Rapid Virological Response and Treatment Duration
for Chronic Hepatitis C Genotype 1 Patients:
A Randomized Trial
Ming-Lung Yu,1,3Chia-Yen Dai,1,3,4Jee-Fu Huang,4,5Chang-Fu Chiu,6Yi-Hsin C. Yang,2Nai-Jen Hou,5Li-Po Lee,1
Ming-Yen Hsieh,1Zu-Yau Lin,1,3Shinn-Cherng Chen,1,3Ming-Yuh Hsieh,1,3Liang-Yen Wang,1,3Wen-Yu Chang,1,3and
ribavirin for 48 weeks. We assessed whether treatment duration of 24 weeks is as effective as
standard treatment in HCV-1 patients with a rapid virological response (RVR; seronegative for
to either 24 or 48 weeks of peginterferon-alpha-2a (180 ?g/week) and ribavirin (1000-1200
mg/day) with a 24-week follow-up. The primary endpoint was a sustained virological response
(SVR; seronegative for HCV RNA at 24-week follow-up). Overall, the 48-week arm had a
significantly higher SVR rate (79%) than the 24-week arm (59%, P ? 0.002). For 87 (43.5%)
patients with an RVR, the 24-week arm had a lower SVR rate [88.9%; 95% confidence interval
(CI): 80%-98%] than the 48-week arm (100%, P ? 0.056). For 52 patients with low baseline
viremia (<400,000 IU/mL) and an RVR, the 24-week arm had rates (CI) of relapse and SVR of
exposure of ribavirin, and baseline viral load. Conclusion: HCV-1 patients derive a significantly
viral loads and an RVR. (HEPATOLOGY 2008;47:1884-1893.)
resistant to interferon-based treatment compared with
HCV-2/3.3Peginterferon/ribavirin combination treat-
ment has been recommended for all HCV-infected pa-
depending on the HCV genotype. For HCV-1 pa-
tients, the recommended treatment duration is 48
weeks, whereas for HCV-2/3 patients the recom-
mended treatment duration is 24 weeks.4,5Neverthe-
less, up to 49% of HCV-1 patients could achieve a
sustained virological response (SVR) with 24 weeks of
peginterferon/ribavirin.6,7Because side effects of anti-
HCV treatment are common and sometimes serious,
an increase in treatment duration may lead to prema-
ture termination of treatment in a significant number
of patients.8,9Thus, to reduce the treatment cost and
the incidence of adverse events, it is desirable to tailor
the treatment regimen to a shorter duration while not
epatitis C virus (HCV) genotype plays an im-
portant role in the response to antiviral treat-
ment.1,2HCV genotype 1 (HCV-1) is more
Abbreviations: CI, 95% confidence interval; EVR, early virological response;
HCV, hepatitis C virus; HCV-1, hepatitis C virus genotype 1; HVL, higher viral
load; LVL, lower viral load; PCR, polymerase chain reaction; RVR, rapid virolog-
ical response; SVR, sustained virological response.
From the1Hepatobiliary Division, Department of Internal Medicine, and2Di-
ical University Hospital, Kaohsiung, Taiwan;3Faculty of Internal Medicine and
4Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical Univer-
Hsiao-Kang Hospital, Kaohsiung, Taiwan; and6Department of Internal Medi-
cine, Paochien Hospital, Pintung, Taiwan.
Received January 11, 2008; accepted March 4, 2008.
Supported by the Taiwan Liver Research Foundation. The sponsor did not par-
ticipate in the study design, patient collection, analysis, or interpretation of data.
Trial Registration # NCT00629967.
Address reprint requests to: Wan-Long Chuang, M.D., Ph.D., Hepatobiliary
Division, Department of Internal Medicine, Kaohsiung Medical University Hospi-
tal, No. 100, Tzyou 1st Road, Kaohsiung 807, Taiwan. E-mail: fish6069@gmail.
com or firstname.lastname@example.org; fax: 886-7-323-4553.
Copyright © 2008 by the American Association for the Study of Liver Diseases.
Published online in Wiley InterScience (www.interscience.wiley.com).
Potential conflict of interest: Nothing to report.
