A randomised study of peginterferon and ribavirin for 16 versus 24 weeks in patients with genotype 2 chronic hepatitis C.
ABSTRACT The recommended treatment for patients infected with hepatitis C virus genotype 2 (HCV2) is pegylated interferon (peginterferon) and ribavirin for 24 weeks.
To assess whether a shorter 16-week treatment is as effective as a standard 24-week treatment.
Patients with HCV2 infection were randomised in a 1:2 ratio to either 16 weeks (n = 50) or 24 weeks (n = 100) of treatment with peginterferon alpha-2a (180 mug/week) and weight-based ribavirin 1000-1200 mg/day, with a 24-week follow-up period. A rapid virological response (RVR) was defined as seronegative for HCV RNA at 4 weeks of treatment, and the primary end point, sustained virological response (SVR), as seronegative for HCV RNA at the 24-week follow-up.
The rate of RVR and SVR was 86% (43/50, 95% confidence interval (CI) 76% to 96%) and 94% (47/50, CI 87% to 100%), respectively, in the 16-week group, which was comparable to 87% (87/100, CI 80% to 94%) and 95% (95/100, CI 91% to 99%) in the 24-week group. Patients with RVR had a significantly higher SVR rate than patients without RVR in both 16-week (100% vs 57%, p = 0.015) and 24-week groups (98% vs 77%, p = 0.002). Multivariate analysis showed that RVR and age were independent factors associated with SVR. Both treatment arms were equally well tolerated. The incidence of alopecia was significantly higher in the 24-week group (49%) than in the 16-week group (20%, p = 0.001).
16 weeks and 24 weeks of peginterferon treatment with weight-based ribavirin at a dose of 1000-1200 mg/day provided equal efficacy in patients with HCV2 who achieved RVR at 4 weeks.
- [show abstract] [hide abstract]
ABSTRACT: A Histology Activity Index has been developed which generates a numerical score for liver biopsy specimens obtained from patients with asymptomatic chronic active hepatitis. Biopsies are graded in four categories: periportal necrosis, intralobular necrosis, portal inflammation, and fibrosis. Under code, three pathologists and three hepatologists evaluated 14 liver biopsy specimens obtained from five patients with asymptomatic chronic active hepatitis. Good correlation was seen between severity of liver biopsy lesions as judged by conventional histological descriptions and Histology Activity Index scores. Significant differences in Histology Activity Index score occurred in only 2 or 28 duplicate scorings of biopsy specimens by two observers. This system provides definitive endpoints for statistical analysis of serial changes in liver histology and offers an alternative to the use of conventional pathological descriptions in following the natural history and treatment responses of asymptomatic chronic active hepatitis.Hepatology 1(5):431-5. · 12.00 Impact Factor
Article: Viral hepatitis C.[show abstract] [hide abstract]
ABSTRACT: More than 170 million people worldwide are chronically infected with the hepatitis C virus (HCV), which is responsible for more than 100000 cases of liver cancer per year, with similar numbers of digestive haemorrhage and ascites episodes. Major breakthroughs have been made in diagnosis and treatment, and advances in molecular biology mean that the replicative state of the virus can now be assessed. Genotype and serum viral load are useful predictors of response to treatment. The combination of pegylated interferon and ribavirin can eradicate the virus in more than 50% of patients. These antiviral treatments reduce liver fibrosis progression and can reverse cirrhosis. Unfortunately, even in developed countries, death due to hepatitis C is increasing because of inadequate detection and treatment.The Lancet 01/2004; 362(9401):2095-100. · 39.06 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Treatment duration in patients with chronic hepatitis C in the era of standard interferon-alpha plus ribavirin was tailored according to hepatitis C virus (HCV) genotype: patients infected with HCV-1 were treated for 48 weeks, patients infected with HCV-2/3 for 24 weeks. The aim of the present study was to investigate this schedule for HCV-2/3 infected patients in the era of pegylated interferon-alpha plus ribavirin. Patients chronically infected with HCV-2 (n=42) or HCV-3 (n=182) were treated with peginterferon alfa-2b 1.5 microg/kg subcutaneously once weekly plus ribavirin 800-1400 mg/day based on body weight for 24 weeks. The end of treatment (EOT) and sustained virologic response (SVR) was higher in patients infected with HCV-2 (100 and 93%, respectively) than in patients infected with HCV-3 (93 and 79%, respectively). Baseline viremia (P=0.020), treatment duration >16 weeks (P<0.001) and steatosis (<5%, P=0.015) were significant independent predictors of SVR. Adverse events resulted in discontinuation in 5% and dose reduction in 22% of patients. Treatment for 24 weeks with peginterferon alfa-2b and ribavirin is sufficient in HCV 2 or 3 infected patients. The lower SVR in patients infected with HCV-3 compared with HCV-2 infected patients may be related to higher levels of steatosis in this population.Journal of Hepatology 07/2004; 40(6):993-9. · 9.86 Impact Factor
A randomised study of peginterferon and ribavirin for 16
versus 24 weeks in patients with genotype 2
chronic hepatitis C
Ming-Lung Yu, Chia-Yen Dai, Jee-Fu Huang, Nai-Jen Hou, Li-Po Lee, Ming-Yen Hsieh, Chang-Fu Chiu,
Zu-Yau Lin, Shinn-Cherng Chen, Ming-Yuh Hsieh, Liang-Yen Wang, Wen-Yu Chang, Wan-Long
............................................................... ............................................................... .....
