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Treatment with daily consensus interferon (CIFN) plus ribavirin
in non-responder patients with chronic hepatitis C:
A randomized open-label pilot study*
Markus Cornberg1, Johannes Hadem1, Eva Herrmann2, Frank Schuppert3,
Hartmut H.-J. Schmidt4,5, Markus Reiser6, Oliver Marschal7, Martin Steffen8,
Michael P. Manns1,*, Heiner Wedemeyer1
1Abt. Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover, Germany2Klinik fur Innere Medizin II, Universitat des Saarlandes, Homburg, Saar, Germany3Medizinische Klinik II, Krankenhaus Bad Oeynhausen, Bad Oeynhausen, Germany
4Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Charite-Campus Mitte, Berlin, Germany5Transplantationshepatologie, Universitatsklinikum Munster, Munster, Germany
6Ruhr-Universitat Bochum, Abt. Gastroenterologie und Hepatologie, Berufsgenossenschaftliche Kliniken Bergmannsheil, Bochum, Germany7Praxis Braunschweig, Braunschweig, Germany
8Medizinischen Klinik I, Franziskus Hospital Bielefeld, Bielefeld, Germany
Background/Aims: Therapeutic options for hepatitis C non-responder patients are limited.
Methods: We initiated an open-label pilot study to investigate the efficacy of CIFN plus ribavirin on viral kinetics,
sustained virological response (SVR), and histological response in hepatitis C non-responder patients. Seventy-seven
patients were enrolled to receive CIFN given daily in combination with 1000/1200 mg ribavirin. An 8-week induction-
dosing regimen of 18 mg CIFN, followed by 9 mg for 40 weeks was compared to 9 mg CIFN for 48 weeks. 90% of patients
were infected with HCV-genotype 1.
Results: Overall, 82% of the patients demonstrated an early virological response, 65% had an end-of-treatment
response, and the SVR was 30%. Interferon/ribavirin non-responders demonstrated a SVR of 22%. Induction-dosing
resulted in a greater first-phase HCV-RNA decay that, however, did not translate to better SVRs, presumably due to
more dose modifications. High ALT, younger age, and second-phase viral kinetics were associated with SVR. Only
sustained responders and relapse patients showed an improved liver histology.
Conclusions: Daily dosing of CIFN plus ribavirin may be a promising concept for selected non-responder patients
before considering therapies which are anti-viral but not curative. However, motivation and compliance are requisites
and a CIFN induction is not required.
q 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Keywords: Hepatitis C virus; Chronic hepatitis C; Consensus interferon; Ribavirin; Non-responder; Induction-dosing;
Daily dosing
Journal of Hepatology 44 (2006) 291–301
www.elsevier.com/locate/jhep
0168-8278/$30.00 q 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.jhep.2005.10.021
Received 27 July 2005; received in revised form 6 October 2005; accepted 24 October 2005; available online 28 November 2005* The authors have declared that they received funding from the drug companies involved to carry out their research.* Corresponding author. Address: Department of Gastroenterology, Hepatology, and Endocrinology, Medizinische Hochschule Hannover,
Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. Tel.: C49 511 532 3305; fax: C49 511 532 6820.
E-mail address: [email protected] (M.P. Manns).
M. Cornberg et al. / Journal of Hepatology 44 (2006) 291–301292
1. Introduction
Despite the enormous advances that have been achieved
in the treatment of chronic hepatitis C over the last decade
[1], there is still a need for improved therapies, especially
for the difficult-to-treat patients such as HCV-genotype 1
infected individuals, patients with liver cirrhosis, or patients
who did not respond to a previous interferon alfa (IFN)-
based therapy [2]. Even the new standard therapy of
pegylated interferon alfa (PEG-IFN) in combination with
ribavirin is not very effective for the so called non-responder
patients. Relapse patients may benefit from re-treatment but
patients infected with HCV-genotype 1 who were true non-
responders to IFN and ribavirin demonstrated only 12%
sustained virological response (SVR) with PEG-IFN and
ribavirin [3,4]. Thus, there is currently no generally
accepted therapeutic strategy for this patient population.
One approach, currently evaluated in clinical trials, is the
long-term maintenance therapy with PEG-IFN in non-
responders with advanced fibrosis or cirrhosis to prevent
hepatocellular carcinoma and/or decompensation (EPIC3,
HALT-C, COPILOT trials [3–5]). However, viral eradica-
tion should be still the first achievable goal whenever
possible. Some study results suggest that consensus
interferon (CIFN), which is a ‘consensus’ molecule of the
type-1 interferons with a higher biological activity in vitro
[6,7], may be more effective than standard IFN for the
difficult-to-treat HCV-genotype 1 patients [8–10]. CIFN
monotherapy demonstrated a substantial SVR in non-
responder patients [11]. To mimic the half-life of PEG-
IFN, CIFN has to be administered on a daily basis. Recently,
one study showed that daily dosing of 9 mg CIFN
significantly increased the SVR compared to a 9 mg tiw
regimen [12]. Preliminary data from a single center study
presented in abstract form, suggested that daily dosing of
CIFN in combination with ribavirin can achieve SVRs of
38–45% in non-responder patients to standard IFN and
ribavirin depending on the CIFN dose [13]. High-dose-
induction, although not effective in studies with standard
IFN [14–16], seemed to have further improved the SVR in
this study [13]. Cotler and colleagues [17] assessed the first-
phase viral kinetics in 20 previous non-responders after a
single dose of 15 or 30 mg CIFN and demonstrated a
significantly sharper decline of the HCV-RNA with the
higher dose after 24 h (0.8 and 1.5, respectively). Whether
high-dose-induction with CIFN may serve as an option to
further increase the SVR in difficult-to-treat patients
remains unknown.
