Tuesday Posters (11/15/2005)– HCV Treatment – 8:00AM – 6:30PM
Abstract ID: 65089
Category: JO7: HCV:
Treatment
Assessment of ribavirin mutagenic properties in vivo and the influence of interferon alpha-induced reduction of hepatitis C virus RNA load upon therapy.
S. Chevaliez, Hopital
Henri Mondor, Universite Paris 12, Creteil, France, R. Brillet, Hopital Henri
Mondor, Universite Paris 12, Creteil, France, C. Hezode, Hopital Henri Mondor,
Universite Paris 12, Creteil, France, D. Dhumeaux, Hopital Henri Mondor,
Universite Paris 12, Creteil, France, J. Pawlotsky, Hopital Henri Mondor,
Universite Paris 12, Creteil, France
In a recent report (Nature 2004;432:922-924), mathematical
modeling of viral load decay during IFN alpha-ribavirin therapy was used to
suggest that ribavirin primarily acts by making HCV virions produced during
therapy less infectious. The hypotheses raised to explain this effect were
that: (i) ribavirin, by being mutagenic, would accelerate the accumulation of
genome mutations leading to the increased generation of non viable HCV variants
(so-called ‘error catastrophe’); (ii) ribavirin’s mutagenic effect would appear
only in patients with a low viral production related to a high antiviral
efficacy of IFN.
OBJECTIVE:
To test these hypotheses in patients with chronic hepatitis C
receiving IFN plus ribavirin.
METHODS:
The HCV genes encoding the full-length NS3 protease and
full-length NS5A protein were
PCR-amplified 14 days before treatment, at baseline, at day 14 and at day 28 of
therapy in 4 patients receiving ribavirin only and in 5 patients treated with IFN
alpha 2b-ribavirin combination. Extensive quasispecies analysis was performed
on the basis of 1360 clones generated and sequenced.
RESULTS:
(I) In the patients receiving ribavirin monotherapy, the rate
of accumulation of mutations did not accelerate during ribavirin administration
compared to the pretreatment period (natural genetic drift). In contrast, it
tended to slow in 2 cases. (ii) In 4 of the 5 patients under IFN-ribavirin
combination therapy, who all experienced a sharp reduction of viral replication
over the study period, the rate of accumulation of mutations did not accelerate
during the first 14 days of treatment compared to pretreatment, nor did it
accelerate during the following 14 days when HCV RNA was consistently reduced
by IFN. (iii) In one patient, however, the rate of accumulation of mutations
exponentially accelerated during treatment, with a very high mutation rate
between day 14 and day 28 when the HCV RNA load decreased from 45,000 down to
200 IU/ml (ie just before becoming negative). Two hypotheses can explain this
finding: a- an artefact related to the selection of minor variants due to the
very low viral load; b- an accelerated mutagenesis by ribavirin in the context
of profound HCV RNA suppression as suggested by mathematical modeling. The
latter hypothesis is currently being tested by analyzing the last HCV
RNA-positive sample in each patient.
CONCLUSIONS:
Ribavirin does not appear to be a mutagenic agent in vivo,
either in monotherapy or in combination with IFN alpha. However, this property
could be revealed when HCV replication is reduced to very low levels by IFN, a
hypothesis currently under study (these results will be presented).
Abstract ID: 65416
Category: JO7: HCV:
Treatment
Clinical and Economic Implications of a 4-Week Viral Negative Response to Peginterferon Alfa-2b plus Ribavirin for Chronic Hepatitis C and Genotype 1 with Low Viral Load.
J. B. Wong, Tufts-New
England Medical Center, Boston, MA, S. Zeuzem, Saarland University Hospital,
Homburg/Saar, Germany, M. P. Manns, Medizinische Hochschule Hannover, Hannover,
Germany, J. Harvey, Schering Plough Research Institute, Kenilworth, NJ, J. K.
Albrecht, Schering Plough Research Institute, Kenilworth, NJ
Introduction:
For chronic hepatitis C infections with genotype 1, monitoring
viral response at week 12 during treatment with peginterferon a-2b plus
ribavirin has become the standard management algorithm, permitting
discontinuation in those unlikely to achieve a sustained viral response (SVR).
An earlier week 4 viral negative response to therapy identifies a subgroup of
patients with genotype 1 and low viral load (£2 million copies/ml) who can be
treated for just 24 weeks.
Aim:
To estimate the clinical and economic consequences of a
4-week viral negative response to peginterferon a-2b plus ribavirin for
patients with genotype 1 and low viral load.
Methods:
We analyzed two trials of peginterferon a-2b plus ribavirin
involving genotype 1 patients with low viral load (Manns Lancet 2001, Zeuzem
EASL 2005). Although both trials dosed peginterferon a-2b at 1.5 mg/kg/week,
they differed in the ribavirin dose and intended duration of therapy: ribavirin
800 mg/day (>10.6 mg/kg) for 48 weeks in Manns and ribavirin 800-1400 mg/day
for 24 weeks in Zeuzem. We examined 4-week virologic and SVR outcomes. Drug
costs were based on US average wholesale drug costs and observed dosages and
duration of therapy in these trials.
Results:
The table shows the viral response data. For genotype 1
patients with low viral loads treated for 24 weeks, a 4-week viral negative
response occured in 46% (95% CI: 39-54%) with an 89% (95% CI: 79-95%)
likelihood of SVR (predictive value positive). The 4-week viral negative
response should not be used as a stopping criteria because many sustained
responders are not viral negative at week 4 (predictive value
negative<100%).
|
|
24
weeks |
48
weeks |
|
Viral Negative Week |
4 110/235 (46%) |
13/38 (35%) |
|
Likelihood of SVR |
98/110 (89%) |
11/13 (85%) |
|
Predictive Value Negative |
96/115 (83%) |
9/25 (36%) |
Drug costs for those viral negative at week 4 were $16,784
using the observed adherence to dosages and therapy duration in the 24 week
study. Assuming the same adherence estimates for 48 weeks, drug costs would
double to $33,567. If instead drug use matched that observed in the 48 week
study, drug costs would equal $23,036 so that limiting treatment to 24 weeks
would reduce costs by $6252, a 27% savings. Discontinuations (14% vs 3%) and
dose reductions (49% vs 25%) were more frequent in the 48 week than in the 24
week trial, so the 27% likely represents a minimum savings.
Conclusion:
A viral negative response at week 4 in genotype 1 patients
with low viral load identifies those who can be treated for just 24 weeks with a
high likelihood of achieving a sustained viral response.
Abstract ID: 65792
Category: JO7: HCV:
Treatment
INCIDENCE OF INFECTIONS DURING COMBINATION TREATMENT OF CHRONIC HEPATITIS C WITH PEGYLATED INTERFERONS ALFA 2B and 2A.
M. Antonini, University of
Brescia, Brescia, Italy, M. Puoti, University of Brescia, Italy, Brescia,
Italy, S. Babudieri, Clinica Malattie Infettive, Sassari, Italy, B. Zanini,
Clinica di Malattie Infettive, University of Brescia, Brescia, Italy, P.
Pagani, Clinica di Malattie Infettive, University of Brescia, Brescia, Italy,
S. Rossi, Clinica di Malattie Infettive, AO Spedali Civili, Brescia, Italy, I.
Maida, Clinica di Malattie Infettive, University of Sassari, Sassari, Italy, V.
Putzolu, Clinica di Malattie Infettive, University of Brescia, Brescia, Italy,
C. Baiguera, Clinica di Malattie Infettive, University of Brescia, Brescia, L.
Fenu, Clinica di Malattie Infettive, University of Sassari, Sassari, Italy, S.
Zaltron, Clinica di Malattie Infettive, AO Spedali Civili, Brescia, Italy, A.
