|
Peginterferon Alfa-2a/ribavirin Treatment in Patients with
Chronic HCV Genotype 1: Efficacy Is Improved in Patients with Early Stages
of Fibrosis
Treatment with
peginterferon and ribavirin (PEGIFN/RBV) is the standard of care for
patients with hepatitis C virus (HCV) infection. Patients with chronic HCV
and
advanced fibrosis or
cirrhosis (CX) are at risk for developing
disease progression and
hepatic decompensation and are therefore candidates for treatment.
In contrast, the
risk:benefit ratio of PEGIFN/RBV therapy is controversial for patients with
mild or no fibrosis (NoF), particularly patients with HCV genotype 1 who
have a lower overall rate of
sustained
virologic response (SVR).
Researchers therefore
examined the relationship between
liver histology, SVR and the incidence of Laboratory abnormalities
(LA) during treatment with
PEGIFN alfa-2a/RBV [Pegasys/Copegus] in patients with HCV
genotype 1.
Data were reviewed from
328 patients with chronic HCV genotype 1 treated with PEGIFN alfa-2a (180
mg/week) [Pegasys]
plus RBV (1000/1200 mg/day) for 48 weeks in two registration trials.
All patients had a
baseline
liver biopsy. A subset of the biopsies were assessed for fibrosis by
a local pathologist and staged as either NoF, portal (PF), incomplete septa
(IS) or CX.
HCV RNA titer was
determined by Roche Amplicor.
SVR and LAs were
examined as a function of baseline
fibrosis score.
Results
The number of patients
and SVR for each fibrosis group are listed in the TABLE below.
·
Patients
with NoF/PF had an SVR of 56% (135/241) whereas 42% (37/87) of patients with
IS/CX achieved SVR (p<0.03).
·
No
significant differences in gender (73% male), race (84% Caucasian), or
baseline HCV RNA titer >800,000 IU/ml (67%) were present between the 2
groups.
·
In contrast,
patients with IS or CX were older (p<0.001).
·
Only grade 3
thrombocytopenia was more frequent in
patients with IS/CX than noF/PF (10 % vs 2%; p<0.001).
·
No grade 4
thrombocytopenia was observed.
Conclusions
The authors conclude,
“Patients with NoF/PF have a superior SVR to patients with IS/CX. These
patients should not defer therapy and wait for evidence of fibrosis
progression as this only reduces their chance for SVR.
|
Baseline Fibrosis
score, N=328 |
N (%) |
SVR |
Age, Mean ±
SD |
ALT, Mean ±
SD |
|
NoF |
65 |
34 (52%) |
38 ±
10 |
84 ±
50 |
|
PF |
176 |
101 (57%) |
43 ±
10 |
114 ±
113 |
|
IS |
51 |
25 (49%) |
48 ±
10 |
133 ±
99 |
|
CX |
36 |
12 (33%) |
50 ±
8 |
151 ±
134 |
05/16/05
Reference
M L Shiffman
and others. Peginterferon Alfa-2a/ribavirin Treatment in Patients with
Chronic HCV Genotype 1: Efficacy Is Improved in Patients with Early Stages
of Fibrosis. Abstract S1568. Digestive Disease Week 2005. May 14-19,
2005. Chicago, IL
http://www.hivandhepatitis.com/2005icr/ddw2005/docs/hcv_051605d.html
Peginterferon Alfa-2b (PegIntron) Therapy for 8 Weeks in
Acute Hepatitis C Genotypes 1 and 4: A Pilot Study
The efficacy and
duration of peginterferon treatment in
acute
hepatitis C have not been adequately evaluated. This
study was designed to determine the efficacy, safety, long term
outcome and cost-effectiveness of 8 weeks
peginterferon alfa (PEG IFN) [PegIntron] monotherapy
in patients with acute hepatitis C virus (HCV)
genotypes 1 or 4.
This intent to treat,
controlled multicenter trial was
designed to treat patients with acute hepatitis C with detectable HCV-RNA at
8 weeks after the first positive PCR.
Sixty-two
patients with
proven acute HCV genotypes 1 (n= 23) and 4 (n=39) were enrolled and
prospectively followed.