Here, we initiated an open-label pilot study to assess the
efficacy of daily dosing of CIFN in combination with
ribavirin on the first- and second-phase of viral kinetics,
sustained virological response, and histological response in
patients with chronic hepatitis C who did not respond to a
prior IFN based therapy. Additionally, we tested if a short-
term induction with a double dose of CIFN would further
enhance the SVR.
2. Methods
2.1. Selection of patients
Adult patients (18–65 years) with chronic hepatitis C infection wereeligible for the study if they were virological non-responders to a previoustherapy with IFN or IFN plus ribavirin (HCV-RNA positive after at least 3MU IFN alfa tiw for 24 weeks). Non-response was further classified as flatnon-response (!1 log10 reduction of HCV-RNA), flat partial response (O1 log10!2 log10 reduction of HCV-RNA), and partial response with asignificant reduction of viral load (O2 log10 reduction of HCV-RNA).However, in a number of patients quantitative HCV-RNA levels of the priortherapy were not available, as this was not standard during former therapies.All patients were seropositive for HCV-RNA by testing with polymerasechain reaction by Roche Amplicorw and had elevated serum alanineaminotransferase activity (ALT). Patients were excluded if they haddecompensated liver disease, liver diseases unrelated to HCV infection,anemia (hemoglobin concentration less than 12 g/dl for women and lessthan 13 g/dl for men), leukocytopenia (less than 3000/ml), thrombocyto-penia (less than 100,000/ml), decompensated renal disease (serumcreatinine above 130 mmol/l), decompensated thyroid disease, HIV orhepatitis B infection, psychiatric conditions, history of seizures, poorlycontrolled autoimmune diseases, previous organ transplantation. Ongoingintravenous drug (IVDA) abuse and lack of abstinence for at least 12months were also exclusion criteria. There were two protocol deviations:two patients were included despite platelets lower than 100,000/ml and oneof them was also 70 years old. Both patients did not respond to therapy (onebreakthrough, one non-response).
3. Study design
The study was an open-label trial with a central
randomization procedure performed in Hannover. Sev-
enty-seven patients were randomly assigned into two groups
without further stratification using sequentially numbered
cards in sealed envelopes. Patients in Group A were treated
with 9 mg CIFN daily for 48 weeks whereas patients in
Group B received an induction therapy of 18 mg CIFN daily
for the first 8 weeks followed by 9 mg CIFN daily for the
remaining 40 weeks. In both groups, ribavirin was given at
the standard dose of 1 g (!75 kg) or 1.2 g daily (O75 kg).
The patients were evaluated as outpatients at the
following visits: screening visit, entry visit, day 1, day 3,
week 1, 2, 4, 12, 18, 24, 30, 36, 42, 48, 52, 60, and 72. The
laboratory of each center performed biochemical and
hematological testing. Serum HCV-RNA levels (IU/ml)
were determined with the Cobas Amplicor Hepatitis C
Monitor Test (v2.0, Roche Diagnostics). Viral genotypes
were determined with the INNO-LiPA HCV II Kit
(Innogenetics, Gent, Belgium).
This protocol was approved by the local ethics
committees, and was conducted according to principles of
the Helsinki Declaration. Written informed consent was
obtained from all participants prior to enrollment.
4. Assessment of efficacy
The primary endpoint was sustained virological response
(SVR), defined as undetectable HCV-RNA in serum 24
weeks after the end-of-treatment (EOT). Secondary
M. Cornberg et al. / Journal of Hepatology 44 (2006) 291–301 293
endpoints were early virological response (EVR: HCV-
RNA declineO2 log10 before week 12) and absence of
serum HCV-RNA at the EOT and normalization of serum
ALT at the end of follow-up. Therapy was discontinued
once the HCV-RNA was detectable at week 24 of treatment.
The first-phase of early viral kinetics was assessed by the
log10 decay during the first 24 h as by Cotler et al. [17]. The
second-phase slope of the initial viral kinetics was
calculated by log-linear regression on measurements of
HCV-RNA at 1, 2, and 4 weeks and rapid virological
response (RVR) was defined as a second-phase slope faster
than K0.10/day as previously [18]. In 37 patients, a second
liver biopsy was performed at the end of the follow-up (24
weeks after end of therapy) and the histology (Ishak score
[19]) was compared to the histology before the initiation of
therapy.