Supplementary material for this article can be found on the HEPATOLOGY Web
the single best predictor of an SVR for anti-HCV treat-
ment.10-14Although three previous studies demonstrated
that a shorter duration of peginterferon/ribavirin over 12
weeks to 16 weeks is as effective as a 24-week regimen for
HCV-2/3 patients with an RVR,13-16a recent large trial
showed that 24 weeks was superior to 16 weeks in all
findings call into question whether shorter treatment du-
ration can yield high SVR rates for HCV-1 patients with
an RVR. A retrospective analysis observed that, among
RVR HCV-1 patients, the SVR rates were comparable
between 24-week and 48-week peginterferon/ribavirin.11
Another single-arm, historical control trial for HCV-1
demonstrated that 24-week and 48-week treatments had
similar SVR rates for RVR patients with low viremia.18
Recently, an Italian group showed that individualized
treatment according to on-treatment virological response
ensures SVR rates similar to standard 48-week treatment
duration for HCV-1 patients.19Nevertheless, racial fac-
tors have been independently associated with treatment
outcome for chronic hepatitis C.20The current random-
role of an RVR as a guide for determining treatment du-
ration for HCV-1 patients.
active-controlled study to determine the role of RVR on
the response to 24 weeks or 48 weeks of peginterferon/
ribavirin for HCV-1 patients. The primary aim of the
current study was to evaluate whether 24 weeks of pegin-
terferon/ribavirin is sufficient to achieve an SVR rate
comparable to that of the standard 48-week regimen in
HCV-1 patients achieving an RVR. The secondary aim
was to investigate the factors associated with RVR and
SVR among patients receiving 24-week or 48-week treat-
Patients and Methods
Selection of Patients. Eligible subjects were previ-
C, aged 18 to 65 years, who (1) were seropositive for
HCV antibodies (third-generation, enzyme immunoas-
say; Abbott Laboratories, North Chicago, IL) and for
HCV RNA by a qualitative polymerase chain reaction
(PCR) assay (Cobas Amplicor Hepatitis C Virus Test,
version 2.0; Roche Diagnostics, Branchburg, NJ; detec-
tion limit: 50 IU/mL); (2) had undergone a liver biopsy
that was consistent with chronic hepatitis within 1 year
notransferase level for at least two measurements within 6
months preceding the trial entry; and (4) had a genotype
1 infection. Other eligibility criteria included neutrophil
count greater than 1500 mm?3, platelet count greater
than 9 ? 104mm?3, hemoglobin level greater than 12
creatinine level less than 1.5 mg/dL, no pregnancy or
lactation, and the use of a reliable method of contracep-
Patients with HCV genotype infections other than
HCV-1, hepatitis B surface antigen, human immunode-
ficiency virus infection, autoimmune hepatitis, primary
biliary cirrhosis, sclerosing cholangitis, Wilson disease,
alpha1-antitrypsin deficiency, decompensated cirrhosis,
overt hepatic failure, a current or history of alcohol abuse
(?20 g daily), psychiatric condition, previous liver trans-
plantation, or with evidence of hepatocellular carcinoma
were excluded from the study.
Study Design. The current study was an investigator-
initiated study. This randomized, open-label, active-con-
trolled trial was carried out in one medical center and
three regional core hospitals in Taiwan from April 2005
to May 2007. The study was approved by the ethics com-
mittees at the participating hospitals and carried out ac-
cording to the guidelines of the International Conference
on Harmonization for Good Clinical Practice. All pa-
tients gave written informed consent before enrollment.
A total of 200 protocol-eligible subjects were assigned
randomly by computer coding with a 1:1 randomization
was centrally accessed through telephone or direct office
visit. The details of the series were contained in a set of
sealed envelopes and unknown to any of the investigators
who enrolled study subjects. Subjects were treated with
peginterferon-?-2a (PEGASYS, Roche, Basel, Switzer-
land; 180 ?g/week subcutaneously) plus oral ribavirin
(1000 mg/day for body weight ?75 kg and 1200 mg/day
for body weight ?75 kg) in two divided doses for either
24 weeks (n ? 100) or 48 weeks (n ? 100), with a 24-
week follow-up period. Subjects had biweekly outpatient
rest of the treatment period as well as during the 24-week
follow-up. At each visit, subjects underwent a physical
ical and hematological testing was done by commercial
assays. HCV genotypes were determined by the method
described by Okamoto et al.21Serum HCV RNA at base-
line, treatment weeks 4 and 12, the end of treatment, and
24 weeks after therapy were determined by qualitative
treatment were measured using the branched DNA assay
(Versant HCV RNA 3.0, Bayer, Tarrytown, NJ; quanti-
fication limit: 615 IU/mL). Liver histology was graded
and staged according to the scoring system described by
HEPATOLOGY, Vol. 47, No. 6, 2008YU ET AL.1885
Knodell and Scheuer22by a single pathologist who was
blinded to the treatment of each patient.
Dose Modifications. Adverse events were graded as
mild, moderate, severe, or potentially life-threatening.
The dose modification of peginterferon and ribavirin was
according to the strategy as described previously,14except
that dose reduction of ribavirin was a 200-mg stepwise
decrease to enhance the adherence.
Assessment of Efficacy. The primary endpoint of this
PCR-seronegative by the end-of-treatment and through-
out the follow-up period. The others were classified as
HCV RNA at 4 weeks of therapy. Early virological re-
sponse (EVR) was defined as PCR-negative or at least a
2-log10decline from baseline of serum HCV RNA at 12
weeks of treatment. End-of-treatment virological re-
sponse was defined as PCR-negative serum HCV RNA at
the end of treatment. Relapse was defined as HCV RNA
achieved an end-of-treatment virological response.