Ten subjects refused
treatment but were followed through the study.
Fifty-two patients
without spontaneous recovery at week 8 were assigned to receive
1.5 mg/kg peginterferon alfa-2b S.C.once
weekly for 8 weeks while patients who still have
detectable HCV-RNA after 8 weeks
of treatment continued
therapy until 12 weeks.
The
primary end point was
sustained
virological response (SVR),
defined as undetectable HCV RNA 48 weeks after end of treatment.
All
patients were followed for 3 years after therapy.
Results
·
Four
untreated subjects (40%) had spontaneous recovery.
·
Among the
52 treated patients, 41 (79%) patients (genotype 4: 32 patients, genotype 1:
9 patients) had
undetectable HCV-RNA
after 8 weeks therapy and treatment was stopped while 11 patients (genotype
1) had persistent viremia so treatment was continued until 12 weeks.
·
The
overall SVR in all treated patients was 92.3% [39/41 (90%) in the 8-week
treatment group and 10/11 (91%) 27 in the 12-week treatment group].
·
SVR after
8 weeks peginterferon alpha-2b therapy was achieved more frequently among
genotype 4 patients irrespective of viral load while in genotype 1 patients
SVR after 8 weeks was more likely in patients with low viral load compared
with those with high viral load.
·
Peginterferon alfa-2b therapy was well tolerated in both groups and was
associated with significant improvement in the
quality of life.
·
None of
patients with
SVR
had detectable HCV-RNA 3 years after completing treatment.
Conclusions
In conclusion, the authors
write, “Peginterferon alfa-2b monotherapy for 8
weeks induces high sustained virologic response rates in patients with acute
hepatitis C virus with genotype 1 and 4.”
“HCV
genotype 1 with high viral load may require longer treatment duration.
Peginterferon alfa
therapy in acute hepatitis C seems cost effective as it reduces
the incidence of chronicity and improves the quality of life.”
05/16/05
Reference
S Kamal and others. Peginterferon Alfa-2b (PegIntron) Therapy for
8 Weeks in Acute Hepatitis C Genotypes 1 and 4: A Pilot Study. Abstract 84
(oral). Digestive Disease Week 2005. May 14-19, 2005. Chicago, IL.
http://www.hivandhepatitis.com/2005icr/ddw2005/docs/hcv_051605c.html
Efficacy of Daily Consensus Interferon (Infergen) and
Ribavirin Compared to Peg-Interferon Alfa2b (PegIntron) and Ribavirin in
Treatment-Naive Patients with HCV Genotype 2 or 3
Consensus interferon (CIFN; Infergen)
is a synthetic type 1
interferon with enhanced in vitro activity compared to conventional IFN-alfa
(IFNa). In the prospective, randomized multicenter PegIntron-Against-Consensus-Trial
(PACT), the efficacy and safety of daily CIFN-treatment and ribavirin is
compared to
peg-IFNa2b [PegIntron] plus ribavirin.
400 patients with chronic
HCV infection and serotype-2 or -3 will randomly be assigned to treatment
with 9 mcg qd CIFN sc. (group A) or peg-IFNa2b (1,5 mcg/kg body weight once
weekly, group B), each in combination with ribavirin (>10,6 mg/kg body
weight) for 24 weeks.
Treatment is interrupted
for primary non-response, if viral load drops by less than 2 log until week
12 or drops by more than 2 log but remains positive at week 16.
Follow up includes further
24 weeks. Viral response rates are analyzed by the Roche COBAS Amplicor HCV
Monitor v2.0 test.
129 patients out of 199
patients enrolled before November 2004 reached at least the end of treatment
at week 24 and represent the base of this interim analysis.
Results
·
There were
no significant differences in patient baseline characteristics between both
treatment groups concerning age, gender, genotype and viral load.