5. Statistical analysis
Data were described by rates, means with standard
deviation, medians, and ranges. Furthermore, groups were
compared by c2 test, Fishers exact test, Man–Whitney and
Kruskal–Wallis test as appropriate. In addition, multivariate
step-wise logistic regression was used to identify indepen-
dent predictors from baseline characteristics which were
associated with SVR in univariate analysis. All p values
Table 1
Baseline characteristics of the 77 patients
Gro
Male patients 27
Mean age [yearsGSD] 45.
Mean body weight [kgGSD] 80.
HCV-genotype distribution
HCV-Genotype 1a/b 34
HCV-Genotype 3a 2 (5
HCV-Genotype 4 or 5 2 (5
HCV-virus loadO850!103 unit/ml 20
Median ALT(Min, Max) [units/ml] 64
Mode of transmission
Blood products/transfusion 19
I.V. drug abuse 2 (5
Surgery, needle stick, tattoo 8 (2
Unknown 9 (2
Liver histology before therapy
No/mild fibrosis (Ishak scora F0-2) 15
Liver fibrosis (Ishak score F3-4) 13
Liver cirrhosis (Ishak score F5-6) 8 (2
Not available 2 (5
Previous therapy
IFN monotherapy 17
IFNCribravin combination therapy 21
Response to prior therapy
Flat non-response(!1 log red. of HCV-RNA) 6 (1
Flat partial response(O1 log !2 red. of HCV-RNA) 5 (1
Significant HCV-RNA reduction(O2 log red. of HCV-RNA) 6 (1
Only qualitative HCV-RNA available 21
reported were two-sided and p values below 5% were
considered significant.
6. Results
6.1. Patients
Between March 2000 and September 2001, 77 patients
were randomized (Group AZ38, Group BZ39 and treated
at eight different sites (Hannover, Bad Oeynhausen, Berlin,
Bochum, Braunschweig, Bielefeld, Kassel, Koblenz). The
baseline characteristics are shown in Table 1. The only
significant difference between the treatment groups was
found in baseline ALT as Group B tended to have lower
ALT levels (pZ0.048).
6.2. Safety
The spectrum of side effects of daily CIFN therapy was
comparable to previous trials with IFN and ribavirin
combination therapy. However, the high-dose-induction-
phase had a high side effect profile. There were four serious
adverse events (suspected drug related) during therapy
(Table 2). A case of menigococcus sepsis occurred during
the last 2 weeks of therapy in Group A. Despite discontinu-
ation of therapy, the patient remained HCV-RNA negative.
up A (nZ38) Group B (nZ39)
(71%) 31 (79%)
2G11.4 44.0G10.5
7G13.3 79.9G12.9
(89%) 35 (90%)
%) 2 (5%)
%) 2 (5%)
(53%) 24 (61%)
(20,198) 40 (18,222) (pZ0.048)
(50%) 21 (54%)
%) 3 (8%)
1%) 7 (18%)
4%) 8 (21%)
(41%) 20 (51%)
(34%) 11 (28%)
1%) 8 (21%)
%) 0 (0%)
(45%) 19 (49%)
(55%) 20 (51%)
6%) 9 (23%)
3%) 3 (8%)
6%) 7 (18%)
(55%) 20 (51%)
Table 2
Laboratory abnormalities and adverse events during the therapy
Laboratory abnormalities and adverse events Group A (nZ38) Group B (nZ39)
Leucopenia (!2000 leucocytes) 6 (16%) 8 (21%)
Thrombopenia (!50,000 platelets) 4 (11%) 3 (8%)
Anemia (Hb!10 g/dl) 9 (24%) 3 (8%)
Flu-like symptoms (myalgia, arthralgia, fever) 25 (66%) 33 (85%)
Gastrointestinal disorder (nausea) 10 (26%) 17 (44%)
Dyspnoe, vertigo 19 (50%) 12 (31%)
Skin (dry skin, hair loss, itching, exacerbation of psoriasis [nZ3, all in B]) 12 (32%) 15 (38%)
Psychiatric disorders (depression, anger, anxiety) 10 (26%) 7 (18%)
Serious adverse events (suspected drug related) 1 (3%) 3 (10%)
Dose modification/discontinuation CIFN before week 8 due to laboratory
abnormalities or adverse events
5 (13%) 19 (49%)
Dose modification/discontinuation CIFN during the complete study period due to
laboratory abnormalities or adverse events
10 (26%) 19 (49%)
Dose modification/discontinuation Ribavirin during the complete study period due to
laboratory abnormalities or adverse eventsa
15 (39%) 7 (18%)
The noted adverse events were moderate to severe (subjective reports from patients) and occurred at least once during the treatment period. Serious adverse
events: (A) meningococcus sepsis; (B) severe weight loss and poor physical condition resulted in drop out, two patients with injection site abscesses resulting in
surgical procedures.a Ribavirin dose reductions did not significantly affect the relapse rate in this study.
M. Cornberg et al. / Journal of Hepatology 44 (2006) 291–301294
All other patients with serious adverse events discontinued
treatment and relapsed or remained HCV-RNA positive.
