Original paper
8
Combined interferon-alpha-2b and ribavirin therapy
in patients with recurring chronic hepatitis C (genotype 1)
following liver transplantation in Hungary
Gabriella Lengyel1, László Kóbori2, Imre Fehérvári2, Balázs Nemes2, Dénes Görög2, Attila Patonai1,
Enikö Sárváry2, Marina Varga2, Krisztina Hagymási1, Ferenc Perner2, János Fehér1, Zsolt Tulassay1, 3
12nd Department of Medicine, Medical Faculty, Semmelweis University, Budapest, Hungary
2Department
of Transplantation Surgery, Medical Faculty, Semmelweis University,
Budapest, Hungary
3Research Department of Gastroenterology and Endocrinology of Hungarian Academy of
Sciences, Budapest, Hungary
Submitted: 1 March 2005
Accepted: 4 April 2005
Arch Med Sci 2005; 1, 1: 8-12
Abstract
O b j e c t i v e s : Hepatitis C virus (HCV) recurrence after liver transplantation is
universal and leads to chronic hepatitis and cirrhosis. Combined interferon and
ribavirin therapy represents the accepted treatment for recurrent chronic hepatitis
C following liver transplantation, according to the literature. Our aim was to
assess the efficacy and safety of the recommended combined interferon and
ribavirin therapy, and evaluation of the rate of long-term remission under
Hungarian circumstances.
Methods: 16 patients with chronic recurrent hepatitis C, who had been HCV-PCR
positive (genotype 1b), received combined treatment with interferon-alpha-2b (3
MU three times a week) and ribavirin (800-1000 mg daily) for 12 months following
transplantation. 12 patients have completed the therapy. Liver biopsies were
performed before commencing and after concluding treatment in every patient.
Virological responses at completion of the 12-month-long treatment and at the
end of the subsequent 6-month-long follow-up period served as endpoints for
the evaluation.
Results: At completion of the 12-month-long treatment 3 patients became HCVPCR-negative. All three patients remained negative at six months following
completion of the treatment.
C o n c l u s i o n s : Efficacy and safety of the combined treatment of transplanted
patients were similar to the therapeutic results in patients with chronic hepatitis
C without liver transplantation.
Key words: chronic hepatitis C, interferon, ribavirin, liver transplantation.
Introduction
There is no sure therapeutic method for the elimination of hepatitis C
virus (HCV) from the human organism. In chronic hepatitis C, elimination of
the virus can be attained with long-term interferon treatment in about 1020% [1, 2, 3], with combined interferon and ribavirin treatment in 20-40%
[1, 4-7], and with pegylated interferon and ribavirin therapy in 40-60% [8, 9]
of the cases. The therapy is more effective in viral genotypes 2 and 3, while
it confers less benefit on genotypes 1 and 4. If elimination of the virus is not
Corresponding author:
Gabriella Lengyel, MD PhD
H-1088 Budapest
Szentkirályi u. 46, Hungary
Phone/fax: 0036 1 317 45 48
E-mail: feher@bel2.sote.hu
Combined interferon and ribavirin treatment in recurring chronic hepatitis C following liver transplantation
possible, end-stage hepatic cirrhosis develops in
patients with chronic hepatitis C. In this case, an
improvement of the patient’s state can only be
assured by liver transplantation.
After transplantation, however, HCV infection
usually returns almost in every case, if the patient
could not be made virus-free previously [10]. Antiviral
therapy is recommended in patients on the waiting
list, even with uncompensated cirrhosis [11]. In
transplanted patients, de novo HCV infection is very
rare due to the regular screening for HCV [12]. The
course of recurrent hepatitis C infection is shown in
figure 1. The severity of the disease is influenced by
several factors [10]. These may be related to viral
characteristics (number of viruses, viral genotype),
may depend on the donor (age, sex, sexual
relations), may be consequences of the surgical
intervention (warming, duration of ischemia), or
properties of the recipient (HLA, state of the immune
system), as well as changes developing because of
external factors (immunosuppressive treatment,
alcohol, concomitant viral infection, years passed
after transplantation, and antiviral therapy).
In this report we have collected our experiences
obtained during the treatment at the 2nd Department
of Medicine of patients with chronic recurrent
hepatitis C, who underwent liver transplantation at
the Department of Transplantation Surgery of the
Semmelweis University, Budapest.