Statistical Analyses. Evaluation of efficacy of antivi-
ral treatment was based on an intention-to-treat analysis.
or ribavirin were analyzed. Anticipating a 10% dropout
rate, the study was designed to detect a difference of 12%
with 80% power or more. SVR and the associated 95%
confidence interval (CI) for the differences were esti-
mated. Frequency was compared between groups using
the chi-square test, with the Yates correction, or Fisher’s
exact test. Group means (presented as mean ? standard
deviation) were compared using analysis of variance and
Student t test, or the nonparametric Mann-Whitney test
when appropriate. Serum HCV RNA levels were ex-
pressed after logarithmic transformation of original val-
ues. The area under the curve was compared using
viral load that would best predict the RVR. The cutoff
point was determined by choosing the point on the re-
ceiver operating characteristics curve with the closest dis-
tance to the point (0,1). Stepwise logistical regression was
used to analyze which variables had a better predictive
value for RVR and SVR. The procedures were performed
using the SPSS 12.0 statistical package (SPSS, Chicago,
IL). All statistical analyses were based on two-sided hy-
pothesis tests with a significance level of P ? 0.05.
completed the study (Supplemental Fig. 1). Patients in
the two groups were well matched for baseline character-
istics (Table 1). All patients were infected with HCV-1b,
except one with HCV-1a. Early discontinuation of treat-
ment was significantly higher in the 48-week group than
in the 24-week group (10% versus 3%, P ? 0.045). One
patient in the 48-week group was lost to follow-up 2
months after cessation of treatment and was classified as a
nonresponder for final analysis.
and end-of-treatment virological response in the 24-week
group were 45% (35%-55%), 95.9% (92%-100%), and
the rates of 42% (32%-52%), 93% (88%-98%), and
90% (84%-96%) in the 48-week group. The relapse rate
was significantly higher than in the 48-week group
(12.2%; CI: 5%-19%; P ? 0.0001). The SVR rate (CI)
was 59% (49%-69%) in the 24-week group, which was
significantly lower than in the 48-week group (79%; CI:
71%-87%; P ? 0.002).
Table 1. Basic Demographic, Virological, and Clinical Features of the Patients
24-Week Group 48-Week Group
Male sex, n
Body weight, kg
Aspartate aminotransferase, IU/L
Alanine aminotransferase, IU/L
Baseline HCV viral load, log IU/mL*
Baseline lower HCV viral load, ?400,000 IU/mL, n
49.7 ? 11.6
65.5 ? 10.0
102 ? 52
156 ? 84
49.1 ? 12
67.5 ? 15.8
90 ? 61
137 ? 92
4.82 ? 2.55 4.41 ? 2.290.241
5.43 ? 1.00
5.66 ? 0.95
NOTE. Values are means ? SD.
*HCV indicates, hepatitis C virus.
1886YU ET AL.HEPATOLOGY, June 2008
The relationship between on-treatment virological re-
sponses and SVR is shown in Table 2. Among patients
with an RVR, the relapse rate in the 24-week group was
higher than that in the 48-week group (P ? 0.056; dif-
ference: 11.1%; CI: ?0.4%-18%), whereas the SVR rate
in the 24-week group was lower than that in the 48-week
group with (P ? 0.056; difference: 11.1%; CI: ?22.6%-
4.2%). Among patients without an RVR, the relapse rate
the 48-week group (P ? 0.0001; difference: 37.5%; CI:
17.2%-53.7%), whereas the SVR rate in the 24-week
group was significantly lower than that in the 48-week
group (P ? 0.002; difference: 29.2%; CI: ?48.7% to
Among patients without an EVR at week 12, the re-
lapse rate was significantly higher and the SVR rate sig-
group (both P ? 0.0001). All patients without an EVR
relapsed; none achieved an SVR.
Factors Associated with RVR, SVR, and Relapse.
Among all patients, factors associated with RVR were
analyzed. They included demographic features, liver en-
dose of ribavirin during the first 4 weeks (Table 3). Based
on receiver operating characteristics analyses, 400,000
IU/mL was optimal for use as the cutoff point of baseline
viral load to best discriminate those patients who might
achieve an RVR. Lower baseline viral load (?400,000
IU/mL) was the only significant factor associated with
RVR, with an odds ratio (CI) of 3.052 (1.706-5.458).
Factors predictive of SVR were analyzed in both
groups. They included demographic features, liver en-
and RVR (Table 4). In the 24-week group, RVR, lower
viremia (?400,000 IU/mL), younger age, and 80/80/80
adherence were associated with a higher SVR rate. Inde-
pendent predictors of SVR in the 24-week group were
RVR and lower viremia with odds ratios (CI) of 10.84
(3.189-36.82) and 3.087 (1.031-9.239), respectively. In
the 48-week group, RVR was the only independent pre-
dictor of SVR, with an odds ratio of infinity.
