HEPATITIS
Peginterferon alfa-2a (40KD) plus ribavirin in
chronic hepatitis C patients who failed previous
interferon therapy

M Sherman, E M Yoshida, M Deschenes, M Krajden, V G Bain, K Peltekian,
F Anderson, K Kaita, S Simonyi, R Balshaw, S S Lee, the Canadian Pegasys Study
Group
 

...............................................................................................................................
 

Gut 2006;55:1631–1638. doi: 10.1136/gut.2005.083113

Background: The management of patients with chronic hepatitis C who have relapsed or failed to respond

to interferon based therapies is an important issue facing hepatologists.

Aims: We evaluated the efficacy and safety of peginterferon alfa-2a (40KD) plus ribavirin in this

population by conducting a multicentre open label study.
See end of article for Patients: Data from adults with detectable serum hepatitis C virus (HCV) RNA who had not responded or

authors’ affiliations

had relapsed after previous conventional interferon or conventional interferon/ribavirin combination

.......................
therapy were analysed.
Correspondence to: Methods: Patients were retreated with peginterferon alfa-2a (40KD) 180 mg/week plus ribavirin 800 mg/day

Dr M Sherman, Toronto

General Hospital, 200 for 24 or 48 weeks at the investigators’ discretion. The study was conceived before the optimal dose of ribavirin
Elizabeth St, Toronto, (1000/1200 mg/day) for patients with genotype 1 was known. The primary endpoint was sustained
Ontario, M5G 2C4 virological response (SVR), defined as undetectable HCV RNA (,50 IU/ml) after 24 weeks of follow up. The
Canada; morris.sherman@ analysis was conducted by intention to treat.

uhn.on.ca

Results: A total of 312 patients (212 non-responders, 100 relapsers) were included. Of these, 28 patients
Revised version received were treated for 24 weeks and 284 for 48 weeks. Baseline characteristics between non-responders and
7 April 2006 relapsers were similar although more non-responders had genotype 1 infection (87% v 69%). Overall SVR
Accepted for publication rates were 23% (48/212) for non-responders and 41% (41/100) for relapsers. When data were analysed

25 April 2006

Published online first by genotype, SVR rates were 24% (61/253) in genotype 1 and 47% (28/59) in genotype 2/3.
27 June 2006 Conclusions: These results in a large patient cohort demonstrate that it is possible to cure a proportion of
....................... previous non-responders and relapsers by retreating with peginterferon alfa-2a (40KD) plus ribavirin.

Pegylated interferon in combination with ribavirin is the obtained with pegylated interferon/ribavirin combination
current treatment of choice for chronic hepatitis C,1 therapy among treatment naive patients, retreatment of prior
producing sustained virological response (SVR) rates of non-responders and relapsers with this combination is an
up to 63% in treatment na.¨ve patients.2–4 Prior to the area of growing interest.
availability of pegylated interferons, the standard therapy Recently, Shiffman et al reported an SVR rate of 18% using
for chronic hepatitis C was conventional interferon mono-the combination of peginterferon alfa-2a (40KD) plus
therapy or conventional interferon plus ribavirin, which ribavirin in a large cohort of previous non-responders to
produced SVR rates of 5–19% and 31–49%, respectively.5–8 As conventional interferon mono-or combination therapy.14
such, a substantial proportion of patients had already been However, these results were obtained in the context of a
unsuccessfully treated with conventional interferon based randomised controlled clinical trial sponsored by the National
regimens when the pegylated interferons were introduced. As Institutes of Health (the Hepatitis C Antiviral Long-Term
chronic infection with the hepatitis C virus (HCV) may result Treatment Against Cirrhosis study; ‘‘HALT-C’’), and it is not
in cirrhosis, liver failure, and hepatocellular carcinoma,19 known whether this response rate can be replicated in clinical
these patients remain at risk of developing progressive liver practice. In another clinical trial, Krawitt and colleagues15
disease, and their retreatment is a focus of ongoing clinical reported overall response rates of 20% for prior non-
investigation. responders and 55% for prior relapsers when retreated with

Patients who fail interferon therapy can be classified as peginterferon alfa-2b and ribavirin.
non-responders (those failing to clear HCV from serum at any In order to assess the efficacy and safety of peginterferon
time point during treatment) and relapsers (those who clear alfa-2a (40KD) with or without ribavirin in patients who had
HCV during treatment only to relapse either while on therapy failed previous therapy with non-pegylated interferons, we
(‘breakthrough’) or after completion of treatment). A conducted an open label study designed to be representative
different pattern of response is generally seen in these two of routine clinical practice.
groups, with retreatment being more effective among
patients who have achieved a partial response to their

previous treatment.10 Using conventional interferon plus
Abbreviations: ALT, alanine aminotransferase; HCV, hepatitis C virus;
ribavirin, retreatment of patients who had previously failed SVR, sustained virological response; EVR, early virological response;
conventional interferon monotherapy has produced SVR BMI, body mass index; ITT, intent to treat; NPV, negative predictive
rates of up to 15%.10–13 Given the increased SVR rates now value; PPV, positive predictive value

