A randomized, prospective trial of ribavirin 400 mg/day versus 800 mg/day in combination with Peginterferon alfa-2a in HCV Genotypes and 3

ArticleinHepatology 47(6):1816-23 · June 2008with26 Reads
Impact Factor: 11.06 · DOI: 10.1002/hep.22262 · Source: PubMed
Abstract

Unlabelled: We compared the efficacy and tolerability of 24 weeks of treatment with ribavirin 800 mg/day (group A) or 400 mg/day (group B) plus peginterferon alfa-2a 180 mug/week in treatment-naive patients infected with hepatitis C virus (HCV) genotype 2 or 3. A total of 97 of 141 patients randomized to group A (68.8%, 95% confidence interval [CI] 60.5%-76.3%) and 90 of 141 patients randomized to group B (63.8; 95% CI 55.3%-71.7%) achieved a sustained virological response, defined as undetectable serum HCV RNA at the end of untreated follow-up (week 48). Among patients infected with genotype 3, the rate of sustained virological response was 67.5% (95% CI 58.4%-75.6%) in group A and 63.9% (95% CI 54.7%-72.4%) in group B, and among patients infected with genotype 2, the rate of sustained virological response was 77.8% (95% CI 54.2%-93.6%) in group A and 55.6% (95% CI 38.4%-83.7%) in group B. Relapse rates in the 2 treatment groups were similar (17% in group A and 20% in group B). The incidence of adverse events, laboratory abnormalities, and dose reductions was similar in the 2 treatment groups. Conclusion: The results suggest that when administered for 24 weeks with peginterferon alfa-2a, ribavirin doses of 400 and 800 mg/day produce equivalent outcomes in patients infected with HCV genotype 3.

Full-text

Available from: Andreas Maieron, Oct 06, 2014
VIRAL HEPATITIS
A Randomized, Prospective Trial of Ribavirin
400 mg/Day Versus 800 mg/Day in Combination
with Peginterferon Alfa-2a in Hepatitis C Virus
Genotypes 2 and 3
Peter Ferenci,
1
Harald Brunner,
2
Hermann Laferl,
3
Thomas-Matthias Scherzer,
1
Andreas Maieron,
4
Michael Strasser,
5
Gabriele Fischer,
6
Harald Hofer,
1
Martin Bischof,
7
Rudolf Stauber,
8
Michael Gschwantler,
9
Petra Steindl-Munda,
1
Katharina Staufer,
1
and Karin L
¨
oschenberger,
10
for the Austrian Hepatitis Study Group
We compared the efficacy and tolerability of 24 weeks of treatment with ribavirin 800 mg/day
(group A) or 400 mg/day (group B) plus peginterferon alfa-2a 180
g/week in treatment-naive
patients infected with hepatitis C virus (HCV) genotype 2 or 3. A total of 97 of 141 patients
randomized to group A (68.8%, 95% confidence interval [CI] 60.5%-76.3%) and 90 of 141
patients randomized to group B (63.8; 95% CI 55.3%-71.7%) achieved a sustained virological
response, defined as undetectable serum HCV RNA at the end of untreated follow-up (week 48).
Among patients infected with genotype 3, the rate of sustained virological response was 67.5%
(95% CI 58.4%-75.6%) in group A and 63.9% (95% CI 54.7%-72.4%) in group B, and among
patients infected with genotype 2, the rate of sustained virological response was 77.8% (95% CI
54.2%-93.6%) in group A and 55.6% (95% CI 38.4%-83.7%) in group B. Relapse rates in the 2
treatment groups were similar (17% in group A and 20% in group B). The incidence of adverse
events, laboratory abnormalities, and dose reductions was similar in the 2 treatment groups.
Conclusion: The results suggest that when administered for 24 weeks with peginterferon alfa-2a,
ribavirin doses of 400 and 800 mg/day produce equivalent outcomes in patients infected with
HCV genotype 3.
(HEPATOLOGY 2008;47:1816-1823.)
T
he prevalence of chronic infection with hepatitis
C virus (HCV) is estimated to range from 1.5%
to 15% depending on the region. In Europe, 8
million to 10 million individuals suffer from chronic hep-
atitis C, and it is expected that over 10 to 20 years, ap-
proximately 20% of these individuals will develop
cirrhosis and its complications and will be in need of liver
transplantation.
1,2
Effective treatment for chronic hepatitis C would re-
duce morbidity and mortality, improve health-related
quality of life, and avoid the huge costs associated with
end-stage liver disease. The current standard of care is a
combination of pegylated interferon and ribavirin, which
produces an overall cure rate of approximately 50% to
60%.
3,4
The most important predictor of successful response to
combination therapy is HCV genotype.
5
On the basis of a
large randomized international study,
4
the optimum
treatment for patients with HCV genotype 1 infection is
considered to be 48 weeks of combination therapy with
pegylated interferon plus ribavirin 1000 or 1200 mg/
Abbreviations: HCV, hepatitis C virus; ULN, upper limit of normal; 95% CI,
95% confidence interval.
