Peginterferon Alfa-2a plus Ribavirin for Chronic Hepatitis C Virus Infection

Abstract

Treatment with peginterferon alfa-2a alone produces significantly higher sustained virologic responses than treatment with interferon alfa-2a alone in patients with chronic hepatitis C virus (HCV) infection. We compared the efficacy and safety of peginterferon alfa-2a plus ribavirin, interferon alfa-2b plus ribavirin, and peginterferon alfa-2a alone in the initial treatment of chronic hepatitis C.
A total of 1121 patients were randomly assigned to treatment and received at least one dose of study medication, consisting of 180 microg of peginterferon alfa-2a once weekly plus daily ribavirin (1000 or 1200 mg, depending on body weight), weekly peginterferon alfa-2a plus daily placebo, or 3 million units of interferon alfa-2b thrice weekly plus daily ribavirin for 48 weeks.
A significantly higher proportion of patients who received peginterferon alfa-2a plus ribavirin had a sustained virologic response (defined as the absence of detectable HCV RNA 24 weeks after cessation of therapy) than of patients who received interferon alfa-2b plus ribavirin (56 percent vs. 44 percent, P<0.001) or peginterferon alfa-2a alone (56 percent vs. 29 percent, P<0.001). The proportions of patients with HCV genotype 1 who had sustained virologic responses were 46 percent, 36 percent, and 21 percent, respectively, for the three regimens. Among patients with HCV genotype 1 and high base-line levels of HCV RNA, the proportions of those with sustained virologic responses were 41 percent, 33 percent, and 13 percent, respectively. The overall safety profiles of the three treatment regimens were similar; the incidence of influenza-like symptoms and depression was lower in the groups receiving peginterferon alfa-2a than in the group receiving interferon alfa-2b plus ribavirin.
In patients with chronic hepatitis C, once-weekly peginterferon alfa-2a plus ribavirin was tolerated as well as interferon alfa-2b plus ribavirin and produced significant improvements in the rate of sustained virologic response, as compared with interferon alfa-2b plus ribavirin or peginterferon alfa-2a alone.

Full text

N Engl J Med, Vol. 347, No. 13
·
September 26, 2002
·
www.nejm.org
·
975
PEGINTERFERON ALFA-2a PLUS RIBAVIRIN FOR HEPATITIS C
PEGINTERFERON ALFA-2a PLUS RIBAVIRIN FOR CHRONIC HEPATITIS C
VIRUS INFECTION
M
ICHAEL
W. F
RIED
, M.D., M
ITCHELL
L. S
HIFFMAN
, M.D., K. R
AJENDER
R
EDDY
, M.D., C
OLEMAN
S
MITH
, M.D.,
G
EORGE
M
ARINOS
, M.D., F
ERNANDO
L. G
ONÇALES
, J
R
., M.D., D
IETER
H
ÄUSSINGER
, M.D., M
OISES
D
IAGO
, M.D.,
G
IAMPIERO
C
AROSI
, M.D., D
ANIEL
D
HUMEAUX
, M.D., A
NTONIO
C
RAXI
, M.D., A
MY
L
IN
, M.S., J
OSEPH
H
OFFMAN
, M.D.,
AND
J
IAN
Y
U
, M.D., P
H
.D.*
A
BSTRACT
Background
Treatment with peginterferon alfa-2a
alone produces significantly higher sustained virologic
responses than treatment with interferon alfa-2a alone
in patients with chronic hepatitis C virus (HCV) infec-
tion. We compared the efficacy and safety of peginter-
feron alfa-2a plus ribavirin, interferon alfa-2b plus ri-
bavirin, and peginterferon alfa-2a alone in the initial
treatment of chronic hepatitis C.
Methods
A total of 1121 patients were randomly
assigned to treatment and received at least one dose
of study medication, consisting of 180 µg of peginter-
feron alfa-2a once weekly plus daily ribavirin (1000
or 1200 mg, depending on body weight), weekly
peginterferon alfa-2a plus daily placebo, or 3 million
units of interferon alfa-2b thrice weekly plus daily ri-
bavirin for 48 weeks.
Results
A significantly higher proportion of patients
who received peginterferon alfa-2a plus ribavirin had
a sustained virologic response (defined as the ab-
sence of detectable HCV RNA 24 weeks after cessa-
tion of therapy) than of patients who received interfer-
on alfa-2b plus ribavirin (56 percent vs. 44 percent,
P<0.001) or peginterferon alfa-2a alone (56 percent
vs. 29 percent, P<0.001). The proportions of patients
with HCV genotype 1 who had sustained virologic re-
sponses were 46 percent, 36 percent, and 21 percent,
respectively, for the three regimens. Among patients
with HCV genotype 1 and high base-line levels of
HCV RNA, the proportions of those with sustained
virologic responses were 41 percent, 33 percent, and
13 percent, respectively. The overall safety profiles of
the three treatment regimens were similar; the inci-
dence of influenza-like symptoms and depression was
lower in the groups receiving peginterferon alfa-2a
than in the group receiving interferon alfa-2b plus ri-
bavirin.
Conclusions
In patients with chronic hepatitis C,
once-weekly peginterferon alfa-2a plus ribavirin was
tolerated as well as interferon alfa-2b plus ribavirin and
produced significant improvements in the rate of sus-
tained virologic response, as compared with interfer-
on alfa-2b plus ribavirin or peginterferon alfa-2a alone.