Spinetti, Clinica di Malattie Infettive, AO Spedali Civili, Brescia, Italy, L.
Biasi, Clinica di Malattie Infettive, AO Spedali Civili, Brescia, Italy, S.
Sassu, Clinica Di Malattie Infettive, University of Sassari, Sassari, Italy, K.
Prestini, Clinica di Malattie Infettive, University of Brescia, Brescia, Italy,
F. Zacchi, Clinica di Malattie Infettive, University of Brescia, Brescia,
Italy, G. Carosi, Clinica di Malattie Infettive, University of Brescia,
Brescia, Italy, M. Mura, Clinica di Malattie Infettive, University of Sassari,
Sassari, Italy
To evaluate incidence and risk factors for neutropenia and
infections occurring during combination therapy for chronic hepatitis C with
pegylated interferons (PEGIFN)s and ribavirin we analysed longitudinal data
from two Italian reference centres. Complete blood count was performed 1, 2 and
4 after starting treatment and then every 4 weeks thereafter but every week if
neutrophils (N) counts<1000/mL. Dose adjustments for neutropenia were made
according to manufacturers’ instructions. The analysis included all consecutive
HCV infected patients without HIV co-infection who were prescribed PEGIFNs from
June 1st 2001 to December 31st 2004. Mann-Whitney, Fisher’s exact test Log Rank
test and Cox’s proportional model were used to assess statistical associations.
We studied 319 patients treated for chronic hepatitis C with once weekly
PEGIFNs: 2b 12 KDa at 1.5 mg/kg (162) or 2a 40KDa at 180 mg flat dose (157), in
combination with ribavirin 10.6-13 mg/kg/d,. Patients treated with PEGIFNa2a
had a significantly higher prevalence of F3-F4 stages at liver biopsy (62% vs.
33%; p<0.0001) showed a significantly higher body weight (72 vs 68 Kg
p=0.03), significantly lower baseline N counts (2.97 vs. 3.3 x103 mL p=0.03) and
were treated for a significantly longer time period (mean 190 vs 175 days
p=0.006). We observed 73 infections: 38 in patients treated with PEGIFNa2b and
35 in patients treated with PEGIFNa2a. Twenty-three were respiratory
infections, 17 cellulitis, 13 dental abscesses, 2 gastro-enteric infections and
18 infections involving other sites. Most of infections were mild; only four
patients (1.2%) required hospitalisation. Proportion of treatment duration with
N< 800/ mL were not significantly different in the two treatment groups
(2.3% vs. 4%) Incidence of neutropenia and infections in persons treated with
PEGIFNa2awere not related to body weight.. No statistically significant
difference in the incidence of all infections and neutropenia was observed
between patients treated with the two PEGIFNs. The incidence of all infections
was significantly associated with age (HR 1.03 per year 95% CI 1.01- 1.05
p<0.001). Incidence of respiratory infection was related with duration of
neutropenia (N< 800/mL) HR 1.013 per day (95% CI 1.0036-1.0225; p=0.0069)
and with usage of PEGIFNa2b HR 2.45 (95% CI 1.001-6.01; p=0.041) but not with
age. Incidence of severe infections was low. However 23% of treated patients
suffered for infectious episodes with an increasing risk in aged subjects.
Respiratory infections were related to the duration of neutropenia and there
was a trend for an independent association between usage of PEGIFNa2b and
respiratory infections.
Abstract ID: 65859
Category: JO7: HCV:
Treatment
Does Hepatic Steatosis affect Sustained Virological Response in chronic Hepatitis C genotype 3 infected patients?
S. Rasool, Department of
Medicine, Karachi, Pakistan, S. Hamid, The Aga Khan University,, Karachi, M.
Zubair, Aga Khan University, Karachi, Pakistan, K. Mumtaz, Aga Khan University,
Karachi, Pakistan, H. Shah, Aga Khan University, Karachi, Pakistan, W. Jafri,
Aga Khan University, Karachi, Pakistan
Hepatic steatosis can be a prominent feature of chronic
hepatitis C virus (HCV) infection, especially in genotype 3 patients, and is
considered to be an independent factor for treatment failure. However, the
association of this observation with different genotypes is not clear.
Prevalence of genotype 3 is very high among chronic HCV patients in our
community (in the range of 85%-90%).
Objectives:
The purpose of this study was to define the role of steatosis
on sustained virological response (SVR) to antiviral therapy in chronic
hepatitis C genotype 3 patients.
Methods:
We analyzed all naïve chronic HCV patients treated in our department
during the last four years. Patients were included in the study only if a
pretreatment liver histopathology was available, were infected with HCV
Genotype 3 patients, completed 6 months of therapy with interferon-α
and ribavirin and had follow up available of at least 6 months. Liver biopsies
were graded according to HAI and steatosis according to Brunt et al.
Results:
A total of 98 eligible patients were studied. Mean age was
38.09±9.02 years and sixty (61%) were males. Steatosis was present in
67/98(68.3 %) of patients. It was mild in 35/98 (35.7%) and moderate to severe
in 32/98 (32.6%) of patients. End treatment response was achieved in 65/98
(66.3%) and SVR in 62/98 (63.3%) patients. SVR was associated with stage of
fibrosis (p=0.02) and pre-treatment platelet count (p=0.05) but was not
associated with age (p=0.92), gender (p=0.39), BMI (p=0.74), grade of
inflammation (0.53) and grade of steatosis (0.28).
Conclusion:
Hepatic steatosis is present in a significant number of
patients with chronic hepatitis C genotype 3 infection but does not affect
sustained virological response.
Abstract ID: 65996
Category: JO7: HCV:
Treatment
Evidence of saturable ribavirin absorption.
K. Lindahl, Div of Infectious
Diseases, I 73, Stockholm, Sweden, R. Schvarcz, Div of Infectious Diseases,
I73, Stockholm, Sweden, L. Ståhle, Dep of Clinical Pharmacology, Stockholm,
Sweden
Aims:
Ribavirin is a nucleoside analogue most commonly used in
combinations therapy with interferon for the treatment of chronic hepatitis C.
Currently dose escalation studies are carried out and the aim of this study was
to analyse the effect of dose on the bioavailability of ribavirin to study the
possibility of saturable absorption. The authors also investigated the
stability of ribavirin blood samples.
Methods:
Twenty-four patients treated for chronic hepatitis C were
included in the study, 10 of which were obtained from a recent study of higher
doses than used in current European guidelines. Ribavirin concentrations were
analysed with a HPLC method. Relative bioavailability was defined as the
observed concentration at steady state divided by the predicted concentration
using a model previously described in a population pharmacokinetic analysis.
Ribavirin stability was studied in whole blood samples obtained from four
patients and stored under different conditions.
Results and conclusion:
Higher ribavirin doses were found to be linearly associated
with a lower bioavailability (r2= 0.36; p<0.01). At the highest dose, the
bioavailability was reduced by 50%. The main finding in this study is that the
bioavailability of ribavirin gradually declines with increasing doses. These
data suggests that ribavirin absorption is saturable and that ribavirin should
be dosed at least thrice daily if higher doses, than recommended in most
current guidelines, are used. It is also shown that there is a markedly
increase of ribavirin concentration in whole blood samples stored for longer
time at room temperature. The ribavirin concentration increased approximately
five times when stored for one week at
room temperature before centrifuged and frozen, compared to ribavirin
concentrations analysed within 3 hours. The recommended practice is to separate
plasma and store samples frozen within 24 hours.
Abstract ID: 66252
Category: JO7: HCV:
Treatment
Factors Associated with Liver Clinic Referral of Hepatitis C Virus (HCV)-Infected Patients.
H. Al-Hashem, Yale
University/VA-CT Hepatitis C Resource Center, New Haven, CT, S.