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Sherman, Yoshida, Deschenes, et al

METHODS

This was an open label, non-controlled, multicentre study
conducted at 18 Canadian centres, from April 2001 to June
2004, as part of a larger multinational trial (study BV16209).
We recruited both treatment naive and previously treated
patients; this paper presents the results from the Canadian
cohort of previously treated patients. The study was designed
and initiated before the optimal treatment regimens for HCV
genotype 1 (48 weeks of treatment; ribavirin 1000/1200 mg/
day) and genotypes 2/3 (24 weeks of treatment; ribavirin
800 mg/day) were determined.3 The study protocol was
approved by the institutional ethics committees at each site
and was conducted according to the Declaration of Helsinki.16
Written informed consent was obtained from each patient
prior to starting treatment.

Patients

We recruited male and female outpatients aged >18 years
with serological evidence of chronic hepatitis C by an anti-
HCV antibody test and quantifiable serum HCV RNA
(.600 IU/ml; Cobas Amplicor HCV Monitor, v2.0, Roche
Diagnostics, Basel, Switzerland). All patients were required to
have a liver biopsy prior to starting treatment that showed
findings consistent with a diagnosis of chronic hepatitis C
infection. Patients with bridging fibrosis/cirrhosis (defined
as F3 or F4 disease using the METAVIR scoring system)
were not excluded but were required to have Child-
Pugh grade A compensated liver disease. Patients with
persistently ‘‘normal’’ alanine aminotransferase (ALT) activity could participate if they had a liver biopsy result
consistent with a diagnosis of chronic hepatitis C and >F2
liver disease.

Patients had to have failed >12 weeks of previous
therapy with either conventional interferon monotherapy or
conventional interferon/ribavirin combination therapy.
Previous treatment regimens included conventional interferon alfa-2a or -2b monotherapy or consensus interferon
monotherapy, or combination therapy with interferon alfa-2b
plus ribavirin. We excluded patients previously treated with
pegylated interferon treatment regimens. Other exclusion
criteria were: hepatic decompensation; haemoglobin ,10 g/dl;
neutrophils ,1500 cells/ml; platelets ,90 000 cells/ml;
autoimmune disease; uncontrolled major psychiatric syndromes; or active substance abuse. Human immunodeficiency virus positive individuals, those with other liver
diseases, or significant disease of other organs were also
excluded.

Treatment

Patients were treated with one of three regimens:

(1) peginterferon alfa-2a (40KD) monotherapy for 48 weeks;
(2) combination therapy with peginterferon alfa-2a (40KD)
plus ribavirin for 24 weeks; or
(3) combination therapy with peginterferon alfa-2a (40KD)
plus ribavirin for 48 weeks.
All patients were followed for a further 24 weeks without
treatment. The treatment algorithm was decided at the
investigator’s discretion. Peginterferon alfa-2a (40KD)
(Pegasys, Roche, Basel Switzerland) was administered subcutaneously at a dose of 180 mg once weekly. Ribavirin
(Copegus; Roche, Basel, Switzerland) was administered
orally at a dose of 800 mg/day in divided doses (400 mg
twice daily). The chosen ribavirin dose of 800 mg/day was
reflective of clinical practice at that time. Doses of peginterferon alfa-2a (40KD) or ribavirin were adjusted for side
effects according to the manufacturer’s recommendations.

Assessments

Quantitative viral titres were obtained at weeks 0 and 12
(Cobas Amplicor HCV Monitor, v2.0; lower limit of detection
600 IU/ml) in all patients. A qualitative HCV RNA assay
(Cobas Amplicor HCV Test, v2.0; lower limit of detection
50 IU/ml) was performed at week 12 only in those patients
who had a low viral load at baseline (.600 IU/ml to
,60 000 IU/ml). Qualitative HCV RNA results were obtained
after 24 weeks of treatment free follow up (week 48 in the
24 week treatment group and week 72 in the 48 week
treatment group). The primary efficacy endpoint was SVR,
defined as undetectable HCV RNA (,50 IU/ml; Cobas
Amplicor HCV Monitor, v2.0) 24 weeks after the last dose
of study medication (week 48 in the 24 week group and week
72 in the 48 week group).

Laboratory parameters were monitored and recorded at
regular intervals throughout the study period and a physical
examination was conducted at the end of treatment. Adverse
events and serious adverse events were recorded throughout
the study and up to week 12 of the follow up period.

Early discontinuation of treatment

It was recommended that treatment be withdrawn in
patients who did not achieve an early virological response
(EVR) by week 12. EVR was defined as a decrease in viral
titre of >2-log10 compared with baseline or a negative HCV
RNA (,50 IU/ml; Cobas Amplicor HCV Monitor, v2.0) result
at week 12 of therapy. After discontinuation, patients who
did not achieve EVR were assessed for safety 4–8 weeks after
their last dose of study drug.