There was a trend towards more severe flu-like symptoms and
nausea in the induction group, which resulted in more frequent
dose modifications early during treatment. Reduction of
leucocytes and platelets were significantly higher in the
induction group during the first 8 weeks of therapy (leucocytes
TW1, TW2, TW4; platelets TW1, Fig. 1). Due to laboratory
abnormalities and the side effects, almost every other patient
required a reduction of the 18 mg CIFN dose before week 8,
while this was the case in only 13% of patients receiving 9 mg
CIFN during the first 8 weeks (pZ0.001, Table 2). Patients in
Group A developed anemia and associated side effects
(dyspnoe, vertigo) more frequently than patients in Group B,
resulting in ribavirin dose modifications in twice as many
patients in Group A than B (pZ0.04). However, the overall
20%
40%
60%
80%
100%
Treatment weeks
% o
f TW
0 va
lue
% o
f TW
0 va
lue
Group A
Group B
20%
40%
60%
80%
100%
0 4 80 4 8 12 16 20 24
Treatm
*** *
* p<0.05, values from at least 61-72 patien
Leucocytes Pla
Fig. 1. Laboratory changes of leucocytes, platelets and hemoglobin during th
plotted (*p!0.05).
percent reduction of the hemoglobin was not different between
both groups. The reason for this finding may have been the
lower hemoglobin concentration in Group A at TW0, which
was almost significant. No signs of diminished liver function
(as measured clinically and by coagulation function and serum
albumin) were noted during therapy. We had no evidence for
hypocalcemia as previously reported for daily dosing of CIFN
[20].
6.3. Efficacy
Overall, 59 patients (77%) completed more than 42
weeks of therapy (O80% of treatment duration), whereas 4
patients dropped out before TW24. In 12 patients, therapy
was stopped at TW24 due to non-response, and 2 patients
discontinued the study between TW24 and TW42 (Fig. 2).
% o
f TW
0 va
lue
12 16 20 24 0 4 8 12 16 20 24
ent weeks
Group A
Group B
20%
40%
60%
80%
100%
Treatment weeks
Group A
Group B
ts for each time-point.
telets Hemoglobin
e first 24 weeks of therapy. Percent of the value at TW0 (Z100%) is
M. Cornberg et al. / Journal of Hepatology 44 (2006) 291–301 295
50 patients (65%) had an EOT response. There was no
difference between the two treatment groups (Fig. 3A).
Unfortunately, 26 of the EOT patients (52%) had a
virological relapse during the follow-up period. Twenty-
three patients (30%) had a SVR and one patient was lost to
follow-up (Fig. 2). Again, there was no difference between
both treatment regimens (Fig. 3A).
Comparing the HCV-RNA levels during therapy, we
observed a more pronounced decline in HCV-RNA in
patients treated with 18 mg CIFN during the first 8 weeks
of therapy. Especially the median log10 drop of HCV-
RNA after 24 and 72 h was 0.29 and 0.57 in Group A,
Discontinuation before week 8
N=3 (all group B)1 patient had> 2 log decline
n= 63 EVR(> 2 log declinebefore week 12)
3 non-responder
N=60HCV-RNA negative
during therapy
N=2 Discontinuationbefore week 40
(<80% of therapy)
N=50End of treatm
Respons(65%)
1 patient stopTW42 (SAE
N=23SustainedVirologicaRespons
(30%)
N=77
d
N=1 Lost
during follow-up
Fig. 2. Response to thera
and 0.30 and 1.03 in Group B (pZ0.16 and 0.002,
respectively). The stronger first-phase decline in HCV-
RNA resulted indeed in a higher virological response at
TW8, as 56% of patients treated with the high dose were
already HCV-RNA negative compared to only 42% in
Group A (Fig. 4A). However, the number of patients
with an EVR defined asO2 log10 reduction at TW12 was
not different between both groups (Fig. 3A).
The RVR as defined by Layden [18], that is a second-
phase slope during TW1 and TW4 faster than K0.1/day,
was not statistically different between the treatment groups
(28% in Group A, 38% in Group B, pO0.2).
N=1 HCV-RNA n.a. 1 non-responder
n= 10 no EVR(< 2 log declinebefore week 12)8 non-responder
1 stopped
ente
ped )
N=9Breakthrough
l e
N=26Relapse
N=1HCV-RNA negative
uring therapy= 1 relapse)
py of all patients.
Fig. 3. (A) Rapid virological response (RVR: second-phase slope faster than K0.1/day), early virological response (EVR:O2 log10 decline of HCV-
RNA before week 12), end of treatment response, sustained virological response, sustained virological response in patients who were treated according
to the protocol, and sustained virological response rates of patients without CIFN modifications in the first 8 weeks are shown. (B) Sutained virological
response rates of patients with different baseline characteristics are shown. Non-responders to IFN monotherapy had the best sustained response and
patients with liver cirrhosis had the poorest sustained response rates.
