Ribavirin with either standard or pegylated interferon to treat recurrent hepatitis C after liver...

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


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.

I FN-a ⁄ RIBAVIR IN THERAPY AFTER L IVER TRANSPLANTAT ION 293



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




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.




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.




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.




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.




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.




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




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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