Materials and methods
16 patients of both sexes (10 male and
6 female), aged between 36 and 63 years (mean
Table I. Baseline values of patients receiving
combined therapy
Number of patients
12
Male/female
8/4
Mean age
45.1 (36-63) years
Number of rejections
before treatment
3
Genotype 1b
12
Mean ALT
159.1 U/L
Mean bilirubin
32.0 µmol/L
Mean HCV-RNA
450 copies/mL (145-1800)
Mean staging score
1.91
Mean grading score
8.27
Mean hemoglobin
140 g/L
Mean platelet count
156x109/L
Mean leucocyte count
4.925 x109/L
Average time lag after liver
transplantation before
the start of the treatment
14.3 (3-36) months
age: 45.1 years), and suffering from chronic
hepatitis C have been enrolled. The diagnosis was
established by the clinical symptoms, on the base
of the serum alanin-aminotransferase (ALT)
activity, the molecular markers of HCV infection
(anti-HCV-positive state, HCV-RNA test), as well as
the histological examination of the liver (Knodellindex). All patients carried the genotype 1b of HCV.
End stage liver disease caused by HCV infection
is the indication of liver transplantation in 35-50% of the cases
Liver transplantation
Recurrent infection is more than 98%
Follow-up for 1-13 months
Acute hepatitis: 25-45%
Factors related
to the virus
Follow-up for 5 years
• HCV induced chronic hepatitis: 80-100%
• Graft cirrhosis related to HCV: 80-30%
• Cholestatic hepatitis: 2-8%
Donor
characteristics
Surgical
factors
Factors
related
to the host
External
factors
Figure 1. Natural course of hepatitis C following liver transplantation
Arch Med Sci, 1 April / 2005
9
Gabriella Lengyel, László Kóbori, Imre Fehérvári, Balázs Nemes, Dénes Görög, Attila Patonai, Enikö Sárváry,
Marina Varga, Krisztina Hagymási, Ferenc Perner, János Fehér, Zsolt Tulassay
Interferon-ribavirin
350
Follow-up
300
U/L
250
200
150
100
50
0
0.
3.
6.
9.
12.
15.
18.
months
* sign. vs. 0. month
Figure 2. Changes in the activities of alanine-aminotransferase during combined interferon-ribavirin
treatment and in the follow-up period
Interferon-ribavirin
250
Follow-up
U/L
200
150
100
50
0
0.
3.
6.
9.
12.
15.
18.
months
* sign. vs. 0. month
Figure 3. Changes in the activities of aspartate-aminotransferase during combined interferon-ribavirin
treatment and in the follow-up period
Baseline data of the treated patients are shown in
Table I.
According to the protocol of the clinical treatment,
the interferon-alpha-2b product (Intron A,
Schering-Plough, Co.) was administered three times
a week, in a dose of 3.0 MU, in subcutaneous
injections; and ribavirin (Rebetol, Schering-Plough,
Co.) was given orally in a daily dose of 800-1000 mg,
depending on the body mass. Duration of the
treatment was one year, and the follow-up period
lasted for further 6 months. Four patients were
withdrawn from the study due to adverse effects,
mainly for severe anemia. Reduction in the dose of
ribavirin in 3 of 12 cases was due to the onset of
anemia.
Clinical and laboratory examinations of the
patients were performed at 1, 2, 4, 6, and 8 weeks
after enrollment into the program, then in every
month. Follow-up observations were performed after
completion of the treatment, at three months’
intervals. Data of the treatment period and values
obtained at six months after completion of the
treatment were taken into consideration for the
evaluation. For data processing, in addition to the
10
clinical symptoms, values of serum ALT activity, the
result of the HCV-PCR test, and the histology of the
liver biopsy performed at completion of the
treatment were also taken into consideration. For
details of the methods of examination, we refer to
our previous publication [6]. Patients were informed
on the particulars of the therapy before treatment,
and they gave a written informed consent to the
medicinal therapy in advance.
Data were analyzed by statistical methods (paired
t-test). Data are expressed as mean ±SEM. P<0.05
was considered to indicate statistical significance.
Results
Three patients of the 12 were sustained
responders, 7 patients gave a partial response, and
2 patients did not respond to the treatment
(non-responders). Mild-moderate side effects, not
necessitating cessation of the treatment, were
observed in 6 cases. Most adverse reactions
consisted of flu-like complaints (headache,
weakness, muscle pain, and fever), and in individual
cases moderate leucopoenia, thrombocytopenia,
and hemolysis of moderate degree occurred as
undesired effects.
The level of the serum ALT decreased significantly
in comparison to the baseline, usually after a few
weeks of treatment; it often reached normal values
(Figure 2), and the main ALT value remained at this
level until completion of the treatment. During the
follow-up period, at the 3 months’ control the main
value increased significantly, but it was considerably
lower that at baseline, and at the 6 months’ control
we found also a reduced ALT activity. Serum
aspartate-aminotransferase (AST) showed essentially
similar changes (Figure 3). Gamma-glutamyl-transpeptidase (GGT) values were scattered significantly,
being unsuitable for drawing definite conclusions.