Ribavirin Dose by Body Weight and SVR. The
Table 2. The Rates of End-of-Treatment Virological Response, Relapse, and Sustained Virological Response According to
On-Treatment Virological Response and Regimen
EOTVR Relapsed SVR
24-Week Group 48-Week Group24-Week Group48-Week Group 24-Week Group48-Week Group
All patients 93/10093 (0.88–0.98) 90/10090 (0.84–0.96)34/9336.6 (0.27–0.47)*
11/9012.2 (0.05–0.19)* 59/100
50 (?0.07 to 1.07)
Statistical significance: *, ‡, §, and **, P ? 0.0001; †,¶, P ? 0.056;?,#, P ? 0.002.
CI, 95% confidence interval; EOTVR, end-of-treatment virological response; EVR, early virological response at week 12; RVR, rapid virological response at week 4;
SVR, sustained virological response.
Table 3. Factors Associated With Rapid Virological Response
RVR (?) RVR (?)
Male sex, n
Body weight, kg
Alanine aminotransferase, IU/L
Fibrosis score, n
Baseline HCV RNA level, log IU/mL*
Baseline HCV RNA level, ?400,000 IU/mL, n
Mean dose of ribavirin by body weight during 1st4 weeks of treatment, mg/kg/day
50.7 ? 11.0
66.0 ? 10.1
140 ? 90
47.8 ? 12.6
67.1 ? 16.5
154 ? 87
4.78 ? 2.414.41 ? 2.440.295
5.86 ? 0.72
17.4 ? 2.66
5.13 ? 1.11
17.3 ? 3.03
RVR indicates rapid virological response, which is defined as HCV RNA PCR-seronegative (?50 IU/mL) at week 4 of treatment. Values are means ? SD.
*HCV, hepatitis C virus.
HEPATOLOGY, Vol. 47, No. 6, 2008 YU ET AL.1887
influence on SVR of mean ribavirin dose by body weight
throughout the treatment period was analyzed. We strat-
of ribavirin, lower (?13.3 mg/kg/day), moderate (13.3-
15.2 mg/kg/day), and higher (?15.2 mg/kg/day), ac-
cording to a previous study.23In the 24-week group,
patients receiving a higher ribavirin dose had a signifi-
(P ? 0.021) than those receiving a lower or moderate
ribavirin dose (Fig. 1). In the 48-week group, patients
receiving a moderate or higher ribavirin dose had a signif-
(P ? 0.064) than those receiving a lower ribavirin dose.
Factors Associated with SVR in All Patients. The
independent predictive value of age, sex, body weight, liver
enzyme and histopathology, baseline viral load, treatment
adherence, received dose of ribavirin, and RVR for the
achievement of an SVR was determined by using stepwise
logistic regression analysis for all 200 patients. The most
important independent predictors for SVR were RVR, fol-
weight, and baseline viral load (Table 5).
Subgroup Analysis for the “Easy-to-Treat” Popula-
tion. Because RVR and low viral load were two major
predictors for a shorter treatment duration of peginter-
feron/ribavirin for HCV-1 patients, we further stratified
patients according to the presence of two favorable pre-
dictors: achievement of an RVR and low viral load
(?400,000 IU/mL).7,24For 52 patients with low viremia
and an RVR, the rates (CI) of relapse and SVR in the
24-week group were 3.6% (?3%-11%) and 96.4%
(89%-103%), respectively, which were comparable with
0% and 100% in the 48-week group (difference: 3.6%;
CI: ?7.2% to 6.6%; ?3.6%; CI: ?14.3% to ?0.6%,
respectively; Fig. 2). For 35 patients with high viremia
and an RVR, the relapse rate was significantly higher
(23.5%; 4 of 17; CI: 3%-44% versus 0%; 0 of 18; P ?
0.045) and SVR rate was significantly lower (76.5%; 13
of 17; CI: 56%-97% versus 100%; 18 of 18; P ? 0.045)
patients with either high viremia or without an RVR, the
relapse rate was significantly higher in the 24-week
(50.8%; CI: 39%-63%) than in the 48-week group
(16.7%; CI: 8%-26%; P ? 0.0001); the SVR rate was
significantly lower in the 24-week (44.4%; CI:
82%; P ? 0.001).