From the
1
Department of Internal Medicine III, Medical University, Vienna,
Austria;
2
Department of Internal Medicine 1, Hospital Hietzing, Vienna, Austria;
3
Department of Internal Medicine, Kaiser-Franz-Josef-Spital, Vienna, Austria;
4
Department of Internal Medicine, Elisabethinen Hospital, Linz, Austria;
5
De
-
partment of Internal Medicine I, St. Josef Hospital, Salzburg, Austria;
6
Department
of Psychiatry, Medical University, Vienna, Austria;
7
Department of Internal Med
-
icine IV, Rudolfsspital, Vienna, Austria;
8
Department of Internal Medicine, Med
-
ical University, Graz, Austria;
9
Department of Internal Medicine IV,
Wilhelminenspital, Vienna, Austria; and
10
Roche Austria, Vienna, Austria.
Received December 4, 2007; accepted January 29, 2008.
Trial registered at Center Watch. Protocol number: ML17087.
Address reprint requests to: Professor Dr. Peter Ferenci, MD, Univ. Klinik fu¨r
Innere Medizin III, Medical University of Vienna AKH, Waehringer Guertel
18-20, A 1090 Wien, Austria. E-mail: peter.ferenci@meduniwien.ac.at; fax: (43)
1 404004735.
Copyright © 2008 by the American Association for the Study of Liver Diseases.
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/hep.22262
Potential conflict of interest: Dr. Gschwantler is on the speakers’ bureau of and
received grants from Hoffmann–La Roche. Dr. Staufer is on the speakers’ bureau of
and received grants from Roche. Dr. Laferl received grants from Roche. Dr. Ferenci
is a consultant for, advises, is on the speakers’ bureau of, and received grants from
Roche.
1816
Page 1
day.
5
In contrast, patients infected with HCV genotype 2
or 3 may be treated with a lower dose of ribavirin (800
mg/day) and for just 24 weeks without compromising
efficacy.
6,7
These findings are reflected in treatment
guidelines for chronic hepatitis C.
5
The use of a lower, fixed 800 mg/day dose of ribavirin
is better tolerated and as effective as the higher 1000 or
1200 mg/day standard dose of ribavirin in patients in-
fected with HCV genotype 2 or 3. Recent attempts to
further simplify treatment for these patients have focused
on shortening the duration to 12 to 16 weeks,
8-11
but it is
now clear that abbreviated regimens result in higher re-
lapse rates when compared with the standard 24-week
regimen.
10
It remains to be determined whether the tol
-
erability of treatment can be improved and the costs re-
duced by further decreasing the dose of ribavirin. For this
reason, we compared the efficacy and tolerability of 24
weeks of treatment with ribavirin at a dosage of 800 or
400 mg/day in combination with peginterferon alfa-2a in
patients infected with HCV genotype 2 or 3.
Patients and Methods
Patients eligible for the trial were treatment-naive
adults aged 18 to 65 years with chronic hepatitis C, HCV
genotype 2 or 3 infection, quantifiable HCV RNA in
serum (600 IU/mL by Cobas Amplicor HCV Monitor
Test v.2.0) and elevated serum ALT activity (1.5 times
the upper limit of normal [ULN] in the previous 6
months and during screening). Patients were required to
have a hemoglobin value 12 g/dL (women) or 13 g/dL
(men), a leukocyte count 3000/
L, a platelet count
100,000/
L, and a serum creatinine level 1.5 times the
ULN.
Women of childbearing potential were required to
have a negative pregnancy test within 24 hours of the
first dose. All fertile male and female participants were
required to use two forms of effective contraception
during treatment and for 6 months after the end of
treatment.
Pregnant or breast-feeding women and male partners
of pregnant women were excluded. Patients were also ex-
cluded if they had received prior treatment with inter-
feron or ribavirin at any time; were coinfected with
hepatitis B virus or human immunodeficiency virus; had
decompensated liver disease or chronic liver disease attrib-
utable to another cause; coronary heart disease; diabetes
mellitus requiring insulin therapy; autoimmune disor-
ders; and/or any other unstable chronic medical condi-
tion. Individuals with severe psychiatric disease, especially
depression, and those with a history of active alcohol or
drug addiction within the previous 6 months were ex-
cluded, although patients on opiate substitution therapy
were eligible if they were treated by the drug treatment
centre in the Department of Psychiatry, Medical Univer-
sity of Vienna.
Study Protocol
Patients entered a 35-day screening phase before ran-
domization in this multicenter study. Eligible patients
were randomized to 24 weeks of treatment with subcuta-
neous peginterferon alfa-2a (Pegasys, Roche, Basel, Swit-
zerland) 180
g/week in combination with oral ribavirin
(Copegus, Roche) at a dosage of either 800 mg/day
(group A) or 400 mg/day (group B). Ribavirin was ad-
ministered twice daily in both treatment groups
Dose reductions were allowed at the investigator’s dis-
cretion. In the event of laboratory abnormalities or ad-
verse events, the dosage of peginterferon alfa-2a could be
reduced, preferably in a stepwise manner from 180 to
135, 90, and 45
g/week.
For patients randomized to treatment with ribavirin
800 mg/day, the dose of ribavirin was to be decreased by
200 mg/day in the event of a decrease in hemoglobin to
10 and 8.5 g/dL in patients without significant car-
diovascular disease or in the event of a 2 g/dL decrease
in hemoglobin over any 4-week period in patients with
stable cardiovascular disease. The dose of ribavirin could
also be reduced in 200 mg/day increments in patients
randomized to treatment with ribavirin 400 mg/day
(group B).