Serum bilirubin level was higher than normal at
baseline, and during the treatment, while varying, but
it usually was lower than at baseline. At six months
after completion of the treatment these data were
found in the normal range (Figure 4).
HCV-RNA studies gave negative results in 3 cases
at completion of the treatment, and the same was
observed at 6 months’ follow-up. In these cases ALT
values were completely normal during the whole
period studied. No rejection occurred in these patients.
In seven cases the HCV-PCR examination remained
positive both at completion of treatment, and at the
6 months’ follow-up, although the viral titer was
reduced significantly in comparison to the baseline.
The activities of ALT were in all cases lower than the
baseline data. Two patients were non-responders.
Histological examination showed a close
correlation with the HCV-RNA and ALT values. In the
three patients with full response the findings of the
control liver biopsy were negative, and in the
Arch Med Sci, 1 April / 2005
Combined interferon and ribavirin treatment in recurring chronic hepatitis C following liver transplantation
In case of an infection with the hepatitis C virus,
chronic hepatitis develops in 85% of the patients, and
it transforms into liver cirrhosis in half of the cases in
spite of the standard treatment with combined
interferon and ribavirin treatment. In the end stage
of the disease, liver transplantation may be the
therapeutic modality. However, within 3-36 months
after liver transplantation in a great part of the
patients – if previous elimination of the virus has not
been attained – acute hepatitis C develops that
becomes chronic in most instances. If the patient
received an antiviral treatment before transplantation
leading to the elimination of the virus, no recurrent
hepatitis develops [10]. The literary data vary
concerning the efficacy of combined interferon and
ribavirin treatment in patients with chronic recurrent
hepatitis after liver transplantation [13-15]. Long-term
complete response, with regard to all genotypes,
usually can be seen in about 21% of the cases after
liver transplantation, like in chronic hepatitis C [16].
In a greater study, complete response was found in
43% of HCV genotype 2-3, and in 12% of genotype
1 following conventional antiviral therapy [7]. In our
current report, all patients carried the virus with
genotype 1. Sustained response was observed in
3 cases out of 12 patients, that is a slightly better rate
than that usually found in the literature. In Hungary,
Telegdy et al. [17] reported their experience concerning
the treatment of a patient with chronic hepatitis C,
who underwent liver transplantation. After 6 months’
treatment with combined interferon and ribavirin
therapy they found a permanently low viral titer and
normal ALT values with a mild hepatic fibrosis, even
at 18 months after the liver transplantation.
In the treatment of chronic hepatitis C the most
recent therapy is the administration of the pegylated
interferon once a week, together with ribavirin
treatment [8, 9]. There are two different forms of
pegylated interferon, a product with a molecular
weight of 12 kD (Pegintron – Schering-Plough), and
another with that of 40 kD (Pegasys – Roche).
Combined treatment with pegylated interferon and
ribavirin in chronic hepatitis C is much more
effective; a success rate of up to 75-80% in genotype
2-3, and 65-70% in genotype 1 can be attained.
A complete response in 40% is possible even in cases
with fibrosis of significant degree [8, 9]. This newer
combination can be supposed to be more effective
in chronic recurring hepatitis C following liver
transplantation, as well [18, 19].
On the basis of data in the literature and our own
observations, we consider the combined inter-
Arch Med Sci, 1 April / 2005
Follow-up
60
umol/L
Discussion
Interferon-ribavirin
70
50
40
30
20
10
0
0.
3.
6.
9.
12.
15.
18.
months
* sign. vs. 0. month
Figure 4. Changes in the bilirubin levels during
combined treatment and thereafter
9
8
7
score
remaining cases we observed an improvement in
the Knodell-index, that is, the grading score was
significantly reduced, while the staging score
remained unchanged (Figure 5).
6
5
4
3
2
1
0
grade
before treatment
stage
after treatment
* sign. vs. before treatment
Figure 5. Changes in the index of histological activity
(Knodell) index during the treatment
feron-ribavirin treatment is advisable in chronic viral
hepatitis C in the case of HCV recurrence following
liver transplantation, even, if a complete remission
can only be observed at a relatively low rate. Based
on the most recent experiences, the combination of
pegylated interferon and ribavirin therapy could be
the treatment modality of choice also in patients, who
underwent liver transplantation.
Re f e r e n c e s
1. Keeffe EB, Hollinger B and the Consensus Interferon Study
Group. Therapy of hepatitis C: Consensus Interferon Trials.
Hepatology 1997; 26 (suppl. 1): 101-10.
2. Ouzan D, Babany G, Valla D, Opolon P. Comparison of high
initial and fixed-dose regimens of interferon-alpha-2a in
chronic hepatitis C: a randomized controlled trial. J Viral
Hepatitis 1998; 5: 53-9.