The mean daily doses of ribavirin were similar among
patients with an RVR and low viremia, patients with an
Table 4. Factors Associated With Sustained Virological Response
24-Week Treatment Group 48-Week Treatment Group
Sustained Virological Response,
n ? 100
Sustained Virological Response,
n ? 100
No. of patients
Male sex, n
Body weight, kg
Alanine aminotransferase, IU/L
Fibrosis score, n
Baseline HCV RNA level, log IU/
?400,000 IU/mL, n
?400,000 IU/mL, n
80/80/80 adherence, n‡
52.4 ? 10.9
67.6 ? 11.0
143 ? 71
47.9 ? 11.8
64.1 ? 9.0
164 ? 91
51.4 ? 9.5
66.7 ? 10.3
127 ? 74
48.5 ? 12.5
67.7 ? 17.1
140 ? 97
5.18 ? 2.65 4.58 ? 2.470.259
4.67 ? 2.504.34 ? 2.240.564
5.92 ? 0.60
5.09 ? 1.08
5.93 ? 0.86
5.58 ? 0.96
Values are means ? SD.
†HCV, hepatitis C virus.
‡Patients who had received ?80% of expected peginterferon and ribavirin dose and completed at least 80% of expected duration.
§RVR, rapid virological response.
1888YU ET AL.HEPATOLOGY, June 2008
and nonresponders of the 24-week group (14.4 ? 3.8
versus 15 mg/kg/day; Fig. 3). For patients with either
high viremia or without an RVR, a significantly lower
daily dose of ribavirin in nonresponders than in sustained
responders was observed in the 24-week group (13.7 ?
3.3 versus 16.1 ? 3.3 mg/kg/day; P ? 0.004, Mann-
Whitney test), but not in the 48-week group (13.9 ? 3.5
versus 13.9 ? 3.4 mg/kg/day).
Safety. Two serious adverse events were reported.
One patient with cirrhosis in the 24-week group expe-
rienced variceal bleeding at the end of treatment. An-
myalgias over the lower back, resulting in disability of
gait during treatment. She was hospitalized for evalu-
ation of neurological and musculoskeletal systems. No
overt neurological finding was discovered; however,
mild spondylolisthesis of the lumbar spine was found.
Her symptoms/signs resolved after 5 days of inpatient
treatment because of adverse events. Ten patients in
the 48-week group discontinued treatment: eight be-
cause of adverse events, one because of increased serum
creatinine level, and one because of insufficient response.
peginterferon or ribavirin; gastrointestinal, psychiatric,
dermatological, and hematological symptoms; and thy-
Fig. 1. Weight-based exposure of ribavirin and treatment response. Patients were stratified according to ribavirin exposure by body weight into three
groups: lower (?13.3 mg/kg/day), moderate (13.3-15.2 mg/kg/day), and higher (?15.2 mg/kg/day). In the 24-week group, patients receiving a
higher ribavirin dose had a significantly lower relapse rate and higher SVR rate than those receiving a lower or moderate ribavirin dose (relapse: 47.2%
versus 22.5%, P ? 0.014; SVR: 49.1% versus 72.1%, P ? 0.021). In the 48-week group, patients receiving a moderate or higher ribavirin dose
had a significantly lower relapse rate and higher SVR rate than those receiving a lower ribavirin dose (relapse: 25% versus 6.5%, P ? 0.013; SVR:
67.7% versus 84.1%, P ? 0.064).
Table 5. Logistic Regression Analysis of Sustained Virological Response
VariablesOdds Ratio 95% Confidence Intervals
Rapid virological response at week 4
Ribavirin dose by body weight
HCV viral load
Per 1 - log increase
HEPATOLOGY, Vol. 47, No. 6, 2008 YU ET AL.1889
roid dysfunction tended to be higher in the 48-week
However, the differences did not reach statistical signifi-
In the current prospective, randomized, controlled
that 24 weeks of peginterferon/ribavirin is inferior to 48
weeks of therapy even if an RVR is attained. Both 24 and
48 weeks of therapy can achieve high SVR rates (?96%)
was the single best predictor of SVR in both the 24-week
and 48-week groups. Patients with higher baseline vire-
mia and suboptimal weight-based exposure of ribavirin
had a higher likelihood of relapse with the shorter treat-
ment duration, which may compromise the response to a
24-week treatment for HCV-1 patients.