(N Engl J Med 2002;347:975-82.)
Copyright © 2002 Massachusetts Medical Society.
From the University of North Carolina, Chapel Hill (M.W.F.); the Med-
ical College of Virginia, Richmond (M.L.S.); the University of Miami, Mi-
ami (K.R.R .); Minnesota Clinical Research Center, St. Paul (C.S.); Prince
of Wales Hospital, Randwick, N.S.W., Australia (G.M.); Cidade Universitária
Zeferino Vaz, Campinas, Brazil (F.L.G.); Heinrich-Heine-Universität, Düs-
seldorf, Germany (D.H.); General Universitario, Valencia, Spain (M.D.);
Università degli Studi Brescia, Brescia, Italy (G.C.); Hôpital Henri Mondor,
Creteil, France (D.D.); University of Palermo, Palermo, Italy (A.C.); and Hoff-
mann–LaRoche, Nutley, N.J. (J.H., A.L., J.Y.). Address reprint requests to
Dr. Fried at the University of North Carolina, CB# 7080, R m. 708, Burnett
Womack Bldg., Chapel Hill, NC 27599.
*Other participants in the study are listed in the Appendix.
LTHOUGH the mechanism of action of
ribavirin remains speculative,
1
the current
standard of care for patients with chronic
hepatitis C is the addition of ribavirin to
interferon-based therapies.
2-7
Unfortunately, some pa-
tients, particularly those with more resistant hepati-
tis C virus (HCV) genotypes, do not respond to these
agents.
Two types of pegylated interferon, which differ in
their pharmacokinetic and chemical properties, have
been developed. Both have demonstrated significant-
ly superior efficacy to non-pegylated interferons in sev-
eral controlled clinical trials.
8-12
Peginterferon alfa-2b
(a 12-kD linear polyethylene glycol moiety) plus ri-
bavirin produced significantly improved sustained vi-
rologic responses as compared with interferon alfa-
2b plus ribavirin.
13
Peginterferon alfa-2a (a 40-kD
branched polyethylene glycol moiety) has an extend-
ed serum half-life that provides constant viral suppres-
sion for seven days, thus allowing once-weekly dosing
and enhanced clinical efficacy.
8-10,14-17
We undertook
the present study to determine whether peginterfer-
on alfa-2a plus ribavirin is more effective than inter-
feron alfa-2b plus ribavirin or peginterferon alfa-2a
alone for the treatment of chronic hepatitis C.
METHODS
Patient Selection
The study was conducted by the Pegasys International Study
Group. Eligible subjects were adult patients who had never re-
ceived interferon and who had at least 2000 copies of HCV RNA
per milliliter of serum according to a polymerase-chain-reaction
(PCR) assay (Cobas Amplicor HCV Monitor Test, version 2.0;
Roche Diagnostics), serum alanine aminotransferase activity above
the upper limit of normal within six months before entry into the
study, and a liver-biopsy result consistent with the diagnosis of
chronic hepatitis C. Serum HCV RNA levels above the linear
A
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976
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·
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The New England Journal of Medicine
range of the PCR (more than 1 million copies per milliliter) were
diluted to within the linear range. Patients were excluded from par-
ticipation if they had neutropenia (fewer than 1500 neutrophils per
cubic millimeter), thrombocytopenia (fewer than 90,000 platelets
per cubic millimeter), anemia (less than 12 g of hemoglobin per
deciliter in women and less than 13 g of hemoglobin per deciliter
in men), human immunodeficiency virus (HIV) infection, decom-
pensated liver disease, a serum creatinine level more than 1.5 times
the upper limit of normal, poorly controlled psychiatric disease,
alcohol or drug dependence within one year before entry into the
study, or substantial coexisting medical conditions.
Study Design
This randomized, controlled clinical trial was conducted at 81
centers worldwide from February 1999 to April 2001. Patients were
randomly assigned in a 2:1:2 ratio (with a block size of five) to re-
ceive subcutaneous, once-weekly injections of 180 µg of peginter-
feron alfa-2a (Pegasys, Hoffmann–LaRoche) plus daily ribavirin
(Hoffmann–LaRoche) or placebo, or subcutaneous, thrice-weekly
injections of 3 million units of interferon alfa-2b plus ribavirin (Re-
betron, Schering-Plough) for 48 weeks. Ribavirin was given orally
at a dose of 1000 mg per day for patients weighing 75 kg or less and
1200 mg per day for those weighing more than 75 kg. Randomiza-
tion was stratified according to country and HCV genotype (HCV
genotype 1 vs. other genotypes). Genotyping was performed by
sequence analysis of a portion of the 5' untranslated region of the
HCV genome.
18
Participants were followed for 24 weeks after ces-
sation of therapy. The sponsor, investigators, and patients who re-
ceived peginterferon alfa-2a were unaware of who received ribavirin
or placebo.
The institutional review boards of the participating centers ap-
proved the protocol, and all patients provided written informed
consent. The study was designed by the sponsor in collaboration
with expert hepatologists. Data were collected by the Pegasys In-
ternational Study Group. Data analysis was performed by the spon-
sor and the authors of this report; the authors had full access to the
data, and the decision to publish was not limited by the sponsor.
The study was conducted according to the guidelines of the Dec-
laration of Helsinki, the applicable provisions of Good Clinical Prac-
tices, or both.