M. Cornberg et al. / Journal of Hepatology 44 (2006) 291–301296
6.4. Factors influencing sustained virological response
It is known that patients who are adherent to therapy
respond much better to therapy than those who are not
compliant [21]. Here, patients who were treated according
to the protocol and did not drop out showed a SVR of 33%
(Fig. 3A). The SVR was even higher in the group of patients
that did not require CIFN dose modifications during the
induction phase.
When comparing baseline characteristics in patients with
and without SVR, only high baseline ALT and low age were
significantly associated in univariate analysis (Table 3) and
both variables remained significant in multivariate logistic
regression (pZ0.001, 0.046, respectively). Interestingly, SVR
was significantly but not exclusively associated with RVR as
13 of 23 (57%) patients with RVR but also still 10 of 47
patients (21%) without RVR achieved a SVR (Table 3).
Nevertheless, patients who were non-responder to an IFN
monotherapy showed a higher chance to achieve a SVR
(39%) than IFN/ribavirin non-responder (22%, pZ0.1,
Fig. 3B). This trend was also seen for patients with a faster
HCV-RNA decay during the previous therapy as the median
log10 decay after 8 weeks of treatment was 3.38 in patients
with a prior HCV-RNA decayO1 log10 compared to 2.35 in
patients with a flat response during the previous therapy
(pZ0.07, Fig. 4B).
For six patients we were able to compare the HCV-RNA
kinetics from the prior therapy to the current CIFN
Fig. 4. Log10 decay of HCV-RNA during and after treatment. Panel A shows all patients differentiated by the treatment groups, Panel B shows all
patients differentiated by virological response of previous therapy.
M. Cornberg et al. / Journal of Hepatology 44 (2006) 291–301 297
treatment (Fig. 5). All six patients were previously treated in
well-documented studies and were compliant according to
the patient records. Interestingly, different patterns of HCV-
RNA kinetics during earlier and current treatment were
observed. Three out of four patients who were treated with 3
MU IFN alfa-2b tiw during the prior therapy had a rapid
viral decline of HCV-RNA and two of these had received
induction dosing of IFN alfa-2b during their prior treatment.
Both were able to clear HCV-RNA during treatment with
CIFN. However, this was not true for patient 67 who seemed
to be resistant also to CIFN therapy (Fig. 5).
6.5. Histological response
All patients underwent liver biopsy before the start of
therapy. Thirty-seven patients had a second liver biopsy at
the end of the follow-up. Patients with SVR had the best
histological response, and relapse patients had a better
response than did non-responders or breakthrough patients
(Table 4). Only three of the non-responder patients had an
improvement in the grading but none of them improved in
the fibrosis score. In contrast, 60% of the patients with a
SVR improved their fibrosis stage.
7. Discussion
Currently, there are no recommendations how to manage
patients with chronic hepatitis C who did not respond to a
prior IFN/ribavirin therapy. Here, we investigated a daily
dosing regimen with CIFN in combination with ribavirin.
As expected for non-responders, our 77 patients showed
baseline characteristics that are associated with a poor
treatment response (Table 1). The treatment with daily
dosing of CIFN plus ribavirin resulted in surprisingly high
EVR of more than 80% but after the end of therapy a high
relapse rate was observed. The overall SVR was 30% for
this difficult-to-treat patient group. The most important
group of patients in our study population, the IFN/ribavirin
non-responder group achieved a SVR of 22%, which is
about 5–10% higher than reported in prior non-responder
studies [3,4,22].
However, it is always a problem to compare studies,
especially non-responder trials. Non-responder patients are
a highly heterogeneous group (Table 1). It is sometimes
difficult to determine if the patients were true non-
responders to the prior therapy or if these patients were
just non-compliant. Another factor contributing to the
heterogeneity of the non-responders is the response kinetic
Table 3
Patient characteristics explored in univariate analysis
Patient characteristics SVR (nZ23) No SVR
(nZ54)
p
Treatment group A(9 mg) /B(18 mg) 12/11 26/28 O0.2
Male/female patients 17/6 41/13 O0.2
Mean age [yearsGSD] 41.5G12.3 45.9G10.3 0.06
Mean body weight [kgGSD] 77.7G13.3 81.4G13.1 O0.2
HCV-genotype distribution O0.2
HCV-Genotype 1a/b 21 43
HCV-Genotype 3a 1 1
HCV-Genotype 4 or 5 1 3
Mean HCV-virus load [Log10 units/mlGSD] 6.1G0.5 6.1G0.5 O0.2
Median ALT(Max) 96 (222) 40 (136) 0.001
Mode of transmission O0.2
Blood products/transfusion 13 27
I.V. drug abuse 1 4
Surgery, needle stick, tattoo 4 11
Unknown 5 12
Liver histology before therapy 0.18
No/mild fibrosis (Ishak Score F0-2) 13 22
Liver fibrosis (Ishak Score F3-4) 5 19
Liver cirrhosis (Ishak Score F5-6) 3 13
Not available 2 0
Previous therapy 0.14
IFN monotherapy/IFNCribavirin combination therapy 14/9 22/32
Response to prior therapy O0.2
Flat non-response(!1 log red. of HCV-RNA) 3 12
Flat partial response(O1 log !2 log red. of HCV-RNA) 2 6
Significant HCV-RNA reduction(O2 log red. of HCV-RNA) 5 8
Only qualitative HCV-RNA available 13 28
First-phase decay of HCV RNA after 24 h [Log10 units/mlGSD] 1.0G1.4 0.9G1.1 O0.2
Rapid virologic response(RVR)/no RVR 13/10 10/37 0.003
Median Second-phase slope (Min, Max) [dayK1] 0.17 (0.09,0.69) 0.07 (0.0,0.31) 0.003
M. Cornberg et al. / Journal of Hepatology 44 (2006) 291–301298
during the previous therapy. The different response kinetics
during prior therapies may influence the response during the
re-treatment. Patients who achieved a O1 log10 decay of
HCV-RNA in the earlier therapy had a sharper viral decline
during the re-treatment (Fig. 4B). One limitation in this
study and in many other studies is that the response kinetic
to the prior therapy is unknown in many patients (Table 1).