See end of article for
Dr Wan-Long Chuang,
Department of Internal
Medical University Hospital,
No 100, Tzyou 1st Road,
Kaohsiung 807, Taiwan;
Revised 26 July 2006
Accepted 30 August 2006
Published Online First
6 September 2006
Gut 2007;56:553–559. doi: 10.1136/gut.2006.102558
Background: The recommended treatment for patients infected with hepatitis C virus genotype 2 (HCV2) is
pegylated interferon (peginterferon) and ribavirin for 24 weeks.
Aim: To assess whether a shorter 16-week treatment is as effective as a standard 24-week treatment.
Methods: Patients with HCV2 infection were randomised in a 1:2 ratio to either 16 weeks (n=50) or
24 weeks (n=100) of treatment with peginterferon a-2a (180 mg/week) and weight-based ribavirin 1000–
1200 mg/day, with a 24-week follow-up period. A rapid virological response (RVR) was defined as
seronegative for HCV RNA at 4 weeks of treatment, and the primary end point, sustained virological
response (SVR), as seronegative for HCV RNA at the 24-week follow-up.
Results: The rate of RVR and SVR was 86% (43/50, 95% confidence interval (CI) 76% to 96%) and 94% (47/
50, CI 87% to 100%), respectively, in the 16-week group, which was comparable to 87% (87/100, CI 80% to
94%) and 95% (95/100, CI 91% to 99%) in the 24-week group. Patients with RVR had a significantly higher
SVR rate than patients without RVR in both 16-week (100% vs 57%, p=0.015) and 24-week groups (98% vs
77%, p=0.002). Multivariate analysis showed that RVR and age were independent factors associated with
SVR. Both treatment arms were equally well tolerated. The incidence of alopecia was significantly higher in
the 24-week group (49%) than in the 16-week group (20%, p=0.001).
Conclusion: 16 weeks and 24 weeks of peginterferon treatment with weight-based ribavirin at a dose of
1000–1200 mg/day provided equal efficacy in patients with HCV2 who achieved RVR at 4 weeks.
Patients infected with HCV genotypes 2 and 3 (HCV2 and
HCV3) have a significantly higher sustained virological
response (SVR) rate to interferon-based treatment than those
with HCV1 infection.4 5Pegylated interferon (peginterferon)
and ribavirin combination treatment has been recommended
for all patients infected with HCV, but the treatment duration
varies depending on the HCV genotype. For patients infected
with HCV1, the recommended treatment duration is 48 weeks,
whereas for patients infected with HCV2 or HCV3, the
recommended treatment duration is 24 weeks.5 6
Although treatment with peginterferon and ribavirin for
24 weeks could achieve an SVR rate of 80–93% in patients with
HCV2 or HCV3,5 7–9side effects are common and sometimes
serious, and increase with the length of the treatment, leading
to premature termination of treatment in a large number of
patients.10–12Hence, it is desirable to tailor the treatment
regimen to a shorter duration without compromising on
efficacy to reduce the cost of treatment and the incidence of
adverse events. Recent studies from Europe13–15have shown
that for patients with HCV2 or HCV3, who had a rapid
virological response (RVR) at 4 weeks, a shorter duration of
treatment over 12–16 weeks is as effective as a 24-week
treatment regimen. However, racial and geographical factors
may influence the treatment outcome for chronic hepatitis C
(CHC),16thus, more studies are required to substantiate these
findings in patients of various ethnicities.17Moreover, previous
studies of short duration13–15have included patients infected
epatitis C virus (HCV) can be classified into six distinct
genotypes, numbered 1–6.1The HCV genotype has an
important role in the response to antiviral treatment.2 3
with HCV2 or HCV3; infection with HCV3 is associated with
lower rates of SVR than with HCV2, hence, virological response
for both genotypes cannot be assessed together. This rando-
mised, controlled study is the first study in Asia to report the
efficacy of 16 weeks of treatment with peginterferon and
ribavirin for Taiwanese patients infected with HCV2.
