrosis
improved in viral non-responders.26, 27
In our study, four of seven (57%) patients with SVR
had improvement in their inflammatory activity, but
only two (29%) of them had an improved or at least
unchanged fibrosis score 12 months after the onset of
therapy. The latter had EVR with no detectable HCV-
RNA in the quantitative HCV-RNA assay after
3 months and concomitant EOTBR. Patients without
SVR had declined inflammation grade in only 37%
(seven of 19) but an improved ⁄ maintained fibrosis
score in 47% (nine of 19). Thus, our data and the
results from previous studies suggest that the
antifibrotic effects of IFN may be independent of its
anti-viral activity.27 The lacking association between
sustained viral clearance and histological response
might also be explained either by (i) other mechanisms
of hepatic injury (e.g. calcineurin inhibitor (CNI)- or
autoimmune-related toxicity and biliary complications)
or (ii) a longer time period until fibrosis regression
occurs in the allograft. Patients with failure to eradicate
HCV but histological response in serial biopsies may
though benefit from IFN therapy. Therefore, we offer
this subgroup of patients a low-dose maintenance
PEG-IFN monotherapy upon completion of this study.
To date, little information has been published about the
histological outcome and viral clearance in the long-
term after IFN therapy. In our study, we followed up
five of seven SVR patients. All these patients remained
HCV-RNA-negative and none developed cirrhosis
within a median post-treatment follow-up period of
37 months. Serial liver biopsies revealed an unchanged
fibrosis and inflammatory activity score in all patients
except one who had progression of fibrosis by 1 point.
Treatment of recurrent HCV infection is complicated
by the lower patient tolerability necessitating frequent
dose adjustment, adjuvant growth factors or treatment
discontinuation.28 A remarkable part of our patients
developed constellations of depression-related symp-
toms (irritability, sleep disturbances, fatigue, loss of
appetite and anxiety) without also reporting significant
sadness, hopelessness, guilt or loss of pleasure in life.
The reasons for these missing findings can only be
speculative and may include the initial dosing regimen
for standard IFN (daily low-dose instead of thrice
weekly), the exclusion of vulnerable psychiatric
patients and meticulous provision of potential coping
strategies and support systems. During therapy, IFN
dose reduction was mandatory in 45% and 40% of the
patients in the standard IFN and the PEG-IFN groups,
respectively. In our study, withdrawal from therapy
became essential in 31% of patients due to severe side
effects. Published standard IFN ⁄ RBV or PEG-IFN ⁄ RBV
combination studies report discontinuation rates
between 18% and 63% compared to about 10% in
immunocompetent patients.8, 29 Toniutto et al.16 found
that treatment with PEG-IFN was associated more fre-
quently with dosage reduction and withdrawal of ther-
apy when compared to unmodified IFN (92% vs. 50%).
The differences were mainly due to haematological
side effects. However, in our study, as in most non-
transplant studies, the adverse event profile of
unmodified IFN was similar to that of PEG-IFN.30, 31
None of our patients discontinued prematurely because
of haematological side effects as cytopenia could be
successfully treated with EPO and ⁄ or G-CSF. Treat-
ment with growth factors increases the costs and com-
plexicity of therapy but seems to be inevitable in the
LT setting to improve treatment adherence rates, and
thus an increase in the anti-viral therapeutic efficacy.
The identification of pretreatment variables for the
prediction of anti-viral response may help to develop
patient selection algorithms to (i) identify patients who
may have benefit from therapy and (ii) avoid ineffi-
cient treatment. Thus, possible recipient-, host- and
virus-related predictive factors were analysed in this
study. In non-immune compromised patients, increas-
ing evidence has shown that HCV genotype, low viral
load, adherence to therapy and combined IFN ⁄ RBV
therapy are the most important factors influencing
the success of anti-viral therapy.32–35 In our study, the
decrease of viral load ‡2 log at 1 month but not the
baseline HCV-RNA titre was associated with EOTVR.