Comparing the response to the prior therapy with the
response to the daily CIFN/ribavirin treatment in individual
patients, it seems that CIFN can indeed have a higher
antiviral potency in some patients (Fig. 5). The high EVR in
our study but on the other hand the high relapse rate may
raise new questions and ideas for further studies. A longer
treatment with CIFN plus ribavirin might be an option for
these patients.
In this specific difficult-to-treat patient group, age and
baseline ALT were independent predictors of SVR whereas
other well-known predictive factors for SVR as, e.g. HCV-
genotype, were not significantly associated with SVR here
(Table 3). In Layden et al. [18], RVR defined as a second-
phase slope during TW1 and TW4 faster than K0.1/day was
highly predictive for SVR in previously untreated patients
receiving CIFN monotherapy. They reported that no patient
without RVR achieved SVR. Here, RVR remained to be
associated with SVR but even 23% of the patients without
RVR achieved SVR. This may be due to combination
therapy with ribavirin, mainly.
Adherence to therapy is another important factor for the
success of the treatment [21]. Therefore, therapies that
induce severe side effects are in the end less effective
despite higher antiviral efficacy. The adherence to therapy
here was comparable to previous tiw CIFN regimens [10].
However, in contrast to a report from the USA in treatment
naıve patients [20], 9 mg daily CIFN in combination with
ribavirin were well tolerated in our study. The selection of
non-responders in our study who are motivated and already
tolerated a prior IFN therapy may account for this
discrepancy. Another German study also reported good
tolerability of a daily 9 mg CIFN plus ribavirin regimen in
non-responders (P. Buggisch personal communication).
However, the induction-dosing of 18 mg CIFN in combi-
nation with ribavirin required early dose modification due to
side effects and laboratory abnormalities in 49% of the
patients such as patient 32 and 70 (Fig. 5). This is in line
with a previous non-responder study from Canada [23].
Three of our patients treated with the high dose even
dropped out due to adverse events before TW8. This might
help to explain why the overall response rates were not
higher in Group B (Fig. 3A) despite the initially higher
response rates (Fig. 4A). The stronger viral decline in the
Fig. 5. HCV-RNA levels of six individual patients during the prior therapy with standard IFN alfa-2b plus ribavirin and during the current therapy
with CIFN plus ribavirin.
M. Cornberg et al. / Journal of Hepatology 44 (2006) 291–301 299
first-phase with the induction-dosing might reflect the
higher antiviral efficacy of a higher dose but due to dose
reductions and the comparable RVR, this effect could not be
transferred into SVR. Layden et al. discussed another
possibility that might help to explain why an induction
regimen is in the end less effective as they speculate that
induction would select for a therapy resistant virus strain
[18]. Overall, our data suggest that the high-daily-dose-
induction is not superior.
The patients with liver cirrhosis had as expected very
low response rates. Patient 67 is an example with almost
no response to therapy (Fig. 5). This male patient had
HCV-genotype-1, was older than 45 years, had relative
low baseline ALT levels, had liver cirrhosis, and had a
flat non-response to the prior IFN/ribavirin therapy.
Furthermore, a dose modification of CIFN was required
due to thrombopenia. Unfortunately, these patients who
would benefit the most from a curative antiviral
treatment have the worst outcome. These patients may
be better treated with low dose interferon maintenance
therapy to prevent complications of liver cirrhosis,
although only one study to date has demonstrated any
benefit in this approach [5].
We were also interested in the effect of CIFN on the
histology as we compared the liver biopsies from 37
patients before and after therapy (Table 4). As expected,
Table 4
Histological response of 37 patients with paired liver biopsies
Patients with paired biopsies (before therapy, week 72) SVR (nZ15) Relapse (nZ14) Breakthrough and
NR (nZ8)
All patients (nZ37)
Staging: Fibrosis (Mean Ishak F)
Before/week 72 2.5/2.0 (n.s.) 3.2/2.9 (n.s.) 3.1/3.6 (n.s.) 2.9/2.7 (n.s.)