Statistical analysis

No formal sample size calculation was performed. Data were
collected and analysed by the Syreon Corporation (British
Columbia, Canada) on an intention to treat (ITT) basis. The
ITT population was defined as all patients who received >1
dose of study medication.

Data were analysed according to the patients’ prior
treatment outcome (non-responders v relapsers), HCV
genotype (1 v 2/3), and previous treatment (conventional
interferon monotherapy v conventional interferon combined
with ribavirin). Non-response to previous therapy was
defined as failure to achieve suppression of HCV RNA to
below the limit of detection at any time point during
treatment. Relapse during or after previous therapy was
defined as reversion to an HCV RNA positive state after
suppression of HCV RNA below the limit of detection while
on therapy or during follow up. This definition of relapse also
included patients with ‘‘breakthrough’’ quantifiable HCV
RNA.

The analysis excluded patients infected with genotypes other
than 1, 2, or 3 due to the small number of patients involved. As
pegylated interferon monotherapy is no longer widely used in
clinical practice, patients who received peginterferon alfa-2a
(40KD) monotherapy (treatment group 1) were also excluded
from the analysis. Patients for whom a post-therapy HCV RNA
result was not available or who were otherwise lost to follow up
were considered treatment failures.

Multivariate logistic regression models were used to
determine significant predictors of SVR for the relapser and
non-responder patient groups. Each model included parameters for genotype (1 v 2/3), age (years), race (Caucasian v
other), sex, weight (kg), body mass index (BMI), METAVIR
fibrosis score (F0, F1, F2 v F3, F4), and log of viral load (IU/
ml).

Efficacy and safety data are presented using descriptive
statistics. The positive predictive value (PPV) (that is, the
probability of achieving an SVR among those patients who
achieved an EVR at week 12) and the negative predictive

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Peginterferon alfa-2a plus ribavirin in chronic hepatitis C

1074 patients
Enrolled in Canada
(previously treated and treatment naïve)
361 patients
Previously treated meeting inclusion criteria
212 patients
Non responders
100 patients
Relapsers
199 patients
Treated with peginterferon
alfa 2a (40KD) plus ribavirin for
48 weeks
49 patients
Excluded from analysis*
13 patients
Treated with peginterferon
alfa 2a (40KD) plus ribavirin for
24 weeks
15 patients
Treated with peginterferon
alfa 2a (40KD) plus ribavirin for
24 weeks
85 patients
Treated with peginterferon
alfa 2a (40KD) plus ribavirin for
48 weeks
0 patients genotype 1
13 patients genotype 2 or 3
184 patients genotype 1
15 patients genotype 2 or 3
0 patients genotype 1
15 patients genotype 2 or 3
69 patients genotype 1
16 patients genotype 2 or 3
3 patients
Withdrew early
1 patient due to AEs or
lab abnormalities
1 patient due to non response
1 patient lost to follow up
107 patients
Withdrew early
79 patients due to non response
11 patients due to AEs or
lab abnormalities
8 patients lost to follow up
7 patients for other reasons
2 patients for personal reasons
3 patients
Withdrew early
2 patients due to AEs or
lab abnormalities
1 patient due to non response
20 patients
Withdrew early
10 patients due to non response
3 patients due to AEs or
lab abnormalities
3 patients lost to follow up
3 patients for other reasons
1 patient for personal reasons
Figure 1 Patient disposition. AEs, adverse events. *Received hepatitis C virus (HCV) medications other than conventional/consensus interferon based
therapies (n = 33); infected with HCV genotypes other than 1, 2, or 3 (n = 11); received peginterferon alfa-2a (40KD) monotherapy (n = 6); and one

patient excluded due to two of these reasons.

value (NPV) (that is, the probability of not achieving an SVR
for those patients who failed to achieve an EVR) were
calculated.

RESULTS
Study population

Patient disposition is shown in fig 1. Information on the total
number of patients screened but not included in the study
was not recorded. Overall, 1074 Canadian patients (including
treatment naive and previously treated patients) were
enrolled. Of these, 361 previously treated patients met the
study inclusion criteria. The results for the treatment naive
population are reported elsewhere.17 Forty nine of 361
previously treated patients were excluded from the analysis.
This included 33 patients who had received prior unsuccessful therapy with HCV medications other than conventional
interferon and 11 patients who were infected with HCV
genotypes other than 1, 2, or 3. In addition, six patients who
were retreated with pegylated interferon monotherapy
(treatment group 1) were also excluded. One patient was
excluded for two of the aforementioned reasons. Thus data
from 312 non-responder/relapser patients retreated with
peginterferon alfa-2a (40KD) plus ribavirin were available
for analysis.

A total of 253 patients (81%) were infected with HCV
genotype 1, and 59 (19%) were infected with either genotype
2 or 3. The majority of patients (n = 244; 78%) had been
previously treated with conventional interferon/ribavirin
combination therapy. Of these, 77 were relapsers and 167
were non-responders. Sixty eight patients (22%) had
previously been treated with conventional interferon mono-
therapy, of whom 23 and 45 were prior relapsers and prior
non-responders, respectively (table 1).