The primary aim of this study was to evaluate whether
treatment with peginterferon and ribavirin for 16 weeks is
sufficient to achieve SVR comparable to that achieved after the
standard treatment duration of 24 weeks in patients infected
with HCV2. The secondary aim was to evaluate the role of RVR
at 4 weeks in the treatment efficacy in both treatment groups.
Selection of patients
Eligible patients were previously untreated Taiwanese patients
with CHC, aged 18–65 years, who (1) were seropositive for HCV
antibodies (third-generation enzyme immunoassay; Abbott
Laboratories, North Chicago, Illinois, USA) and for HCV RNA
PCR; (2) had undergone a liver biopsy within 1 year before
entry, the result of which was consistent with chronic hepatitis;
(3) displayed an increased serum alanine transaminase level,
defined as >1.5 times the upper limit of the normal range for
at least two measurements within 6 months preceding the
trial entry; and (4) had HCV2 infection. Other eligibility
criteria included neutrophil count .1500/mm3, platelet count
Abbreviations: CHC, chronic hepatitis C; ETVR, end-of-treatment
virological response; HCV, hepatitis C virus; RVR, rapid virological
response; SVR, sustained virological response
.96104/mm3, haemoglobin concentration .12 g/dl for men
and 11 g/dl for women, serum creatinine concentration
,1.5 mg/dl, no pregnancy or lactation, and the use of a reliable
method of contraception for women.
Patients with an HCV genotype infection other than type 2
infection, hepatitis B surface antigen, HIV infection, auto-
immune hepatitis, primary biliary cirrhosis, sclerosing cholan-
decompensated cirrhosis (Child–Pugh class B or C), overt
hepatic failure, current alcohol misuse or history of alcohol
misuse (>20 g/day), psychiatric condition, previous liver
transplantation, or evidence of hepatocellular carcinoma were
excluded from the study.
This study was an investigator-initiated study. This random-
ised, open-label, active-controlled trial was carried out in a
medical centre and three regional core hospitals in Taiwan from
September 2003 to December 2005. The study was approved by
the ethics committees at the participating hospitals and carried
out according to the guidelines of the International Conference
on Harmonisation for Good Clinical Practice. All patients gave
written informed consent before enrolment. A total of 326
patients were screened and 150 protocol-eligible patients were
assigned randomly by computer coding with a 1:2 randomisa-
tion ratio (fig 1). Fifty patients (16-week group) received
Switzerland) at a dose of 180 mg/week subcutaneously, and
oral ribavirin 1000–1200 mg/day in two divided doses for
16 weeks. The other 100 patients (24-week group) received a
comparable 24-week course of peginterferon and ribavirin. In
both groups of patients, the dose of ribavirin was based on body
weight (1000 mg ribavirin for weight (75 kg and 1200 mg
ribavirin for weight .75 kg).