·
The
virological response rates analyzed as intent-to-treat are shown in the
Table:
| |
Group A
|
Group B
|
| |
wk 12
(n=67) |
wk 24
(n=68) |
wk 48
(n=43) |
wk 12
(n=60) |
wk 24
(n=61) |
wk 48
(n=38) |
|
PCR neg |
99% |
93% |
95% |
92% |
94% |
95% |
·
Thus, end-of
treatment response (ETR) rates as well as sustained virological response (SVR)
rates were very high and identical in both treatment groups.
·
This was
also true for all subgroup analyses, including analysis according to
baseline viral load (< vs. ≥ 800.000 IU/ml) gender, body weight (< vs. ≥ 75
kg) and age (< vs. ≥ 60 yrs).
·
Treatment
was rather well tolerated in both treatment groups, as there were no
significant differences in the numbers of serious adverse events or preterm
treatment discontinuations.
Conclusions
In conclusion, the authors
write, “In treatment-naive patients with chronic hepatitis C and serotype-2
or -3 infection, daily treatment with CIFN combined with ribavirin has the
same antiviral efficacy and safety profile as weight adjusted peg-IFNa2b.
Further analyses will show whether some subgroups might preferentially
benefit from one or the other interferon.”
05/18/05
Reference
W Bocher
and others. Interim Results From the PACT-Trial: High Antiviral Efficacy Of
Daily Consensus Interferon/ribavirin Compared To Peg-Interferon Alfa2b/ribavirin
in Treatment-Naive Patients With Chronic Hepatitis C and Serotype-2 or -3.
SABstract S1531. Digestive Disease Week 2005. May 14-18, 2005.
Chicago, IL.
http://www.hivandhepatitis.com/2005icr/ddw2005/docs/hcv_051805e.html
No Correlation Found Between Steatosis and Liver Fibrosis
in HCV Genotype 1 Infection
Liver steatosis
is generally regarded as a risk factor for chronic liver disease. Moreover,
steatosis is considered in HCV-related chronic active hepatitis (CAH) as an
adjunctive factor of progression and evolution of liver disease. In
particular, steatosis is thought to be specifically related to the course of
the disease in
genotype 3a patients with CAH.
The aim of this study
was to test the role of steatosis in liver damage (fibrosis)
in a consecutive case-study of
genotype 1b patients who have undergone
liver biopsy because of an increase of serum ALT.
180 patients ( sex:
M98/F82; median age: 51 range 17 - 68) underwent
ultrasound examination and liver biopsy.
Based on
liver histology patients were divided according to steatosis into
four classes: 1 (no steatosis), 2 (steatosis < 30%), 3 (steatosis 30 – 50
%), 4 (steatosis > 50 %).
Results:
·
Histological
Activity Index (HAI) was evaluated according to ISHAK’ s score.
·
Median fibrosis value was S 2 (ranging 0 – 6; 23 patients
showed liver cirrhosis) in all the 4 classes and no statistical significance
was found between groups.
·
Virological and epidemiologic characteristics, biochemical
data, BMI, Apparent Duration of Disease (ADD) of all patients were recorded
and statistical correlation checked.
·
A univariate
and multivariate analysis vs fibrosis were performed in all the patients and
tested statistically significant only for age, ADD, diabetes and ALT (p<
0.00), but not for steatosis.
Conclusion
The authors conclude,
“Steatosis does not seem to be an independent adjunctive risk factor of
liver disease progression in CAH/genotype 1b HCV-infected patients….Age,
ADD,
diabetes and
increase
of ALT seem to be the only independent factors associated with
liver fibrosis progression.”
05/02/05
Reference
M Persico and others.
NO CORRELATION BETWEEN FAT
LIVER ACCUMULATION AND LIVER FIBROSIS IN GENOTYPE 1B HCV RELATED CHRONIC
LIVER DISEASE. Abstract 593. 40th EASL. April 13-17, 2005. Paris,
France.
|
HCV genotype 5 has a similar response to peginterferon plus
ribavirin as genotype 1 |
|
By Jillian L. Lokere, MS
April 16, 2005 —
Patients infected with HCV genotype 5 have responses to peginterferon plus
ribavirin similar to those with genotype 1 infection, according to a poster
presented by Francois D'heygere and colleagues from the Algemeen Ziekenhuis
Groeninge, Kortrijk, Belgium at the 40th Annual Meeting of the European
Association for the Study of the Liver.
