Meta-Analysis of Interferon Randomized Trials in the
Treatment of Viral Hepatitis C: Effects of Dose and Duration
THIERRY POYNARD, VINCENT LEROY, MARIELLE COHARD, THIERRY THEVENOT, PHILIPPE MATHURIN, PIERRE OPOLON,
AND JEAN PIERRE ZARSKI
The aims of this study were to evaluate the benefits
of higher doses or of longer duration in comparison with
a standard interferon regimen (3 MU three times per
week for 6 months) in chronic hepatitis C, and to assess
the efficacy of interferon in acute hepatitis C. Meta-anal-
ysis made use of the Peto et al. and the Der Simonian
and Laird methods, with heterogeneity and sensitivity
analyses. In chronic hepatitis, a total of 17 trials versus
controls and of 16 trials comparing different interferon
regimens were included. Standard regimen, 3 MU three
times per week for 6 months, was associated with an
increase of the complete alanine transaminase (ALT) re-
sponse rate and sustained (ALT) response rate by 45%
(95% confidence interval: 35% to 55%; P õ .001) and 21%
(13% to 28%; P õ .001), respectively, with the natural
course being less than 2% of spontaneous responses.
There was a significant dose effect (6 vs. 3 MU three
times per week) upon the sustained response rate at 12
months, with a mean 17% increase (7% to 28%; P õ .001),
but not at 6 months. There was a significant duration
effect (12 vs. 6 months) upon the sustained response rate
both at the dose of 3 MU with a mean of 16% (9% to 23%;
P õ .001), and at the dose of 6 MU three times per week
with a mean of 20% (7% to 33%; P Å .003). In acute hepati-
tis C, 3 months of interferon treatment showed signifi-
cant efficacy versus controls (4 trials), upon the com-
plete ALT response (69% vs. 29%; P õ .001), the sustained
response rate during the 12 months following treatment
(53% vs. 32%; P Å .02), and hepatitis C virus (HCV)-RNA
clearance (41% vs. 4%; P õ .001). The best efficacy/risk
ratio was in favor of 3 MU three times per week for at
least 12 months in patients with chronic hepatitis C who
had never been treated with interferon. Patients with
acute hepatitis should be treated with at least 3 MU
three times per week for 3 months. (HEPATOLOGY
1996;24:778-789.)
Since the first meta-analysis published by Tine et al. in
1991,1 who analyzed 18 randomized clinical trials (RCTs), 88
new references of interferon trials in the treatment of acute
or chronic hepatitis C have been identified. The aim of this
overview was to complete and to expand that first meta-anal-
ysis. For chronic hepatitis C, the following questions were
Abbreviations: RCT, randomized clinical trial; ALT, alanine transaminase; HCV, hepati-
tis C virus; CI, confidence interval.
From the Service d’Hépato-Gastroenterologie, Groupe Hospitalier Pitié-Salpêtrière,
CNRS URA 1484, Paris, Hôpital Michallon, Grenoble, France.
Received May 28, 1996; accepted May 30, 1996.
Dr. Thevenot had a grant from Recherche et Partage.
Address reprint requests to: Thierry Poynard, M.D., Service d’Hépato-Gastroentérologie,
Groupe Hospitalier Pitié-Salpêtrière, 47-83 Boulevard de l’Hôpital, 75651, Paris, Cedex 13,
France.
Copyright q 1996 by the American Association for the Study of Liver Diseases.
0270-9139/96/2404-0005$3.00/0
778
AID Hepa 0031 / 5P14$$$601 09-12-96 15:49:40
addressed: 1) What is the level of efficacy of interferon at the
usual dose and duration, that is, at 3 MU three times per
week for 6 months, versus a control group in terms of alanine
transaminase (ALT) response rate, sustained response rate,
and histological improvement?; and 2) Is an increase in the
duration or dose associated with an increase in interferon
efficacy in comparison with the usual regimen? For acute
hepatitis C, the aim was to assess whether interferon was
effective compared with absence of treatment.
MATERIALS AND METHODS
Meta-analyses were conducted according to a predetermined pro-
tocol following the recommendations of Sacks et al.,2 but were not
limited to the English-language RCTs.
Literature Search. Medline and manual searches were combined,
because we had previously demonstrated that the Medline search
alone is not sensitive enough.3 The key words ‘‘chronic hepatitis non-
A non-B, non-C clinical trials’’ were used. General reviews, references
from published RCTs, letters to pharmacological companies, and
Current Contents (Clinical Medicine, Institute for Scientific Informa-
tion, Data Base Publishing Division, Inc. January 1985, Vol. 13, No.
1-December 1995, Vol. 23 No. 49.) were also used.
Criteria for Inclusion. To be included in this meta-analysis, an
RCT had to fulfill a set of criteria. It had to be published as an article,
be clearly randomized, be using interferon alone, and be using at
least one clinical endpoint among the following: normalization of
ALT during treatment (complete ALT response); sustained ALT nor-
malization in the months following the end of treatment (sustained
ALT response); and improvement in histological lesions when biopsy
after treatment was compared with biopsy before treatment (histo-
logical improvement). All of these endpoints had to have been as-
sessed qualitatively or semiquantitatively to be used. For acute hepa-
titis, the disappearance of hepatitis C virus (HCV) RNA in the serum
at the end of the follow-up study was analyzed. Some patients were
RNA-negative at randomization. They were considered failure for
this end point.
Criteria for Exclusion. RCTs that were not clearly randomized or
that were using only quantitative endpoints were excluded. RCTs in
patients with chronic hepatitis C including only treatment by a dose
of interferon of less than 3 MU three times per week with a duration
of treatment shorter than 6 months, or in combination with another
drug, were excluded. RCTs with an interferon regimen that was
dependent on the initial ALT response were excluded. Trials that
involved previously treated patients, nonresponders, or relapsers
were excluded. Trials that were only published as abstracts or as
interim reports were excluded.
Range of Patient Characteristics, Diagnoses, and Treatments. The
following items were recorded as potentially useful in assessing the
clinical heterogeneity between RCTs: mean age; sex ratio; percentage
of patients with cirrhosis; mean duration of hepatitis when known;
and type of interferon (alfa 2a, alfa 2b, lymphoblastoid, or other).
Criteria of Possible Combinations. RCTs were combined only if the
same drug was investigated, and if at least one given endpoint was
assessed. For each RCT, the exact drug dosage and duration of treat-
ment was administered. For each drug, the following methods were
used to assess possible combinations: the comparison of each end-
point improvement in control groups with the x2 test; the heterogene-
ity tests by the Peto method;4 and the Der Simonian and Laird meth-
ods.5 Seven sensitivity analyses were performed and are detailed in
the statistical section.
hpta WBS: Hepatology
AID
Hepa 0031
TABLE 1. Characteristics of 17 Included Trials, Published Full Papers, Comparing Interferon With Controls in the Treatment of Chronic Hepatitis C