3. Poynard T, Leroy V, Cohard M, Cohard M, Opolon P, Zarski
JP. Meta-analysis of interferon randomized trials in the
treatment of viral hepatitis C: Effects of dose and duration.
Hepatology 1996; 24: 778-89.
4. Bizollon T, Palazzo U, Ducerf C, Chevallier M, Elliott M,
Baulieux J et al. Pilot study of the combination of interferon
alfa and ribavirin as a therapy of recurrent hepatitis C after
liver tansplantation. Hepatolog, 1997; 26: 500-4.
11
Gabriella Lengyel, László Kóbori, Imre Fehérvári, Balázs Nemes, Dénes Görög, Attila Patonai, Enikö Sárváry,
Marina Varga, Krisztina Hagymási, Ferenc Perner, János Fehér, Zsolt Tulassay
5. Brown JL. Efficacy of combined interferon and ribavirin for
treatment of hepatitis C. Lancet 1998; 351: 78-9.
6. Fehér J, Lengyel G, Bálint T. The combined interferon-alfa2b and ribavirin treatment in chronic hepatitis C.
Observations in 100 patients treated for one year. Orv Hetil
(Hung Med J) 1999; 140: 1235-8.
7. McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee
WM, Rustgi VK et al. Hepatitis Interventional Therapy
Group. Interferon alfa-2b alone or in combination with
ribavirin as initial treatment for chronic hepatitis C. N Eng
J Med 1999; 33: 1485-92.
8. Manns MP, McHutchison JG, Gordon SC, Rustgi VK,
Shiffman M, Reindollar R et al. Peginterferon alpha-2b plus
ribavirin compared with interferon alpha-2b plus ribavirin
for initial treatment of chronic hepatitis C: a randomised
trial. Lancet 2001; 358: 958-65.
9. Zeuzem S, Feinman SV, Rasenack J, Heathcote EJ, Lai MY,
Gane E et al. Peginterferon alfa-2a in patients with chronic
hepatitis C. N Eng J Med 2000; 343: 1666-72.
10. Berenguer M, Lopez-Labrador FX, Wright TL. Hepatitis C
and liver transplantation. J Hepatol 2001; 35: 666-78.
11. Forns X, Garcia-Retortillo M, Serrano T, Feliu A, Suarez F, de
la Mata M et al. Antiviral therapy of patients with
decompensated cirrhosis to prevent recurrence of hepatitis
C after liver transplantation. J Hepatol 2003; 39: 389-96.
12. Prieto M, Berenguer M, Rimola A, Loinaz C, Barrios C,
Clemente G et al. Liver transplantation in hepatitis C.:
a Spanish multicenter experience. Eur J Gastroeneterol
Hepatol 1998; 10: 771-6.
13. Lavezzo B, Franchello A, Smedile A, David E, Barbui A, Torrani
M et al. Treatment of recurrent heaptitis C in liver transplants:
efficacy of a six versus a twelve month course of interferon
alfa 2b with ribavirin. J Hepatol 2002; 37: 247-52.
14. Mazzaferro V, Regalia E, Pulvirenti A, Tagger A, Andreola S,
Pasquali M et al. Prophylaxis against HCV recurrence after
liver transplantation. Effect of interferon and ribavirin
combination. Transpl Proc 1997; 29: 519-21.
15. Schirren CA, Zachoval R, Gerlach JT, Ulsenheimer A, Gruener
NH, Diepolder HM et al. Antiviral treatment of recurrent
hepatitis C virus (HCV) infection after liver transplantation:
association of a strong, multispecific, and long lasting CD4+
T cell response with HCV-elimination. J Hepatol 2003; 39:
397-404.
16. Samuel D, Bizollon T, Feray C, Roche B, Ahmed SN,
Lemonnier C et al. Interferon-alpha 2b plus ribavirin in
patients with chronic hepatitis C after liver transplantation:
a randomized study. Gastroenterol 2003; 124: 642-650.
17. Telegdy L, Görög D, Horányi M, Schaff Zs. Severe relapse of
hepatitis C following liver transplantation. Successful
treatment with a combination of interferon-alpha +
ribavirin. Orv Hetil (Hung Med J) 1999; 140: 1891-3.
18. Dumortier J, Scoazec JY, Chevallier P, Boillot O. Treatment
of recurrent hepatitis C after liver transplantation: a pilot
study of peginterferon alfa-2b and ribavirin combination.
J Hepatol 2004; 40: 669-674.
19. Rodriguez-Luna H, Khatib A, Sharma P, De Petris G,
Williams JW, Ortiz J et al. Treatment of recurrent hepatitis
C infection after liver transplantation with combination of
pegylated interferon alpha2b and ribavirin: an open-label
series. Transplantation 2004; 77: 190-194.