There are at least 6 different HCV genotypes throughout the world.
Genotype 1 is the most prevalent, accounting for 40% to 80% of all
infections. Genotype 5 is generally confined to South Africa, but small
pockets of genotype 5 infection have been reported in Western Europe.
Sustained virologic response (SVR) rates to peginterferon plus ribavirin
treatment differ by genotype, with clinical studies reporting a response
rate of about 50% for genotype 1. Because so few patients who are infected
with genotype 5 receive such treatment, there are few data about SVR rates
in this population. Preliminary evidence has suggested that genotype 5 may
respond better than genotype 1.
To clarify, D'heygere and colleagues compared SVR rates between genotype
1 and genotype 5 HCV-infected patients in Belgium. A total of 21 patients
with genotype 5 infection were selected from a database of 443 patients who
were enrolled in the Belgian Randomised Trial for Naive and Relapsers
(BERNAR-1). This trial used either standard interferon alfa-2a 6 MIU 3 times
weekly for 8 weeks, followed by 3 MIU 3 times weekly for 40 weeks, or
peginterferon alfa-2a 180 µg weekly for 48 weeks. All patients also received
ribavirin 1000 to 1200 mg daily. The 21 selected patients were about evenly
divided between the interferon group and the peginterferon group, and 81% of
them were treatment-naive. An additional 21 patients with genotype 1
infection were then selected to match those with genotype 5 infection on the
basis of age, gender, baseline viral load, cirrhosis status, pretreatment
status, and treatment group.
At 24 weeks after the end of treatment, 48% of patients in the genotype 5
group and 38% of patients in the genotype 1 group had an SVR, a difference
which was not quite statistically significant. Among those who received
peginterferon rather than standard interferon, the SVR rate was 55% in both
groups.
The investigators concluded that patients with genotype 5 infection
respond to peginterferon plus ribavirin treatment similarly to those with
genotype 1 infection, although genotype 5 patients appeared to respond less
well to standard interferon treatment.
Reference
D'heygere F,George C, Nevens F, et al. Patients infected with HCV-5
present the same response rate as patients infected with HCV-1: results from
the Belgian Randomised Trial for Naive and Relapsers (BERNAR-1). Program and
Abstracts of the 40th Annual Meeting of the European Association for the
Study of the Liver. Abstract 558.
http://clinicaloptions.com/hep/news/news_EASL2005_558.asp
The
Effectiveness of Standard and Pegylated Interferon Plus Ribavirin in
Treatment-naïve Patients with Chronic Hepatitis C Virus Genotype 5 in
France
The prevalence of
HCV genotype 5 in France is 2%. Little is known about virological
response in this population. Individuals with HCV genotype 5 have poor
responses to interferon/ribavirin therapy and are usually treated for 48
weeks The aim of the present study was to assess the antiviral response in
naïve patients treated woth
standard
Interferon or
Pegylated
Interferon plus Ribavirin for 48 weeks.
French researchers
performed a retrospective study in order to estimate the virological
response after a treatment of 48 weeks in treatment-naïve HCV genotype 5
patients. A total of 82 patients were included. Twenty eight patients
received standard Interferon (3 MU*3/week) (G1) and 54 were treated with
Peg-Interferon 1.5 mcg/kg/week
(PegIntron)
or 180 mcg/week [Pegasys] (G2)
plus Ribavirin (800-1200 mg/day).
Sustained
virological response (SVR)
was defined as an
undetectable HCV RNA at week 72. Patients were considered as
adherent if they received ≥ 80% of both their total Interferon and Ribavirin
doses for ≥ 80% of the expected duration of therapy (AASLD 2004).
Results
Baseline characteristics
were: mean age 58 years, sex ratio 1.4 (M/W), fibrosis score (Metavir): 63%
≥ F2, 22% F4 and pre-therapeutic viral load > 800000 UI/mL: 52%.
Transmission routes were: transfusions (54%), intravenous drug use (2%),
others (18%) and unknown (39%).