Wongcharatrawee, Yale University/VA CT- Hepatitis C Resource Center, New Haven,
CT, J. Stratidis, Yale University/VA CT- Hepatitis C Resource Center, New
Haven, CT, G. Garcia-Tsao, Yale University/VA CT- Hepatitis C Resource Center,
West Haven, CT
Screening and testing for HCV is a priority at the VA
Healthcare System with the ultimate goal of increasing the number of HCV
patients who have appropriate information and timely access to medical
evaluation, enabling them to reach a decision regarding antiviral therapy.
Reaching this goal depends on appropriate referral to providers who treat HCV.
Objective:
To determine the rate of referral of HCV patients to the
liver clinic and to determine predictors associated with referral.
Methods:
Retrospective cohort study of HCV-infected veterans
identified in the period between September 1, 2003 and June 30, 2004 using the
local HCV registry that contains data on patients with positive anti-HCV test
or an HCV diagnosis. Prior to this period, several provider-training sessions
regarding appropriate referral to liver clinic took place among local
providers, particularly those from mental health clinics.
Results:
Of 235 patients identified, 34 were excluded because of a
negative confirmatory test (prior to referral). The study comprises 201
HCV-infected patients with a median age of 52 years; 95% were male and 62% were
Caucasian; 83% had a history of substance use and/or mental illness. Only 100
(50%) were referred to the liver clinic. Compared to non-referred patients,
those referred were more likely to have an assigned primary care provider (PCP)
(78% vs. 57%, p=0.002), be referred from a primary care clinic (PCC) (82% vs.
61%, p=0.002), have documented risk factors (89% vs. 62%, p<0.001) and have
abnormal liver tests (LT) (66% vs. 34%, p<0.0001). There were no differences
between groups regarding age, race, type of provider (MD vs. non-MD), and
presence of medical or psychiatric co-morbidities. Independently predictive
determinants of referral (stepwise logistic regression) were referral from PCC
and abnormal LT. Analysis of the subgroup of patients with abnormal LT (n=102)
reveals that only 66 (65%) were referred. Compared to non-referred patients,
those referred were more likely to have an assigned PCP (82% vs. 50%, p=0.001),
be referred from a PCC (82% vs. 56%, p=0.006) and have documented risk factors
(91% vs. 75%, p=0.032). On multivariable analysis, the strongest predictor of
referral of patients with abnormal LT was having an assigned PCP.
Conclusions:
At a VA facility, only half of HCV-infected patients are
referred to liver clinic. The main predictors of referral (both in all HCV
patients and in those with abnormal LT) were related to patient enrollment in
the PCC. Future efforts should be aimed at ensuring enrollment of all veterans
in a primary care clinic and at creating referral electronic reminders for
primary care providers.
Abstract ID: 67446
Category: JO7: HCV:
Treatment
Ribavirin plasma concentration is predictive of sustained virological response in HCV infected patients. A prospective study.
D. Breilh, Hopital Haut
Leveque, Pessac, France, L. Castera, Hopital Haut-Leveque, Pessac, France, P.
Trimoulet, Hopital Pellegrin, Bordeaux, France, J. Foucher, Hopital
haut-Leveque, Pessac, France, S. Djabarouti, Hopital Haut Leveque, Pessac,
France, P. Bernard, Hopital Saint-Andre, Bordeaux, France, J. Bertet, Hopital
Haut Leveque, Pessac, France, P. Couzigou, Hopital Haut Leveque, Pessac,
France, M. Saux, Hopital Haut-Leveque, Pessac, France, V. de Ledinghen, Hopital
Haut-Leveque, Pessac, France
Background & aims:
Combination therapy with pegylated interferon and ribavirin
is the standard treatment for chronic hepatitis C virus (HCV) infection.
However, a relationship between virological response and ribavirin
concentration has been previously reported. The aim of this prospective study
was to define the target ribavirin concentration at week 12 associated with
virological response at week 12, and 6 months after the end of treatment
(sustained virological response, SVR).
Methods:
HCV infected naïve consecutive patients treated with standard
regimen of pegylated interferon and ribavirin (800-1200 mg/day, according to
genotype) were assessed for ribavirin plasma concentration at week 12. Residual
plasma ribavirin concentration (12 hours after the previous dose) was obtained
using a validated high performance liquid chromatography assay. Response at
week 12 was defined as undetectable HCV-RNA or HCV-RNA drop ≥ 2 Log.
Results:
56 patients (19 males, mean age 50 ± 12 years, genotype 1
52%, mean viral load 912000 ± 1260000 UI/l) were included. Response at week 12,
and SVR were observed in 80%, and 67.5% of patients, respectively. Median
ribavirin plasma concentration at week 12 was 3.19 mg/l (range:0.41-7.23).
Responders at week 12 and SVR had significantly higher plasma ribavirin
concentration at week 12 than non responders: 3.29 vs 2.85 mg/l (p=0.005), and
3.47 vs 2.85 mg/l (p=0.023), respectively. A Chi2 step by step analysis
indicated that the threshold of 3 mg/l at week 12 gave the best sensitivity
(65.4%) and specificity (64.3%) for SVR. Using this threshold, ribavirin plasma
concentration at week 12 had positive predictive value of 77% for SVR.
Conclusion.
Patients with SVR had higher ribavirin plasma concentration
at week 12 than non-responders. Three in four patients with a concentration
higher than 3 mg/l at week 12 were SVR. Therefore, early determination during
treatment of plasma ribavirin concentration (with a target concentration of 3
mg/l at week 12) could be useful for monitoring HCV therapy. The impact of
ribavirin dosage optimization, to obtain such a target concentration, on SVR
rates should be further investigated.
Abstract ID: 67955
Category: JO7: HCV:
Treatment
High Frequency of Anemia in HCV-HIV Coinfected Persons Receiving Weight-based Ribavirin and Zidovudine.
K. E. Sherman, University
of Cincinnati College of Medicine, Cincinnati, OH
Among patients with HCV infection, treatment with
Pegylated-Interferon (PEG-IFN) and Ribavirin (RBV) is often associated with
anemia due to a combination of marrow suppression and ribavirin-induced
hemolytic anemia. Anemia may lead to dose reduction and/or use of growth
factors (e.g. epopoietin). Despite a tendency towards anemia among HCV/HIV
coinfected subjects prior to PEG-IFN/RBV administration, previous studies
suggested relatively good tolerability when ribavirin was administered at a
dose of 800 mg/day. There is little data regarding treatment-associated anemia
when weight-based ribavirin dosing is utilized. An unexpected degree of anemia
in ACTG 5178 was observed and further analyses were performed.
METHODS:
ACTG 5178 is a PEG-IFN/RBV treatment trial for subjects with
HCV/HIV coinfection. Inclusion criteria
mandated hemoglobin (HGB) of >11 g/dl for men and >10 g/dl for women. All
patients must have been on stable ART for 8 weeks prior to entry. All subjects
were treated with PEG-IFN alfa 2a 180 mcg q week + ribavirin 1000/1200 mg/day
based upon body weight. Toxicity grade for change in HGB level was determined
according to standard DAIDS/ACTG criteria.
RESULTS:
50 enrolled subjects had baseline and at least one subsequent
on-treatment HGB determination. Following study drug initiation, twelve subjects
(24.5%) had Grade 1 or greater anemia. Of these four reported Grade 2 anemia.
Forty percent of subjects were on ART containing ZDV at entry. Among the 20
subjects actively receiving ZDV, eight (40%) had anemia meeting at least Grade
1 criteria. In contrast, only 4/30 (13.3%) of subjects not on concurrent ZDV
had Grade 1 or greater anemia (P= 0.04). Dose modification of ribavirin was
noted in 13 subjects. The majority (9) cited anemia as the reason for a change
of ribavirin dosing.