Most patients (n = 284; 91%) were retreated with peg-
interferon alfa-2a (40KD) plus ribavirin for 48 weeks; only 28
patients received 24 weeks of treatment. Table 1 shows
patient demographics and baseline characteristics according
to treatment regimen. In total, 280 patients (90%) were
Caucasian. The 48 week treatment group contained a higher
proportion of men (71% v 64%). More patients were infected
with HCV genotype 1 in the non-responder group versus the
relapser group (87% v 69%). All patients infected with HCV
genotype 1 received 48 weeks of treatment. Of note,
approximately one half of all patients (n = 154; 49%) were
found to have histological evidence of bridging fibrosis
(METAVIR F3) or cirrhosis (METAVIR F4) on liver biopsy.
In total, 81 (26%) had a histological score of F4 while a
further 73 (23%) had a score of F3.

Efficacy of peginterferon alfa-2a (40KD) plus ribavirin
in the retreatment of patients with chronic hepatitis C

Table 2 provides a summary of efficacy data. A greater
proportion of relapsers (84/100; 84%) achieved an EVR at
week 12 compared with non-responders (123/212; 58%). EVR
status was unknown in 12 patients.

In total, 48/212 previous non-responders (23%) and 41/100
(41%) relapsers achieved an SVR (table 2, fig 2). When data
were analysed according to HCV genotype, an SVR was
observed in 61/253 (24%) genotype 1 patients and in 28/59
(47%) genotype 2 or 3 patients.

Efficacy of peginterferon alfa-2a (40KD) plus ribavirin
according to previous treatment

Conventional interferon monotherapy

The overall response rate was higher in relapsers compared
with non-responders (fig 2). In total, 27% (12/45) of previous

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Sherman, Yoshida, Deschenes, et al

Table 1 Patient demographics and baseline characteristics
Peginterferon alfa-2a (40KD) +ribavirin
24 week (n = 28) 48 weeks (n = 284) Total (n = 312)
Sex (n (%) male) 18/28 (64.3) 202/284 (71.1) 220/312 (70.5)
Mean age (y)
Non-responders 45.1 47.3 47.2
Relapsers 48.3 47.1 47.3
Caucasian (n (%))
Non-responders 11/13 (84.6) 178/199 (89.9) 189/312 (60.6)
Relapsers 15/15 (100) 76/85 (89.4) 91/312 (29.2)
Asian (n (%))
Non-responders 1/13 (7.7) 13/199 (6.5) 14/312 (4.5)
Relapsers 0/15 (0) 7/85 (8.2) 7/312 (2.2)
Other race (n (%))
Non-responders 1/13 (7.7) 8/199 (4.0) 9/312 (2.9)
Relapsers 0/15 (0) 2/85 (2.4) 2/312 (0.6)
Mean BMI (kg/m2)
Non-responders 24.7 27.7 27.5
Relapsers 27.1 27.3 27.3
HCV genotype (n (%))
Non-responders
1 0/13 (0.0) 184/199 (92.5) 184/312 (86.8)
2 or 3 13/13 (100.0) 15/199 (7.5) 28/312 (13.2)
Relapsers
1 0/15 (0.0) 69/85 (81.2) 69/312 (69.0)
2 or 3 15/15 (100.0) 16/85 (18.8) 31/312 (31.0)
HCV viral load (IU/ml) (n (%))
Non-responders
.850 000 1/13 (7.7) 63/199 (31.7) 64/312 (30.2)
(850 000 12/13 (92.3) 136/199 (68.3) 148/312 (69.8)
Relapsers
.850 000 6/15 (40.0) 34/85 (40.0) 40/312 (40.0)
(850 000 9/15 (60.0) 51/85 (60.0) 60/312 (60.0)
Bridging fibrosis (F3) (n (%))
Non-responders 5/13 (38.5) 43/199 (21.6) 48/312 (15.4)
Relapsers 1/13 (7.7) 24/199 (12.1) 25/312 (8.0)
Cirrhosis (F4)
Non-responders 2/15 (13.3) 56/85 (65.9) 58/312 (18.6)
Relapsers 7/15 (46.7) 16/85 (18.8) 23/312 (7.4)
Previous HCV therapy (n (%))
Non-responders
Monotherapy 5/13 (38.5) 40/199 (20.1) 45/312 (21.2)
Combination therapy 8/15 (61.5) 159/85 (79.9) 167/312 (78.8)
Relapsers
Monotherapy 8/13 (53.3) 15/199 (17.7) 23/312 (23.0)
Combination therapy 7/15 (46.7) 70/85 (82.4) 77/312 (77.0)
BMI, body mass index; HCV, hepatitis C virus.
Monotherapy, interferon alfa-2b, interferon alfa-2a, interferon alfacon-1
Combination therapy, interferon alfa-2b plus ribavirin.
non-responders to conventional interferon monotherapy had
an SVR. For patients infected with HCV genotype 1, 22% (8/
36) had an SVR, and for patients with HCV genotype 2 or 3,
the SVR rate was 44% (4/9).