/
Mean
Score IFN Follow- Armsc Mean % of Drug Disease
HEPATOLOGY Vol. 24, No. 4, 1996

d
Author (ref) MSa Type IFN Schedule Subgroup Upb (IFN/C) Excluded Agee Men Transfusion Abuse Cirrhosis Durationf

g
Causse 1991 13 a 2b 3 MU TIW 6 mo vs. placebo 3 MU 6 mo 6 30/30 2/1 47/50 43/37 10/15 3/4 11/15 —
Cimino 1991 12 a 2a 3 MU TIW 6 mo vs. control 3 MU 6 mo 4 33/33 0/0 51/48 36/46 — — 20/16 —
Davis 1989 15 a 2b 3 MU TIW 6 mo vs. controlg 3 MU 6 mo 6 58/51 4/1 54/50 52/63 52/42 — 29/22 —
Giudici 1991 12 a 2b 3 MU TIW 6 mo vs. control 3 MU 6 mo 12 15/15 0/0 50/33 60/80 4/2 2/1 2/2 —

5P14$$0031
Marcellin 1991 12 a 2b 3 MU TIW 6 mo vs. controlg 3 MU 6 mo 6 18/18 2/0 42/41 67/50 9/10 5/5 3/2 4/4
Saito 1994 10 a n-1h 3 MU TIW 6 mo vs. control 3 MU 6 mo 6 10/10 0/0 59/63 20/50 4/5 — 10/10
Saracco 1990 12 a 2b 3 MU TIW 6 mo vs. controlg 3 MU 6 mo 6 26/25 3/5 48/47 62/60 12/12 14/13 13/6 —
Angelini 1995 13 a 2b 6 MU TIW 1 mo fb 3 MU TIW 11 mo vs. 3 MU 12 mo 12 27/25 4/0 44/39 56/88 — — 4/1 —
control
Camps 1993 14 a n-1h 3 MU/D8W fb 3MU TIW 3 mo fb 1.5 MU TIW 3 MU 12 mo 15 36/36 0/0 44/43 67/61 11/18 6/3 10/9 5/5
6 mo vs. control
Diodati 1994 13 a 2a 6 MU TIW 1mo fb 3 MU TIW 3 mo fb 1 MU 3 MU 12 mo 6 30/30 1/5 49/55 77/43 7/7 — 15/12 8.7
TIW 8 mo vs. control
Makris 1991 12 a 2b 1 MU TIW 1 mo fb 2 MU TIW 1 mo fb 3 MU 3 MU 12 mo 6 10/8 1/0 38/38 100/100 10/8 0/0 1/1 —

09-12-96 15:49:40
TIW 10 mo vs. control
Mazella 1994 13 a n-1h 3 MU TIW 12 mo vs. control 3 MU 12 mo 16 30/30 1/0 45/48 68/50 — — — 5/5
Rumi 1995 16 aa 6 MU TIW 2 mo fb 3 MU TIW 10 mo vs. 3 MU 12 mo 12 38/36 3/4 48 63 — — 23 —
control

hpta
Capra 1995 12 a 2a 6 MU TIW 6 mo vs. control Other 0 21/19 3/0 52/40 38/78 — 4/8 10/4 —
Gomez-Rubio 1991 12 a 2b 5 MU TIW 2 mo fb 1.5 MU TIW 16 mo vs. Other 6 15/15 2/0 41/40 60/53 9/11 1/1 4/1 7/8
control
Saez-Royuela 1991 12 a 2c 15 MU TIW 3 mo fb 10 MU TIW 3 mo fb 5 MU Other 6 10/10 2/0 36/39 60/60 4/5 — 3/3 4/7
TIW 6 mo vs. controlg
Weiland 1990 13 a 2b 3 MU TIW 9 mo vs. control Other 12 21/12 2/0 54/56 91/92 21/12 0/0 0/0 3/4

Abbreviations: C, control; IFN, interferon; MS, methodological score; TIW, three times per week.
a
, methodological score.
b
, follow-up after end of treatment (mo).
c
, size of treated and control groups.
d

WBS: Hepatology
, dropped out and treatment interruption because of side effects in treated and control groups.
e
, mean age (y) in treated and control groups.
f
, mean duration (y) of hepatic disease.
g
, other arm excluded.
h
, n-1; lymphoblastoid.
—, nonreported.
POYNARD ET AL.
779
780 POYNARD ET AL. HEPATOLOGY October 1996

0 estimated)/variance(observed 0 estimated)] with an estimate of

the 95% confidence interval (CI). Then, an estimation of the overall
size differences between the groups is performed with its CI, with a
graphical representation, with a test on the statistical significance
of the overall difference, and with a test on the homogeneity of the
results obtained in the individual studies. For the Der Simonian and
Laird method the hypothesis is that the studies are a random sample
from a population of studies (random model). The mean of the popula-
tion of studies is the ‘‘true effect.’’ The random effects model incorpo-
rates the heterogeneity of the studies. The overall treatment effect
is estimated, as in the fixed effects model, by a weighted average
of the individual effects with weights inversely proportional to the
variance of the observed effects. The estimate is expressed by the
difference of percentages (risk of treated 0 risk of controls). These
two methods were performed for every analysis, and all significant
results were concordant.
When a significant difference was observed, the following seven
sensitivity analyses were performed using meta-analysis after the
inclusion or exclusion of RCTs to the core group: 1) after the inclusion
of RCTs published only as abstracts and without other criteria of
exclusion; 2) the core group without RCTs with quality °10; 3) the
core group without RCTs with prevalence cirrhosis ú30%; 4) the core
group without RCTs with a mean age of ú47 years; 5) the core group
without RCTs with a mean disease duration of ú5 years; 6) the core
group without RCTs with a follow-up of less than 12 months (and,
therefore, a definition of sustained response for less than 12 months);
and 7) the core group without RCTs assessing non-2b interferons.
Sensitivity analyses were shown only for the sustained response
rates according to dose and duration.
Methodological quality assessment was performed by two observ-
ers who independently used a previously validated questionnaire.6
A significance level of 5% was taken as the a risk. Each estimate
was given with its 95% CI. A comparison of the odds ratio and of
the percentages between strata was performed using their 95% CI.
Detailed results were given in the figures for the Der Simonian and
Laird method. The Peto et al. analyses were not shown.