CONCLUSION:
Unexpectedly high levels of anemia and ribavirin dose
reduction were observed following initiation of ACTG 5178 compared to other
treatment trials utilizing a lower dose of ribavirin. Data analysis suggests
that concomitant ZDV use is highly associated with a higher frequency of Grade
1 or higher anemia compared to subjects on other drug-containing regimens.
Increased early monitoring of HGB in these patients is recommended.
Abstract ID: 65345
Category: JO7: HCV:
Treatment
Baseline neutralizing responses predict the virological response to pegylated interferon alpha-ribavirin combination therapy.
P. Woerther, Hopital Henri
Mondor, Universite Paris 12, Creteil, France, Y. Morice, Hopital Henri Mondor,
Universite Paris 12, Creteil, France, L. Barbotte, Hopital Henri Mondor,
Universite Paris 12, Creteil, France, F. Montestruc, Roche Laboratories,
Neuilly-sur-Seine, France, D. Lavillette, Ecole Normale Superieure, Lyon,
France, M. Bouvier-Alias, Hopital Henri Mondor, Universite Paris 12, Creteil,
France, J. Bronowicki, Hôpital Brabois, Nancy, France, C. Hezode, Hopital Henri
Mondor, Universite Paris 12, Creteil, France, I. Lonjon-Domanec, Roche
Laboratories, Neuillysur- Seine, France, B. Bartosch, Ecole Normale Superieure,
Lyon, France, F. Cosset, Ecole Normale Superieure, Lyon, France, J. Pawlotsky,
Hopital Henri Mondor, Universite Paris 12, Creteil, France
The mechanisms underlying the success or failure of pegylated
interferon (PegIFN)-ribavirin combination therapy in chronic hepatitis C are
multifactorial, intricate, and poorly understood. Virological and host factors
have been studied, but the role of anti-HCV humoral responses (in particular
the neutralizing response) remains unknown, mainly due to the lack of reliable
assays.
OBJECTIVES:
To determine the relationship between anti-HCV neutralizing
responses and baseline parameters and the virological responses to
pegIFN-ribavirin therapy.
METHODS:
524 patients with genotype 1 chronic hepatitis C were treated
with a combination of PegIFN-alpha 2a (Pegasys, Roche), 180microg qw, and
ribavirin (Copegus,), 0.8 g/d. At week 24 the virological responders(HCV RNA
negative) were randomized into continuing on combination therapy or on pegIFN
alone. Serum neutralizing activity was measured at baseline by means of arecently
developed in vitro neutralization assay based on the use of infectious
retroviral pseudo-particles expressing the folded HCV envelope glycoproteins at
their surface. This assay was optimized for high throughput and intrinsic
performance.
RESULTS:
Results are available for 179 patients (the final results
with the 524 patients will be presented). Neutralizing responses ranged from 0
(no detectable neutralizing response) to 100% (complete neutralization of HCV
pseudoparticles infectivity in vitro by serum). Multivariate analysis showed a
significant relationship between baseline neutralizing responses and the age
(more or less than 44 years, p=0.0352) and the occurrence of a 2 log HCV RNA
decrease at week 2 of therapy (p=0.0018). Both variables interacted, so that
the relationship between baseline neutralizing response and the virological
response at week 2 was stronger in the patients under 44 years of age (less
than 44 years: 70.4% [65.0%-75.8%] in more than 2 log responders vs 85.0%
[79.1%-91.0%] in less than 2 log responders; more than 44 years: 81.6%
[76.9%-86.3%] vs 85.4% [78.9%-91.8%]). The baseline neutralizing response was
also significantly related to the virological response (negative HCV RNA) at
week 24 and to the sustained virological response in univariate analysis, but
both responses were related to the virological response at week 2 which had the
strongest relationship in multivariate analysis.
CONCLUSION:
Baseline neutralizing activity of HCV genotype 1-infected
patients is significantly related to the age and the virological response to
pegIFN-ribavirin therapy. A weaker neutralizing activity is associated with a
more rapid HCV RNA decline and a greater likelihood of a sustained virological
response.
Abstract ID: 63189
Category: JO7: HCV:
Treatment
Expectant management of chronic hepatitis C infection – the patient perspective.
O. S. Khokhar, University
of Illinois College of Medicine - Peoria, Peoria, IL, J. H. Lewis, Georgetown
University Medical Center, Washington, DC
OBJECTIVE:
To assess patient satisfaction and the rationale behind the
informed decision to be treated expectantly for chronic hepatitis C virus (CHC)
infection.
METHODS:
A retrospective open access clinic-based chart review was completed
on all patients with ICD-9 code 070.54 generated from hospital billing
databases. Variables that were recorded included patient demographics, liver
biopsy results, liver imaging results, peak alanine transaminase (ALT) level,
comorbid conditions, source of infection, duration of infection, and rationale
for expectant treatment by patient. A follow-up telephone communication
consisting of a structured questionnaire was made at least one year after
initial consultation was done. Patients were asked about their current health
status, confirmation of expectant management, and awareness of pegylated
interferon.
RESULTS:
A total of 446 patient charts were reviewed. Out of these,
115 (26%) patients made an informed choice for expectant management after consultation.
Sixty-eight patients (59%) were genotype 1A, and 37 (32%) were genotype 1B. The
remaining ten patients were genotype 3A, 3B, 2A, 2B, or 4. The major reasons
for choosing expectant management were: the absence of any symptoms [n=51
(44.3%)]; concerns regarding adverse effects [n=25 (21.7%)]; medical
contraindications [n=23 (20.0%)]; social circumstances interfering with
effective treatment [n=11 (9.6%)]; and doubts regarding efficacy [n=5 (4.3%)].
A total of 75 patients were successfully contacted. Fifty-eight patients (77.3%
[95% CI, 67.8% - 87.8%]) were comfortable with their initial decision and
wished to remain expectantly followed. Eight patients (10.7% [95% CI, 3.7% -
17.7%]) stated that they were moderately satisfied, and six (8.0%) patients
expressed dissatisfaction with their decision. Two patients (2.7%) had since
chosen interferon treatment, while one patient died while awaiting transplant.
CONCLUSIONS:
A significant majority of patients with HCV infection choose
to be followed expectantly. Reasons for this important decision include the
asymptomatic nature of infection, concern of adverse effects and efficacy,
medical contraindications, and social circumstances preventing optimal
treatment. Furthermore, it is noted that the majority of patients remained
satisfied with their initial informed decision to be followed expectantly.
Based on our findings, we recommend that candidates for interferon treatment
continue to be educated regarding efficacy and adverse effects. In addition,
patients with changeable social conditions preventing treatment should be
closely monitored for resolution of those issues and reevaluation.
Abstract ID: 63583
Category: JO7: HCV:
Treatment
Efficacy of Peginterferon alfa-2a (40KD) and Ribavirin in patients with chronic hepatitis C in Germany – a contribution to health care research.
E. Zehnter, Centre of
Gastroenterology Dortmund, Dortmund, Germany, S. Mauss, Centre of
Gastroenterology and Hepatology, Düsseldorf, Germany, C. John , Centre of
Gastroenterology Dr. John, Berlin, Germany, R. Heyne , Centre of
Gastroenterology Dr. Heyne, Berlin, Germany, B. Möller , Centre of
Gastroenterology, Dr. Möller, Berlin, Germany, B. Bokemeyer , Centre of
Gastroenterology, Minden, Minden, Germany, G. Moog , Centre of Gastroenterology,
Kassel, Kassel, Germany, U. Alshuth, Hoffmann-La Roche AG, Germany,
Grenzach-Wyhlen, Germany, D. Hüppe, Centre of Gastroenterology Herne, Herne,
Germany
Introduction
In an effort to measure the quality of treatment of patients
with chronic hepatitis C the Association of German independent
Gastroenterologists (bng) in cooperation with Hoffmann-La Roche, is conducting
a nationwide observational study that consists of documenting screening and
treatment data.