Treatment with ribavirin was to be discontinued if the
hemoglobin level fell below 8.5 g/dL in a patient without
significant cardiovascular disease or if the hemoglobin
level remained below 10 g/dL despite 4 weeks of treat-
ment at the reduced dosage of 600 mg/day in patients
enrolled in group A. The use of erythropoietin-stimulat-
ing agents (i.e., Neorecormon, Roche, Basel) was allowed
at the discretion of the investigator if the hemoglobin level
fell to 10.5 g/dL. In the event that ribavirin was discon-
tinued, monotherapy with peginterferon alfa-2a could be
continued; however, monotherapy with ribavirin was not
permitted.
Upon resolution of the event that precipitated the dose
reduction, investigators were allowed to increase the dose
of peginterferon alfa-2a or ribavirin to the originally as-
signed dose.
Blocked randomization was performed centrally and
was stratified according to HCV genotype (2 versus 3)
and baseline HCV RNA level (2 versus 2 10
6
cop
-
ies/mL [800,000 versus 800,000 IU/mL]). The eth-
ics committees of all participating hospitals approved the
protocol, and patients gave written informed consent be-
fore enrollment.
HEPATOLOGY, Vol. 47, No. 6, 2008 FERENCI ET AL. 1817
Page 2
The primary efficacy end point was sustained virolog-
ical response, defined as undetectable HCV RNA (50
IU/mL) by qualitative PCR assay (Cobas Amplicor HCV
Test v.2.0) after 24 weeks of untreated follow-up (week
48). The safety and tolerability of treatment were second-
ary end points.
Specimen Collection and Virological Tests
Blood was collected in 9-mL tubes (Vacuette, Greiner
bio-one GmbH, Kremsmu¨nster, Austria) and centrifuged
at 1,500g for 20 minutes at room temperature within 4
hours of venipuncture. Immediately after centrifugation,
serum aliquots were frozen at 70°C until tested. Serum
HCV RNA assays were performed according to the man-
ufacturer’s package inserts.
Statistical and Analytical Methods
Sample Size Calculation. On the basis of the results
of a large, randomized, multinational trial,
6
we assumed
that the rate of sustained virological response would be
78% in both treatment groups and that the maximum
acceptable difference between these rates was 15%. The
total sample size of 192 patients with HCV genotype 3
infection was considered sufficient to compare the sus-
tained virological response rates between the two treat-
ment groups with a power of 80% and a significance level
of 5% using a one-sided equivalence test of proportions. It
was expected that a small proportion of patients with
genotype 2 would be recruited. For this reason, sample
size calculation was based on patients with HCV geno-
type 3 infection. After recruitment was initiated, patients
with genotype 2 infection were enrolled until the required
number of patients with genotype 3 had been enrolled.
Statistical Analysis. The analysis was conducted ac-
cording to the intention-to-treat principle. Patients with
missing results at the end of follow-up were considered
not to have a sustained virological response.
For the primary efficacy parameter (sustained virolog-
ical response), a 95% confidence interval using a Coch-
ran-Mantel-Haenszel (CMH) statistic stratified by
genotype and viral load was calculated for the treatment
difference in the per-protocol analysis (group B group
A). The two regimens were considered equivalent if the
lower limit of this confidence interval was determined to
be greater than 15%. The rate of virological response at
the end of treatment and at the end of follow-up (that is,
sustained virological response) and two-sided 95% confi-
dence intervals were calculated for each treatment group.
The influence of various baseline variables on the rate
of sustained virological response in both treatment groups
was investigated by multiple logistic regression analysis.
Results
The flow of patients through the study is shown in Fig.
1. A total of 291 patients were screened and 282 patients
were randomized to treatment. The first patient was en-
rolled in May 2003 and the last patient completed fol-
low-up in December 2006. Baseline characteristics are
presented in Table 1.
Thirty-five patients did not complete 24 weeks of
treatment (group A, 13; group B, 22). Eleven patients
discontinued treatment because of adverse events: five
in group A for sepsis with multiorgan failure (1), cere-
bellar infarction (1), herpes simplex (1), pneumonia
(1), and depression (1); and six in group B because of
circulatory collapse (1), hematuria (1), and psychiatric
problems (4). Two of these patients who discontinued
treatment prematurely for adverse events (in weeks 14
and 18, respectively) were HCV RNA negative in week
48 and thus had a sustained virological response. Treat-
ment of two patients was terminated because of proto-
col violations (one was HCV RNA negative at baseline,
one was randomized to receive ribavirin 400 mg/day
but took 800 mg/day by mistake); one patient was
jailed; and three patients withdrew consent. The re-
maining 18 patients who discontinued treatment pre-
maturely were noncompliant. Nine patients who had
an end-of-treatment response did not return for the
examination at the end of follow-up and were consid-
ered not to have achieved a sustained virological re-
sponse in the efficacy analysis.
Efficacy. Overall and in the different genotypes,
there was no significant difference in the rate of sustained
virological response between the two treatment groups
(Table 2).
According to the intention-to-treat analysis, 97 of 141
patients (68.8%, 95% confidence interval [95% CI]
60.5%-76.3%) randomized to ribavirin 800 mg/day and
90 of 141 patients (63.8; 95% CI 55.3%-71.7%) ran-
domized to ribavirin 400 mg/day achieved a sustained
virological response.
Among patients infected with genotype 3, the rate of
sustained virological response was 67.5% (83 of 123,
95% CI 58.4%-75.6%) in those randomized to ribavirin
800 mg/day and 63.9% (78 of 122, 95% CI 54.7%-
72.4%) in those randomized to ribavirin 400 mg/day.