RESULTS

FIG. 1. (A) Complete ALT response: Der Simonian & Laird. Interferon in Interferon Versus Control Groups in Chronic Hepati-
chronic hepatitis C; a meta-analysis of trials assessing interferon effect on tis. Among the 43 references identified, 17 RCTs published
complete ALT response vs. control (stratified by duration). The difference in as full papers, which fulfilled the criteria of inclusion, were
rates between interferon-treated and control-treated patients is represented
by the vertical bar, with the 95% CI shown by a horizontal line. When the rate
the core group of the meta-analysis of interferon versus con-
difference is at the right of the vertical line (rate difference 0.0), the difference trol.7-23 The clinical characteristics are described in Table 1.
is in favor of interferon. When the horizontal line does not cross the vertical The definitions of complete response had been arbitrarily
line, a significant difference exists between interferon and control. (B) Sus- classified in three groups: Class 1, only one mention of ALT
tained ALT response: Der Simonian & Laird. Interferon in chronic hepatitis
C; a meta-analysis of trials assessing interferon effect on sustained ALT re-
normalization, without reference to the end of the treatment
sponse vs. control (stratified by duration). or to a persistent normalization: 6 RCTs ‘‘if the value became
normal,’’12 ‘‘ALT levels normalized,’’13 ‘‘normalization during
treatment,’’16 ‘‘with normal ALT levels,’’19 ‘‘normalization of
Selection and Data-Extraction Bias. All RCTs considered for inclu- the serum ALT value,’’23 ‘‘normalization of ALT (i.e., the de-
sion were analyzed independently by two observers at a time (Poyn-
ard, Cohard, or Leroy), who conferred with one another in case of
disagreement. The decision as to the inclusion or exclusion of RCTs
was not related to results.
Source of Support. This meta-analysis was not supported by any
pharmaceutical company, by any governmental agency, or by other
grants.
Statistical Methods. For the ALT endpoints, all analyses were per-
formed according to the intention-to-treat method, i.e., they included
all randomized patients; patients without the endpoint were consid-
ered as failures. When not given in the publication, the response
rate according to the intention-to-treat method was recalculated. Be-
cause of the percentage of patients without a second biopsy, the
percentage of patients with histological improvement was estimated
according to the per-protocol method, i.e., after the exclusion of miss-
ing data which were not considered as failures. For each endpoint,
the following strategy was used: 1) the assessment of heterogeneity
of results between the control groups; 2) the assessment of drug
efficacy by the Peto et al. method; and 3) the assessment of drug
efficacy by the Der Simonian and Laird method. The Peto et al.
method is a variant from the classical Mantel-Haenszel test, the
hypothesis being that there is a single ‘‘true’’ effect, and that each
study combined with another provides an unbiased estimate of this FIG. 2. Interferon in chronic hepatitis C; a meta-analysis summary of trials
true effect (fixed model). In each study, a quantification of the size vs. control groups. Upper panel: 3 MU during 12 months vs. controls; lower
differences observed between the two groups (i.e., interferon vs. con- panel: 3 MU during 6 months vs. controls. All differences were significant (P
trol) is performed using the odds ratio (odds ratio Å Exp.[(observed õ .001).

AID Hepa 0031 / 5P14$$$602 09-12-96 15:49:40 hpta WBS: Hepatology

HEPATOLOGY Vol. 24, No. 4, 1996
crease to values lower than mean) / 2 SD of healthy sub-
jects,’’20; Class 2, mention of ALT normalization by the end
of the treatment without reference to a persistent normaliza-
tion: 5 RCTs9-11,14,21; and Class 3, mention of persistent nor-
malizations: 6 RCTs; ‘‘persistent normalization of ALT during
therapy,’’7,15 in one by ‘‘ALT during the first 3 months of
therapy fell to the normal range and remained there until
the end of treatment,’’22 ‘‘by the end of treatment sustained
for at least one month,’’17 ‘‘stable normalization for at least
three consecutive months and until the end of treatment,’’18
‘‘patients who showed normal serum ALT levels after 4
months of treatment.’’8
Sustained response was defined as normalization of ALT
during treatment and of persistence of normalization after
the end of treatment for 4 months,8 for 6 months in 8
RCTs7,9,11-13,16,17,22 for 7 months,21 for 10 months,23 for 12
months in 4 RCTs,14,15,18,19 or for 18 months.10 Seven RCTs
that fulfilled the criteria of inclusion but were published only
as abstracts have been only analyzed in a sensitivity analy-
sis.24-30
The reject log contained 19 RCTs published as papers: 6
RCTs, which are in duplicate form, included RCTs31-36; 4
RCTs with a low dose of interferon,37-40 including the same
RCT published twice37,40; 5 RCTs with a short duration of
treatment41-45; 1 RCT without sufficient details46; and 3 RCTs
with a regimen that was complicated.47-49 Four abstracts were
FIG. 3. (A) Sustained ALT response. Interferon in chronic hepatitis C; a
meta-analysis of trials assessing dose effect on complete ALT response (stra-
tified by duration). (B) Complete ALT response. Interferon in chronic hepatitis
C; a meta-analysis of trials assessing dose effect on sustained ALT response
(stratified by duration).
AID Hepa 0031 / 5P14$$$602 09-12-96 15:49:40
POYNARD ET AL. 781
FIG. 4. Meta-analysis summary: dose effect of interferon. Upper panel:
summary of trials comparing 5-6 MU during 6 months to 3 MU during 6
months; lower panel: summary of trials comparing 5-6 MU during 12 months
with 3 MU during 12 months.
excluded: 2 RCTs with a low dose of interferon50,51; 1 too
short52; and 1 without sufficient details.53
A meta-analysis comparing interferon with the controls,
using the Der Simonian and Laird method, is shown in Fig.
1A for the complete response and in Fig. 1B for the sustained
ALT response rate. Meta-analysis summary is shown in
Fig. 2.
The standard regimen, 3 MU three times per week for 6
months, was associated with an increase of the complete ALT
and sustained ALT response rate by 45% (95% CI: 35% to
55%; P õ .001) and by 21% (13% to 28%; P õ .001), respec-
tively, with the natural course being less than 2% of the
spontaneous responses. The indirect comparison between the
improvement rates of the sustained ALT responses versus
the control was in favor (P Å .06) of the 12-month period at
3 MU three times per week: 35% (95% CI: 28% to 43%) versus
21% (13% to 28%) for the 6-month period at the same dose.
Ten RCTs gave results concerning the histological improve-
ment.7,13-17,19,21-23 For the 2 RCTs7-13 using the standard regi-
men, the mean percentage of histological improvement at
6 months (biopsy performed at the end of the 6 months of
treatment) was 55% (95% CI: 23% to 86%), 67% (33 of 49
patients) in the interferon group versus 15% in the control
group (7/45; P õ .001).
Five RCTs14-17,19 compared the histological improvement
after treatment by 3 MU, 12 months to controls. The histolog-
ical improvement was defined in one trial14 as an improve-
ment of at least one grade in the classification of Scheuer
(moderate, mild chronic active, and persistent hepatitis). His-
tological improvement was defined as an improvement of the
Knodell’s activity index (or slightly modified) in three tri-
als,15-16,19 of at least one point15,19 or of 2 points.16 In one trial,
the histological improvement was defined as an improvement
of at least one point in a ‘‘Sheffield score’’ and by the Knodell
score, and it was stated that ‘‘both methods of analysis pro-
duced similar results and conclusions.’’17 For 2 of them,15,17
the biopsy was performed at the end of the 12-month treat-
ment, and the mean percentage of histological improvement
was 91% in the interferon group versus 30% in the control
hpta WBS: Hepatology
 782