Methods
Between March 2003 and March 2005 data from >8000 patients
has been documented at > 500 centres. A total of 7156 patient screenings
have been completed and 2988 patients (41.8%) have been treated with
peginterferon alfa-2a (40KD) and ribavirin. Results of treatment, compliance
and side effects were recorded.
Results:
Demographic data are available for 2987 treated patients:
mean age 41,5 y, 61.7% male, naive/relapser/unknown 84.3/12 .4/4.5%
respectively, BMI 24.9 kg/m2, mean duration of infection: 11.4y, source of
infection (>1 answer possible): iv drug abuse 44.8%, transfusion 17.8%,
medical action 9.2%, contact to HCV infected person 81.%, tattoo/piercing 4.2%,
accident/injury 1.1% (multiple answers possible) and unknown 22.6%. The distribution of genotypes: GT1 59.6%
(1780), GT2 7.2% (214), GT3 29.8% (889), GT4-6 3.5% (104).
ALT: In 20.4% of the
patients ALT was normal (male max 50 U/l; female max. 35 U/L)
Concomitant diseases were reported in 51.1% of the
patients. Important diseases were abuse of
drugs/alcohol (31.7% of patients with concomitant disease), psychiatric
diseases (17.9%), cardiac diseases (13.2%), diabetes mellitus (7.5%), HIV/HCV
coinfection (7.0%), thrombocytopenia (3.9%) (multiple answers possible).
96% of patients were treated with a combination therapy. As
of March 2005 925/1164 patients with GT1 (79.5%) and 594/634 with GT2/3 (93.7%)
reached an Early Virological Response at week 12 ( EVR = ≥2-log10 drop in
HCV RNA or HCV RNA undetectable).
To date, 76.1% GT-1 (N=547/719) and 95.6% GT2/3 (N=538/563)
have achieved EOT Responses. Complete treatment data are available for 737
patients, who were treated according to consensus recommendations. Sustained
Virological Response (SVR) were achieved by 234/381 GT-1/4/5/6 (61.4%) and 302/357
GT2/3-patients (84.6%). To date 147 GT1/4/5/6
and 55 GT2/3 were nonresponders.
Discontinuations: A total of 443 (14.8%) patients have discontinued therapy:
40.5%, due to virological nonresponse 25.2% for poor tolerability, 13.8% were
lost to follow-up, 9.0% for personal reasons and 9.7% for lack of compliance
multiple answers possible).
The mean duration of absence from work was 11.4 days for
genotype 1/4/5/6-patients and 8.8 days
for genotype 2/3-patients.
Conclusion:
The results of this observational trial show that
peginterferon alfa-2a (40KD) and ribavirin therapy is effective and well
tolerated in patients with chronic hepatitis C in real world clinical practice.
When treated according to current guidelines, patients
achieved results similar to those achieved in controlled clinical trials. This
observational study contributes importantly to health care research of patients
with chronic hepatitis C.
Abstract ID: 64484
Category: JO7: HCV:
Treatment
VIRAL FACTORS INFLUENCE SVR IN PTS WITH HCV-RELATED BRIDGING FIBROSIS BUT NOT CIRRHOSIS.
A. Mangia,
GASTROENTEROLOGY DIVISION IRCCS, San Giovanni Rotondo, Italy, G. Scotto,
Infectious Diseases Division, Foggia, Italy, R. Cozzolongo, Gastroenterology
Division, Castellana Grotte, Italy, D. Bacca, Internal Medicine Division,
Casarano, Italy, N. Minerva, Internal Medicine Division, Canosa, Italy, V.
Carretta, Internal Medicine Division, Venosa, Italy, F. Spirito,
GASTROENTEROLOGY DIVISION IRCCS, San Giovanni Rotondo, Italy, A. Andriulli,
GASTROENTEROLOGY DIVISION IRCCS, San Giovanni Rotondo, Italy
BACKGROUND:
In patients with HCV-related bridging fibrosis or cirrhosis,
combination of RBV and PEG-IFN results in SVR rates which are 10-15% lower than
in those with milder fibrosis. AIM: To investigate whether viral- or disease
related factors, and adherence might account for these reduced rates.
PATIENTS AND METHODS:
Patients with either histologic or clinically apparent
advanced hepatic damage underwent treatment with PEG-IFN α 2a or α 2b
plus RBV (1000-1200 mg /daily) for standard duration depending on genotypes.
Mean age was 57.5 yrs (range 18-70), 67% were males. Genotypes 1 or 4 were
represented in 56% and viremia > 800.000 UI/ml in 60% of cases Platelets
counts, splenomegaly, oesophageal varices, albumin and cholesterol levels, and
prothrombin activity were recorded. Pts with ascites were excluded. Portal
Hypertension. was defined as the occurrence of oesophageal varices and/or
splenomegaly (>12 cm in size). Advanced disease was defined as presence of cirrhosis
with or without PH. Adherence to therapy was evaluated from the number of pts
with dose reduction of antiviral agents, and from the number of those withdrawn
from therapy for side effects .
RESULTS:
250 patients completed so far 24 weeks follow up. SVR was
achieved in 46% of pts overall (49% in F3 and in 44% in cirrhotic pts, P=0.44).
At univariate analysis factors associated with SVR in pts with bridging
fibrosis or cirrhosis are shown in the table. At multivariate analysis only
genotype independently predicted SVR in pts with bridging fibrosis (p= 0.001;
OR 3.9, 95% CI 2.1-7.1), whereas in advanced disease, platelets >110.000
μl (p=0.022, OR 2.4, 95% CI 2.1-5.1) and genotype (p=0.024, OR 2.4, 95% CI
1.1-5.3) were predictive of SVR.
CONCLUSIONS:
In pts with advanced disease high platelets counts and
favourable genotypes are predictors of SVR, whereas signs of portal
hypertension and suboptimal adherence are not.
Bridging fibrosis P value Advanced disease P value
Abstract ID: 64866
Category: JO7: HCV:
Treatment
RANDOMIZED, OPEN LABEL TRIAL COMPARING EFFICACY AND SAFETY OF PEGYLATED INTERFERON ALFA 2A VS ALFA 2B TREATMENT OF PATIENTS WITH CHRONIC HEPATITIS C INFECTED WITH NON 2/3 GENOTYPES – 12 WEEK VIROLOGICAL RESPONSE ANALYSIS.
H. Berak, Hospital of Infectious Diseases, Warsaw, Poland, A. Horban, Hospital of Infectious Diseases, Warsaw, Poland, M. Wasilewski, Hospital of Infectious Diseases, Warsaw, Poland, J. J. Stanczak, Hospital of infectious Diseases, Warsaw, Poland, A. Kolakowska- Rzadzka, Hospital of Infectious Diseases, Warsaw, Poland
Therapeutical efficiency of interferon alfa 2a (Pegasys, 40
KD) versus interferon alfa 2b (Pegintron, 12 KD) both in combination with
ribavirin was analyzed at 12 week of treatment.
PATIENTS:
237 patients (pts) with chronic hepatitis C were
consecutively divided into two groups. The A group (116 pts – 49%) was treated
with interferon alfa 2a; the B group (121 – 51%) with interferon alfa 2b. There
was no statistically significant difference in male/female ratios in both
groups (p>1,0). Genotyping score was similar in both group (101 pts - 87% vs
111 pts - 92% non 2 or 3 genotype, respectively). The highest percentage of patients in both groups were of
staging 1 – 48,2% and 42,6%, followed by staging 2 – 34,5% and 31,3%,
respectively.