Conflicting results do exist in the literature about the
predictive value of baseline HCV on viral response in
transplant recipients.17, 18, 27, 36 Therefore, larger trials
300 V . R . C IC INNAT I et al.
ª 2007 The Authors, Aliment Pharmacol Ther 26, 291–303
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need to be conducted to further elucidate the influence
of baseline HCV-RNA on viral response.
In our study, HCV genotype non-1 was identified
as a predictive factor for EOTVR as well as SVR to
IFN treatment. This was reflected by a sustained
response rate of only 21% in patients with genotype
1 vs. 71% in those with other genotypes. Several
studies in the non-transplant setting have demonstra-
ted that HCV genotype 1 correlated with high viral
titres in serum.32, 37 In our study, the baseline viral
load was higher in genotype 1 hepatitis C-infected
patients when compared to those with other geno-
types; this difference, however, was not statistically
significant.
There is ongoing discussion if the type of calcineu-
rin inhibitor impacts the outcome of therapy. Interest-
ingly, a recently published Spanish group found an
almost significantly better effect of TAC on SVR when
compared to CSA.36 Other studies have reported that
CSA suppresses HCV in cell cultures;38, 39 however, it
has been shown that the results from in vitro experi-
ments can not to be necessarily transferred into the
clinical setting.40, 41 In a previously published report
from our transplant centre42 and in this present study,
no significant differences between TAC and CSA
monotherapy with regard to post-transplant viral load
and to viral response upon IFN treatment became evi-
dent. Our findings are concordant with results from
recent studies by Berenguer et al. and Murkherjee
et al. 27, 43
The optimal time point of initiation of anti-viral
therapy after LT has not been determined yet. A
recently published study including patients after at
least 12 months of LT reported the best outcome upon
2–4 years after LT.36 Our study consisted of patients
who received anti-viral therapy after a median time of
2.3 years (range: 4.3 months to 9.3 years) after LT. We
found a negative correlation between the length of
time between LT and the sustained response to IFN
therapy.
In this study, half of the patients experienced a bio-
chemical response to anti-viral therapy. Baseline ALT
values were observed to be more than two times the
UNL in 58% of patients (range: normal to 12 times the
UNL) and, as among immunocompetent patients,6, 44
the presence of high ALT values was predictive of SVR
by univariate and multivariate regression analysis.
In immune competent patients, it has been shown
that a high BMI may be associated with lower biologi-
cal response rates to IFN.45–47 This is in line with our
data demonstrating that patients with normal BMI
(<25 kg ⁄ m2) had a greater likelihood of EOTBR and
EOTHR. Pharmacological effect of IFN on the induc-
tion of 2,5¢-oligoadenylatesynthetase, a key enzyme in
the IFN-elicited anti-viral response, has been shown to
be reduced in obese patients;48 moreover, initial
absorption of subcutaneously administered IFN may be
impaired in high abdominal fat mass thus contributing
to low response rates in this patient group.
In conclusion, based on the results of this prospect-
ive trial, daily standard IFN ⁄ RBV as well as daily
standard IFN ⁄ RBV followed by PEG-IFN ⁄ RBV therapy
are comparable in their safety and efficacy profiles.
Furthermore, this study shows a histological benefit in
patients with anti-viral treatment when compared to
untreated controls. Growth factors should be used
more amply to ensure adequate anti-viral drug dosing.
Histological response rather than SVR may be consid-
ered as primary end point of IFN treatment. Serial
biopsies under therapy and prolonged histological fol-
low-up investigations are necessary to determine the
progression of fibrosis following post-transplant anti-
viral therapy. Recommendations regarding appropriate
patient selection in the LT setting remain problematic.
Several pretreatment variables have been associated
with response or non-response to anti-viral treatment.
These parameters may facilitate in providing advice to
patients and in the estimation of the risk-benefit of
anti-viral therapy. However, variables associated with
viral response still vary between studies and yet, none
of these factors has proven to be sufficiently reliable
to allow exclusion of a transplant patient from IFN
therapy.
ACKNOWLEDGEMENTS
Authors’ declaration of personal interests: None.
Declaration of funding interests: This study was funded
by Essex Pharma GmbH, Munich, Germany (PO4203),
ID number 00-164-1519Z.
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