12
Arch Med Sci, 1 April / 2005
Original paper
8
Combined interferon-alpha-2b and ribavirin therapy
in patients with recurring chronic hepatitis C (genotype 1)
following liver transplantation in Hungary
Gabriella Lengyel1, László Kóbori2, Imre Fehérvári2, Balázs Nemes2, Dénes Görög2, Attila Patonai1,
Enikö Sárváry2, Marina Varga2, Krisztina Hagymási1, Ferenc Perner2, János Fehér1, Zsolt Tulassay1, 3
12nd Department of Medicine, Medical Faculty, Semmelweis University, Budapest, Hungary
2Department
of Transplantation Surgery, Medical Faculty, Semmelweis University,
Budapest, Hungary
3Research Department of Gastroenterology and Endocrinology of Hungarian Academy of
Sciences, Budapest, Hungary
Submitted: 1 March 2005
Accepted: 4 April 2005
Arch Med Sci 2005; 1, 1: 8-12
Abstract
O b j e c t i v e s : Hepatitis C virus (HCV) recurrence after liver transplantation is
universal and leads to chronic hepatitis and cirrhosis. Combined interferon and
ribavirin therapy represents the accepted treatment for recurrent chronic hepatitis
C following liver transplantation, according to the literature. Our aim was to
assess the efficacy and safety of the recommended combined interferon and
ribavirin therapy, and evaluation of the rate of long-term remission under
Hungarian circumstances.
Methods: 16 patients with chronic recurrent hepatitis C, who had been HCV-PCR
positive (genotype 1b), received combined treatment with interferon-alpha-2b (3
MU three times a week) and ribavirin (800-1000 mg daily) for 12 months following
transplantation. 12 patients have completed the therapy. Liver biopsies were
performed before commencing and after concluding treatment in every patient.
Virological responses at completion of the 12-month-long treatment and at the
end of the subsequent 6-month-long follow-up period served as endpoints for
the evaluation.
Results: At completion of the 12-month-long treatment 3 patients became HCVPCR-negative. All three patients remained negative at six months following
completion of the treatment.
C o n c l u s i o n s : Efficacy and safety of the combined treatment of transplanted
patients were similar to the therapeutic results in patients with chronic hepatitis
C without liver transplantation.
Key words: chronic hepatitis C, interferon, ribavirin, liver transplantation.
Introduction
There is no sure therapeutic method for the elimination of hepatitis C
virus (HCV) from the human organism. In chronic hepatitis C, elimination of
the virus can be attained with long-term interferon treatment in about 1020% [1, 2, 3], with combined interferon and ribavirin treatment in 20-40%
[1, 4-7], and with pegylated interferon and ribavirin therapy in 40-60% [8, 9]
of the cases. The therapy is more effective in viral genotypes 2 and 3, while
it confers less benefit on genotypes 1 and 4. If elimination of the virus is not
Corresponding author:
Gabriella Lengyel, MD PhD
H-1088 Budapest
Szentkirályi u. 46, Hungary
Phone/fax: 0036 1 317 45 48
E-mail: feher@bel2.sote.hu
Combined interferon and ribavirin treatment in recurring chronic hepatitis C following liver transplantation
possible, end-stage hepatic cirrhosis develops in
patients with chronic hepatitis C. In this case, an
improvement of the patient’s state can only be
assured by liver transplantation.
After transplantation, however, HCV infection
usually returns almost in every case, if the patient
could not be made virus-free previously [10]. Antiviral
therapy is recommended in patients on the waiting
list, even with uncompensated cirrhosis [11]. In
transplanted patients, de novo HCV infection is very
rare due to the regular screening for HCV [12]. The
course of recurrent hepatitis C infection is shown in
figure 1. The severity of the disease is influenced by
several factors [10]. These may be related to viral
characteristics (number of viruses, viral genotype),
may depend on the donor (age, sex, sexual
relations), may be consequences of the surgical
intervention (warming, duration of ischemia), or
properties of the recipient (HLA, state of the immune
system), as well as changes developing because of
external factors (immunosuppressive treatment,
alcohol, concomitant viral infection, years passed
after transplantation, and antiviral therapy).
In this report we have collected our experiences
obtained during the treatment at the 2nd Department
of Medicine of patients with chronic recurrent
hepatitis C, who underwent liver transplantation at
the Department of Transplantation Surgery of the
Semmelweis University, Budapest.