METHODS:
Liver biopsies were analyzed according to the Knodell’s and
Scheuer’s scores. Patients’ age and body weight were determined and their
influence on treatment efficiency was analyzed. HCV genotypes were determined
with VERSANT-LIPA HCV II Test (INNOGENETICS); HCV RNA was determined with HCV
RNA ASSAY and viral load (VL) with CA HCV MONITOR TEST (both of ROCHE DIAGN
SYS.). The levels of ALT activity were determined with routine tests. Treatment
efficiency was estimated at 12 week. Early virologic response (ERV) was defined
as decrease of VL >2 log or undetectable HCV RNA.
RESULTS:
During therapy 3 pts from each group were excluded due to
side effects. 4 of them had genotype non 2/3 and they were included into the
group with treatment failure. Efficiency of therapy was analyzed in 208 pts
with genotype other than 2 or 3 – 98 pts in the A group and 110 pts in the B
group. The overall EVR rate was 79,3% (168/212). The EVR rate for the A group
was 85,1% (86/101) and 73,8% (82/111) in the B group. The difference is
statistically significant.
Therapeutical efficacy after 12 weeks of treatment
THERAPEUTICAL EFFICACY TOTAL GROUP A GROUP B
CONCLUSIONS:
Early therapeutical efficiency of interferon alfa 2a is significantly
higher comparing to those observed with interferon alfa 2b.
Abstract ID: 65337
Category: JO7: HCV:
Treatment
Economic evaluation of standard-therapy (ST) for chronic hepatitis C (CHC) with Peginterferon alfa-2a (40KD) (PegIFN 2a) plus Ribavirin versus Peginterferon alfa-2b (12KD) (PegIFN 2b) plus Ribavirin: Ready-to-use syringe (SYR) versus Injector (INJ).
H. D. Janisch,
Internistische Schwerpunktpraxen Erlangen, Erlangen, Germany, D. Hüppe, Centre
of Gastroenterology Herne, Herne, Germany, B. Möller , Centre of
Gastroenterology, Dr. Möller, Berlin, Germany, S. Mauss, Centre of
Gastroenterology and Hepatology, Düsseldorf, Germany, M. Rössle, Centre of
Gastroenterology Freiburg, Freiburg, Germany, S. Pape, Centre of
Gastroenterology Paderborn, Paderborn, S. Christensen, Independent General
Practice CIM, Münster, Germany, P. Hartmann, Centre of Gastroenterology Dr.
Hartmann, Münster, Germany
Background:
PegIFN 2a and PegIFN 2b are approved for therapy of CHC in
Europe. They have different pharmacological properties, which require different
formulations for administration.
Objective:
Evaluate and compare economic and handling aspects of
commercial formulations of PegIFN 2a (SYR) and PegIFN 2b (INJ) in the initial
phase of CHC-ST in routine medical practice in Germany.
Methods:
Patients were allocated to therapy with PegIFN 2a or PegIFN
2b at the investigators discretion. During the first 8 weeks of CHC-ST a
questionnaire was administered to physicians and nurses (at weeks 0, 2, 4, 8),
and to patients (at weeks 2, 4, 8). The questionnaire was concerned with time
required for patient education and drug administration, as well as documenting
difficulties encountered with the two formulations.
Results:
95 patients were recruited. As of May 2005 complete data are
available for 75 patients (37 SYR, 38 INJ). Mean total physician time consumed
in the 8 week study period, including time required for initial patient
education and drug administration (if necessary) plus additional patient
education (if necessary), was 3.9 and 7.8 minutes per patient for SYR and INJ,
respectively. A total of 13.0 and 17.6 minutes of nursing time was consumed by
the use of SYR and INJ, respectively. On the basis of 75 €/h for physician time
and 15 €/h for nursing time, total personnel costs per patient amounted to 8.2
€ for SYR and 14.1 € for INJ, respectively. Problems with self-administration
by patients occurred in 2.8% of SYR vs. 16.0% of INJ applications. The most
frequent problem was related to preparation of the injection. Additional
patient education for self-administration was necessary for 2.7% of SYR
patients vs. 23.7% of INJ patients. From the physicians’ perspective
self-administration led to problems in 14.3% of SYR applications and 45.8% of
INJ applications. Self-administration of SYR was considered to be user friendly
by 91.8% of patients, and of INJ by 71.3% of patients.
Conclusion:
In the initial phase of ST for CHC in routine medical
practice, therapy with PegIFN 2a using SYR is less time consuming and less cost
intensive with respect to handling than PegIFN 2b using INJ. The use of SYR is
associated with less handling problems than INJ, and self-administration of SYR
was judged to be more user friendly by the majority of physicians and patients.
Abstract ID: 65628
Category: JO7: HCV:
Treatment
Peripheral insulin resistance during the treatment of chronic C hepatitis with pegylated interferon plus ribavirin.
V. B. Mello, Federal
University of Bahia, Salvador, Brazil, R. Parana, Federal university of Bahia,
Salvador, Brazil, M. Simões, Federal University of Bahia, Salvador, Brazil, G.
R. Nuñez, Federal University of Bahia, Salvador, Brazil, T. R. Cruz, Federal
university of Bahia, Salvador, Brazil, N. Fabrizio, Federal university of
Bahia, Salvador, Brazil, M. Cruz, Federal university of Bahia, Salvador, Brazil
Patients with hepatitis C vírus (HCV) infection have a
highaer risk of developing type 2 diabetes mellitus. However, the mechanism of
this association and the role of antiviral treatment are still unclear. Our
study aimed to investigate the relationship between the use of peguilated
interferon and the development of insulin resistance on these patients.
Methods:
HOMA (homeostasis model assessment) was performed in 30 HCV-infected
patients just before and during the first 6 months of treatment with peguilated
interferon plus ribavirin. Antropometric parameters and glucose/cholesterol
profile were also monitored.
Results:
There was no change in HOMA after 6 months of treatment.
Glucose levels decreased but not significantly (p=0.059). Patients with higher
HOMA index after 6 months of treatment also had higher aminotransferases levels
(p=0.03), higher fat index on computed tomography (p=0.011), longer time of
exposure to the virus (p=0.021), and a positive smoking history when compared
to non-insulin resistant patients (p=0.045). There was no influence of fibrosis
stage on liver biopsy in the insulin resistance development, even though
insulin resistant patients had a greater necro-inflamatory index (p=0.02).
Conclusions:
There was no change in insulin resistance after six months of
treatment. Insulin resistence is related to abdominal fat and antropometric
parameters rather than antiviral treatment.
Abstract ID: 65944
Category: JO7: HCV:
Treatment
Week 4 Virological Response with Peginterferon Alfa-2a (40KD) (PEGASYS®) Plus Ribavirin (RBV, COPEGUS®) Portends a Sustained Virological Response (SVR) After 24 Weeks in Genotype 1 Chronic Hepatitis C Patients with Persistently ‘Normal’ ALT Activity.
N. Gitlin, Emory
University School of Medicine, Atlanta, GA, M. Manns, Medizinische Hochschule
Hannover, Hannover, Germany, K. Sherman, Univ. of Cincinnati College of
Medicine, Cincinnati, OH, T. Berg, Humboldt-Universitat zu Berlin Med Klinik,
Berlin, Germany, P. Pockros, The Scripps Clinic, La Jolla, CA, C. Hézode,
Hôpital Henri Mondor, Créteil, France, S. Roberts, The Alfred Hospital,
Melbourne, Australia, S. Zeuzem, Saarland University Hospital, Homburg, Germany
Introducation
SVR rates in HCV genotype 1 patients with persistently
‘normal’ ALT activity were significantly higher after 48 than 24 wks of
treatment with peginterferon alfa-2a (40KD) (PEGASYS®) plus RBV (COPEGUS®) (40%
vs 13%, p<0.001; Zeuzem et al. Gastroenterology 2004). We evaluated whether
a rapid virological response (RVR) at week 4, defined as undetectable HCV RNA
(<50 IU/mL) portended an SVR in patients treated for 24 wks in this study.