·
SVR rate in
intent-to-treat analysis was achieved in 61% (64% in G1 and 60% in G2, p:
NS).
·
In
univariate analysis, the rate of SVR did not depend on age (<vs.≥ 45 years),
sex, fibrosis score (<vs.≥ F2) or viral load (<vs.≥ 800000 UI/mL).
·
SVR was 84%
(16/19) in adherent and 54% (32/59) in non adherent patients (p<0.05).
·
I35 patients
received a Ribavirin dose ≤ 800 mg/day. SVR rate was significantly
associated with Ribavirin adherence alone. SVR rate was statistically
superior (p<0.01) in Ribavirin adherent patients 86% (18/21) versus non
adherent patients 53% (30/57).
The authors conclude
·
Combination
therapy (standard or Peg-Interferon plus Ribavirin) is efficient in 61% of
HCV genotype 5 infected patients.
·
Adherence to
Ribavirin strongly improves SVR (86%).
·
This is the
first study conducted in a large cohort of HCV genotype 5 patients showing
that these patients can have a good response to combination therapy.
05/13/05
Reference
C Bonny and
others. EFFICACY OF INTERFERON (STANDARD OR PEGYLATED) PLUS RIBAVIRIN IN
NAÏVE PATIENTS WITH HEPATITIS C VIRUS GENOTYPE 5. A FRENCH NATIONAL STUDY.
Abstract 549. 40th EASL. April 13-17, 2005. Paris, France.
In Genotype 1 Patients with Low Viral Load Who Become HCV
RNA Negative at Week 4, Treatment with Peginterferon Alfa-2b (PegIntron) for
24 Weeks Has Similar High Efficacy with Superior Safety Compared to 48-week
Therapy
The results of prior studies suggest that patients with
genotype 1 patients and
low HCV viral load (G1LVL) have
high sustained virologic response rates (SVR)
similar to
genotype 2/3 patients. Recent data
also have demonstrated that genotype 2/3 patients respond similarly with 24
weeks of therapy as historical 48-week treated controls.
No
similar data exist for G1LVL patients. The objective of the current study
was to compare the efficacy of 24 weeks of
peginterferon alfa-2b/ribavirin (PegIntron/ribavirin/
P/R) with a historical control treated for 48 weeks with
PegIntron plus a similar ribavirin dose (>10.6 mg/kg) (Manns, Lancet 2002).
Treatment-naïve G1LVL patients (≤2 million copies/mL) were treated for 24
weeks with PEG-Intron 1.5 µg/kg/week subcutaneously plus oral ribavirin
800-1400 mg/day based on body weight. Plasma HCV RNA was determined at
treatment weeks 4, 12, 24 and follow-up weeks 12 and 24 using quantitative
PCR assay (Taq-Man/sensitivity 29 IU/ml). Genotype was determined by
sequencing the PCR product.
Results
·
A total of 235 G1LVL patients were treated (237 enrolled).
·
End of treatment (EOT) virologic response
was 81% and SVR was 50% with 24 weeks treatment.
·
The 48 week historical control had similar EOT of 74% but
higher SVR of 71%. This difference was due to high virologic relapse rate
after 24 weeks of therapy (37%) compared to historical control (4%).
·
A subset of patients treated for 24 weeks, those who became
HCV RNA negative at treatment week 4, had a similarly high SVR (89%)
compared to the historical control (85%).
·
In contrast, SVR was low (25%) and
relapse high (75%) in those patients who
first had an undetectable HCV RNA at week 12.
·
Discontinuation (3%) and
dose reductions (25%) for
adverse events were lower than in
the historical control (14%, 49%, respectively).
Conclusion
Overall, 24 week treatment with P/R in G1LVL patients achieves similar EOT
response, but lower SVR compared to a 48-week treated historical control.
However, for patients who become HCV RNA negative at week 4, treatment for
24 weeks has similar high efficacy with superior safety compared to 48 week
therapy.