AID
TABLE 2. Characteristics of 31 Included Trials Comparing Different Interferon Regimens in the Treatment of Chronic Hepatitis C

Mean
Score IFN Follow- Mean % of Drug Disease
Author MSa Type IFN Schedule Subgroup Upb Armsc Excludedd agee Men Transfusion Abuse Cirrhosis Durationf

Hepa 0031
Alberti 1993 10 a 2a RCT1: 6 MU TIW 6 mo vs. 3 MU 6 MU 6 mo 8 51/54 — 45/48 76/66 — — 9/14 —
a n-1g TIW 6 moh 6 MU 12 mo 61/58 — 44/47 69/63 — — 8/11 —
POYNARD ET AL.

/
RCT2: 6 MU TIW 6 mo fb 3 MU
TIW 6 mo vs. 3 MU TIW 12
mo
Hagiwara 1993 10 a n-1 6 MU/d 2 weeks fb 6 MU TIW 6 6 MU 6 mo 6 30/30 3/4 47/49 82/65 22/42 — — —
mo
Hakozaki 1995 11 a 2b 6 MU TIW 6 mo vs. 3 MU TIW 6 6 MU 6 mo 12 26/35 0/1 46/46 92/94 12/15 — 8/10 7/9
mo
Lin 1995 16 a 2b 5 MU TIW 6 mo vs. 3 MU TIW 6 6 MU 6 mo 24 75/72/83 7/7/18 39/38/42 76/72/63 21/29/24 47/46/37 31/22/25 —

5P14$$0031
mo vs.3 MU TIW 2 y 12 mo 3 MU
Picciotto 1995 11 a n-1 6 MU TIW 6 mo vs. 3 MU TIW 6 6 MU 6 mo 3 30/30 3/3 49/50 73/67 6/5 3/5 4/2 4/4
mo
Caporaso 1993 14 a 2a 6 MU TIW 12 mo vs. 3 MU TIW 6 MU 12 mo 12 39/42 3/2 50/50 59/79 6/1 1/2 15/20 5/7
12 mo
Chemello 1995 16 a 2a 6 MU TIW 6 mo fb 3 MU TIW 6 6 MU 12 mo 12 59/61/54 4/4/2 42/47/44 75/62/74 — — 9/12/10 5/6/6
mo vs. 3 MU TIW 12 mo vs. 6 12 mo 6 MU
MU TIW 6 mo
Enriquez 1995 13 a n-1 10 to 5 MU TIW 6 mo vs. 5 to 3 Dose other 9 45/45 2/0 49/47 64/67 11/19 — 4/5 5/4
MU TIW 6 mo

09-12-96 15:49:40
Marcellin 1995 15 a 2b 3 MU TIW 8 w fb 5 MU TIW 8 w Dose other 6 50/25 7/1 43/44 53/68 31/17 16/8 4/5 12/12
fb 10 MU TIW 8w vs. 3 MU
TIW 6 mo
Matsumoto 1994 8 a 2a 9 MU/d 2 w fb 9 MU TIW 6 mo Dose other 6 12/12 0/0 48/45 75/74 3/4 — — —

hpta
vs. 3 MU/d 2 w fb 3 MU 6 mo
Jouet 1993 13 a 2b 3 MU TIW 6 mo fb 2 MU TIW 3 12 mo 3 MU 6 61/59 ú5 47/50 61/59 32/41 16/10 23/16 —
mo fb 1 MU TIW 3 mo vs. 3
MU tiw 6 mo
Poynard 1995 16 a 2b 3 MU TIW 18 mo vs. 3 MU TIW 12 mo 3 MU 24 103/99/101 31/-/ 49/50/51 51/49/55 54/47/45 — 28/23/27 6/7/9
6 mo vs. 3 MU TIW 6 mo fb 1
MU 12 mo
Saracco 1993i 10 a 2b 3 MU TIW 12 mo vs. 3 MU TIW 12 mo 3 MU 36 14/26 — — — — — — —
6 mo
Kasahara 1995 12 a n-1 5 MU TIW 6 mo vs. 5 MU TIW 6 12 mo 6 MU 6 48/45 3/2 47/47 78/86 11/14 — 0 8/9
mo fb 5 MU 2 tw 6 mo