Assessment of Efficacy
The primary efficacy end point was sustained virologic response,
defined as the absence of detectable HCV RNA at the end of fol-
low-up according to a PCR assay (Cobas Amplicor HCV Test, ver-
sion 2.0; lower limit of detection, 100 copies [50 IU] per milliliter).
For patients with at least 20 weeks of follow-up, the last observed
HCV RNA level was used in assessments of efficacy. All patients
with follow-up of less than 20 weeks were considered to have had
no response to treatment.
Assessment of Safety
Safety was assessed by laboratory tests and evaluation of adverse
events at weeks 1, 2, 4, 6, and 8; monthly thereafter during treat-
ment; and at weeks 52, 60, and 72. Patients who discontinued ther-
apy prematurely because of intolerance were encouraged to remain
in the study. Stepwise reductions in the peginterferon alfa-2a dos-
ages to 135, 90, or 45 µg per week and reductions in ribavirin
dosages to 800 or 600 mg per day were allowed to manage ad-
verse events or laboratory abnormalities that had reached predeter-
mined thresholds of severity. If the adverse event resolved or im-
proved, a return to initial dosing levels was permitted unless the
patient had received the reduced dose for more than four weeks.
Patients were withdrawn from treatment if they continued to have
viremia at week 24, if they missed four consecutive doses, or at
the discretion of the investigator.
Statistical Analysis
For the primary efficacy end point, a closed testing procedure was
planned to allow for all possible pairwise comparisons among the
three treatment groups.
19,20
The global hypothesis of no differences
among the three treatment groups was tested at a significance level
of 0.05; if there was a significant difference among the three treat-
ment groups, each treatment comparison was then tested at a signif-
icance level of 0.05. The Cochran–Mantel–Haenszel test was used
for both types of analysis and was stratified according to the com-
bination of country and HCV genotype (HCV genotype 1 vs. other
genotypes).
21
Because the simulated error rate (with the use of the
Cochran–Mantel–Haenszel test for a single stratum) for each pair-
wise treatment comparison under this closed testing procedure was
approximately 0.025, a two-sided 97.5 percent confidence interval
for the odds ratios was reported for each pairwise treatment com-
parison. Stepwise, backward, and multiple logistic-regression mod-
els were used to explore base-line factors predicting a sustained
virologic response. All patients who received at least one dose of
study medication were included in all efficacy analyses, and if they
had undergone at least one safety assessment after base line, they
were included in the safety analysis.
RESULTS
Patient Demographics
Of the 1459 patients screened, 1149 were random-
ly assigned to treatment and 1121 were randomly as-
signed to treatment and received at least one dose of
study medication. The patients who were excluded
from the study did not have elevated alanine amino-
transferase levels, refused to participate, or failed to
meet other inclusion criteria. Twenty-eight patients
were randomly assigned to treatment but did not re-
ceive at least one dose of study medication because
they refused or did not come for treatment, because
they did not meet inclusion criteria, or for other rea-
sons, including administrative reasons that were iden-
tified after randomization. The pretreatment charac-
teristics of patients in the treatment groups were
similar (Table 1).
Virologic Response
Significantly more patients treated with peginter-
feron alfa-2a plus ribavirin had end-of-treatment viro-
logic responses than patients treated with interferon
alfa-2b plus ribavirin (69 percent vs. 52 percent, P<
0.001) or peginterferon alfa-2a plus placebo (69 per-
cent vs. 59 percent, P=0.01) (Fig. 1). Significantly
more patients treated with peginterferon alfa-2a plus
ribavirin had a sustained virologic response (i.e., no
detectable HCV RNA 24 weeks after cessation of ther-
apy) than those treated with interferon alfa-2b plus
ribavirin (56 percent vs. 44 percent, P<0.001) or
peginterferon alfa-2a plus placebo (56 percent vs.
29 percent, P<0.001) (Fig. 1).
Forty-six percent of patients with HCV genotype 1
who received peginterferon alfa-2a plus ribavirin had
a sustained virologic response, as compared with 36
percent of those who received interferon alfa-2b plus
ribavirin (P=0.01) and 21 percent of those who re-
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PEGINTERFERON ALFA-2a PLUS RIBAVIRIN FOR HEPATITIS C
N Engl J Med, Vol. 347, No. 13
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·
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·
977
ceived peginterferon alfa-2a plus placebo (P<0.001)
(Table 2). Among the patients with HCV genotype 2
or 3, significantly more of those treated with peginter-
feron alfa-2a plus ribavirin had a sustained virologic
response than of those treated with interferon alfa-2b
plus ribavirin (76 percent vs. 61 percent, P=0.005)
(Table 2). Among patients with HCV genotype 1 and
high base-line viral RNA levels (more than 2 million
copies per milliliter), 41 percent of those receiving
peginterferon alfa-2a plus ribavirin had a sustained
virologic response, as compared with 33 percent of
those receiving interferon alfa-2b plus ribavirin (Table
2). Among patients with cirrhosis, 43 percent of those
treated with peginterferon alfa-2a plus ribavirin and
33 percent of those treated with interferon alfa-2b plus
ribavirin had a sustained virologic response (Table 2).
Independent Factors Associated with a Sustained
Virologic Response
In multivariable analyses to identify predictors of
sustained virologic response among patients who re-
ceived peginterferon alfa-2a plus ribavirin, our final
multiple logistic-regression model, including the fol-
lowing factors, was entered in the final stepwise re-
gression analysis: sex, race (white vs. nonwhite), age
(«40 years vs. >40 years), body weight («75 kg vs.