In patients who had relapsed during prior interferon
monotherapy, the overall percentage of patients with an
SVR was 52% (12/23). The percentage of genotype 1 patients

with an SVR was 47% (7/15), and the percentage of genotype
2/3 patients with an SVR was 63% (5/8).

Conventional interferon/ribavirin combination
therapy

Overall, 22% (36/167) of non-responders to prior interferon
combination therapy had an SVR. For those with genotype 1

Table 2 Early virological response (EVR) and sustained virological response (SVR)
following retreatment with peginterferon alfa-2a (40KD) plus ribavirin
Peginterferon alfa-2a (40KD) +ribavirin
24 weeks (n = 28) 48 weeks (n = 284) Total (n = 312)
EVR (n (%))*
Non-responders 11/13 (84.6) 112/199 (56.3) 123/212 (58.0)
Relapsers 11/15 (73.3) 73/85 (85.9) 84/100 (84.0)
SVR (n (%))
Non-responders 5/13 (38.5) 43/199 (21.6) 48/212 (22.6)
Relapsers 8/15 (53.3) 33/85 (38.8) 41/100 (41.0)
*Decrease in hepatitis C virus (HCV) RNA >2-log10, or undetectable HCV RNA (,50 IU/ml) at week 12 of
therapy.
Negative HCV RNA (,50 IU/ml) at the end of 24 weeks of untreated follow up.
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Peginterferon alfa-2a plus ribavirin in chronic hepatitis C


Figure 2 Sustained virological response (SVR) in non-responder and
relapse groups by genotype.

infection, the SVR rate was 20% (29/148) and for genotype 2/
3 infection it was 37% (7/19).

Of those who relapsed after previous combination therapy,
the overall percentage of patients with an SVR was 38% (29/
77). In genotype 1 patients, the SVR rate was 31% (17/54),
and in genotype 2/3 patients, 52% (12/23) (fig 2).

Predictors of response to peginterferon alfa-2a
(40KD) plus ribavirin

Efficacy data from each group were analysed separately in
the logistic regression analysis. For relapser patients, HCV
genotype (p = 0.0178), race (Caucasian v non-Caucasian;
p = 0.0225) and HCV viral load (p = 0.0005) were significant
predictors of SVR (table 3). For previous non-responders, sex
(p = 0.0107), weight (p = 0.0435), BMI (p = 0.0118), fibrosis
(p = 0.0158), and viral load (p = 0.0113) were significant
predictors of SVR (table 3).

Predictability at week 12

There were too few genotype 2 or 3 patients to examine the
predictability of a week 12 virological response. Data for
patients infected with genotype 1 are shown in fig 3.

Non-responders to previous HCV therapy

Of the genotype 1 non-responders to previous HCV therapy
(n = 184), EVR data were not available for six patients. Of the


Figure 3 (A) Week 12 predictability in previous non-responders
infected with hepatitis C virus (HCV) genotype 1. EVR, early virological
response; NPV, negative predictive value; SVR, sustained virological
response. *HCV RNA unquantifiable (,600 IU/ml) or drop of >2-log10
by polymerase chain reaction at week 12. Six patients EVR unknown.

(B) Week 12 predictability in previous relapsers infected with HCV
genotype 1. *HCV RNA unquantifiable (,600 IU/ml) or drop of >2log10
by polymerase chain reaction at week 12. Two patients EVR
unknown
remaining 178 patients, more than half (57%) had an EVR
and 37% went on to have an SVR. Of the 77 patients without
an EVR, none achieved an SVR (NPV = 100%) (fig 3A).

RelapserstopreviousHCV therapy

Of those with HCV genotype 1, 87% achieved an EVR, and
40% had an SVR. For genotype 1 patients who failed to
achieve EVR, the NPV for non-response was 100% (fig 3B).

The majority of genotype 1 infected patients who had an
EVR (122 of 159 patients; comprising 51 relapsers and 71
non-responders) achieved a >2-log10 drop in HCV RNA at
week 12 and were also below the limit of quantitation (HCV
RNA ,600 IU/ml). Of these, 52/122 went on to achieve an