WBS: Hepatology
Abbreviations: IFN, interferon; MS, methodological score; TIW, three times per week.
a
, methodological score.
b
, follow-up after end of treatment (mo).
c
, size of treated and control groups.
d
, dropped out and treatment interruption because of side effects in treated and control groups.
e
, mean age (yr) in treated and control groups.
f
, mean duration (yr) of hepatic disease.
g
, lymphoblastoid.
h
, IFN-a 2b in group 6 MU and IFN a lymphoblastoid in group 3 MU.
i
, Distance of 6 mo between two groups for the treatment.
—, nonreported.
HEPATOLOGY October 1996
HEPATOLOGY Vol. 24, No. 4, 1996 POYNARD ET AL. 783

group (P õ .001); that is a 58% mean difference (95% CI:

33% to 83%). For 3 of them,14,16,19 the biopsy was performed
6 months after the end of the treatment. The mean percent-
age of histological improvement was 56% in the interferon
group versus 14% in the control group (P õ .001); that is a
39% difference (95% CI: 23% to 54%).
Comparisons of Different Interferon Regimens in Chronic
Hepatitis. Among the 37 references identified, 16 RCTs, pub-
lished in 14 full papers, which fulfilled the criteria of inclu-
sion were the core group in the meta-analysis of interferon
versus interferon; 10 were included in the dose-effect analy-
sis54-63; in the article by Alberti et al.,54 there were 2 RCTs;
in the article by Lin et al.57 and in the article by Chemello
et al.,60 there was a dose and a duration comparison; 6 were
included for the duration-effect analysis.57,60,64-67 Clinical
characteristics are described in Table 2.
Ten RCTs, which fulfilled the criteria of inclusion but were
published only as abstracts, have only been analyzed in the
sensitivity analyses.68-77 In the abstract by Bellobuono et al.,68
there were four comparisons, including two doses and two
durations.
The reject log contained 6 RCTs published as papers: 2
RCTs with a short duration of treatment78,79; and 4 RCTs
with a regimen that was complicated.80-83 Six abstracts were
excluded; one without enough details84; and five with a regi-
men that was complicated.85-89 Clinical characteristics are
given in Table 2.

FIG. 6. Meta-analysis summary: duration effect. Upper panel: summary

of trials comparing 3 MU during at least 12 months with 3 MU during 6
months; lower panel: summary of trials comparing 5-6 MU during 12 months
with 5-6 MU during 6 months.

The definitions of complete response were: Class 2, mention

FIG. 5. (A) Complete ALT response. Interferon in chronic hepatitis C; a
meta-analysis of trials assessing duration effect on complete ALT response
(stratified by dose). (B) Sustained ALT response. Interferon in chronic hepatitis
C; a meta-analysis of trials assessing duration effect on sustained ALT re-
sponse (stratified by dose).
of ALT normalization by the end of the treatment without
referring to a persistent normalization: RCTs54-56,58,61,62,64,66,67;
and Class 3, mention of persistent normalizations: RCTs;
‘‘complete normalization of ALT during treatment which per-
sisted as indicated by three separate measurements until the
completion of therapy,’’57 in one by ‘‘ALT were consistently
normal,’’59 ‘‘normalization of ALT during therapy confirmed
on at least two consecutive monthly determinations, indepen-
dent of whether response was maintained up to the end of
therapy,’’60 in one by ‘‘a normal ALT at the 2 last months of
therapy.’’65 One RCT did not define a complete response dur-
ing or at the end of treatment.63 A sustained response was
defined as the normalization of ALT during treatment and
the persistence of normalization after the end of treatment
for 3 months58; for 6 months in 6 RCTs,55,57,62,63,64,67 for 8
months,54 for 9 months61 and; for 12 months in 3 RCTs,56,59,60
for 24 months,65 or for 36 months.66
Dose Effect: 6 MU Versus 3 MU at 6 Months and 12
Months. There was a significant 15% (5% to 25%; P Å .005)
improvement of a complete response at the end of the treat-
ment for 6 MU versus 3 MU at 12 months; the mean complete
response rate in the 6 MU group was 69% versus 54% in
the 3 MU group. There was no significant dose effect on the
complete response rate at 6 months with a mean 9% increase
(01% to 18%; P Å .07); the mean complete response rate was
62% in the 6 MU group versus 53% in the 3 MU group. There
was a significant dose effect (6 vs. 3 MU three times per
week) on the sustained response rate at 12 months, with a
mean 17% increase (7% to 28%; P õ .001). The mean sus-
tained response rate in the 6 MU group was 46% versus 28%
in the 3 MU group. There was no significant dose effect on
the sustained response rate at 6 months with a mean 9%
increase (03% to 21%; P Å .13); the mean sustained response
rate was 28% in the 6 MU group versus 18% in the 3 MU
group (Fig. 3A, 3B, and 4).

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784 POYNARD ET AL. HEPATOLOGY October 1996

TABLE 3. Sensitivity Analyses on the Sustained Response Rates

Dose Effect 6 vs. 3 MU Duration Effect 12 vs. Duration Effect 12 vs.
Models Dose Effect 6 vs. 3 MU for 6 mo for 12 mo 6 mo 3 MU 6 mo 6 MU

Models of Sensitivity Number of Number of 95% Number of 95% Number of 95%

Analyses RCTs Difference 95% CI RCTs Difference CI RCTs Difference CI RCTs Difference CI

Core group alone 5 9% -3 21 3 17% 7-28 4 16% 9-23 2 20% 7-33

Core group plus abstracts 6 6% -4 15 5 17% 9-25 6 17% 11-23 5 15% 8-22
Core group without RCTS
with quality ° 10 3 2% -12 16 2 18% 5-31 3 14% 7-21 2 20% 7-33
Core group without RCTs
with prevalence
cirrhosis ú 30% 3 11% -5 27 2 17% 5-29 3 17% 6-28 2 20% 7-33
Core group without RCTs
with mean age ú 47
years 3 13% -5 30 2 17% 5-29 2 24% -3-51 2 20% 7-33
Core group without RCTs
with mean disease
duration ú 5 years 4 7% -6 20 1 ND ND 2 25% 0-50 1 ND ND
Core group without RCTs
with follow-up õ 12 mo 2 7% -15 29 2 18% 5-31 3 17% 6-28 1 ND ND
Core group without RCTs
assessing non-2b
interferon 2 7% -15 29 0 ND ND 4 16% 9-23 0 ND ND

Abbreviation: ND, not determined.