>75 kg), pretreatment viral load («2 million copies
per milliliter vs. >2 million copies per milliliter), pre-
treatment alanine aminotransferase quotient (>3 vs.
«3), pretreatment histologic diagnosis (cirrhosis vs.
noncirrhosis), and HCV genotype (1 vs. non-1). Three
factors independently and significantly increased the
odds of achieving a sustained virologic response: an
*Plus–minus values are means ±SD. Because of rounding, not all percentages total 100.
†The body-mass index is the weight in kilograms divided by the square of the height in meters.
‡The alanine aminotransferase quotient is the average of the two serum alanine aminotransferase
values that qualified patients for participation, divided by the upper limit of normal.
§The average of two pretreatment values meeting the entry criteria was calculated.
T
ABLE
1.
C
HARACTERISTICS
OF
THE
P
ATIENTS
AT
B
ASE
L
INE
.*
C
HARACTERISTIC
P
EGINTERFERON
A
LFA
-2a
PLUS
R
IBAVIRIN
(N=453)
I
NTERFERON
A
LFA
-2b
PLUS
R
IBAVIRIN
(N=444)
P
EGINTERFERON
A
LFA
-2a
PLUS
P
LACEBO
(N=224)
Sex — M/F (% male) 324/129 (72) 325/119 (73) 151/73 (67)
Age — yr 42.8±10.1 42.3±9.6 42.4±8.9
Weight — kg 79.8±17.5 78.4±17.5 79.1±17.9
Body-mass index† 26.8±5.0 26.4±5.3 26.5±4.7
Body-surface area — m
2
1.9±0.2 1.9±0.2 1.9±0.2
Race — no. (%)
White
Black
Asian
Other
372 (82)
27 (6)
28 (6)
26 (6)
385 (87)
13 (3)
24 (5)
22 (5)
186 (83)
13 (6)
12 (5)
13 (6)
Mode of infection — no. (%)
Injection-drug use
Transfusion
Other
Unknown
190 (42)
85 (19)
46 (10)
132 (29)
180 (41)
97 (22)
45 (10)
122 (27)
80 (36)
47 (21)
26 (12)
71 (32)
Alanine aminotransferase quotient — no. (%)‡
>1–1. 5
>1.5–3
>3–7
>7
95 (21)
193 (43)
142 (31)
23 (5)
81 (18)
207 (47)
136 (31)
20 (4)
46 (21)
106 (47)
63 (28)
9 (4)
Alanine aminotransferase — U/liter§ 90.2±65.2 90.7±61.3 87.3±55.7
Mean HCV RNA level — copies/ml ¬10
¡6
6.0±7.3 6.0±7.3 5.9±7.4
HCV genotype — no. (%)
1a
1b
1 other
2
3
4
Other
141 (31)
155 (34)
2 (<1)
54 (12)
86 (19)
13 (3)
2 (<1)
154 (35)
122 (27)
9 (2)
61 (14)
84 (19)
11 (2)
3 (<1)
70 (31)
68 (30)
7 (3)
37 (17)
32 (14)
9 (4)
1 (<1)
Histologic diagnosis — no. (%)
No cirrhosis
Cirrhosis or bridging fibrosis
397 (88)
56 (12)
390 (88)
54 (12)
190 (85)
34 (15)
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978
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·
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The New England Journal of Medicine
HCV genotype other than 1 (odds ratio, 3.25; 95 per-
cent confidence interval, 2.09 to 5.12; P<0.001), an
age of 40 years or less (odds ratio, 2.60; 95 percent
confidence interval, 1.72 to 3.95; P<0.001), and a
body weight of 75 kg or less (odds ratio, 1.91; 95 per-
cent confidence interval, 1.27 to 2.89; P=0.002).
Predictive Value of Early Virologic Response
By week 12, 86 percent of patients (390 of 453)
treated with peginterferon alfa-2a plus ribavirin had
had a virologic response, defined as a 2-log decrease
from base-line HCV RNA levels (97 patients) or no
detectable serum HCV RNA (293 patients) (Fig. 2).
The absence of an early virologic response was not as-
sociated with early treatment discontinuation (before
week 12) or dose modification (data not shown). Of
those with early virologic responses, 65 percent sub-
sequently had a sustained virologic response. Those
with no detectable HCV RNA by week 12 were more
likely to have a sustained virologic response than those
who had only a 2-log decrease in HCV RNA (221 of
293 vs. 32 of 97). In contrast, among the 63 patients
who did not have an early virologic response, 61 (97
percent) did not have a sustained virologic response.
Safety
The proportions of patients withdrawn from treat-
ment because of laboratory abnormalities or other
adverse events were similar in the groups receiving
peginterferon alfa-2a plus ribavirin (3 percent for lab-
oratory abnormalities and 7 percent for other adverse
events), peginterferon alfa-2a plus placebo (1 percent
and 6 percent, respectively), and interferon alfa-2b
plus ribavirin (1 percent and 10 percent) (Table 3).
The most common types of events leading to discon-
tinuation were psychiatric disorders (mainly depres-
sion-related events). The frequency and major causes
of dose modifications are detailed in Table 3. Among
patients who had an early virologic response with
peginterferon alfa-2a plus ribavirin, the proportion
with a sustained virologic response was similar among
those who had a substantial dose reduction (to <80
percent of both study medications) and those who
maintained the full dosing schedule (67 percent and
75 percent, respectively).