Fibrosis improved 9 (60%) 5 (36%) 0 (0%) 14 (38%)
Fibrosis not changed 4 (27%) 6 (43%) 4 (50%) 14 (38%)
Fibrosis worsened 2 (13%) 3 (21%) 4 (50%) 9 (24%)
Grading: inflammation (Mean Ishak A–D) before/week 72 5.3/3.5 (pZ0.007) 6.1/4.0 (pZ0.006) 5.3/5.2 (pZ0.9) 5.6/4.0 (pZ0.0001)
Periportal necroinflammation (Mean Ishak A) 1.7/1.1 (pZ0.09) 1.9/1.3 (pZ0.04) 1.8/2.1 (pZ0.3) 1.8/1.4 (pZ0.07)
Bridging and confluent necrosis (Mean Ishak B) 0.1/0.1 (n.s.) 0.1/0.1 (n.s.) 0.0/0.0 (n.s.) 0.1/0.1 (n.s.)
Focal lobular necrosis/apoptosis (Mean Ishak C) 1.3/0.8 (pZ0.009) 1.6/0.9 (pZ0.02) 1.3/1.1 (pZ0.6) 1.4/0.9 (pZ0.0005)
Portal inflammation (Mean Ishak D) 2.3/1.5 (pZ0.01) 2.5/1.7 (pZ0.03) 2.3/1.9 (pZ0.3) 2.4/1.6 (pZ0.0006)
Inflammation improved 10 (67%) 9 (64%) 3 (38%) 22 (59%)
Inflammation not changed 5 (33%) 4 (29%) 2 (25%) 11 (30%)
Inflammation worsened 0 (0%) 1 (27%) 3 (38%) 4 (11%)
M. Cornberg et al. / Journal of Hepatology 44 (2006) 291–301300
the patients who demonstrated a SVR had the
best improvement in staging and grading (Table 4).
Only 2 of the 15 sustained responder analyzed had a
worsening in the fibrosis score. Both patients had
elevated transaminases at the end of follow-up and high
gamma-GT values, possibly due to alcohol consumption.
Also the relapse patients showed a histological benefit
after the end of follow-up (Table 4). In contrast, patients
with only short-term virus suppression (breakthrough) or
a complete non-response demonstrated no histological
benefit. This data suggest that only a long-term virus
suppression or clearance can lead to a histological
response.
In conclusion, before starting long-term maintenance
therapies with IFN in all non-responder patients, one may
consider alternative therapies such as daily dosing of CIFN
plus ribavirin to achieve viral clearance. Selected, highly
motivated and compliant patients may benefit from this type
of therapy.
8. Study group
Medizinische Hochschule Hannover (M.P. Manns, M.
Cornberg, H. Wedemeyer, J. Hadem, M. Basturk, A.
Schuler, H.L. Tillmann, C. Trautwein), Krankenhaus Bad
Oeynhausen (F. Schuppert, O. Becker, W. Steuber), Charite
Berlin (E. Gentz, A. Roske, J. Jetschmann, H.H.-J.
Schmidt), Ruhr-Universitat Bochum (W. Schmiegel, M.
Reiser), Praxis Braunschweig (O. Marschal), Franziskus-
Hospital Bielefeld (M. Steffen, R. Muller), Klinikum Kassel
(J. Pausch), Praxis Koblenz (G. Hermesdorf).
Acknowledgements
The study was supported by an unrestricted research
grant from Yamanouchi Pharma GmbH (now Astellas
Pharma GmbH), Germany, the German competence net-
work for viral hepatitis (Kompetenznetz Hepatitis), and the
clinical research unit (KFO 129, supported by the Deutsche
Forschungsgemeinschaft). M.P. Manns is a consultant to
companies marketing alfa-interferons. We thank N. Kothe,
P. Magerstedt, Hannover, and K.H. Schweickert for
technical assistance, and L.A. Wilkinson and F.S. Saccoccio
for reading the manuscript and helpful discussion.
References
[1] Cornberg M, Wedemeyer H, Manns MP. Treatment of chronic
hepatitis C with PEGylated interferon and ribavirin. Curr Gastro-
enterol Rep 2002;4:23–30.
[2] Shiffman ML. Management of patients with chronic hepatitis C virus
infection and previous nonresponse. Rev Gastroenterol Disord 2004;
4(Suppl. 1):S22–S30.
[3] Shiffman ML, Di Bisceglie AM, Lindsay KL, Morishima C,
Wright EC, Everson GT, et al. Peginterferon alfa-2a and ribavirin in
patients with chronic hepatitis C who have failed prior treatment.
Gastroenterology 2004;126:1015–1023.
[4] Poynard T, Schiff ER, Terg R, Goncales F, Diago M, Reichen J, et al.
Sustained virological response (SVR) in the EPIC3 trial: week 12
virology predicts SVR in previous interferon/ribavirin treatment
failures receiving PEG-intron/rebetol (PR) weight based dosing
(WBD). J Hepatol 2005;42(Suppl. 2):40–41.