Among patients infected with genotype 2, the rate of
sustained virological response was 77.8% (14 of 18, 95%
CI 54.2%-93.6%) in those randomized to ribavirin 800
mg/day and 63.2% (12 of 19, 95% CI 38.4%-83.7%) in
those randomized to ribavirin 400 mg/day.
Relapse rates in the 2 treatment groups were similar.
Among patients randomized to ribavirin 800 mg/day, 21
1818 FERENCI ET AL. HEPATOLOGY, June 2008
Page 3
of 123 individuals (17%) with an end-of-treatment viro-
logical response relapsed during follow-up, as did 23 of
117 (20%) individuals randomized to ribavirin 400 mg/
day. One patient treated with ribavirin 800 mg/day re-
sumed injection drug use and was reinfected with HCV
genotype 1a during follow-up. For the purposes of the
analysis, this individual was considered to have had a vi-
rological relapse.
By univariate analysis, no baseline factors were statisti-
cally significant predictors of sustained virological re-
sponse. Baseline characteristics are presented according to
virological response in Table 3.
Safety. The two regimens were well tolerated with a
low but similar frequency of adverse events. The most
common adverse events were flu-like syndrome, fa-
tigue, and/or epigastric discomfort, which were re-
Screened
N = 291
9 patients screened,
but not randomized
Randomized
N = 282 (213)
Peginterferon alfa-2a (40KD)
+800 mg ribavirin/day
N = 141 (123)
Completed 24 weeks of treatment
n = 131 (112)
Nonresponder
N= 5 (3)
RELAPSE
N= 21 (21)
SVR
N= 97 (83)
SVR
N= 90 (78)
RELAPSE
N= 23 (20)
EOT Responder
N= 123 (109)
Lost to follow-up
N= 5 (5)
Completed follow-up
n = 118 (104)
Completed follow-up
n = 113 (90)
Lost to follow-up
N= 4 (4)
EOT Responder
N= 117 (102)
Nonresponder
N=4 (4)
Completed 24 weeks of treatment
n = 119 (101)
early
termination
13 (11)
early
termination
22* (16)
Peginterferon alfa-2a (40KD)
+400 mg ribavirin/day
N = 141 (122)
Fig. 1. Flow of patients in the study. Figures in brackets refer to patients with genotype 3. *Two (1) patients who withdrew from treatment
prematurely returned for follow-up and were HCV RNA negative in weeks 24 and 48.
HEPATOLOGY, Vol. 47, No. 6, 2008 FERENCI ET AL. 1819
Page 4
ported collectively by 51 patients in group A and 61
patients in group B. Pruritus and/or exanthemas were
reported by 48 patients in group A and 50 patients in
group B. Psychiatric adverse events, for the most part
depression, were reported by 49 patients in group A
and 56 patients in group B. A total of 48 patients
complained of hair loss (group A, 25; group B, 23).
The incidence of laboratory abnormalities and pegin-
terferon alfa-2a dose reductions was similar in the two
treatment groups (Table 4). Hemoglobin was lower in
patients receiving ribavirin 800 mg/day than in those re-
ceiving 400 mg/day (Fig. 2), and more patients random-
ized to a dosage of 800 than 400 mg/day had the dose
reduced. Among the nine patients in whom the dose of
ribavirin was reduced, six achieved a sustained virological
response, two were lost to follow-up, and one individual,
who discontinued treatment after one 1 week, did not
have a sustained virological response. Although permit-
ted, erythropoietin-stimulating agents were not given to
any patient.
Discussion
The results of this study indicate that the dose of riba-
virin can be reduced from 800 to 400 mg/day without
increasing the relapse rate in HCV genotype 3 patients
treated for 24 weeks with the standard of care. The overall
rate of sustained virological response in genotype 3 pa-
tients was similar to that reported in the large randomized
international ACCELERATE trial.
