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: manns.michael@mh-hannover.de (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.

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