Materials and methods
16 patients of both sexes (10 male and
6 female), aged between 36 and 63 years (mean
Table I. Baseline values of patients receiving
combined therapy
Number of patients
12
Male/female
8/4
Mean age
45.1 (36-63) years
Number of rejections
before treatment
3
Genotype 1b
12
Mean ALT
159.1 U/L
Mean bilirubin
32.0 µmol/L
Mean HCV-RNA
450 copies/mL (145-1800)
Mean staging score
1.91
Mean grading score
8.27
Mean hemoglobin
140 g/L
Mean platelet count
156x109/L
Mean leucocyte count
4.925 x109/L
Average time lag after liver
transplantation before
the start of the treatment
14.3 (3-36) months
age: 45.1 years), and suffering from chronic
hepatitis C have been enrolled. The diagnosis was
established by the clinical symptoms, on the base
of the serum alanin-aminotransferase (ALT)
activity, the molecular markers of HCV infection
(anti-HCV-positive state, HCV-RNA test), as well as
the histological examination of the liver (Knodellindex). All patients carried the genotype 1b of HCV.
End stage liver disease caused by HCV infection
is the indication of liver transplantation in 35-50% of the cases
Liver transplantation
Recurrent infection is more than 98%
Follow-up for 1-13 months
Acute hepatitis: 25-45%
Factors related
to the virus
Follow-up for 5 years
• HCV induced chronic hepatitis: 80-100%
• Graft cirrhosis related to HCV: 80-30%
• Cholestatic hepatitis: 2-8%
Donor
characteristics
Surgical
factors
Factors
related
to the host
External
factors
Figure 1. Natural course of hepatitis C following liver transplantation
Arch Med Sci, 1 April / 2005
9
Gabriella Lengyel, László Kóbori, Imre Fehérvári, Balázs Nemes, Dénes Görög, Attila Patonai, Enikö Sárváry,
Marina Varga, Krisztina Hagymási, Ferenc Perner, János Fehér, Zsolt Tulassay
Interferon-ribavirin
350
Follow-up
300
U/L
250
200
150
100
50
0
0.
3.
6.
9.
12.
15.
18.
months
* sign. vs. 0. month
Figure 2. Changes in the activities of alanine-aminotransferase during combined interferon-ribavirin
treatment and in the follow-up period
Interferon-ribavirin
250
Follow-up
U/L
200
150
100
50
0
0.
3.
6.
9.
12.
15.
18.
months
* sign. vs. 0. month
Figure 3. Changes in the activities of aspartate-aminotransferase during combined interferon-ribavirin
treatment and in the follow-up period
Baseline data of the treated patients are shown in
Table I.
According to the protocol of the clinical treatment,
the interferon-alpha-2b product (Intron A,
Schering-Plough, Co.) was administered three times
a week, in a dose of 3.0 MU, in subcutaneous
injections; and ribavirin (Rebetol, Schering-Plough,
Co.) was given orally in a daily dose of 800-1000 mg,
depending on the body mass. Duration of the
treatment was one year, and the follow-up period
lasted for further 6 months. Four patients were
withdrawn from the study due to adverse effects,
mainly for severe anemia. Reduction in the dose of
ribavirin in 3 of 12 cases was due to the onset of
anemia.
Clinical and laboratory examinations of the
patients were performed at 1, 2, 4, 6, and 8 weeks
after enrollment into the program, then in every
month. Follow-up observations were performed after
completion of the treatment, at three months’
intervals. Data of the treatment period and values
obtained at six months after completion of the
treatment were taken into consideration for the
evaluation. For data processing, in addition to the
10
clinical symptoms, values of serum ALT activity, the
result of the HCV-PCR test, and the histology of the
liver biopsy performed at completion of the
treatment were also taken into consideration. For
details of the methods of examination, we refer to
our previous publication [6]. Patients were informed
on the particulars of the therapy before treatment,
and they gave a written informed consent to the
medicinal therapy in advance.
Data were analyzed by statistical methods (paired
t-test). Data are expressed as mean ±SEM. P<0.05
was considered to indicate statistical significance.
Results
Three patients of the 12 were sustained
responders, 7 patients gave a partial response, and
2 patients did not respond to the treatment
(non-responders). Mild-moderate side effects, not
necessitating cessation of the treatment, were
observed in 6 cases. Most adverse reactions
consisted of flu-like complaints (headache,
weakness, muscle pain, and fever), and in individual
cases moderate leucopoenia, thrombocytopenia,
and hemolysis of moderate degree occurred as
undesired effects.
The level of the serum ALT decreased significantly
in comparison to the baseline, usually after a few
weeks of treatment; it often reached normal values
(Figure 2), and the main ALT value remained at this
level until completion of the treatment. During the
follow-up period, at the 3 months’ control the main
value increased significantly, but it was considerably
lower that at baseline, and at the 6 months’ control
we found also a reduced ALT activity. Serum
aspartate-aminotransferase (AST) showed essentially
similar changes (Figure 3). Gamma-glutamyl-transpeptidase (GGT) values were scattered significantly,
being unsuitable for drawing definite conclusions.