22
In contrast, discontinua-
tion despite an early virologic response was associat-
ed with a decrease in efficacy in this treatment group
(rate of sustained response, 12 percent).
22
The median hemoglobin values decreased between
weeks 1 and 8 in all treatment groups, then stabilized,
and then returned to near base-line values after treat-
ment was completed. The maximal decrease was great-
er in patients treated with peginterferon alfa-2a plus
ribavirin (3.7 g per deciliter) or interferon alfa-2b plus
ribavirin (3.6 g per deciliter) than in patients treated
with peginterferon alfa-2a plus placebo (2.2 g per dec-
iliter). There was no association between the incidence
of serious cardiovascular events and the incidence of
anemia.
The median neutrophil counts decreased from base
line in all treatment groups, particularly during the
first two weeks of treatment, and then stabilized for
the remainder of the treatment period, increasing rap-
Figure 1.
End-of-Treatment Virologic Response (Panel A) and
Sustained Virologic Response (Panel B), According to Intention-
to-Treat Analysis.
A virologic response was defined as an undetectable level of
HCV RNA (<100 copies per milliliter). Differences were assessed
by the Cochran–Mantel–Haenszel test stratified according to
country and HCV genotype.
100
80
60
40
20
0
29%
44%
56%
P<0.001 for all comparisons
Percent of Patients
Peginterferon
Alfa-2a
plus Placebo
Interferon
Alfa-2b
plus Ribavirin
Peginterferon
Alfa-2a
plus Ribavirin
100
80
60
40
20
0
P=0.01
P=0.06
59%
N=224
N=444
N=453
N=224
N=444
N=453
52%
69%
P<0.001
Percent of Patients
Peginterferon
Alfa-2a
plus Placebo
Interferon
Alfa-2b
plus Ribavirin
Peginterferon
Alfa-2a
plus Ribavirin
A
B
End-of-Treatment Response
Sustained Response
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PEGINTERFERON ALFA-2a PLUS RIBAVIRIN FOR HEPATITIS C
N Engl J Med, Vol. 347, No. 13
·
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·
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·
979
idly to base-line values after the completion of treat-
ment. Four patients (three receiving peginterferon alfa-
2a plus ribavirin and one receiving interferon alfa-2b
plus ribavirin) discontinued treatment because the
neutrophil count was below 500 per cubic millimeter.
The median platelet counts remained close to base-line
values throughout treatment with interferon alfa-2b
plus ribavirin but decreased progressively during the
first eight weeks of treatment with peginterferon alfa-
2a plus ribavirin or placebo, before stabilizing. After
treatment was completed, the median platelet counts
returned to normal within four weeks. Two patients
with thrombocytopenia (one receiving peginterferon
alfa-2a plus placebo and the other receiving interfer-
on alfa-2b plus ribavirin) had serious bleeding. Five
patients (four receiving peginterferon alfa-2a plus ri-
bavirin and one receiving peginterferon alfa-2a plus
placebo) discontinued treatment because of thrombo-
cytopenia.
Most adverse events in all study groups were those
commonly associated with interferon-based treatment
(Table 3). Patients treated with peginterferon alfa-2a
plus ribavirin or placebo had a lower incidence of in-
fluenza-like symptoms, such as pyrexia, myalgia, and
rigors, than those treated with interferon alfa-2b plus
ribavirin. Although few patients had a history of de-
pression or active depression at base line (1 to 2 per-
cent and 3 to 5 percent, respectively), a substantial mi-
nority reported depression during the study. Patients
treated with peginterferon alfa-2a plus ribavirin or
placebo had a lower incidence of depression than those
treated with interferon alfa-2b plus ribavirin (22 per-
cent and 20 percent vs. 30 percent). Three patients
died after the end of treatment. One patient who had
*A sustained virologic response was defined as no detectable hepatitis C virus (HCV) RNA
24 weeks after the cessation of therapy.
†Six patients had other genotypes.
‡P<0.001 for the comparison between peginterferon alfa-2a plus ribavirin and interferon alfa-2b
plus ribavirin.
§P=0.01 for the comparison between peginterferon alfa-2a plus ribavirin and interferon alfa-2b
plus ribavirin.
¶P=0.005 for the comparison between peginterferon alfa-2a plus ribavirin and interferon alfa-2b
plus ribavirin.
¿No P value was calculated, because of the small sample size.
**Base-line HCV RNA values were missing for three patients.
††P=0.04 for the comparison between peginterferon alfa-2a plus ribavirin and interferon alfa-2b
plus ribavirin.
‡‡P=0.003 for the comparison between peginterferon alfa-2a plus ribavirin and interferon alfa-2b
plus ribavirin.
T
ABLE
2.