All patients were monitored for a further 24 weeks after the
end of the treatment. They had biweekly outpatient visits
during the first month and monthly visits during the rest of the
treatment period and during the 24-week follow-up period. At
each visit, they underwent a physical examination, and adverse
events were recorded. Biochemical and haematological testing
was performed by commercial assays. HCV genotypes 1a, 1b,
2a, 2b and 3a were determined by the method described by
Okamoto et al.18Serum HCV RNA levels at baseline and during
treatment week 4 were measured using the branched DNA
assay (Versant HCV RNA 3.0, Bayer, Tarrytown, New Jersey,
USA; quantification limit: 615 IU/ml). Serum HCV RNA at
baseline, during treatment weeks 4 and 12, at the end of
treatment and at 24 weeks after treatment was determined by
standardised automated qualitative PCR (Cobas Amplicor
Hepatitis C Virus Test, V.2.0; Roche Diagnostics, Branchburg,
New Jersey, USA; detection limit: 50 IU/ml). Liver histology
was graded and staged according to the scoring system
described by Scheuer19and Knodell,20by a single pathologist
who was blinded to the treatment of each patient. Hepatic
steatosis was scored from 0 (none) to 3 (severe).21
Adverse events were graded as mild, moderate, severe or
potentially lifethreatening. The dose of peginterferon was
decreased by 50% and the dose of ribavirin lowered to
600 mg/day when severe adverse events occurred or when
laboratory results showed haemoglobin concentraion,10 g/dl
in patients with no cardiac disease, haemoglobin decrease
.2 g/dl in those with cardiac disease, white cell counts ,3000/
mm3or platelet counts ,50 000/mm3. Full doses could be
resumed when the event resolved. If the event persisted, both
drugs were discontinued. Treatment was permanently discon-
tinued for life-threatening events or when laboratory results
showed a haemoglobin concentration ,7.5 g/dl in patients
with no cardiac disease, haemoglobin concentration ,12 g/dl
in those with cardiac disease, after 4 weeks of dose reduction,
white cell count ,1500/mm3, platelet count ,30 000/mm3or
serum creatinine concentration .2 mg/dl.
Assessment of efficacy
The primary end point of this study was to assess SVR, which
was defined as PCR-negative serum HCV RNA by the end of
treatment and throughout the follow-up period. Patients not
achieving this were classified as non-responders. RVR was
defined by PCR-negative serum HCV RNA at 4 weeks of
treatment. End-of-treatment virological response (ETVR) was
defined as PCR-negative serum HCV RNA at end of treatment.
Relapse was defined as reappearance of HCV RNA during the
follow-up period in patients who achieved an ETVR.
Randomisation sequence with 1:2 ratio using a computer-
generated code was generated by a contract research organisa-
tion independent of the study, centrally accessed through
telephone or direct office visit. The details of the series were
contained in a set of sealed envelopes and were unknown to
any of the investigators who enrolled the patients for the study.
At the time of conceiving this study plan, no published reports
were available for the efficacy of 16 weeks of treatment.
Assuming an SVR rate of 82% when treated for 24 weeks,5
and no SVR if untreated, the study was powered to detect a
difference of >24.6% with 80% power, anticipating a 10%
dropout rate. The margin we proposed is equivalent to other
published data.15Evaluation of efficacy of antiviral treatment
was based on an intention-to-treat analysis. All patients
receiving a treatment dose of peginterferon or ribavirin were
Frequency was compared between groups using the x2test,
with the Yates correction, or Fisher’s exact test. Group means,
presented as mean values (standard deviation (SD)) were
compared using analysis of variance and the Student’s t test, or
nonparametric Mann–Whitney U test when appropriate. Serum
Trial profile. HCV, hepatitis C virus.
554 Yu, Dai, Huang, et al
HCV RNA levels were expressed after logarithmic transforma-
tion of original values. Stepwise logistical regression was used
to analyse which variables had a better predictive value for SVR.
The procedures were performed using the SPSS V.12.0
statistical package. All statistical analyses were based on two-
sided hypothesis tests with a significance level of p,0.05.
Patient demographic and other baseline characteristics
All 150 randomised patients completed the study and were
included in the final analysis (fig 1). Patients in the two
treatment groups were well matched for baseline characteristics
(table 1). The mean doses of peginterferon and ribavirin were
comparable between the two groups. The 16-week group
tended to have higher rate of 80/80/80 adherence (86%; 95%
confidence interval (CI) 76% to 96%), defined as patients who
had received >80% of expected peginterferon and ribavirin
doses and completed at least 80% of the expected duration,12
than the 24-week group (73%; 95% CI 64% to 82%).
At week 4, RVR was achieved by 86% of patients (43/50; 95% CI
76% to 96%) in the 16-week group and by 87% of patients (87/
100, 95% CI 80% to 94%) in the 24-week group (fig 2). An ETVR
was achieved by all patients in the 16-week group and by 98%
(98/100; 95% CI 95% to 100%) of patients in the 24-week group.
The primary end point, SVR, was achieved by 94% of patients
(47/50; 95% CI 87% to 100%) in the 16-week group and by 95%
of patients (95/100; 95% CI 91% to 99%) in the 24-week group,
without any significant between-group difference (difference
21%; 95% CI 9% to 7%). The relapse rate was higher in the 16-
week group (6%; 3/50; 95% CI 0%–7%) than in the 24-week
group (3.1%; 3/98; 95% CI 21% to 13%). However, the
difference did not reach significance (95% CI 210.4% to 4.5%).