Saarland
University Hospital, Homburg/Saar, Germany, Hospital Vall D'Hebron,
Barcelona, Spain,
University Clinic of Vienna, Vienna, Austria , Ikem, Prague, Czech
Republic, Hopital Saint LUC - UCL, Bruxelles, Belgium, Warsaw Medical
University, Warsaw, Poland, St. Laszlo Hospital, Budapest, Hungary, Huddinge
University Hospital, Stockholm, Sweden, Schering-Plough Research Institute,
Kenilworth NJ, USA .
04/18/05
Reference
S Zeuzem and others. EFFICACY OF 6 MONTHS TREATMENT WITH
PEG-INTERFERON ALFA-2B PLUS RIBAVIRIN (P/R) IN PATIENTS INFECTED WITH
HEPATITIS C WITH GENOTYPE 1 OF LOW VIRAL LOAD (G1LVL). Abstract 625. 40th
EASL. April 13-17, 2005. Paris, France.
http://www.hivandhepatitis.com/2005icr/easl/docs/041805_f.html
2005
H.E. Harris1,
K.P. Eldridge1, C-G. Teo2, S. Harbour2,
M.E.B. Ramsay1
1Immunisation Department,
Centre for Infections, Health Protection Agency, London, UK
2Sexually Transmitted And Blood-Borne Virus Laboratory, Centre
for Infections, Health Protection Agency, London, UK
Introduction
It is not known whether differences in
the natural history of hepatitis C virus (HCV) can be explained by
differences in the infecting genotype.
Aim
The aim of this study was to describe the prevalent
genotypes in a national cohort of patients who acquired HCV infection at a
known date and to investigate whether there was any evidence to suggest that
the natural history of their infections might vary with the infecting type.
Methods
Data on clinical outcomes were extracted from the HCV
National Register and mortality data were taken from death certification.
Sera were available for 749 cases who had been enrolled in the UK HCV
National Register. HCV RNA-positive specimens were genotyped and HCV
RNA-negative specimens were serotyped. Logistic regression analysis was used
to investigate the effect of HCV type on viral clearance and histological
stage of liver disease. 444 of the sera were found to carry HCV RNA. The
most prevalent HCV types were 1 (52%), 3 (29%) and 2 (16%). Of the 305
specimens found to be HCV RNA-negative, it was possible to serotype 160 of
them; serotypes 1 (58%), 3 (24%) and 2 (13%) were the most common. There was
no evidence of any association between viral type and: mortality, signs and
symptoms of liver disease or histological grade of liver disease. A
significant association was observed between viral type and response to
treatment, with type 1 infections being associated with poor response to
treatment when compared to types 2 or 3 (P=0.003). Viral type was
independently associated with spontaneous viral clearance, with type 1 being
more likely to clear spontaneously than non-1 types (OR 0.50, 95% CI
0.30–0.84, P= 0.009). Viral type was also independently associated with
histological stage of liver disease, with type 1 being associated with stage
scores above the median when compared to non-1 types (OR 2.03; 95% CI
1.07-3.83; P=0.03).
Results
The results of this study suggest that HCV
type 1 infection is more likely to be associated with spontaneous clearance
but is clinically more aggressive than type non-1 infection when it
persists.
http://www.hcvadvocate.org/news/reports/EASL_2005/April%2015.htm#April15_3
Nine of 10 Chronic Hepatitis C
Patients Achieve a Cure 24 Weeks Post-treatment with High Dose Ribavirin
Plus Standard Dose Peginterferon Alfa-2a (Pegasys)
By Ronald Baker, PhD
Ninety percent of
genotype 1 patients with a high viral load enrolled in a pilot study in
Sweden achieved
undetectable HCV RNA 24 weeks post-treatment with a regimen of high dose
ribavirin plus standard dose peginterferon alfa-2a (Pegasys). By standard
definitions, this means they were cured. Results of the small pilot study
appear in the current issue of Hepatology (February 2005). |
24
weeks post treatment), nine of ten patients had undetectable HCV RNA.
The primary goal of this small pilot study was to determine feasibility
and safety of the treatment, and not virological outcome. However, in
this difficult-to-treat patient population with genotype 1 and a high
viral load, nine of ten patients were cured by standard definitions,
which seems to be a better response than that found in studies using
standard ribavirin doses.