10
Infection with
HCV genotype 2 is rare in Austria; thus, the results in the
small group of patients infected with this genotype were
inconclusive about whether a ribavirin dose of 400 mg/
day produces outcomes equivalent to those achieved with
the recommended dose of 800 mg/day. Although the
mean hemoglobin level was lower in patients randomized
to ribavirin 800 rather than 400 mg/day (see Fig. 2), the
incidence of severe anemia requiring ribavirin dose reduc-
tion was similar in the two treatment groups; thus, the
tolerability of ribavirin treatment cannot generally be im-
proved by reducing the initial dose of ribavirin below 800
Table 1. Baseline Characteristics of All Randomized Patients
Genotype 2 Genotype 3 All patients
Group A (ribavirin
800 mg/day),
n 18
Group B (ribavirin
400 mg/day),
n 19
Group A (ribavirin
800 mg/day),
n 123
Group B (ribavirin
400 mg/day),
n 122
Group A (ribavirin
800 mg/day),
n 141
Group B (ribavirin
400 mg/day),
n 141
Age, years 46.8 10.8 43.9 11.3 35.5 10.6 34.3 9.4 36.8 11.1 36.2 10.7
SEx, male/female 8/10 9/10 76/47 78/44 84/57 87/54
Mean baseline HCV RNA
(log
10
IU/mL)
5.9 0.5 5.8 0.9 5.7 0.8 5.6 0.8 5.9 0.7 5.7 0.8
Body weight (kg) 72.9 17.3 73.8 19.2 70.6 13.6 73.1 14.9 71.1 14.0 73.1 15.4
Mean BMI (kg/m
2
)
24.6 4.6 24.8 3.8 23.7 4.0 23.8 3.9 23.9 4.1 23.9 4.0
Means by which HCV
acquired, n (%)
Blood transfusion 12 (9%) 10 (7%)
Intravenous drug use 81 (57%) 79 (56%)
Other 17 (12%) 12 (9%)
Unknown 31 (22%) 40 (28%)
Table 2. Sustained Virological Response Rates
Group A (ribavirin 800 mg/day) Group B (ribavirin 400 mg/day)
Intention-to-treat analysis
All patients, SVR/N (%,95% CI) 97/141(68.8%,60.5%–76.3%) 90/141(63.8%,55.3%–71.7%)
Difference: 5.0; 6.8 to 16.70
Genotype 3, SVR/N (%, 95% CL) 83/123(67.5%,58.4%–75.6%) 78/122(63.9%,54.7%–72.4%)
Difference: 3.6; 9.2 to 16.2
Genotype 2, SVR/N, (%, 95% CI) 14/18(77.8%, 54.2%–93.6%) 12/19(63.2%, 38.4%–83.7%)
Difference: 14.6
Per protocol analysis
All patients, SVR/N (%, 95%CI) 97/123(78.9%,70.6%–85.7%) 90/117(76.9%,68.2%–84.2%)
Difference: 2.0; 9.4 to13.3
Genotype 3, SVR/N (%,95%CI) 83/107(77.6%,68.5%–85.1%) 78/102(76.5%,67.0%–84.3%)
Difference: 1.1; 11.2 to 13.5
Genotype 2, SVR/N (%, 95%CI) 14/16(87.5%, 61.7%–98.4%) 12/15(80.0%, 51.9%–95.7%)
Difference: 7.5
SVR, sustained virological response; 95% CI, 95% confidence interval. Differences between groups A and B were not statistically significant.
1820 FERENCI ET AL. HEPATOLOGY, June 2008
Page 5
mg/day. Nevertheless, the ribavirin dose can be decreased
in patients not tolerating the drug without compromising
the efficacy of antiviral therapy.
At the time when the study was designed, the impact of
rapid virological response on treatment outcomes was un-
known; thus, measurement of serum HCV RNA in week
4 was not required in the protocol. However, HCV RNA
was measured at the largest center, which recruited 85 of
the 282 patients enrolled in the trial and confirmed that
rapid virological response was the best predictor of sus-
tained virological response.
12
How should the findings of the present study be incor-
porated into clinical practice? It is not possible to predict
whether any given patient will tolerate or comply with 24
weeks of treatment. Thus, initiating treatment with a
ribavirin dose of 400 mg/day may place patients at in-
creased risk of treatment failure should they not complete
the full 24-week course of therapy. For this reason, it is
best to follow current recommendations and initiate riba-
virin treatment at a dose of 800 mg/day. This and other
studies have shown that some patients will not tolerate
this dose of ribavirin and will require dose reductions.
However, our results provide reassurance that the proba-
bility of a sustained virological response is not diminished
in the small number of patients who require dosage re-
ductions; indeed, six of nine patients randomized to riba-
virin 800 mg/day achieved a sustained virological
response after having the dose of ribavirin reduced. Such a
strategy also leaves open the possibility of shortening the
planned duration of treatment if ribavirin is well tolerated
and a patient achieves a rapid virological response in week
4, although as noted below, this approach increases the
probability of relapse, regardless of the dose of ribavirin.
Aside from having implications for clinical practice,
the results of the trial add a further twist to the story of
ribavirin in the treatment of chronic hepatitis C. The
recent trend has been to increase the dose of ribavirin
because it was thought that this would minimize the like-
lihood of relapse. In sharp contrast, we have shown that
the dosage required to maximize the probability of a sus-
tained virological response may actually be lowered when
treatment is administered for the “optimal” duration.
Several theories have been proposed to explain the mech-
anism by which ribavirin exerts its antiviral effect on
HCV.
13
These include depletion of guanosine triphos
-
phate pools through inhibition of inosine monophos-
phate dehydrogenase, inhibition of viral RNA-dependent
RNA polymerase, immunomodulatory effects, and in-
duction of viral mutations rendering a fraction of newly
produced virions noninfectious.
14-17
The probability of
eradicating HCV with combination therapy is signifi-
cantly influenced by the dose of ribavirin and the duration
of treatment. Although fixed durations of treatment are
recommended in the guidelines, the duration can be
modified on the basis of the rapidity of viral clearance
from blood.
18
In patients infected with HCV genotype 1,
Table 3. Baseline Characteristics of Patients According to Virological Response
SVR (n 187) Relapse (n 44) NR (n 9)
Mean log
10
HCV-RNA SD
5.70 0.69 5.84 0.78 5.98 0.61
HCV-RNA 800,000 versus 800,000, n (%) 103/84 (53.9%) 15/29 (34.1%) 3/6 (33.3%)
Mean body weight (kg) SD 70.4 13.6 78.8 15.1 78.9 15.1
Mean BMI (kg/m
2
) SD
23.7 4.1 24.8 4.1 25.3 4.8
Mean age (years) SD 35.0 10.5 41.7 10.1 43.4 10.8
Sex (male/female) 105/82 29/15 7/2
Pooled data from both study groups. Patients who withdrew prematurely or were lost to follow-up were excluded from this analysis.