Factors affecting SVR and relapse rate
The influence of prognostic factors on the SVR rate was
analysed in both groups. They included baseline demographical
features, liver histopathology, viral loads, 80/80/80 adherence
and received doses of peginterferon and ribavirin, and on-
treatment response (table 2). Patients who achieved RVR at
week 4 had a significantly higher SVR rate than those who did
not in both the 16-week (100% vs 57%; p=0.002) and 24-week
groups (98% vs 77%; p=0.015). Sustained virological respon-
ders were significantly younger than non-responders in the 24-
week group (p=0.041). The independent predictive value of
and ribavirin of the patients
Basic demographical, virological, and clinical features and doses of peginterferon
24-week group16-week groupp Value
Mean (SD) age (years)
Sex, n (%)
Mean (SD) body weight (kg)
Mean (SD) body mass index (kg/m2)*
Mean (SD) alanine aminotransferase (IU/l)
Mean (SD) aspartate aminotransferase (IU/l)
Mean (SD) necroinflammatory activity
Fibrosis, n (%)
Steatosis, n (%)
Moderate to severe (2–3)
Pretreatment HCV viral load (log IU/ml)
Mean (SD) dose of peginterferon (mg/kg/week)
Mean (SD) dose of ribavirin (mg/kg/day)
80/80/80 adherence, n (%)?
4.84 (2.34)5.48 (3.32) 0.226
HCV, hepatits C virus.*The body mass index is the weight in kilograms divided by the square of the height in metres.
?Patients who had received .80% of expected peginterferon and ribavirin doses, and completed at least 80% of
24 week, n = 100
16 week, n = 50
RVR ETVR SVR RRRVR ETVR SVR RR
virological response (ETVR), sustained virological response (SVR) and
relapse rate (RR). The rates of RVR (defined as seronegative for hepatitis C
virus (HCV) RNA at 4 weeks of treatment), ETVR (defined as seronegative
for HCV RNA at end of treatment), SVR (defined as seronegative for HCV
RNA at end of treatment and throughout the follow-up period) and RR
(defined as HCV RNA reappearance during the follow-up period for
patients with ETVR) of patients infected with HCV genotype 2 treated for 24
or 16 weeks with peginterferon a and ribavirin.
The rates of rapid virological response (RVR), end-of-treatment
16 weeks of peginterferon and ribavirin for HCV2555
age, sex, body weight, body mass index, necroinflammatory
serum concentrations of alanine aminotransferase and HCV RNA,
mean doses of peginterferon and ribavirin, adherence, RVR at
was determined by using stepwiselogistic regression analysis. The
factorssignificantly associatedwithSVRin 150 patientswere RVR
at week 4 and patient’s age, with an odds ratio (OR, 95% CI) of
40.76 (5.964 to 278.6) and 0.834 (0.721 to 0.965), respectively,
whereas the treatment duration was not associated with SVR (OR
1.241; 95% CI 0.186 to 8.279).
Between-group difference in relapse and SVR rates was
analysed by stratification of baseline and on-treatment factors
(table 3). For patients without RVR at week 4, the relapse rate
was higher in the 16-week (42.9%; 95% CI 27% to 92%) group
than in the 24-week group (9.1%; 95% CI 211% to 29%), and
the SVR rate was lower in the 16-week group (57%; 95% CI 20%
to 94%) than in the 24-week group (77%; 95% CI 54% to 99%).
However, the differences of both relapse rate and SVR rate
between the 16-week and 24-week groups did not reach
significance. For patients who did not achieve 80/80/80
adherence, received ribavirin dose , 13 mg/kg/day, had a dose
modification of peginterferon and/or ribavirin and had dose
modification of ribavirin, the relapse rate tended to be higher in
the 16-week group (14.3%, 16.7%, 11.5% and 13%, respectively)
than in the 24-week group (3.8%, 4.5%, 3.8% and 4%,
respectively). Nevertheless, all the differences were not
As RVR at week 4 was the most important factor associated
with SVR in both the 16-week and 24-week groups, we
stratified patients by RVR to evaluate the influence of ribavirin
dose expressed per kilogram of body weight on SVR. For
patients without RVR at week 4, the mean dose of ribavirin was
comparable between sustained responders and non-responders
of the 24-week group throughout the treatment period;
however, the mean dose of ribavirin from 5th to 16th weeks
of treatment was significantly lower in non-responders of the
16-week group than in sustained responders of the 16-week
group (11.3 (2.5) vs 16.1 (0.8) mg/kg/day; p=0.034; fig 3A).