[5] Curry M, Cardenas A, Afdhal NH. Effect of maintenance PEG-Intron
therapy on portal hypertension and its complications: results from the
COPILOT study. J Hepatol 2005;42(Suppl. 2):40.
[6] Blatt LM, Davis JM, Klein SB, Taylor MW. The biologic activity and
molecular characterization of a novel synthetic interferon-alpha
species, consensus interferon. J Interferon Cytokine Res 1996;16:
489–499.
[7] Ozes ON, Reiter Z, Klein S, Blatt LM, Taylor MW. A comparison of
interferon-con1 with natural recombinant interferons-alpha: antiviral,
antiproliferative, and natural killer-inducing activities. J Interferon
Res 1992;12:55–59.
[8] Tong MJ, Reddy KR, Lee WM, Pockros PJ, Hoefs JC, Keeffe EB,
et al. Treatment of chronic hepatitis C with consensus interferon: a
multicenter, randomized, controlled trial. Consensus interferon study
group. Hepatology 1997;26:747–754.
M. Cornberg et al. / Journal of Hepatology 44 (2006) 291–301 301
[9] Sjogren MH, Sjogren R, Holtzmuller K, Winston B, Butterfield B,
Drake S, et al. Interferon alfacon-1 and ribavirin versus interferon
alpha-2b and ribavirin in the treatment of chronic hepatitis C. Dig Dis
Sci 2005;50:727–732.
[10] Fattovich G, Zagni I, Minola E, Felder M, Rovere P, Carlotto A, et al.
A randomized trial of consensus interferon in combination with
ribavirin as initial treatment for chronic hepatitis C. J Hepatol 2003;
39:843–849.
[11] Heathcote EJ, Keeffe EB, Lee SS, Feinman SV, Tong MJ, Reddy KR,
et al. Re-treatment of chronic hepatitis C with consensus interferon.
Hepatology 1998;27:1136–1143.
[12] Rustgi VK, Bonkovsky HL, Arora S, Zeuzem S, Manns M, Blatt LM.
Daily versus three-times-weekly IFN alfacon-1 in previously
untreated HCV patients results in a significant greater rate of SVR:
final results of an international phase 4 study. Gastroenterology 2005;
128(Supp. 2):A-716.
[13] Kaiser S, Hass HG, Gregor M. Successful retreatment of inter-
feron/ribavirin nonresponders with daily dosing of consensus
interferon. J Hepatol 2005;42(Suppl. 2):207–208.
[14] Carithers RL, Zeuzem S, Manns MP, McHutchison JG, Perrillo RP,
Bailey R, et al. Multicenter, randomized, controlled trail comparing
high dose daily induction interferon plus ribavirin versus standard
interferon alfa-2b plus ribavirin. Hepatology 2000;32:317A.
[15] Fried MW, Shiffman M, Sterling RK, Weinstein J, Crippin J,
Garcia G, et al. A multicenter, randomized trial of daily high-dose
interferon-alfa 2b for the treatment of chronic hepatitis c: pretreatment
stratification by viral burden and genotype. Am J Gastroenterol 2000;
95:3225–3229.
[16] Hadziyannis AS, Papaioannou C, Spanou F, Manesis EK,
Hadziyannis SJ. Induction interferon therapy in naive patients with
chronic hepatitis C: increased end-of-treatment virological responses
but absence of long-term benefit. Aliment Pharmacol Ther 2001;15:
551–557.
[17] Cotler SJ, Layden JE, Neumann AU, Jensen DM. First phase hepatitis
c viral kinetics in previous nonresponders patients. J Viral Hepat
2003;10:43–49.
[18] Layden TJ, Layden JE, Reddy KR, Levy-Drummer RS, Poulakos J,
Neumann AU. Induction therapy with consensus interferon (CIFN)
does not improve sustained virologic response in chronic hepatitis C.
J Viral Hepat 2002;9:334–339.
[19] Ishak K, Baptista A, Bianchi L, Callea F, De Groote J, Gudat F, et al.
Histological grading and staging of chronic hepatitis. J Hepatol 1995;
22:696–699.
[20] Pockros PJ, Reindollar R, McHutchinson J, Reddy R, Wright T,
Boyd DG, et al. The safety and tolerability of daily infergen plus
ribavirin in the treatment of naiive chronic hepatitis C patients. J Viral
Hepat 2003;10:55–60.
[21] McHutchison JG, Manns M, Patel K, Poynard T, Lindsay KL,
Trepo C, et al. Adherence to combination therapy enhances sustained
response in genotype-1-infected patients with chronic hepatitis C.
Gastroenterology 2002;123:1061–1069.
[22] Krawitt EL, Ashikaga T, Gordon SC, Ferrentino N, Ray MA,
Lidofsky SD. Peginterferon alfa-2b and ribavirin for treatment-
refractory chronic hepatitis C. J Hepatol 2005;43:243–249.
[23] Moskovitz DN, Manoharan P, Heathcote EJ. High dose consensus
interferon in nonresponders to interferon alpha-2b and ribavirin with
chronic hepatitis C. Can J Gastroenterol 2003;17:479–482.