Table 3 Logistic regression analysis of factors predictive of sustained virological
response in relapsers and non-responders
Parameter Odds ratio 95% CL p Value
Relapsers (n = 94)
Genotype (1 v 2 or 3) 0.263 0.087 0.793 0.0178
Age (y) 0.981 0.916 1.049 0.5723
Race (Caucasian v non-Caucasian) 0.098 0.013 0.720 0.0225
Sex (male v female) 0.704 0.178 2.779 0.6159
Weight (kg) 0.952 0.890 1.018 0.1482
BMI (kg/m2) 1.053 0.865 1.282 0.6085
Fibrosis (F0, F1, F2 v F3, F4) 2.394 0.801 7.157 0.1181
Log HCV viral load 0.436 0.273 0.697 0.0005
Non-responders (n = 198)
Genotype (1 v 2 or 3) 0.383 0.143 1.021 0.0551
Age (y) 0.973 0.926 1.022 0.2682
Race (Caucasian v non-Caucasian) 0.342 0.115 1.015 0.0533
Sex (male v female) 3.850 1.367 10.843 0.0107
Weight (kg) 1.058 1.002 1.117 0.0435
BMI (kg/m2) 0.785 0.650 0.948 0.0118
Fibrosis (F0, F1, F2 v F3, F4) 2.513 1.189 5.311 0.0158
Log HCV viral load 0.670 0.492 0.913 0.0113
BMI, body mass index; HCV, hepatitis C virus; 95% CL, 95% confidence limits.
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Sherman, Yoshida, Deschenes, et al

Table 4 Laboratory abnormalities and dose modifications
Abnormality (n (%))
Peginterferon alfa-2a (40KD) +ribavirin
24 weeks (n = 28) 48 weeks (n = 284)
Neutropenia*Grade 3
Non-responders 2 (15.4) 37 (18.6)
Relapsers 2 (13.3) 20 (23.5)
Grade 4
Non-responders 0 (0%) 2 (1.0)
Relapsers 0 (0%) 2 (2.4)
Dose modification for neutropenia Non-responders 2 (15.4) 37 (18.6)
Relapsers 2 (13.3) 20 (23.5)
Thrombocytopenia`Grade 3
Non-responders 1 (7.7) 5 (2.5)
Relapsers 0 (0.0) 6 (7.1)
Dose modification for thrombocytopenia Non-responders 1 (7.7) 11 (5.5)
Relapsers 0 (0.0) 6 (7.1)
Anaemia1Hb ,10 g/dl
Non-responders 0 (0.0) 15 (7.5)
Relapsers 1 (6.7) 9 (10.6)
Dose modification for anaemia Non-responders 0 (0.0) 14 (7.0)
Relapsers 1 (6.7) 9 (10.6)
ALT elevation**Non-responders 0 (0.0) 4 (2.0)
Relapsers 0 (0.0) 0 (0.0)
Dose modification for ALT elevation Non-responders 0 (0.0) 3 (1.5)
Relapsers 0 (0.0) 0 (0.0)
ALT, alanine aminotransferase; Hb, haemoglobin.
*Grade 3 neutropenia defined as an absolute neutrophil count of 500–700 cells/ml; grade 4 neutropenia defined
as an absolute neutrophil count of ,500 cells/ml.
Deemed related to peginterferon alfa-2a (40KD).
`Grade 3 thrombocytopenia defined as ,50 000 platelets/ml.
1Anaemia defined as Hb ,10 g/dl.
Deemed related to ribavirin.
**ALT elevation defined as a progressive increase in ALT over baseline values.
SVR (PPV = 43%). The numbers of patients who achieved a
2-log10 drop in HCV RNA, but remained above the limit of
quantitation (.600 IU/ml; n = 19), and the number of
patients whose HCV RNA was undetectable (,50 IU/ml;
n = 10) were too small to allow any meaningful comparison
of predictability using different criteria to be made.

Safety and tolerability

Twelve patients in the non-responder group (6%) and five
patients in the relapser group (5%) prematurely withdrew
from the study due to adverse events. The withdrawal rate
due to adverse events in the 24 week group (3/28; 11%) was
more than double that in the 48 week group (14/284; 5%)
(fig 1).

The most frequent non-serious adverse events were
neutropenia (24%), anaemia (9%), and thrombocytopenia
(7%). Fifteen patients (5%) reported a total of 16 different
serious adverse events. No difference in the frequency of
serious or non-serious adverse events was seen between the
non-responder and relapser groups.

Table 4 details laboratory abnormalities and resulting dose
modifications. The incidences of neutropenia, thrombocytopenia, anaemia, and ALT elevations were higher in the
48 week treatment group than in the 24 week group.
Neutropenia was the most common cause of dose modifications (14220% of patients).

Early withdrawal from the study

Premature withdrawals are shown for each treatment group
in fig 1. In the prior non-responder group, 110 of 212 patients
(52%) withdrew from the study early. In the relapser group,
the withdrawal rate was lower (23/100 patients; 23%). The
main reason for early withdrawal in both groups was non-
response to study medication (80/212 (38%) of non-responders and 11/100 (11%) relapsers). Although the study
protocol recommended that patients who were HCV RNA
positive at week 12 stop treatment, 71/93 patients without an

EVR at week 12 were maintained on therapy at the discretion
of the investigator or at the insistence of the patient.