For patients with RVR at week 4, all patients achieved SVR in
the 16-week group; the mean dose of ribavirin from 5th to 16th
weeks of treatment was lower in non-responders of the 24-
week group (9.7 (8.9) mg/kg/day) than in sustained responders
of the 24-week group (14.8 (3.7) mg/kg/day). However, the
difference was not significant (p=0.395, Mann–Whitney U
test; fig 3B).
No serious adverse event was reported. One patient in the 24-
week group discontinued treatment because of anaemia and
leucopenia at week 23. A total of 4 (8%) patients in the 16-week
group and 9 (9%) in the 24-week groups required dose
reduction of peginterferon because of adverse events (5
patients), leucopenia (3), anaemia (4) and thrombocytopenia
(1). Adverse events were typical of those previously reported for
peginterferon and ribavirin combination treatment (table 4).
Incidence rates for most adverse events were similar between
the 16-week and 24-week treatment groups, except that the
incidence of alopecia was significantly higher in the 24-week
group (49%) than the 16-week group (20%; p=0.001).
In this study, we showed that a shorter course of 16-week
peginterferon and weight-based ribavirin 1000–1200 mg/day is
as effective as a standard 24-week course in Taiwanese patients
infected with chronic HCV2 who achieved RVR at week 4.
Achievement of RVR at week 4 and patient’s age, but not
treatment duration, were independent factors associated with
Factors associated with sustained virological response
24-week treatment group16-week treatment group
Sustained virological response,
Sustained virological response,
Patients, n (%)
Mean (SD) age (years)
Male sex, n (%)
Mean (SD) body weight (kg)
Mean (SD) body mass index (kg/m2)?
Mean (SD) alanine aminotransferase (IU/l)
Fibrosis score, n (%)
Steatosis, n (%)
Moderate to severe (2–3)
Mean (SD) baseline HCV RNA level (log IU/ml)
Mean (SD) mean dose of peginterferon (mg/kg/week)
Mean (SD) mean dose of ribavirin (mg/kg/day)
80/80/80 adherence, n (%)`
RVR at 4 weeks, n (%)1
4.79 (2.37) 5.80 (1.3)0.349
5.32 (3.34)8 (2)0.178
HCV, hepatitis C virus; RVR, rapid virological response
?The body mass index is the weight in kilograms divided by the square of the height in metres.
`Patients who had received >80% of expected peginterferon and ribavirin doses, and completed at least 80% of expected duration.
1RVR, rapid virological response, seronegative of HCV RNA at week 4 of treatment.
556 Yu, Dai, Huang, et al
SVR. The shorter duration of treatment resulted in a lower
incidence of adverse events such as alopecia and in lower cost
of treatment. An insufficient dose of ribavirin after 4 weeks of
treatment may compromise the response to a 16-week
treatment in patients without RVR at week 4.
For patients infected with HCV2, peginterferon/ribavirin for
24 weeks is the standard recommended treatment,5which
could achieve SVR rates similar to those treated with a 48-week
course.8Subsequently, three European studies13–15have shown
that a shorter course of treatment over 12–16 weeks with
peginterferon/ribavirin is as effective as a 24-week course for
patients with HCV2 with RVR at 4 weeks. These previous
studies used RVR at week 4 as an indicator for choosing the
treatment period. Only patients who had RVR were assigned to
groups that had shorter treatment periods.13–15Thus, no data
were available for shorter courses of treatment in patients who
did not achieve RVR. In our study, Taiwanese patients with
chronic HCV2 infection were randomly assigned to either 16 or
24 weeks of treatment with peginterferon/ribavirin regardless
of their RVR. Our results clearly showed that a rapid response at
week 4 is an important factor that can significantly affect the
outcome of treatment in both the 16-week and 24-week groups.