Methods
Treatment-naïve patients with persistently ‘normal’ ALT
activity and quantifiable HCV RNA (>600 IU/mL) were randomized to 24 or 48
wks of treatment with peginterferon alfa-2a (40KD) 180 μg/wk + RBV 800
mg/d (the trial was initiated before the optimal regimen for genotype 1 was
known: 48wks with an RBV dose of 1000/1200 mg/d). Multiple logistic regression
(MLR) was used to identify baseline factors (sex, age, weight, HCV RNA level,
ALT, histological diagnosis, fibrosis score and region) predictive of an SVR in
patients treated for 24 wks.
Results
144 genotype 1 patients were randomized to 24 wks of
treatment, 140 had a wk 4 virological test result and 130 completed therapy.
Patients with an RVR had higher end of-treatment (EOT) virological response and
SVR rates (table) and lower relapse rates between EOT and end of follow-up (25
vs 93%) than those without an RVR. MLR analysis revealed baseline HCV RNA level
to be the only significant predictor of SVR in patients treated for 24 wks.
Those with baseline HCV RNA ≤ 200,000 IU/mL (n=21) were significantly
more likely to achieve an SVR than those with serum HCV RNA >200,000 IU/mL
(n=123) [odds ratio (OR) 4.6; 95%CI 1.6-13.7, p=0.0057]. When the week 4 test
result was included in the model, only SVR was a significant predictor of SVR
[OR 39.2; 95%CI 10.9-144.8; p<.0001).
Conclusion
- The
proportion of genotype 1 patients who achieved an RVR with peginterferon
alfa-2a (40KD) (PEGASYS) plus ribavirin (COPEGUS) was similar, regardless
of ALT activity, in multinational, randomized, phase III trials. Overall, 39/276 patients (14%) with persistently
‘normal’ ALT and 181/1024 patients (18%) with elevated ALT achieved an
RVR.
- An
RVR at week 4 is highly significant predictor of an SVR after 24 weeks’
treatment.
- Nearly
three quarters (12/17 (71%)) of genotype 1 patients with an RVR achieved an
SVR after 24 weeks with peginterferon alfa-2a (40KD) plus ribavirin
therapy.
- Low
baseline RNA was a significant predictor of SVR in genotype 1 patients
treated for 24 weeks with peginterferon alfa -2a (40KD) plus
ribavirin. However, the week 4 test
result was included in the analysis, RVR was the only significant
predictive factor for an SVR.
- Although
virological relapse rates were higher in patients treated for 24 or 48
weeks without an RVR, relapse rates were lower in patients treated for 48
versus 24 weeks. As such, further
study is required before this criterion can be used as a guide to
treatment duration in patients with HCV genotype 1 and persistently
‘normal’ levels.
Abstract ID: 66069
Category: JO7: HCV:
Treatment
Specific mechanisms of HCV-3 on hypocholesterolemia. Long-term effect of sustained virological response.
C. M. Fernandez-Rodriguez, Fundacion Hospital Alcorcon, Madrid, P. Lopez
Serrano, Fundacion Hospital Alcorcon, Madrid, Spain, M. Gutierrez Garcia,
Fundacion Hospital Alcorcon, Madrid, Spain, J. Lledó Navarro, Fundacion
Hospital Alcorcon, Madrid, Spain, M. Nevado, Fundacion Hospital Alcorcon,
Madrid, Spain
Background:
Genotype-3 of hepatitis-C virus has been associated with
hypocholesterolemia and liver steatosis. Reversal of these changes in patients
with sustained virological response (SVR) has been reported. Yet, the long-term
effect of this response is not known.
Objectives and methods:
To define baseline differences of serum cholesterol, its
relationship with liver steatosis in patients infected with genotype 3 and in
those infected with genotype 1 and its long-term time-course with treatment. A
cohort of 215 patients with chronic hepatitis C referred to our unit was
studied (genotype 1, n: 158; genotype 2, n: 4; genotypes 4 and 5, n: 12 and
genotype 3, n: 41) and 25 patients with chronic hepatitis B. Covariates were
age, body mass index (BMI), gender, alcohol intake, serum lipids, glycaemia,
serum ALT, AST, GGT, grade and stage (metavir and scheuer), degree of liver
steatosis and SVR.
Results:
Patients infected by genotype 3 had age-adjusted
hypocholesterolemia and more frequent hepatic steatosis (p<0.001). Steatosis
inversely correlated with serum cholesterol (p<0.01). In patients with
genotype-3 and SVR, serum cholesterol raised from 140 mg/dl (CI 120-151) to 185
mg/dl (CI 171-199) twelve months after the end of treatment (p: 0.0001). By
contrast, serum cholesterol did not change in non-responders with genotype-3 or
in patients with genotype 1 regardless of virological response. Once excluded
patients with genotype-3, there were not differences regarding serum
cholesterol between patients with HCV and those with HBV.
Conclusions:
Besides causing hepatic steatosis, genotype-3 specifically
decreases serum cholesterol. This interference with the metabolic lipid pathway
reverses with SVR and it is sustained on a long-term basis.
Abstract ID: 66208
Category: JO7: HCV:
Treatment
Persistence with Hepatitis C Therapy in African Americans and Patients with Depression in the Department of Veterans Affairs (VA).
F. Cunningham, Hines VA
Hospital, Hines, IL, A. Lee, Boston University School of Public Health, Boston,
MA, S. Usman Iqbal, Boston University School of Public Health, Boston, MA, D.
R. Miller, Boston University School of Public Health, Boston, MA, A. W. Law,
Roche Laboratories, Nutley, NJ, L. Kazis, Boston University School of Public
Health, Boston, MA
Introduction
Certain populations infected with Hepatitis C virus (HCV)
have been reported to have a decreased
response to treatment. The African American (AA) population and those patients
suffering from depression have been identified as two groups with a lower response
to Hepatitis C treatment.
The specific reasons for a decrease in response have not been
clearly identified. Moreover, persistence with prescribed HCV therapy has not
been adequately studied in these populations. The goal of this study is to
evaluate persistence in the AA and depressed patients undergoing treatment for
HCV in the Department of Veterans Affairs.
Objective
To evaluate and compare treatment persistence in African
American patients infected with HCV who received combination therapy with
either peginterferon alfa-2a with ribavirin (peg-INF alpha–2a/Rib) or
peginterferon alfa-2b with ribavirin (peg-INF alpha-2b/Rib)
To evaluate and compare treatment persistence in patients
diagnosed with depression infected with HCV who received combination therapy
with either peginterferon alfa-2a with ribavirin (peg-INF alpha–2a/Rib) or
peginterferon alfa-2b with ribavirin (peg-INF alpha-2b/Rib)
Study Design
A retrospective inception cohort claims analysis on treatment
naïve patients diagnosed with HCV.
Data Sources
The pharmacy databases (PBM v 3.0), the National Patient
Files, and the Beneficiary Identification and Record Location (BIRLS) files of
the Department of Veterans Affairs (VA) were utilized for the study.
Study Period
The study population included patients who had a diagnosis
for hepatitis C virus between October 1, 2002 and September 30, 2004 (Fiscal
Years 2003 - 2004) and a prescription for combination peginterferon (peg-IFN
alpha-2a/Rib, PEG-IFN alpha-2b/Rib) during the same time period. The index date
was defined as the date of the first claim of the specified drugs. The period
of October 2000 to September 2002 (or 24 months prior to receiving treatment)
was used to assess patients for comorbid conditions listed under the exclusion
criteria.