Although inferior to the 48-week treatment, 24 weeks’
use of peginterferon/ribavirin can achieve an SVR rate of
more than one third for HCV-1 patients.6,7Therefore, it
is very important to identify simple, noninvasive markers
for the easy-to-treat subgroup. A retrospective post hoc
analysis of data collected during a randomized, multina-
tional study observed that for HCV-1 patients with an
RVR, the SVR rates were comparable among patients
with 24 or 48 weeks of peginterferon/ribavirin (88% ver-
sus 83%, respectively).6,11These findings have encour-
aged the use of RVR as the marker of shorter treatment
duration for HCV-1 treatment. However, we observed
that 24 weeks of peginterferon/ribavirin could not pro-
vide equal efficacy for HCV-1 patients with an RVR
when compared with a 48-week regimen. Only for pa-
tients with an RVR and baseline viremia less than
400,000 IU/mL, which has been reported as the optimal
cutoff point to best predict HCV-1 response to peginter-
feron/ribavirin,24is 24-week treatment as effective as the
standard 48-week treatment. Our findings are consistent
with a previous single-arm, historical-controlled study.18
In that study, HCV-1 patients with baseline viremia less
than 600,000 IU/mL were treated with peginterferon/
ribavirin for 24 weeks. The 24-week regimen provided
equal efficacy for the subgroup with an RVR when com-
pared with a 48-week regimen (89% versus 85%, respec-
tively). A recent Italian study demonstrated that for
HCV-1 patients with an RVR, the SVR rate in patients
with 24-week treatment was substantial (77.2%) but
lower than that in those with 48-week treatment
(87.1%).19RVR patients with baseline viremia less than
400,000 IU/mL achieved an SVR rate of 84.4% with
24-week treatment, which was comparable to the 83.3%
rate in the 48-week group; however, RVR patients with
baseline viremia greater than 400,000 IU/mL achieved
lower SVR rates when treated for 24 weeks than for 48
weeks (73.1% versus 86.8%; P ? 0.14).19These findings
Fig. 2. Relapse and SVR rates in patients with an RVR and lower viral load. Rates of relapse and SVR, according to RVR and baseline viral load,
among patients receiving 24 or 48 weeks of treatment. SVR, sustained virological response; RVR, rapid virological response at week 4; LVL, lower
viral load, defined as baseline HCV viral load ?400,000 IU/mL; HVL, higher viral load, defined as baseline viral load ?400,000 IU/mL.
1890YU ET AL.HEPATOLOGY, June 2008
reinforce the RVR and baseline viral load as important
signposts in the individualized treatment for HCV-1 pa-
Because RVR is the best predictor of SVR, character-
ization of the predictors of RVR is very important and
eral factors were reported to predict an RVR. First, pa-
tients with viral loads less than 400,000 or less than
Second, HCV-1b had a higher chance of achieving an
RVR than HCV-1a.11Third, a standard weight-based
dose of ribavirin has been associated with a higher RVR
rate (1000-1200 mg/day; 22.6%) when compared with a
low dose (800 mg/day; 16.5%).11A recent study demon-
strated that the first 4 weeks of ribavirin exposure was the
second-most important predictor of an RVR (17.5% ver-
sus 10% for ribavirin exposure greater than 13 versus less
than 13 mg/kg/day; odds ratio: 2.15; CI: 1.41-3.27).25
Only four of our patients received ribavirin exposure less
than 13 mg/kg/day during the first 4 weeks, so we were
unable to detect any potential difference. Nevertheless,
during the first 4 weeks, a dose-related response of RVR
was not observed in our study (data not shown). The
achievement of RVR remains to be studied.
Patients who achieve an RVR have a greater likelihood
of achieving an SVR. In the current study, 43.5% (CI:
36.6%-50.4%) of patients achieved a RVR, which was
similar to 47% in a previous European study for lower
viremic HCV-1 patients.18By contrast, the RVR rate was
only 23.7% in Mangia et al.’s study,1919.7% in Jensen et
al.’s study,11and 15.1% in Rodriguez-Torres et al.’s
study,25which were enriched for a difficult-to-treat pop-
ulation. Compared with the current study, these three
studies had a higher population of HCV-1a (44.5% in
Jensen et al.’s study; 0.5% in our study), a higher propor-
tion of patients with viral loads greater than 400,000
IU/mL (86.8% in Rodriguez-Torres et al.’s study; 76.3%
proportion of patients receiving ribavirin dose less than
13 mg/kg/day during the first 4 weeks (31.6% in Rodri-
guez-Torres et al.’s study; 2% in our study). Approxi-
mately half of the patients in Jensen et al.’s study were
assigned a lower dose of ribavirin (800 mg/day). The
77 to 78 kg in Jensen et al.’s study and 82.4 kg in Rodri-
guez-Torres et al.’s study. The ribavirin exposure by 4
weeks was 17.4 mg/kg/day in the current study. In con-
trast, patients would have an exposure of no more than
14.5 mg/kg/day (starting dose of 1000-1200 mg/day) in
patients with starting dose of 800 mg/day) in Jensen et
al.’s study.11All of these factors might contribute to the
lower chance of achieving an RVR.