Consistent with previous European studies,13–15this study also
showed that 16 and 24 weeks of peginterferon/ribavirin
treatment provided equal efficacy for patients with HCV2 who
achieved RVR at week 4, with an SVR rate of 98–100%. Recent
data also suggest that 24 weeks of treatment is effective and
sufficient for achieving SVR in patients with HCV1 or HCV4
who exhibit RVR at 4 weeks, compared with a recommended
standard course of 48 weeks of treatment.22–24These findings
emphasise the importance of RVR at 4 weeks in the individua-
lised treatment for CHC.
Other studies examining shorter treatment durations in
patients with HCV2 and HCV3 have shown higher relapse rates
with the shorter treatment duration.14 15We also observed that
the 16-week group had a lower SVR rate and a higher relapse
rate than the 24-week group for patients who did not achieve
RVR. However, too few patients had a relapse for this to be a
meaningful comparison. The between-group difference showed
a tendency towards ribavirin dose reduction with a higher
relapse rate and lower SVR rate. We also found that a
significantly lower mean dose of ribavirin by body weight after
4 weeks of treatment was observed in non-responders who did
not achieve RVR at week 4 after 16 weeks treatment, even with
a limited number of cases. Significant incremental virological
response rates with adherence were not detected for patients
with HCV2 or HCV3 with 24 or 48 weeks of treatment.12Our
observation suggested that ribavirin adherence and ribavirin
dose by body weight after 4 weeks of treatment may play a role
in the response to a shorter course of treatment for patients
with HCV2 without RVR at week 4. Further large-scale studies
are needed to confirm these findings.
Between-group difference in relapse rate and sustained virological response (SVR) rate
Relapse rate, % (n/N)
SVR rate, % (n/N)
HCV RNA level
,800 000 IU/ml
.800 000 IU/ml
RVR at 4 weeks
Mean ribavirin dose
Peginterferon and/or ribavirin
HCV, hepatitis C virus; RVR, rapid virological response; SVR, sustained virological response.
*The body-mass index is the weight in kilograms divided by the square of the height in meters.
? Patients who had received at least 80% of total peginterferon dose, at least 80% of total ribavirin dose and completed at least 80% of total study duration.
16 weeks of peginterferon and ribavirin for HCV2557
For patients without RVR, a 16-week regimen is obviously
suboptimum. Nevertheless, the efficacy remains unsatisfactory
in this relatively difficult-to-treat subgroup even with a 24-
week course of treatment (SVR rate 77% in this study and 50–
72% in European studies13 14). Whether an extended course of
treatment .24 weeks is of benefit for this subgroup remains to
The SVR rate of patients with HCV2 with RVR at 4 weeks
using a shorter course of peginterferon and ribavirin is slightly
higher in our study than observed in previous studies
conducted in Europe.13–15 25A greater response to peginter-
feron/ribavirin in Taiwanese patients with chronic HCV-1b than
in Caucasian patients was also observed in previous studies.26 27
There may be a few reasons for this diffference. Firstly, racial
factors have been shown to influence the virological response
even when peginterferon/ribavirin are given for the standard
duration of treatment.16 17Ethnic and racial differences in
immunogenetics, peginterferon pharmacokinetics, signal trans-
duction pathway or viral kinetics may play a role in determin-
ing the outcome of HCV infections.3 28 29Secondly, geographical
variations of HCV by the emergence of quasispecies may have
influenced the virological response.30Thirdly, the mean body
weight was lower in our study population than in previous
European populations, with a mean difference of 3–10 kg. The
higher average doses of peginterferon or ribavirin per kilogram
body weight in our patients might contribute to a higher
Previous study showed that peginterferon and ribavirin at a
dose of 800 mg/day is as effective as peginterferon and ribavirin
at a dose of 1000–1200 mg/day in patients with HCV2 or HCV3
infections with a 24-week regimen.33Thus, peginterferon and
ribavirin at a dose of 800 mg/day for 24 weeks is recommended
for patients with HCV2 or HCV3.6In our study we used a higher
ribavirin dose of 1000–1200 mg/day to lower the relapse rate in
patients treated for 16 weeks. More recently, the ACCELERATE
Trial, evaluating 16 or 24 weeks of peginterferon a-2a 180 mg/
week and ribavirin 800 mg/day for patients with HCV2 and
HCV3 with quantifiable serum HCV RNA (.600 IU/ml),
showed that SVR was significantly greater with 24 rather than
16 weeks of treatment for patients with HCV2 (82% vs 65%;
p,0.001).25In the ACCELERATE Trial, the mean body weight
of patients with HCV2 was around 84 kg, with a mean ribavirin
dose of 9.52 mg/kg/day for a daily dose of 800 mg, in contrast to
15.3 mg/kg/day in our study. The difference may explain the
conflict in the results between the ACCELERATE Trial and this
study. Whether a higher weight-based dose of ribavirin is
required for a shorter duration of treatment without compro-
mising the efficacy for treating patients with HCV2 through the
reduction of the relapse rate remains to be studied.