Serum bilirubin level was higher than normal at
baseline, and during the treatment, while varying, but
it usually was lower than at baseline. At six months
after completion of the treatment these data were
found in the normal range (Figure 4).
HCV-RNA studies gave negative results in 3 cases
at completion of the treatment, and the same was
observed at 6 months’ follow-up. In these cases ALT
values were completely normal during the whole
period studied. No rejection occurred in these patients.
In seven cases the HCV-PCR examination remained
positive both at completion of treatment, and at the
6 months’ follow-up, although the viral titer was
reduced significantly in comparison to the baseline.
The activities of ALT were in all cases lower than the
baseline data. Two patients were non-responders.
Histological examination showed a close
correlation with the HCV-RNA and ALT values. In the
three patients with full response the findings of the
control liver biopsy were negative, and in the
Arch Med Sci, 1 April / 2005
Combined interferon and ribavirin treatment in recurring chronic hepatitis C following liver transplantation
In case of an infection with the hepatitis C virus,
chronic hepatitis develops in 85% of the patients, and
it transforms into liver cirrhosis in half of the cases in
spite of the standard treatment with combined
interferon and ribavirin treatment. In the end stage
of the disease, liver transplantation may be the
therapeutic modality. However, within 3-36 months
after liver transplantation in a great part of the
patients – if previous elimination of the virus has not
been attained – acute hepatitis C develops that
becomes chronic in most instances. If the patient
received an antiviral treatment before transplantation
leading to the elimination of the virus, no recurrent
hepatitis develops [10]. The literary data vary
concerning the efficacy of combined interferon and
ribavirin treatment in patients with chronic recurrent
hepatitis after liver transplantation [13-15]. Long-term
complete response, with regard to all genotypes,
usually can be seen in about 21% of the cases after
liver transplantation, like in chronic hepatitis C [16].
In a greater study, complete response was found in
43% of HCV genotype 2-3, and in 12% of genotype
1 following conventional antiviral therapy [7]. In our
current report, all patients carried the virus with
genotype 1. Sustained response was observed in
3 cases out of 12 patients, that is a slightly better rate
than that usually found in the literature. In Hungary,
Telegdy et al. [17] reported their experience concerning
the treatment of a patient with chronic hepatitis C,
who underwent liver transplantation. After 6 months’
treatment with combined interferon and ribavirin
therapy they found a permanently low viral titer and
normal ALT values with a mild hepatic fibrosis, even
at 18 months after the liver transplantation.
In the treatment of chronic hepatitis C the most
recent therapy is the administration of the pegylated
interferon once a week, together with ribavirin
treatment [8, 9]. There are two different forms of
pegylated interferon, a product with a molecular
weight of 12 kD (Pegintron – Schering-Plough), and
another with that of 40 kD (Pegasys – Roche).
Combined treatment with pegylated interferon and
ribavirin in chronic hepatitis C is much more
effective; a success rate of up to 75-80% in genotype
2-3, and 65-70% in genotype 1 can be attained.
A complete response in 40% is possible even in cases
with fibrosis of significant degree [8, 9]. This newer
combination can be supposed to be more effective
in chronic recurring hepatitis C following liver
transplantation, as well [18, 19].
On the basis of data in the literature and our own
observations, we consider the combined inter-
Arch Med Sci, 1 April / 2005
Follow-up
60
umol/L
Discussion
Interferon-ribavirin
70
50
40
30
20
10
0
0.
3.
6.
9.
12.
15.
18.
months
* sign. vs. 0. month
Figure 4. Changes in the bilirubin levels during
combined treatment and thereafter
9
8
7
score
remaining cases we observed an improvement in
the Knodell-index, that is, the grading score was
significantly reduced, while the staging score
remained unchanged (Figure 5).
6
5
4
3
2
1
0
grade
before treatment
stage
after treatment
* sign. vs. before treatment
Figure 5. Changes in the index of histological activity
(Knodell) index during the treatment
feron-ribavirin treatment is advisable in chronic viral
hepatitis C in the case of HCV recurrence following
liver transplantation, even, if a complete remission
can only be observed at a relatively low rate. Based
on the most recent experiences, the combination of
pegylated interferon and ribavirin therapy could be
the treatment modality of choice also in patients, who
underwent liver transplantation.
Re f e r e n c e s
1. Keeffe EB, Hollinger B and the Consensus Interferon Study
Group. Therapy of hepatitis C: Consensus Interferon Trials.
Hepatology 1997; 26 (suppl. 1): 101-10.
2. Ouzan D, Babany G, Valla D, Opolon P. Comparison of high
initial and fixed-dose regimens of interferon-alpha-2a in
chronic hepatitis C: a randomized controlled trial. J Viral
Hepatitis 1998; 5: 53-9.