Shorter treatment durations have been associated with
higher relapse rates when compared with the standard
recommended treatment,13,15even in patients with an
RVR.17For RVR patients, we observed that the 24-week
group was more likely to relapse with a subsequent lower
SVR rate than was the 48-week group. The lower SVR
rate with shorter treatment duration mainly exists in the
Fig. 3. Mean daily dose of ribavirin throughout the treatment period
and treatment response, stratified by RVR, baseline viral load, and
treatment duration. Mean daily dose of ribavirin was expressed per
kilogram of body weight for (A) patients with lower viral load and an RVR
and (B) patients with either high viral load or without an RVR. For patients
with low viral load and an RVR, all patients achieved an SVR in 48-week
group with a mean ribavirin dose of 14.9 ? 3.5 mg/kg/day; the mean
dose of ribavirin was comparable between sustained responders and
nonresponders of the 24-week group (14.4 ? 3.8 mg/kg/day versus 15
mg/kg/day, P ? 0.857). For patients with either high viral load or
without an RVR, a significantly lower daily dose of ribavirin in nonre-
sponders than in sustained responders was observed in the 24-week
group (13.7 ? 3.3 mg/kg/day versus 16.1 ? 3.3 mg/kg/day, P ?
0.004, Mann-Whitney test*), but not in the 48-week group (13.9 ? 3.5
mg/kg/day versus 13.9 ? 3.4 mg/kg/day; P ? 0.676). RVR, rapid
virological response; LVL, lower viral load, defined as baseline HCV viral
load ?400,000 IU/mL; HVL, higher viral load, defined as baseline viral
load ?400,000 IU/mL.
HEPATOLOGY, Vol. 47, No. 6, 2008YU ET AL.1891
subgroup of patients with high viremia, which is consis-
tent with previous findings that for HCV-1/4 patients
with an RVR, the SVR rate was lower in patients with
found that the association between lower weight–based
exposure of ribavirin and treatment failure to 24-week
peginterferon/ribavirin only existed among patients with
high viremia or without an RVR but not among those
starting dose of ribavirin (15.2 mg/kg/day) with erythro-
had lower relapse and higher SVR rates when compared
with standard weight-based ribavirin.23The ribavirin ex-
posure of our sustained responders in the 24-week group
was as high as 15.3 mg/kg/day, suggesting that ribavirin
adherence and weight-based exposure of ribavirin may
play a role in the response to a shorter treatment duration
for subgroup of HCV-1 patients with high viremia or
without an RVR, in terms of reducing the relapse rate.
RVR relapsed with the 24-week regimen, in contrast to
none with the 48-week regimen. Whether treatment du-
ration between 24 and 48 weeks could achieve a satisfac-
tory response for the subgroup needs further study. More
than one third of non-RVR patients remained refractory
to the recommended 48-week regimen. Recently, the
TeraViC-4 study randomly allocated non-RVR patients
to either 48-week or 72-week peginterferon/ribavirin; the
SVR rate was significantly higher in the 72-week group,
primarily through the reduction of relapse.27The Italian
group also demonstrated that the 72-week treatment at-
ment did (38.1%, P ? 0.068) among patients who
Consistent with previous studies,7,14a better response
to peginterferon/ribavirin was observed in Taiwanese pa-
tients than the reports for white patients. Lower viremia
contribute to a higher SVR rate in Taiwanese patients. In
addition, Asian race was shown to be an independent
predictor of achieving an SVR, when compared with
whites with chronic hepatitis C.20These findings sug-
gested a genetic influence on the antiviral response.
One limitation of the current study is that patients
were not randomized according to baseline viral load and
tive randomized trials on noninferiority of shorter treat-
ment duration among patients with low viremia and
RVR. Nevertheless, our findings should be sufficient to
allow clinicians to formulate treatment strategies for
HCV-1 patients with an aim toward reducing pharmaco-
logical costs.28The European Commission has approved
revised dosing instructions for a 24-week course of pegin-
terferon-alpha-2b/ribavirin for HCV-1 patients with low
viremia and an RVR.29
In conclusion, this study demonstrates that HCV-1
patients derive a significantly better SVR from 48 weeks
versus 24 weeks of peginterferon/ribavirin even if they
attain an RVR. HCV-1 patients require 48 weeks of ther-
apy unless they have low baseline viral loads (?400,000
IU/mL) and achieve an RVR at week 4.
1. Poynard T, Yuen MF, Ratziu V, Lai CL. Viral hepatitis C. Lancet 2003;
2. Dai CY, Chuang WL, Chang WY, Chen SC, Lee LP, Hsieh MY, et al.
dicts response to combination therapy in hepatitis C virus infection. J In-
fect Dis 2006;193:98-101.
3. 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.
4. NIH Consensus Statement on the Management of Hepatitis C. National
Institutes of Health. Consensus conference statement 2002. Available
5. Strader DB, Wright T, Thomas DL, Seeff LB. Diagnosis, management,
and treatment of hepatitis C. HEPATOLOGY 2004;39:1147-1171.
6. Hadziyannis SJ, Sette Jr H, 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.
trial of 24- vs. 48-week courses of PEG interferon alpha-2b plus ribavirin
for genotype-1b-infected chronic hepatitis C patients: a pilot study in
Taiwan. Liver Int 2006;26:73-81.