A shorter treatment period can benefit patients by reducing
the cost of treatment and the incidence of adverse events.14As
the mean doses of peginterferon and ribavirin were not
different between the groups in our study, the reduced
incidence of adverse events can be considered to be a benefit
of shorter treatment duration. Shorter treatment duration can,
in particular, reduce the incidence of delayed side effects of
peginterferon treatment. In our study, the incidence of alopecia,
Ribavirin dose (mg/kg/day)
014 121086 2220 18162442
Patients without RVR at week 4
Non-SVR, 24-week group, n = 3
SVR, 24-week group, n = 10
Non-SVR, 16-week group, n = 3
SVR, 16-week group, n = 4
Week of treatment
Ribavirin dose (mg/kg/day)
0 14121086 22 2018 162442
Week of treatment
Patients with RVR at week 4
Non-SVR, 24-week group, n = 2
SVR, 24-week group, n = 85
SVR, 16-week group, n = 43
by rapid virological response (RVR) at week 4 (seronegative for hepatitis C
virus RNA at 4 weeks of treatment), sustained virological response (SVR)
and treatment regimen. Mean ribavirin dose was expressed per kilogram
of body weight for patients without RVR at week 4 (A) and with RVR at
week 4 (B). *For patients without RVR, the mean dose of ribavirin from the
5th to 16th weeks of treatment was significantly lower in non-responders of
the 16-week group than in sustained responders of the 16-week group
(11.3 (2.5) vs 16.1 (0.8) mg/kg/day; p=0.034, Mann–Whitney U test);
for patients without RVR, the mean dose of ribavirin from the 5th to 16th
weeks of treatment in non-responders of the 24-week group was 9.7
(8.9) mg/kg/day, compared with 14.8 (3.7) mg/kg/day in sustained
responders of the 24-week group (p=0.395, Mann–Whitney U test).
Mean ribavirin dose throughout the treatment period, stratified
to the treatment group
Adverse events and dose modifications according
n=100, n (%)
n=50, n (%)
Dose modification for adverse events or laboratory abnormalities
Peginterferon a-2a 9 (9)
Peginterferon a-2a or
Anorexia 46 (46)
Diarrhoea 9 (9)
Depression 10 (10)
Hair loss 49 (49)
Skin rash54 (54)
Leucopenia (white cell count
level ,10 g/dl)
Abnormal thyroid function
1 (1)0 (0)1
54 (54)26 (52)
2 (2)1 (2)1
53 (53)27 (54)0.908
1 (1)0 (0)1
13 (13)4 (8)0.362
558Yu, Dai, Huang, et al
a common late side effect of peginterferon,34was significantly
less in the short-duration treatment group.
In conclusion, this study shows that for patients with CHC
infected with HCV2 who achieved RVR at 4 weeks, the efficacy
of peginterferon a-2a and weight-based ribavirin at a dose of
1000–1200 mg/day administered for 16 weeks is comparable
with treatment duration of 24 weeks. A shorter duration of
treatment can reduce the incidence of adverse events and the
cost of treatment. Our results provide information necessary for
decision making of individualised treatment based on response
at 4 weeks in CHC patients with HCV2 infections.
Ming-Lung Yu, Li-Po Lee, Ming-Yen Hsieh, Zu-Yau Lin, Hepatobiliary
Division, Department of Internal Medicine, Kaohsiung Medical University
Hospital, Kaohsiung, Taiwan
Shinn-Cherng Chen, Ming-Yuh Hsieh, Liang-Yen Wang, Wen-Yu Chang,
Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical
University, Kaohsiung, Taiwan
Chia-Yen Dai, Nai-Jen Hou, Department of Internal Medicine, Kaohsiung
Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan
Jee-Fu Huang, Department of Internal Medicine, Foo Yin Hospital, Pintung,
Chang-Fu Chiu, Department of Internal Medicine, Paochien Hospital,
Funding: Taiwan Liver Research Foundation.
Competing interests: None.
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