P
ROPORTION
OF
P
ATIENTS
WITH
A
S
USTAINED
V
IROLOGIC
R
ESPONSE
AS
A
F
UNCTION
OF
HCV G
ENOTYPE
AND
HCV G
ENOTYPE
PLUS
B
ASE
-L
INE
HCV RNA.*
V
ARIABLE
P
EGINTERFERON
A
LFA
-2a
PLUS
R
IBAVIRIN
(N=453)
I
NTERFERON
A
LFA
-2b
PLUS RIBAVIRIN
(N=444)
PEGINTERFERON
ALFA-2a
PLUS PLACEBO
(N=224)
no./total no. (%)
HCV genotype†
All patients
Genotype 1
Genotype 2 or 3
Genotype 4
255/453 (56)‡
138/298 (46)§
106/140 (76)¶
10/13 (77)¿
197/444 (44)
103/285 (36)
88/145 (61)
4/11 (36)
66/224 (29)
30/145 (21)
31/69 (45)
4/9 (44)
Base-line HCV RNA**
«2¬106 copies/ml
>2¬106 copies/ml
99/159 (62)††
156/293 (53)‡‡
78/150 (52)
119/292 (41)
32/69 (46)
34/155 (22)
HCV genotype and base-line HCV RNA
Genotype 1
«2¬106 copies/ml
>2¬106 copies/ml
64/115 (56)
74/182 (41)
40/94 (43)
63/189 (33)
17/44 (39)
13/101 (13)
Genotype 2 or 3
«2¬106 copies/ml
>2¬106 copies/ml
30/37 (81)
76/103 (74)
34/52 (65)
54/93 (58)
11/19 (58)
20/50 (40)
Histologic diagnosis
Cirrhosis 24/56 (43) 18/54 (33) 7/34 (21)
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980 ·N Engl J Med, Vol. 347, No. 13 ·September 26, 2002 ·www.nejm.org
The New England Journal of Medicine
received interferon alfa-2b plus ribavirin died of hy-
pertensive heart disease, and two who had received
peginterferon alfa-2a plus placebo died, one from
drowning and the other from liver cancer. None of
the deaths were considered related to treatment.
DISCUSSION
Peginterferon alfa-2a plus ribavirin was significant-
ly more effective than interferon alfa-2b plus ribavirin
or peginterferon alfa-2a alone for the treatment of
chronic hepatitis C. Overall, the rate of sustained vi-
rologic response was similar to that reported with
peginterferon alfa-2b plus ribavirin.13 In the current
study, improved efficacy was seen in subgroups of pa-
tients with disease generally considered to have treat-
ment-resistant characteristics.13 In particular, patients
with all HCV genotypes and those with high base-line
levels of HCV RNA (more than 2 million copies per
milliliter) were more likely to have a sustained virologic
response when treated with peginterferon alfa-2a plus
ribavirin than when treated with interferon alfa-2b
plus ribavirin. Among patients considered to have the
most treatment-resistant disease — that is, those with
both HCV genotype 1 and high base-line viral levels
— a substantially higher proportion of those treated
with peginterferon alfa-2a plus ribavirin had a sus-
tained virologic response than of those treated with
interferon alfa-2b plus ribavirin.
Early prediction of virologic response to interferon-
based therapy can help identify patients who are un-
likely to have a sustained response and allow clinicians
the option to discontinue treatment, saving patients
the side effects and cost of additional therapy. In the
current study, 97 percent of patients who did not have
an early virologic response to peginterferon alfa-2a
plus ribavirin by week 12 never had a sustained viro-
logic response. The incremental benefit of continuing
therapy beyond 12 weeks for patients who have not
had an early virologic response must be considered for
each patient individually.
This study was designed to treat patients for 48
weeks, regardless of HCV genotype. Therefore, we
cannot comment on shorter treatment periods.
Several adverse events typically associated with the
use of interferon (including influenza-like symptoms
and depression) occurred less frequently with peginter-
feron alfa-2a, alone or in combination with ribavirin,
than with interferon alfa-2b plus ribavirin. Monother-
apy with peginterferon alfa-2a was generally better tol-
erated than the ribavirin-containing regimens. As is
usual with interferon-based therapy, there were reduc-
tions in neutrophil and platelet counts with all treat-
ments. Although these decreases were greater in pa-
tients treated with peginterferon alfa-2a plus ribavirin
than in those treated with interferon alfa-2b plus ri-
bavirin, they did not appear to be associated with se-
Figure 2. Predictability of Sustained Virologic Response.
At week 12, 86 percent (390 of 453) of the patients treated with peginterferon alfa-2a plus ribavirin ei-
ther had a 2-log drop in HCV RNA levels or had undetectable levels of HCV RNA. Of these patients, 65
percent (253 of 390) went on to have a sustained virologic response. Of the 63 patients who did not
have a 2-log drop or undetectable levels of HCV RNA at week 12, 61 (97 percent) did not have a sus-
tained virologic response.
Week 12
(N=453)
2-log drop or
undetectable
HCV RNA
N=63
(14%)
N=390
(86%)
N=253
(65%)
N=137
(35%)
N=2
(3%)
N=61
(97%)
Yes
Sustained virologic
response
No sustained virologic
response
Sustained virologic
response
No sustained virologic
response
No
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PEGINTERFERON ALFA-2a PLUS RIBAVIRIN FOR HEPATITIS C
N Engl J Med, Vol. 347, No. 13 ·September 26, 2002 ·www.nejm.org ·981
rious sequelae and were effectively managed by dose
modifications. Interestingly, for patients treated with
peginterferon alfa-2a plus ribavirin who had an early
virologic response, completion of therapy with dose
reduction was not associated with a substantial de-
crease in efficacy.
Peginterferon alfa-2a offers significantly enhanced
sustained virologic responses in all patients, regardless
of HCV genotype and viral load, and a once-weekly
dosing schedule. We think that the ability to predict
the absence of sustained virologic response from HCV
RNA levels at week 12 will be a useful clinical tool.
The results of this study show that combination ther-
apy with peginterferon alfa-2a plus ribavirin provides
a considerable clinical advantage over therapy with
interferon alfa-2b plus ribavirin.