Duration-Effect: 12 Months or More Versus 6 Months at 3
MU and at 6 MU. There was a significant duration effect (12
months or more vs. 6 months) on the sustained response rate
at 3 MU, with a mean 16% increase (9% to 23%; P õ .001);
the mean sustained response rate in the 12-months-or-more
group was 35% versus 14% in the 6-month group. (Figs. 5A,
5B, and 6) There was also a significant duration effect on the
sustained response rate at 6 MU with a mean 20% increase
(7% to 33%; P Å .003); the mean sustained response rate was
49% in the 12-months-or-more group versus 29% in the 6-
month group. Concerning complete ALT response, there was
no significant duration effect.
There was no significant heterogeneity of all the meta-
analyses performed.
Sensitivity Analyses. The sensitivity analyses did not re-
veal any significant influence on these results, according to
the abstracts’ inclusion and to the exclusion of RCTs with
low methodological quality (prevalence of cirrhosis ú30%;
mean age ú47 years; mean disease duration ú5 years; follow-
up õ12 months; ALT sustained response was defined with
less than 12 months’ follow-up); and the exclusion of RCTs
assessing non-2b interferons (Table 3).
Acute Hepatitis C. Among the eight references that were
identified, a total of eight trials were identified.90-97 Two were
excluded because they were published twice96-97; one was not
controlled95; and one trial was probably not randomized but
was included for sensitivity analysis.90 The core group, there-
fore, involved four RCTs.91-94
The clinical analysis characteristics are given in Table 4
and the meta-analysis is given in Fig. 7A for the complete
ALT response at the end of the treatment. Figure 7B shows
the sustained ALT response, and Fig. 7C shows the HCV-
RNA disappearance rate 12 months after the end of treat-
ment. The meta-analysis summary is shown in Fig. 8. There
were a significant differences for these three analyses with
or without the inclusion of the trial not clearly randomized.
With interferon the percentage of complete ALT response at
the end of the treatment was 69% versus 29% in the control
groups, with a mean difference of 40% (95% CI: 25% to 55%;
P õ .001); the sustained ALT response rate 12 months after
the end of the treatment was 53% versus 32% in the control
groups, with a mean difference of 21% (95% CI: 3% to 39%;
P Å .02); and the HCV-RNA disappearance rate 12 months
after the end of the treatment was 41% versus 4% in the

TABLE 4. Characteristics of 4 Included Trials Comparing Interferon With Controls in Patients With Acute Hepatitis C
RNA Mean
Score IFN Follow- Armsc Positive Mean % of Drug Disease
Author MSa Type IFN Schedule Upb (IFN/C) (IFN/C) Excluded d
Agee Men Transfusion Abuse Durationf

Lampertico 13 a 2b 3 MU TIW 3 mo vs. 15 27/21 18/9 1/2 49/44 65/47 27/21 0 7/9
1994 control
Omata 12 b 3 MU/D 5 D fb 3 MU TIW 12 11/14 10/12 0 40/38 36/50 8/10 — —
1994 3 weeks vs. control
Viladomiu 7 a 2b 3 MU TIW 3 mo vs. 9 15/13 — 0 54/51 60/70 15/13 0 7/7
1992 control
Hwang 13 a 2b 3 MU TIW 3 mo vs. 12 17/16 17/16 0/1 53/55 75/71 17/16 0/0 9/10
1995 control

Abbreviations: C, control; IFN, interferon; MS, methodological score; TIW, three times per week.
a
methodological score.
b
follow-up after end of treatment (mo).
c
size of treated and control groups.
d
dropped out and treatment interruption because of side effects in treated and control groups.
e
mean age (yr) treated and control groups.
f
mean duration (wk) of hepatic disease.

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HEPATOLOGY Vol. 24, No. 4, 1996
FIG. 7. (A) ALT response end-treatment. Interferon in acute hepatitis C;
a meta-analysis of trials assessing effect on complete ALT response vs. control.
(B) ALT response 15-month. Interferon in acute hepatitis C; a meta-analysis
of trials assessing effect on sustained ALT response vs. control. (C) Serum
HCV RNA clearance. Interferon in acute hepatitis C; a meta-analysis of trials
assessing effect on serum HCV-RNA disappearance vs. control.
control groups, with a mean difference of 34% (95% CI: 18%
to 51%; P õ .001).
After the inclusion of Alberti et al.,54 RCT results do not
change significantly; the mean differences being respectively
47% for ALT response at the end of the treatment, 27% for
ALT sustained response 12 months after the end of treat-
ment, and 38% for the HCV-RNA disappearance rate.
Side Effects of Interferon. The side effects observed in the
included RCTs and in the abstracts with inclusion criteria
are summarized in Table 5. For the standard regimen, the
three most frequent clinically adverse events described dur-
ing the 6-month treatment period were the flulike syndrome
(41%), alopecia (16%), and depression (7%). In the groups
that were treated for 6 months by a dose ¢ 5 MU, there was
more of a dose decrease (22% vs. 9%; P Å .01) and more of
flulike symptoms (76% vs. 41%; P õ .001) than in the groups
that were treated by 3 MU during 6 months.
DISCUSSION
Among 88 references, this overview identified 37 RCTs
published as full papers between 1989 and 1995, in compari-
son with only the 18 that were identified by Tine et al.1 This
increase in information justified a new overview to assess the
efficacy in chronic hepatitis C of higher doses or of longer
durations of interferon treatment. It was also possible to as-
sess the efficacy of the use of interferon in patients with acute
hepatitis C. Two recent meta-analyses98,99 did not focus on
these endpoints.
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POYNARD ET AL. 785
Our results confirm the results of Tine et al. for the ‘‘stan-
dard regimen,’’ i.e., 3 MU three times per week for 6 months:
45% and 21% increases for the complete and sustained re-
sponses, respectively, the natural course being less than 2%
of spontaneous responses.
This meta-analysis also led to an assessment of whether
interferon alfa had a ‘‘dose effect’’ or a ‘‘duration effect.’’ This
was possible by pooling the RCTs and by directly comparing
higher doses or longer duration with the standard regimen
of 3 MU three times per week for 6 months. This was also
possible by pooling the RCTs that assessed the duration effect
by the comparison of 12 versus 6 months of the regimen of 6
MU three times per week and by pooling the RCTs that as-
sessed the dose effect by the comparison of 6 MU versus 3
MU three times per week for 12 months.
From these multiple comparisons, there appeared to be a
significant duration effect on the sustained response rate at
both 3 and 6 MU three times per week. Because of the quality
of trials, of the greater number of patients included, of the
greater number of RCTs published as full articles, of the
better stability to sensitivity analyses and of the same differ-
ences that had been observed in RCTs versus controls the
duration effect at 3 MU appeared to be more consistent than
at 6 MU. With 3 MU three times per week during 12 months
or more, a 16% increase in the sustained response rate was
obtained in comparison with the 6-month duration. Very few
trials have analyzed the differences in liver lesions. For an
18-month duration, there was a very significant improvement
in comparison with that of 6 months,65 even in patients with-
out the normalization of ALT.
The dose effect (6 vs. 3 MU) was also significant and homo-
geneous for the complete ALT response rate at the end of 12
months of treatment, with a mean of 15% improvement. At
6 months, there was no significant dose effect on the ALT
sustained response. This negative result could be related to
a lack of power, but based on these data, this regimen should
not be recommended. In contrast, there was a significant dose
effect (6 vs. 3 MU three times per week) at 12 months, with
a mean 17% increase in the sustained response rate.
Our meta-analysis did not find any advantage in terms of
ALT sustained response in the 3 RCTs,61-63 which analyzed
the escalating or the deescalating regimen.
Because of the heterogeneity in the quality of the adverse-
events description and the absence of a placebo, the percent-
age of adverse events that attributed to interferon are diffi-
cult to interpret. It was difficult from these data to estimate
the dose effects and duration effects on the incidence of side
effects. Nevertheless, the 6-month incidence of 16% alopecia
and of 7% depression is useful information to give and to
explain to patients before starting treatment. We have ob-
served, on this small sample size, more dose decreases and
flulike symptoms in the groups treated by 5 to 6 MU than
by 3 MU for the same 6-month duration.
FIG. 8. Summary meta-analysis of interferon trials in the treatment of
acute hepatitis C.
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786 POYNARD ET AL. HEPATOLOGY October 1996