DISCUSSION

At present there are limited data available on the efficacy of
retreating previous treatment failures with pegylated interferon plus ribavirin. Here we report SVR data for previous
treatment failures who were retreated with peginterferon
alfa-2a (40KD) plus ribavirin. This relatively large cohort of
patients underwent treatment as part of standard clinical
care. We defined previous treatment failure as either non-
response or relapse. In non-responders, patients were positive
for HCV RNA at all times during previous therapy. There is
some uncertainty in this definition because the frequency of
HCV RNA testing during the previous course of therapy was
not specified, and it is possible that HCV RNA could have
been transiently below the limit of quantitation. Relapsers
were defined as those who initially responded to therapy by
clearing virus from serum, only to become HCV RNA positive
once more, either during treatment or after treatment was
complete. This definition also includes patients with ‘‘breakthrough’’ viraemia during treatment.

Several studies presented as abstracts have reported that
the percentage of patients achieving an SVR when retreated
with peginterferon plus ribavirin varies from 10% to 20%.18–21
In the first reported study in this population to date, which
was conducted exclusively in non-responder patients with
advanced fibrosis/cirrhosis, 18% of patients reported an SVR
following retreatment with peginterferon alfa-2a (40KD)
plus ribavirin.14 Krawitt and colleagues15 have recently
reported their results in retreating patients who failed
previous interferon based therapy with pegylated interferon
alfa-2b plus ribavirin. Our results are similar to those
reported by Krawitt and colleagues.15 Direct comparisons
are difficult because Krawitt et al did not stratify their results
in the same manner as we did. For example, in their study,
prior genotype 1 non-responders to any treatment had an

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Peginterferon alfa-2a plus ribavirin in chronic hepatitis C

SVR of 17% whereas in our study non-responders to prior
monotherapy had a 22% SVR rate, and non-responders to
prior combination therapy had an SVR rate of 20% with
retreatment. Both studies showed that the response in
genotypes 2 or 3 was better than in genotype 1, and that
relapsers responded better than prior non-responders. Both
studies also showed that patients who failed prior mono-
therapy did better than those who failed prior combination
therapy. In our study, the SVR rate in those who failed
conventional interferon monotherapy was 35%, and in those
who failed conventional interferon/ribavirin combination
therapy, 27%.

Since this study was conducted, it has been recognised that
the optimal dose of ribavirin for patients infected with HCV
genotype 1 is 1000/1200 mg/day dosed according to body
weight, and that these patients should be treated for
48 weeks.13 We used a ribavirin dose (800 mg/day) that
would now be recognised as inadequate for genotype 1. Had
all genotype 1 patients in our study been treated with the
optimal ribavirin dose, the overall response rate would likely
have been higher.

As expected, the SVR rate was higher in those who had
relapsed during previous treatment (41%) than in those who
were previous non-responders (23%), which both compare
favourably with the SVR rate reported by Shiffman and
colleagues14 and Krawitt and colleagues.15 Consistent with
previous findings,2–4 patients with HCV genotype 2 or 3
infection showed a higher SVR rate (48%) than those
infected with genotype 1 (24%). In this study, the percentage
of genotype 1 infected relapsers who had an SVR was 35%
compared with 46251% reported in treatment na.¨ve patients
in the large registration studies using an optimal dose of
ribavirin.2–4 For genotype 2/3 relapsers, our study found an
SVR rate of 55% compared with a previously reported rate of
76–78% for treatment naive patients.2–4 Unfortunately, the
relatively small number of patients with HCV genotype 2 or 3
in this study (n = 59) meant it was not possible to make a
meaningful comparison of the response rates between the
two genotypes, or to accurately assess whether retreatment
for 48 weeks produces better response rates than retreatment
for 24 weeks.

In clinical trials of peginterferon plus ribavirin combination
therapy, absence of an EVR at week 12 has been shown to
have a high NPV for the probability of achieving an SVR.222 23
In the study of peginterferon alfa-2a (40KD) plus ribavirin by
Fried et al, 97% of those who did not have an EVR failed to
achieve an SVR, and 65% of patients with an EVR
subsequently achieved an SVR.2 Due to the sensitivity of this
assessment, EVR has become widely used in clinical practice
to identify patients who are unlikely to respond to ongoing
therapy. Early discontinuation of treatment can be considered in these patients because the likelihood of a long term
response is so poor. Our study confirms that lack of an EVR is
an accurate predictor of non-response, as no patient who
failed to achieve an EVR subsequently went on to achieve an
SVR (overall NPV = 100%). Thus, the week 12 ‘‘decision
point’’ is also valid in retreatment of previous non-responders
and relapsers.