*Values are based on patients randomly assigned to treatment who received at least one dose of study medication (453
who received peginterferon alfa-2a plus ribavirin, 444 who received interferon alfa-2b plus ribavirin, and 224 who received
peginterferon alfa-2a plus placebo).
†Laboratory abnormalities included neutropenia, thrombocytopenia, and abnormal alanine aminotransferase levels.
‡Values are based on randomized patients who received at least one dose of study medication and had at least one
post–base-line safety evaluation (451 who received peginterferon alfa-2a plus ribavirin, 443 who received interferon alfa-2b
plus ribavirin, and 223 who received peginterferon alfa-2a plus placebo).
§Some patients who required dose modification had both an adverse event and a laboratory abnormality.
¶Patients may have had more than one adverse event. The adverse events listed are those that occurred in at least 20 percent
of patients.
¿This symptom is one of the influenza-like symptoms often seen with interferon treatment.
** P<0.001 for the comparison with the group given peginterferon alfa-2a plus ribavirin by Fisher’s exact test.
†† P=0.02 for the comparison with the group given peginterferon alfa-2a plus ribavirin by Fisher’s exact test.
‡‡ P=0.01 for the comparison with the group given peginterferon alfa-2a plus ribavirin by Fisher’s exact test.
TABLE 3. INCIDENCE OF DISCONTINUATION, DOSE MODIFICATION, AND ADVERSE EVENTS.
VARIABLE
PEGINTERFERON ALFA-2a
PLUS RIBAVIRIN
INTERFERON ALFA-2b
PLUS RIBAVIRIN
PEGINTERFERON ALFA-2a
PLUS PLACEBO
number (percent)
Discontinuation*
Patients who withdrew
during wk 1–48
Insufficient response
Adverse event
Laboratory abnormality†
Refusal of treatment
Violation of entr y criteria
Failure to return
Other violation
100 (22)
34
32
12
15
0
5
2
140 (32)
59
43
4
22
2
7
3
72 (32)
49
13
2
5
0
3
0
Patients who withdrew
during wk 49–72
19 (4) 14 (3) 6 (3)
Dose modification‡§
PEGINTERFERON
ALFA-2a RIBAVIRIN
INTERFERON
ALFA-2b RIBAVIRIN
PEGINTERFERON
ALFA-2a PLACEBO
Adverse event 48 (11) 95 (21) 47 (11) 97 (22) 14 (6) 39 (17)
Laboratory abnormality
Anemia
Neutropenia
Thrombocytopenia
111 (25)
4 (1)
91 (20)
18 (4)
108 (24)
99 (22)
6 (1)
2 (<1)
36 (8)
13 (3)
24 (5)
1 (<1)
84 (19)
83 (19)
1 (<1)
0
54 (24)
0
38 (17)
14 (6)
9 (4)
8 (4)
0
1 (<1)
Advers e eve nts‡¶
Fatigue¿
Headache¿
Pyrexia¿
Myalgia¿
Insomnia
Nausea
Alopecia
Arthralgia
Irritability
Rigors¿
Pruritus
Depression
Decreased appetite
Dermatitis
242 (54)
211 (47)
195 (43)
189 (42)
168 (37)
130 (29)
128 (28)
121 (27)
109 (24)
106 (24)
101 (22)
100 (22)
96 (21)
95 (21)
244 (55)
230 (52)
247 (56)**
220 (50)††
174 (39)
145 (33)
151 (34)
112 (25)
123 (28)
157 (35)**
88 (20)
134 (30)‡‡
98 (22)
80 (18)
98 (44)
115 (51)
85 (38)
94 (42)
52 (23)
58 (26)
48 (21)
64 (29)
56 (25)
52 (23)
41 (18)
45 (20)
24 (11)
29 (13)
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982 ·N Engl J Med, Vol. 347, No. 13 ·September 26, 2002 ·www.nejm.org
The New England Journal of Medicine
Supported by grants from Hoffmann–LaRoche, Basel, Switzerland, and
the University of North Carolina General Clinical Research Centers pro-
gram, Division of Research Resources, National Institutes of Health
(RR00046).
Ms. Lin, Dr. Hoffman, and Dr. Yu are employees of Hoffmann–LaRoche.
Drs. Fried, Shiffman, Reddy, and Craxi served as consultants for Hoffmann–
LaRoche. Drs. Fried, Shiffman, Reddy, and Craxi served as lecturers for
Hoffmann–LaRoche. Dr. Reddy served as a consultant for Schering-Plough.
Drs. Fried, Shiffman, Reddy, and Craxi ser ved as lecturers for Schering-
Plough. Drs. Fried, Shiffman, and Craxi received grant support from Hoff-
mann–LaRoche. Drs. Fried, Shiffman, Reddy, and Craxi received grant sup-
port from Schering-Plough.
We are indebted to Dr. Sugantha Govindarajan of Rancho Los
Amigos Medical Center, Downey, California, for her work as the cen-
tral pathologist in this study and to Farhad Sedarati, Ph.D., for crit-
ical review during the preparation of the manuscript.
APPENDIX
In addition to the authors, the following members of the Pegasys Inter-
national Study Group participated in this study: A. Abergel, Hôtel-Dieu
Hospital, Clermont-Ferrand, France; A. Alberti, Università degli Studi di
Padova, Padua, Italy; J. Areias, Hospital de Santo Antonio, Porto, Portugal;
B.R. Bacon, Bethesda General Hospital, St. Louis; C. Berg, University of
Virginia Health Systems, Charlottesville; F. Bianchi, Università degli Studi
di Bologna, Bologna, Italy; M.-A. Bigard, Hôpitaux de Brabois, Vandoevre-
les-Nancy, France; F. Bonino, Azienda Ospedaliera Pisana, Pisa, Italy; H.