NR, nonresponse; SVR, sustained virological response .
No differences were statistically significant.
Table 4. Laboratory Abnormalities and Dose Reductions
Group A (ribavirin 800 mg/day) n 141 Group B (ribavirin 400 mg/day) n 141
Hemoglobin 8.5 10 g/dL (%) 7 (5.0%) 4 (2.8%)
Hemoglobin 8.5 g/dL, n (%) 2 (1.4%) 1 (0.7%)
Neutrophils 1000/mm
3
66 (46.8%) 64 (45.4%)
Neutrophils 500/mm
3
7 (5.0%) 7 (5.0%)
Platelets 20,000 and 50,000/mm
3
5 (3.5%) 6 (4.3%)
Platelets 20,000/mm
3
1 (0.7%) 0 (0.0%)
Dose reductions
Peginterferon alfa-2a* 23 (16.3%) 22 (15.6%)
Ribavirin, n (%) 9 (6.4%) 0 (0.0%)
*Dose of peginterferon alfa-2a was reduced because of depression in two patients and because of neutropenia or thrombocytopenia in all others. Treatment with
the drug was stopped in one patient because of neutropenia.
HEPATOLOGY, Vol. 47, No. 6, 2008 FERENCI ET AL. 1821
Page 6
ribavirin prevents virological breakthrough during ther-
apy and relapse during follow-up after the end of treat-
ment. Retrospective analysis of data from a large trial in
which a fixed 800 mg/day dosage of ribavirin was used
showed that higher exposure to ribavirin (on a milligram/
kilogram basis) resulted in higher rates of sustained viro-
logical response.
3
Subsequent randomized trials have
confirmed that the sustained virological response rate of
patients with genotype 1 infection is significantly higher
in those treated with a standard dose of ribavirin (1,000/
1,200 mg/day) or higher compared with 800 mg/day.
6,7
Maintenance of the full planned dose of ribavirin
throughout treatment is required to achieve this goal.
19
Ribavirin also prevents relapse in patients infected with
HCV genotype 2 or 3. The rate of sustained virological
response after monotherapy with conventional interferon
or pegylated interferon is substantially lower than that
achieved after combination therapy.
4,20
The duration of
treatment for patients with HCV genotype 2 or 3 can be
reduced from 48 to 24 weeks without compromising ef-
ficacy
6,7
; however, further reduction in the treatment du
-
ration from 24 to 12 or 16 weeks is associated with an
increase in the rate of virological relapse,
9,10
even among
those with a rapid virological response at week 4, and
cannot be generally recommended.
In summary, the results of our study suggest that when
administered for 24 weeks in combination with peginter-
feron alfa-2a, ribavirin doses of 400 and 800 mg/day pro-
duce equivalent outcomes in patients infected with HCV
genotype 3. Further research is needed to confirm
whether this less intensive regimen is suitable for patients
infected with HCV genotype 2.
Acknowledgment: This study was made possible by
an unrestricted grant by Roche Austria. The Main Asso-
ciation (Hauptverband) of the Austrian Health Insurers
paid for the study medication, Dr. A Klingler performed
the statistical analysis, and Dr. Harald Kessler performed
the virological analysis. We would also thank Blair Jarvis
(Health Interactions Ltd., UK), who provided editorial
support on behalf of Roche. Members of the Austrian
Hepatitis study group: Graz—Bernhard Bauer, Nicole
Hueter, Gu¨nther J. Krejs, Csilla Putz-Bankuti, Rudolf
Stauber, Barbara Sutter, Gernot Zollner; Innsbruck
Wolfgang Jessner, Karin Nachbaur, Bernhard Nilica,
Wolfgang Vogel; Krems—Hartwig Bognar; Linz—Franz
Hackl, Rainer Hubmann, Andreas Maieron, Susanne
Mild, Andreas Raml, Sabine Metz; Ried—Bjo¨rn Jagdt,
Fritz Renner; Oberpullendorf—Felix Stockenhuber, Sal-
zburg—Christian Datz, Hildegard Doppelmayr, Michael
Strasser; Vienna—Susanne Bach, Martin Bischof, Harald
Brunner, Barbara Bognar, Ulrike Bergholz, Nina Ebner,
Daniela Ferenci-Foerster, Peter Ferenci, Gabriele Fischer,
Elisabeth Formann, Alfred Gangl, Michael Gschwantler,
Calin Gurguta, Gerold Hartmann, Brigitte Hellmich,
Harald Hofer, Hermann Laferl, Karin Mittischek, Chris-
tian Mu¨ller, Parnaz Ordubadi, Ali Reza Pourbyiabani,
Markus Peck-Radosavljevic, Marianne Rosenbeiger, Kurt
Schu¨tze, Thomas-Matthias Scherzer, Katharina Staufer,
Petra Steindl-Munda, Anika Stu¨ckler, Christoph We-
nisch; Villach—Rudolf Foditsch; Wels—Peter Knoflach,
Bernhard Stadler
References
1. Alter H. HCV natural history: The retrospective and prospective in per-
spective. J Hepatol 2007;43:550-552.
2. Ferenci P, Ferenci S, Datz C, Rezman I, Oberaigner W, Strauss R. Mor-
bidity and mortality in paid Austrian plasma donors infected with hepatitis
C at plasma donation in the 1970s. J Hepatol 2007;47:31-36.
3. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M,
Reindollar R, et al. Peginterferon alfa-2b plus ribavirin compared with
interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C:
a randomised trial. Lancet 2001;358:958-965.
4. Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL
Jr, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus
infection. N Engl J Med 2002;347:975-982.
5. Dienstag JL, McHutchison JG. American Gastroenterological Association
medical position statement on the management of hepatitis C. Gastroen-
terology 2006;130:225-230.
6. Hadziyannis SJ, Sette H Jr, Morgan TR, Balan V, Diago M, Marcellin P,
et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic
hepatitis C: a randomized study of treatment duration and ribavirin dose.
Ann Intern Med 2004;140:346-355.
7. Jacobson IM, Brown RS Jr, Freilich B, Afdhal N, Kwo PY, Santoro J, et al.
Peginterferon alfa-2b and weight-based or flat-dose ribavirin in chronic
hepatitis C patients: A randomized trial. H
EPATOLOGY 2007;46:971-981.
8. Dalgard O, Bjoro K, Hellum KB, Myrvang B, Ritland S, Skaug K, et al.
Treatment with pegylated interferon and ribavarin in HCV infection with
genotype 2 or 3 for 14 weeks: a pilot study. H
EPATOLOGY 2004;40:1260-
1265.
Fig. 2. Mean hemoglobin concentrations during treatment and fol-
low-up in patients who completed treatment with peginterferon alfa-2a
plus ribavirin 800 mg/day (group A) or 400 mg/day (group B). The
difference between groups A and B was statistically significant (P
0.048, by repeated-measures ANOVA).
1822 FERENCI ET AL. HEPATOLOGY, June 2008
Page 7
9. Mangia A, Santoro R, Minerva N, Ricci GL, Carretta V, Persico M, et al.
Peginterferon alfa-2b and ribavirin for 12 vs. 24 weeks in HCV genotype 2
or 3. N Engl J Med 2005;352:2609-2617.
10. Shiffman ML, Suter F, Bacon BR, Nelson D, Harley H, Sola R, et al.
Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2
or 3. N Engl J Med 2007;357:124-134.
11. von Wagner M., Huber M, Berg T, Hinrichsen H, Rasenack J, Heintges T, et al.
Peginterferon-alpha-2a (40KD) and ribavirin for 16 or 24 weeks in patients with
genotype 2 or 3 chronic hepatitis C. Gastroenterology 2005;129:522-527.
12. Scherzer T, Staufer K, Steindl-Munda P, Holzmann H, Ferenci P. Early viral
kinetics in patients with chronic hepatitis C genotype 2 or 3 treated with
peginterferon alfa2a and ribavirin [abstract 645]. J Hepatol 2007;46:S244.
13. Pawlotsky JM. How does ribavirin improve interferon-a response rates in
hepatitis C virus infection? J Hepatol 2007;42:951-953.
14. Lau JY, Tam RC, Liang TJ, Hong Z. Mechanism of action of ribavirin in
the combination treatment of chronic HCV infection. H
EPATOLOGY 2002;
35:1002-1009.
15. Pawlotsky JM, Dahari H, Neumann AU, Hezode C, Germanidis G, Lon-
jon I, et al. Antiviral action of ribavirin in chronic hepatitis C. Gastroen-
terology 2004;126:703-714.
16. Crotty S, Cameron CE, Andino R. RNA virus error catastrophe: direct
molecular test by using ribavirin. Proc Natl Acad SciUSA2001;98:6895-
6900.
17. Hultgren C, Milich DR, Weiland O, Sallberg M. The antiviral com-
pound ribavirin modulates the T helper (Th) 1/Th2 subset balance in
hepatitis B and C virus-specific immune responses. J Gen Virol 1998;
79:2381-2391.
18. Jensen DM, Morgan TR, Marcellin P, Pockros PJ, Reddy KR, Hadziyan-
nis SJ, et al. Early identification of HCV genotype 1 patients responding to
24 weeks peginterferon alpha-2a (40 kd)/ribavirin therapy. H
EPATOLOGY
2006;43:954-960.
19. Reddy KR, Shiffman ML, Morgan TR, Zeuzem S, Hadziyannis S,
Hamzeh FM, et al. Impact of ribavirin dose reductions in hepatitis C virus
genotype 1 patients completing peginterferon alfa-2a/ribavirin treatment.
Clin Gastroenterol Hepatol 2007;5:124-129.
20. McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi
VK, et al. Interferon alfa-2b alone or in combination with ribavirin as
initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy
Group. N Engl J Med 1998;339:1485-1492.