Our study was conducted in a combined academic/
community setting and was intended to be reflective of
practice conditions in most communities. Although there is a
perception that it may be difficult to replicate the efficacy
rates of randomised clinical trials in routine clinical practice,
we were able to achieve a comparable SVR rate to Shiffman
and colleagues.14 Furthermore, the adverse event discontinuation rate in the present study was comparable with those
seen in the large scale registration studies of peginterferon
alfa-2a (40KD) plus ribavirin.23 Withdrawals due to adverse
events were more frequent among patients treated for

24 weeks compared with those treated for 48 weeks (11% v
5%). However, this is likely a statistical anomaly because of
the small number of patients in the 24 week treatment
group. Successful outcome of therapy in this study is likely
related to the availability of expert nursing assistance within
many of the centres, which may have contributed substantially to maintaining patients on therapy. All of the
physicians participating in the study were highly experienced
in the management of chronic hepatitis C. We believe that
these factors were crucial in our ability to obtain such good
results. In addition, using similar eligibility criteria as the
pivotal trials of peginterferon alfa-2a (40KD)/ribavirin meant
that potentially problematic patients such as those with
decompensated cirrhosis or ongoing substance abuse were
excluded. This may have further contributed to the good SVR
rate in our study.

In the HALT-C study, 18% of previous non-responders
retreated with peginterferon alfa-2a (40KD) plus ribavirin
achieved an SVR.14 This cohort was treated with ribavirin
1000/1200 mg/day but was also composed exclusively of
patients with advanced fibrosis/cirrhosis. In contrast, in our
study, 49% of patients had bridging fibrosis/cirrhosis. As the
presence of advanced fibrosis and cirrhosis is independently
associated with a decreased SVR rate,24 25 the lower proportion of such patients included in our study may explain why
our results appear better than those of Shiffman and
colleagues,14 despite the suboptimal dose of ribavirin used
in genotype 1 patients in our study.

In conclusion, the results obtained using peginterferon
alfa-2a (40KD) plus ribavirin suggest that there is merit in
retreating patients who failed either conventional interferon
monotherapy or conventional interferon plus ribavirin
combination therapy, and that acceptable response rates
can be achieved in clinical practice. Even in the most
refractory patient group, genotype 1 non-responders to
interferon plus ribavirin, an SVR rate of 20% was obtained.
The overall response rates of 23% for non-responders and
41% for relapsers may be improved further by using the
optimal dose of ribavirin according to genotype. In the future,
retreatment of previous non-responders to all interferon
based therapies, including pegylated interferon/ribavirin
combination therapy, will continue to be an important focus
of clinical trials, and future studies should aim to address
how we may optimise the therapeutic response to retreatment in this important group of patients.

ACKNOWLEDGEMENTS

The other contributing members of the Canadian Pegasys Study
Group were:
Robert Bailey, Royal Alexandra Hospital, Edmonton, Alberta,
Canada; Victor Feinman, Mount Sinai Hospital, Toronto, Ontario,
Canada; Susan Greenbloom, Toronto Digestive Disease Associates
Inc., Toronto, Ontario; Jenny Heathcote, University Health Network,
Toronto Western Hospital, Toronto, Ontario, Canada; Nir Hilzenrat,
Montreal Jewish General Hospital, Montreal, Quebec, Canada; Paul
Marotta, London Health Sciences Centre Research, London, Ontario,
Canada; Linda Scully, The Ottawa Hospital, Civic Campus, Ottawa,
Ontario, Canada; Bernard Willems, CHUM-Hoˆpital Saint-Luc,
Montreal, Quebec, Canada; Helga Witt-Sullivan, Hamilton Health
Sciences Corp. General Site, Hamilton, Ontario, Canada; Lawrence
Worobetz, Royal University Hospital, Saskatoon, Saskatchewan,
Canada.
We thank Amanda Yu and Rohinish Gunadasa, Syreon Corporation,
British Columbia, Canada, for statistical analysis and logistical
support, and Trisha Hutzul, Roche Mississauga, Ontario, Canada
for help with logistical issues in the early phases of the study.



Conflict of interest: declared (the declaration can be
viewed on the Gut website at http://www.gutjnl.com/
supplemental).

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Sherman, Yoshida, Deschenes, et al

.....................


Authors’ affiliations
M Sherman, University Health Network, Toronto General Hospital,
Toronto, Ontario, Canada
E M Yoshida, Vancouver Hospital Health Sciences Centre, Vancouver,
British Columbia, Canada
M Deschenes, Royal Victoria Hospital, Montreal, Quebec, Canada
M Krajden, British Columbia Centre for Disease Control, Vancouver,

British Columbia, Canada
V G Bain, University of Alberta, Edmonton, Alberta, Canada
K Peltekian, QEII-Health Sciences Centre, Hepatology Services, Halifax,

Nova Scotia, Canada
F Anderson, The Liver and Intestinal Research Centre, Vancouver, British
Columbia, Canada
K Kaita, Viral Hepatitis Investigative Unit, University of Manitoba,
Winninpeg, Manitoba, Canada
S Simonyi, Roche, Mississauga, Ontario, Canada
R Balshaw, Syreon Corporation, British Columbia, Canada
S S Lee, University of Calgary, Calgary, Alberta, Canada

The design, collection, analysis, and interpretation of data in the
Canadian extended access program, as well as the resulting manuscript,
were supported by a grant from Roche Canada.

Conflict of interest: None declared.

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