Bonkovsky, University of Massachusetts Medical Center, Worcester; F.
Bosques, Hospital Universitario Jose E. Gonzalez, Monterrey, Mexico; M.
Bourlière, St. Joseph Hospital, Marseilles, France; J.P. Bronowicki, Centre
Hospitalier Universitaire, Nancy, France; J.T. Brouwer, Academic Hospital
Rotterdam, Rotterdam, the Netherlands; R . Brown, Columbia University
College of Physicians and Surgeons, New York; M. Buhl, Marselisborg Hos-
pital, Aarhus, Denmark; G. Cadeo, Università degli Studi di Brescia, Brescia,
Italy; P. Cales, Hôpital Hôtel-Dieu, Angers, France; O. Campollo, Hospital
Civil de Guadalajara, Guadalajara, Mexico; R. Carithers, University of
Washington, Seattle; A . Carvalho, Hospitais da Universidade de Coimbra,
Coimbra, Portugal; W.G.E. Cooksley, Royal Brisbane Hospital, Herston,
Queensland, Australia; P. Couzigou, Haut-Leveque Hospital, Bordeaux,
France; A. Craxì, University of Palermo, Palermo, Italy; P. Desmond, St.
Vincent’s Hospital, Fitzroy, Victoria, Australia; D. Dieterich, Cabrini Med-
ical Center, New York; M. Farkkila, Helsinki University Central Hospital,
Helsinki, Finland; K. Fawaz, New England Medical Center, Boston; P. Fer-
enci, Allgemeines Krankenhaus Wien, Vienna, Austria; J. Franco, Medical
College of Wisconsin at Froedtert Hospital, Milwaukee; A. Gibas, Regional
Gastroenterology Associates, Lancaster, Pa.; R. Gish, California Pacific Med-
ical Center, San Francisco; E. Godofsky, Bach and Godofsky, Bradenton,
Fla.; S. Hadziyannis, Evgenidion Hospital, Athens, Greece; T. Hassanein,
University of California, San Diego; K.B. Hellum, Akershus Central Hos-
pital, Nordbyhagen, Norway; Y. Horsmans, Cliniques Universitaires St. Luc,
Brussels, Belgium; A . Horta E Vale, Clínica Diagnostics Medico Integral,
Vila Nova de Gaia, Portugal; D. Jensen, Rush–Presbyterian–St. Luke’s
Medical Center, Chicago; M.-Y. Lai, National Taiwan University, Taipei,
Taiwan; D. Larrey, Hôpital St.-Eloi, Montpellier, France; S.-D. Lee, Veter-
ans General Hospital, Taipei, Taiwan; A.S. Lok, University of Michigan
Medical Center, Ann Arbor; P. Marcellin, Hôpital Beaujon, Clichy, France;
P. Martin, University of California, Los Angeles; D.K . Moonka, Henry
Ford Health System, Detroit; R. Moreno, Hospital Universitario de la Princ-
esa, Madrid; A. Mouro, Hospital Pulido Valente, Lisbon, Portugal; F. Nevens,
University Hospital Gasthuisberg, Leuven, Belgium; G. Pastore, Policlinico
di Bari, Bari, Italy; G.R . Piexe, Hospital Egas Moniz, Lisbon, Portugal; R.
Poupon, Hôpital St.-Antoine, Paris; T. Poynard, Hôpital de la Salpétrière,
Paris; F. Ramalho, Hospital Santa Maria, Lisbon, Portugal; H.W. Reesink,
Academic Medical Center, Amsterdam; J. Reichen, Universität, Bern, Swit-
zerland; S. Roberts, Alfred Hospital, Prahran, Victoria, Australia; J. Rodes,
Clinico y Provincial, Barcelona, Spain; F.J. Salmeron, Hospital Clinico San
Cecilio de Granada, Granada, Spain; D. Schulman, Digestive Health Con-
sultants, Burbank, Calif.; H. Sette, Jr., Instituto de Infectologia Emílio Rib-
as, São Paulo, Brazil; S. Shedlofsky, University of Kentucky Medical Center,
Lexington; K.E. Sherman, University of Cincinnati Medical Center, Cin-
cinnati; F. Siddiqui, Harper Hospital, Detroit; M. Sulkowski, Johns Hopkins
University, Baltimore; M.J. Tong, Huntington Medical Research Institutes,
Pasadena, Calif.; R . Trejo, Centro Medico Nacional S. XXI, Mexico City,
Mexico; C. Trepo, Hôpital Hôtel-Dieu, Lyons, France; D.J. van Leeuwen,
University of Alabama, Birmingham; D. Vetter, Hôpital Civil, Strasbourg,
France; T.L. Wright, University of California, San Francisco; J.-P. Zarski,
Hôpital de la Tronche, Grenoble, France; S. Zeuzem, Klinikum der J.W.
Goethe-Universität, Frankfurt, Germany. Safety Review Board: E. Krawitt,
University of Vermont Medical Center, Burlington; V. Feinman, Mount Sinai
Hospital, Toronto; V. Rustgi, Metropolitan Research, Fairfax, Va.
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