3. Poynard T, Leroy V, Cohard M, Cohard M, Opolon P, Zarski
JP. Meta-analysis of interferon randomized trials in the
treatment of viral hepatitis C: Effects of dose and duration.
Hepatology 1996; 24: 778-89.
4. Bizollon T, Palazzo U, Ducerf C, Chevallier M, Elliott M,
Baulieux J et al. Pilot study of the combination of interferon
alfa and ribavirin as a therapy of recurrent hepatitis C after
liver tansplantation. Hepatolog, 1997; 26: 500-4.
11
Gabriella Lengyel, László Kóbori, Imre Fehérvári, Balázs Nemes, Dénes Görög, Attila Patonai, Enikö Sárváry,
Marina Varga, Krisztina Hagymási, Ferenc Perner, János Fehér, Zsolt Tulassay
5. Brown JL. Efficacy of combined interferon and ribavirin for
treatment of hepatitis C. Lancet 1998; 351: 78-9.
6. Fehér J, Lengyel G, Bálint T. The combined interferon-alfa2b and ribavirin treatment in chronic hepatitis C.
Observations in 100 patients treated for one year. Orv Hetil
(Hung Med J) 1999; 140: 1235-8.
7. McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee
WM, Rustgi VK et al. Hepatitis Interventional Therapy
Group. Interferon alfa-2b alone or in combination with
ribavirin as initial treatment for chronic hepatitis C. N Eng
J Med 1999; 33: 1485-92.
8. Manns MP, McHutchison JG, Gordon SC, Rustgi VK,
Shiffman M, Reindollar R et al. Peginterferon alpha-2b plus
ribavirin compared with interferon alpha-2b plus ribavirin
for initial treatment of chronic hepatitis C: a randomised
trial. Lancet 2001; 358: 958-65.
9. Zeuzem S, Feinman SV, Rasenack J, Heathcote EJ, Lai MY,
Gane E et al. Peginterferon alfa-2a in patients with chronic
hepatitis C. N Eng J Med 2000; 343: 1666-72.
10. Berenguer M, Lopez-Labrador FX, Wright TL. Hepatitis C
and liver transplantation. J Hepatol 2001; 35: 666-78.
11. Forns X, Garcia-Retortillo M, Serrano T, Feliu A, Suarez F, de
la Mata M et al. Antiviral therapy of patients with
decompensated cirrhosis to prevent recurrence of hepatitis
C after liver transplantation. J Hepatol 2003; 39: 389-96.
12. Prieto M, Berenguer M, Rimola A, Loinaz C, Barrios C,
Clemente G et al. Liver transplantation in hepatitis C.:
a Spanish multicenter experience. Eur J Gastroeneterol
Hepatol 1998; 10: 771-6.
13. Lavezzo B, Franchello A, Smedile A, David E, Barbui A, Torrani
M et al. Treatment of recurrent heaptitis C in liver transplants:
efficacy of a six versus a twelve month course of interferon
alfa 2b with ribavirin. J Hepatol 2002; 37: 247-52.
14. Mazzaferro V, Regalia E, Pulvirenti A, Tagger A, Andreola S,
Pasquali M et al. Prophylaxis against HCV recurrence after
liver transplantation. Effect of interferon and ribavirin
combination. Transpl Proc 1997; 29: 519-21.
15. Schirren CA, Zachoval R, Gerlach JT, Ulsenheimer A, Gruener
NH, Diepolder HM et al. Antiviral treatment of recurrent
hepatitis C virus (HCV) infection after liver transplantation:
association of a strong, multispecific, and long lasting CD4+
T cell response with HCV-elimination. J Hepatol 2003; 39:
397-404.
16. Samuel D, Bizollon T, Feray C, Roche B, Ahmed SN,
Lemonnier C et al. Interferon-alpha 2b plus ribavirin in
patients with chronic hepatitis C after liver transplantation:
a randomized study. Gastroenterol 2003; 124: 642-650.
17. Telegdy L, Görög D, Horányi M, Schaff Zs. Severe relapse of
hepatitis C following liver transplantation. Successful
treatment with a combination of interferon-alpha +
ribavirin. Orv Hetil (Hung Med J) 1999; 140: 1891-3.
18. Dumortier J, Scoazec JY, Chevallier P, Boillot O. Treatment
of recurrent hepatitis C after liver transplantation: a pilot
study of peginterferon alfa-2b and ribavirin combination.
J Hepatol 2004; 40: 669-674.
19. Rodriguez-Luna H, Khatib A, Sharma P, De Petris G,
Williams JW, Ortiz J et al. Treatment of recurrent hepatitis
C infection after liver transplantation with combination of
pegylated interferon alpha2b and ribavirin: an open-label
series. Transplantation 2004; 77: 190-194.
12
Arch Med Sci, 1 April / 2005