HEPATOLOGY, Vol. 47, No. 6, 2008 FERENCI ET AL. 1823
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    • "SVR rates after 14 weeks of treatment were achieved more frequently among subtype 3a patients with low viral load and absence of bridging fibrosis/cirrhosis. A further study compared reduced doses of RBV (400 and 800 mg/day) for 24 weeks with equivalent outcomes in patients infected with HCV-G3 [13]. "
    [Show abstract] [Hide abstract] ABSTRACT: The standard treatment regimen for chronic HCV genotype 3 (HCV-G3) hepatitis consists of PEGylated interferon-α (IFN-α) and ribavirin at varying doses ranging from 400 to 1,200 mg and results in response rates of 80%. However, this therapy has substantial side-effects including anemia, is teratogenic, and costly. To reduce the side-effects of therapy, the role of monotherapy consisting of only IFN-α was investigated. A retrospective analysis of individual therapy courses of HCV-G3-infected patients who were treated with IFN-α(2a) monotherapy or a combination therapy with attention to the treatment outcome and the presence of IL28B rs12979860 and IL28B rs8099917 single-nucleotide polymorphism genotypes was performed. Conventional prognostic features in each case were assessed as well. In the study, 15/30 (50%) of patients treated with IFN-α(2a) monotherapy and 32/36 (89%) treated with combination therapy achieved a sustained virological response (SVR). In addition, 7/11 (64%) of those treated initially with monotherapy and subsequently with combination therapy achieved an SVR. An "ultra-rapid" virological response occurring within 2 weeks of initiation of therapy (p = 0.005), young age (<40; p < 0.001) and low initial γ-GT/ALT-ratio (p = 0.03) were associated with a SVR to IFN-α(2a) monotherapy. An SVR in those treated with combination therapy was found to be associated with a rapid virological response (RVR) (p = 0.03). The absence of histologic steatosis was associated with SVR in all patient groups (p = 0.01). Therapy duration (24 vs. 48 weeks) did not affect the SVR in either group. As expected, combination therapy resulted in more hematological side-effects than did monotherapy. An "ultra-rapid" virological response, young age, low initial γ-GT/ALT-ratio and absence of steatosis were each associated with an SVR in those receiving IFN-α(2a) monotherapy. Therefore, monotherapy in these patients should still be discussed independently of the existence of the IL28B polymorphisms.
    Full-text · Article · Nov 2011 · Digestive Diseases and Sciences
    0Comments 6Citations
    • "While reducing RBV dose in patients treated for 24 weeks did not affect the efficacy of treatment [11], the results of this follow up study indicate that shortened treatment duration with a reduced RBV dosage is associated with lower SVR rates mostly due to high relapse rates. The results support also the findings of Shiffman [13] that shortened treatment duration leads to inferior results. "
    [Show abstract] [Hide abstract] ABSTRACT: Chronic hepatitis C (CHC) Patients, infected with genotype (GT) 2 or 3 are treated with Peg-IFN and ribavirin (RBV) (800 mg/day) for 24 weeks. Treatment duration can be shortened to 12-16 weeks if a higher dose of RBV (1.000/1.200 mg/day) was used without considerable loss of responsiveness or increased risk of relapse. Previously we have shown that in patients with CHC, GT 2/3 RBV can be reduced to 400 mg/day if administered for 24 weeks without an increase in relapse rates. Therefore we investigated the efficacy of a reduced RBV dosage of 400 mg/day with shorter treatment duration (16 weeks). Treatment naïve patients with CHC, GT 2/3 were randomized to receive 180 μg peginterferonα2a/week in combination with either 800 (group C) or 400 mg/d (group D) for 16 weeks. The primary endpoint was SVR. 12 months after the first patient was randomized a inferior outcome of group D as compared to group C was noted, therefore the study was terminated. At study termination 89 patients were enrolled (group C: 31, D: 51). The SVR rate was statistically different in the two study groups with 51.6% in group C and 28.4% in group D (p = 0.038). Patients with low viral load had higher SVR rates (C: 67%, D: 33%) than those with high viral load (C: 33%, D: 21%). Both treatment duration and the dose of RBV play a major role to optimize outcome of patients with GT3. If one intends to shorten the treatment weight based RBV dose should be used, if lower RBV doses are used patients should be treated for at least 24 weeks as. A treatment regimen with a reduced RBV dosage and shortened treatment duration is associated with low SVR rates due to high relapse rates. NCT01258101.
    Full-text · Article · Jun 2011 · BMC Research Notes
    0Comments 0Citations
    • "However, the side effect profile and quality of life of patients who discontinued RBV tended to improve. Recently, Ferenci et al. have been investigated efficacy and tolerability of 24 weeks of treatment with RBV 800 mg/day or 400 mg/day plus PEG-IFN alpha-2a 180 µg/week in 141 treatment-naïve patients who were infected HCV genotype 2 or 3. Data suggests that 400 mg/day of RBV enough in patients infected with HCV genotype 3 to achieve as high SVR rates as those attained by the standard 800 mg/day dosing (SVR: 63.9% versus 67.5%), whereas the same results could not be replicated in patients with HCV genotype 2. In the latter patients the SVR rates following low-dose RBV were significantly lower than those attained with a standard dose of RBV (55.6% versus 77.8%) [28]. "
    [Show abstract] [Hide abstract] ABSTRACT: Approximately 170 million people worldwide are chronically infected by hepatitis C virus (HCV), which can result in progressive hepatic injury and fibrosis, culminating in cirrhosis and end-stage liver disease. The benchmark therapy for untreated HCV patients is a combination of pegylated interferon-alpha (PEG-IFN) and ribavirin (RBV). Several studies have suggested several potential new approaches to improve HCV therapy-optimization of the dose and duration of RBV therapy, accompanied by careful clinical management, is crucial in ensuring the greatest likelihood of a long response to therapy. RBV causes serious side effects, but in clinical practice, there are no alternatives for the treatment of HCV infection. Based on our results, weight-based doses of RBV are advantageous for genotype 1-infected patients, but its success in genotype 2- and 3-infected patients is unknown, particularly for shorter treatment durations.
    Full-text · Article · Apr 2011 · Hepatitis Monthly
    0Comments 9Citations
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