TABLE 5. Side Effects Observed in Interferon Trials in Patients With Chronic Hepatitis C
Stopped Dose Low Thyroid Flulike
Author Schedule Arms Treatmenta Decreaseb Leucopenia Platelets Depression Disease Alopecia Syndrome

Causse 1991 3 MU TIW 6 mo 30 0 3 — — 2 0 0 ///

Placebo 30
Cimino 1991 3 MU TIW 6 mo 33 0 0 0 0 0 0 0 ///
Control 33
Davis 1989 3 MU TIW 6 mo 58 1 8 2 2 8 — 14 32
Control 51 0 0 4 — 0 3
Marcellin 1991 3 MU TIW 6 mo 18 0 3 2 1 0 0 0 18
Control 18
Saito 1994 3 MU TIW 6 mo 10 0 0 — — 0 0 0 10
Control 10 0 0 0 0 0 0 0 0
Saracco 1990 3 MU TIW 6 mo 26 2 — — — — — — /
Control 25
Weiland 1990 3 MU TIW 9 mo 21 1 1 9 0 0 0 0 18
Control 12
Camps 1993 3 MU/D 8 W fb 3 MU 36 1 4 9 5 3 0 4 30
TIW 3 mo fb 1,5 MU
TIW 6 mo 36
Control
Diodati 1994 6 MU TIW 1m fb 3 MU 30 1 — — — — — 7 24
TIW 3 mo fb 1 MU
TIW 8 mo 30
Control
Makris 1991 1 MU TIW 1 m fb 2 MU 10 0 2 0 1 0 0 2 6
TIW 1 m fb 3 MU
TIW 10 mo 8
Control
Mazella 1994 3 MU TIW 12 mo 30 1 — — — — — 8 19
Control 30 — —
Capra 1993 6 MU TIW 6 mo 21 0 — — — — — 4 ///
Control 19
Rumi 1995 6-3 MU TIW 12 mo 38 2 — 0 1 2 2 6
Control 36
Gomez-Rubio 1991 5 MU TIW 2 mo fb 1,5 15 2 0 0 0 2 0 2 14
MU TIW 16 mo
Control 15
Saez-Royuela 1991 15 MU TIW 3 mo fb 10 10 0 1 1 1 0 1 5 10
MU TIW 3 mo fb 5
MU TIW 6 mo 10
Control
Hakozaki 1995 6 MU TIW 6 mo 35 1 — / / 1 — — /
3 MU TIW 6 mo 26 0 — / / 0 — — /
Caporaso 1993 6 MU TIW 12 mo 39 1 — — — — — — —
3 MU TIW 12 mo 42 1 — — — — — — —
Chemello 1995 6 MU TIW 6 mo fb 3 59 4 — 0 2 4 0 1 36
MU TIW 6 mo
vs. 3 MU TIW 12 mo 61 4 — 10 4 10 0 13 20
vs. 6 MU TIW 6 mo 54 2 — 5 2 12 0 13 34
Enriquez 1995 10 to 5 MU TIW 6 mo 45 2 10 8 2 0 2 6 41
vs. 5 to 3 MU TIW 6 mo 45 0 4 10 2 0 3 9 30
Marcellin 1995 3 MU TIW 8 w fb 5 MU 50 6 — — — — — — ///
TIW 8 w 25 1 ///
fb 10 MU TIW 8 w vs. 3
MU TIW 6 mo
Poynard 1995 3 MU TIW 18 mo 103 19 — 23 10 10 1 18 11
3 MU TIW 6 mo 99 9 — 17 13 9 4 20 16
Total side effects for 3 MU TIW 6 mo number/patients 13/325 14/164 21/244 16/196 19/274 4/190 34/215 76/185
at risk (%) 4% 9% 9% 8% 7% 2% 16% 41%
Total side effects for dose ¢ 5 MU TIW 6 mo number/ 11/205 10/45 13/99 4/99 13/134 2/99 23/120 75/99
patients at risk (%) 5% 22% 13% 4% 10% 2% 19% 76%

Abbreviation: TIW, three times per week.

a
treatment stopped because of side effects only.
b
decrease in dose because of side effects.