8. Yu ML, Dai CY, Lee LP, Hsieh MY, Hou NJ, Huang JF, et al. Outcome
interferon-alpha plus ribavirin combination therapy. Antivir Ther 2006;
al. Adherence to combination therapy enhances sustained response in ge-
notype-1-infected patients with chronic hepatitis C. Gastroenterology
10. Yu ML, Chuang WL, Dai CY, Lee LP, Hsieh MY, Lin ZY, et al. Different
viral kinetics between hepatitis C virus genotype 1 and 2 as on-treatment
predictors of response to a 24-week course of high-dose interferon-alpha
plus ribavirin combination therapy. Transl Res 2006;148:120-127.
11. Jensen DM, Morgan TR, Marcellin P, Pockros PJ, Reddy KR, Hadziyan-
24 weeks peginterferon alpha-2a (40 kd)/ribavirin therapy. HEPATOLOGY
12. Kamal SM, El Kamary SS, Shardell MD, Hashem M, Ahmed IN, Mu-
hammadi M, et al. Pegylated interferon alpha-2b plus ribavirin in patients
with genotype 4 chronic hepatitis C: the role of rapid and early virologic
response. HEPATOLOGY 2007;46:1732-1740.
13. Mangia A, Santoro R, Minerva N, Ricci GL, Carretta V, Persico M, et al.
or 3. N Engl J Med 2005;352:2609-2617.
14. Yu ML, Dai CY, Huang JF, Hou NJ, Lee LP, Hsieh MY, et al. A random-
ised study of peginterferon and ribavirin for 16 versus 24 weeks in patients
with genotype 2 chronic hepatitis C. Gut 2007;56:553-559.
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;
1892YU ET AL.HEPATOLOGY, June 2008
16. Dalgard O, Bjoro K, Hellum KB, Myrvang B, Ritland S, Skaug K, et al.
Treatment with pegylated interferon and ribavirin in HCV infection with
genotype 2 or 3 for 14 weeks: a pilot study. HEPATOLOGY 2004;40:1260-
17. 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.
18. Zeuzem S, Buti M, Ferenci P, Sperl J, Horsmans Y, Cianciara J, et al.
Efficacy of 24 weeks treatment with peginterferon alfa-2b plus ribavirin in
patients with chronic hepatitis C infected with genotype 1 and low pre-
treatment viremia. J Hepatol 2006;44:97-103.
Individualized treatment duration for hepatitis C genotype 1 patients: a
randomized controlled trial. HEPATOLOGY 2008;47:43-50.
20. Missiha S, Heathcote J, Arenovich T, Khan K. Impact of Asian race on
response to combination therapy with peginterferon alfa-2a and ribavirin
in chronic hepatitis C. Am J Gastroenterol 2007;102:2181-2188.
al. Characterization of the genomic sequence of type V (or 3a) hepatitis C
22. Scheuer PJ. Classification of chronic viral hepatitis: a need for reassess-
ment. J Hepatol 1991;13:372-374.
al. Treatment of chronic hepatitis C virus genotype 1 with peginterferon,
ribavirin, and epoetin alpha. HEPATOLOGY 2007;46:371-379.
24. Zeuzem S, Fried MW, Reddy KR, Marcellin P, Diago M, Craxi A, et al.
sustained virological response (SVR) in patients infected with hepatitis C
genotype 1 treated with peginterferon alfa-2a (40KD) (PEGASYS (R))
25. Rodriguez-Torres M, Sulkowski M, Chung RT, Hamzeh FM, Jensen D.
Association of pretreatment and on-treatment factors with rapid virologi-
cal response in HCV genotype 1-infected patients with peginterferon alfa-
2a/ribavirin [Abstract]. HEPATOLOGY 2007;46(Suppl):817A.
26. Ferenci P, Laferl H, Elisabethinnen K, Datz C, Oberndorf K, Bischof M,
et al. Is shorter treatment with peginterferon alfa-2a (40KD) (PEGASYS)
plus ribavirin (COPEGUS) possible in HCV genotype 1 ‘super-respond-
ers’? Preliminary results of a prospective randomized clinical trial [Ab-
stract]. HEPATOLOGY 2005;42(Suppl 1):218A.
27. Sanchez-Tapias JM, Diago M, Escartin P, Enriquez J, Romero-Gomez M,
Barcena R, et al. Peginterferon-alfa2a plus ribavirin for 48 versus 72 weeks
in patients with detectable hepatitis C virus RNA at week 4 of treatment.
28. Buti M, Casado MA, Esteban R. Evaluating the cost of sustained virologic
response in naive chronic hepatitis C patients treated a la carte. Aliment
Pharmacol Ther 2007;26:705-716.
with genotype 1 and low viral load. Available at: http://www.hivandhepa-
titis.com/hep_c/news/2005/ad/100705_a.html. Accessed December 1,
HEPATOLOGY, Vol. 47, No. 6, 2008YU ET AL.1893