A high number of RCTs that were identified were published
as abstracts, and this could be a bias of publication. However,
the significant difference that was observed persisted in the
sensitivity analyses after the inclusion of RCTs that were
published only in abstracts. The risk of bias related to non-
published RCTs was not totally excluded, because we were
unable to determine whether some RCTs had ever been pub-
lished, even in abstract form. Another weakness was the ab-
sence of an analysis that combined individual data, which
would have permitted a better analysis of the treatment ef-
fect by taking into account a per-patient heterogeneity in the
multivariate analyses. A third weak point was the absence
of a histological endpoint for comparisons between doses and
durations. The histological data at the end of treatment or

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HEPATOLOGY Vol. 24, No. 4, 1996
in the follow-up are particularly difficult to obtain. Even in
trials that focus on the histological criteria, the number of
patients who had undergone a second biopsy is generally
between 50% and 60%.65 The fourth weak point was the ab-
sence of virological data, genotype, and quantitative viremia,
which may be important factors in heterogeneity. The disap-
pearance of serum hepatitis C RNA polymerase chain reac-
tion at the end of and during follow-up studies could be accu-
rate endpoints that were identified for acute hepatitis trials
only. The fifth weak point was the variability of endpoints.
The ALT complete response definitions varied from one to
four consecutive normal ALT during treatment. The ALT sus-
tained response definition varied from 4 to 36 months follow-
up with periodicity of ALT testing usually not clearly de-
scribed. However, sensitivity meta-analyses, including these
stratifications, did not show different results either for the
comparison to controls (data not shown) or between different
regimens. To reduce the heterogeneity between trials and to
avoid bias, all missing data were considered as failures. The
histological estimate may have been biased by the exclusion
of patients without second biopsy data, because we used the
per-protocol analysis, excluding the missing data contrary to
ALT responses that were estimated by the intention-to-treat
method, i.e., including missing data as failures.
In comparison with the first meta-analysis that was pub-
lished, the total number of patients who were included was
considerably increased. However, the mean number of pa-
tients included per trial was still low, with only one RCT65
having included 100 patients per group. This weakness in the
sample size was striking in the comparison between different
regimens, because this type of comparison requires more
power than does the comparison with control groups. This
meta-analysis permitted us to increase the power and to re-
duce the risk of false-negative conclusions caused by small
trials. Furthermore, our meta-analysis included less hetero-
geneous RCTs, because we excluded RCTs with doses lower
than 3 MU, with a duration of less than 6 months, or with
protocols considered too complicated. The exact level of effi-
cacy of interferon versus control was better estimated for the
complete ALT response and for the sustained response. The
increase in trials versus Controls with different regimens
also revealed, by the indirect meta-analysis, a trend toward
greater efficacy of the 12-month treatment duration (35% vs.
21%; P Å .06). The increase in the histological improvement
for the standard regimen was of the same magnitude as the
ALT complete response (55%), but the spontaneous improve-
ment in histological features was higher (15% at 6 months).
The discrepancy between ALT and histological responses sug-
gests a natural evolution toward a decrease in histological
activity (necrosis and inflammatory lesions), as observed for
hepatitis B but also substantial variability in histological
endpoints. Intrapatient variability is difficult to reduce be-
cause it is not easy to perform two biopsies in two different
parts of the liver. However, it is possible to reduce the in-
traobserver and interobserver variability by using a stan-
dardized scoring system with high reproducibility. We have
demonstrated that it was possible to increase the concordance
rate that was observed for the Knodell scoring system by
using the METAVIR scoring system.100 Finally, the discrep-
ancy observed between the ALT and the histological response
raises the question as to the best endpoint for the evaluation
of treatment in hepatitis C.65 As was the case for ALT, the
predictive values of the new virological markers, i.e., poly-
merase chain reaction disappearance, must be assessed by
the histological and hard clinical endpoints, such as mortal-
ity. The improvement rate 6 months after the end of the 12-
month treatment was 19% lower than the improvement rate
that was observed at a biopsy performed just at the end of
the 12 months of treatment (58% vs. 39%). The interpretation
of this difference is difficult because the biopsies were not
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POYNARD ET AL. 787
performed on the same patients, because the spontaneous
improvement rates in the control groups were also different,
and because it is a retrospective analysis. However, this
underlines the necessity in such randomized trials to give
the timing of liver biopsies.
In acute hepatitis C, a 3-month interferon treatment had
a favorable effect both on the ALT response rate during treat-
ment and on the sustained response rate during the 12
months following the treatment. There was also a clear differ-
ence in favor of interferon for the clearance of serum HCV
RNA 12 months after the end of the treatment. One weakness
was the small number of trials and patients that were in-
cluded. These RCTs are very difficult to perform because
acute hepatitis is rarely clinically identified. Furthermore,
because of the high sensitivity of the most recent generation
of HCV antibody testing, the decrease in posttransfusion hep-
atitis will preclude new RCTs. The RCTs included were het-
erogeneous for race, diagnosis, and type of interferon (three
2b and one b), but there was no statistical heterogeneity in
the responses to interferon. From the pooling of results in
the control groups, the observed rates were those expected
from the literature: spontaneous ALT normalization in 30%,
i.e., 70% of chronic infection. One other possible weakness
might have been the difficulty of distinguishing between
acute and chronic hepatitis without pretransfusion polymer-
ase chain reaction. This criticism was ruled out by the de-
scription of ALT among control groups. The 30% ALT sponta-
neous sustained response rate has never been observed in
chronic hepatitis C. Among the patients who were included
in these trials, some were HCV-RNA–negative at randomiza-
tion, and therefore they can be interpreted as patients with
non-A, non-B, non-C acute hepatitis or with serum polymer-
ase chain reaction false-negative hepatitis C. Because our
meta-analysis has been performed with the intention to treat,
i.e., patients with initial negative HCV RNA were considered
as failure, the efficacy level of interferon in acute hepatitis
C has probably been underestimated.
Finally, based on these analyses, the best efficacy-risk ratio
is in favor of 3 MU three times per week for at least 12
months in patients with chronic hepatitis C, not previously
treated with interferon. Patients with acute hepatitis should
be treated by interferon alfa, at least 3 MU three times per
week for 3 months.
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