Defining Variables
Persistence: A patient with a no-fill period of
more than 60 days after a prescription of the study drugs was termed as
discontinued. Persistence time was defined as the period from the date of first
prescription to the date of discontinuation for the therapy initially
prescribed.
Data Management and
Analyses Plan:
Patient demographics were abstracted and analyzed from the VA
administrative databases. Persistence rates were calculated for each of the two
treatment groups using the Kaplan-Meier method.
Likelihood ratio test of equality between the two treatment groups was
performed to detect any differences in persistence rates. Key variables for
stratification included (1) race - white and African American and, (2) those
diagnosed with depression.
Inclusion criteria
· Male and female
veterans > 18 years of age
· At least one pharmacy
claim for a 30-day supply of peginterferon alfa-2a, peginterferon alfa-2a/Rib,
peginterferon alfa-2b, or peginterferon alfa-2b/Rib
· An inpatient discharge
diagnosis or at least 1 outpatient diagnosis for HCV in the 12 months prior to
the index date.
· Treatment-naïve as
defined by no HCV treatment in the 12 months prior to the index date.
· At least one clinic
visit or inpatient diagnosis in the subsequent twelve months following the index
date to assure contact with the VA system.
Exclusion Criteria
· Presence of ICD-9 codes
for any of the following comorbidities during the 24 months prior to the index
date: HIV, Hepatitis B, Thrombocytopenia, Neutropenia, Anemia, Hemorrhage or
active bleeding, Chronic renal failure, Bone marrow disorder, Cancer.
· Patients with pharmacy
claim(s) for a 60-day or 90-day supply of peginterferon alfa-2a, peginterferon
alfa-2a/Rib, peginterferon alfa-2b, or peginterferon alfa-2b/Rib
Results
The study sample consisted of 816 (27%) AA patients and 1,984
(35%) patients with a history of depression.
Persistence with peginterferon alfa-2a/Rib was not significantly
different (p=0.28) between AA and whites. The median duration of therapy was
5.3 months for whites vs. 4.7 months for blacks in the peginterferon
alphs-2a/Rib group. Persistence was
significantly lower in AA compared to whites in the peginterferon alfa-2b/Rib
group (p=0.0063). The median duration of therapy was 4.6 months for whites vs.
3.6 months for AA in the peginterferon alpha-2b/Rib group. There was no
difference in persistence with either therapy
CONCLUSION
· There was no difference
in treatment in duration of therapy or persistence between AA and whites in the
pegylated interferon alfa-2A/Rib treatment group.
· The mean duration of
therapy and persistence for pegylated interferon alfa-2B/Rib was significantly
lower in the AA population compared to whites.
· Further study is needed
to determine if the differential persistence that exists between the two
therapeutic groups is reflected in the response to treatment.
Abstract ID: 66238
Category: JO7: HCV:
Treatment
Directly Observed Therapy (DOT) for the Treatment of Hepatitis C Virus (HCV) Infection in Injection Drug Users (IDUs) – An Interim Analysis.
J. Grebely, University of
British Columbia, Vancouver, Canada, F. Duncan , Pender Community Health
Centre, Vancouver, Canada, M. Viljoen, Pender Community Health Centre,
Vancouver, Canada, C. Meagher, Coolaid Community Health Centre, Victoria,
Canada, M. Khara, Pender Community Health Centre, Vancouver, Canada, J. Raffa,
University of British Columbia, Vancouver, Canada, K. Genoway, University of
British Columbia, Vancouver, Canada, C. Fraser, Coolaid Community Health Centre,
Victoria, Canada, S. deVlaming, Pender Community Health Centre, Vancouver,
Canada, B. Conway, University of British Columbia, Vancouver, Canada
Objective:
To document the safety and efficacy of treatment of HCV
infection in IDUs who qualify for such treatment according to current clinical
guidelines.
Methods:
HCV-infected IDUs attending our clinics who were viremic,
non-cirrhotic, with ALT levels >1.5x ULN and in whom there was a reasonable
expectation of adherence to therapy were offered 24-48 weeks (based on HCV
genotype) of combination therapy with ribavirin (RBV, 800-1200 mg/day, based on
weight) along with interferon-a2b (IFN--a2b, 1.5 mg/kg thrice-weekly) replaced
by PEG- interferon-a2b (PEG-IFN-a2b, 1.5 mg/kg once weekly) as it became available.
Staff administered all injections under direct observation. A physician
evaluated patients weekly, with appropriate interventions for side effects or
toxicity. For this interim analysis, success was defined as an end-of-treatment
response (ETR) with normal ALT levels.
Results:
In total, 34 patients (28 males) received therapy
· Standard interferon
-IFN-a2b (12 patients) -6 patients (genotype 1); 2 patients (genotype 2), 3
patients genotype 3 and 1 patient with mixed genotypes (2 and 3).
· Peginterferon alfa 2b –
10 patients (genotype 1); 2 patients (genotype 2) and 10 patients (genotype 3).
The mean baseline age, body weight, ALT and duration of
infection were 43 years, 83 kg, 138 U/L and 12 years, and 13/34 (38%) reported
illicit drug use in the past 6 months, 71% (24/34) reported previous anxiety or
depression. Only 7 patients did not complete therapy, 3 due to toxicity
(tinnitus, neutropenia, depression) and 4 due to nonadherence. Overall ETR was
65% (22/34), 78% (14/18) in subjects with genotype 2/3 infection. All 15
patients receiving the entire course of PEG-IFN-based therapy achieved an ETR,
as did 58% (7/12) who experienced an addiction relapse on treatment.
Discussion
·
The overall ETR in IDUs receiving
IFN-based therapy with ribavirin was 65% by ITT, 92% OT.
·
This was achieved in a population
including 47% infected with genotype 1, 71% with a history of
anxiety/depression and 35% with a relapse of drug use on therapy.
·
Drug use prior to and during HCV treatment
did not reduce its overall efficacy.
·
5/7 premature treatment
discontinuations were due to drug use relapse or depression.
·
The expansion of DOT programs for
the treatment of HCV infection in a multi-disciplinary care clinics may provide
us with an effective means of addressing the HCV epidemic in our inners cities.
·
Further studies are needed to
evaluate sustained virologic response rates and the incidence of re-infection
after treatment in inviduals with continued high-risk behaviour for HCV acquisition.
Abstract ID: 66695
Category: JO7: HCV:
Treatment
Early Viral Response to Consensus Interferon plus Ribavirin Therapy in Patients who are Nonresponders or Relapsers to Prior PEG IFN plus Ribavirin Therapy.
R. Ghalib, Liver Institute
at Methodist Dallas, Dallas, TX, C. D. Levine, Liver Institute at Methodist
Dallas, Dallas, TX, M. Mouti, Liver Institute at Methodist Dallas, Dallas, TX,
J. Weinstein, Liver Institute at Methodist Dallas, Dallas, TX, A. Schwartz,
Liver Institute at Methodist Dallas, Dallas, TX, S. Cheng, Liver Institute at
Methodist Dallas, Dallas, TX
Purpose:
To describe the early viral response to consensus interferon
(CIFN) plus ribavirin combination therapy in patients who were nonresponders or
relapsers to prior therapy with PEG IFN plus ribavirin therapy for chronic
hepatitis C (HCV).
Methods:
This is an interim analysis of the first 12 weeks of
retreatment in patients who failed prior therapy. Patients were started on CIFN
15 mcg daily plus weight based ribavirin therapy. HCV RNA was monitored at week
4, and every 3 months. Growth factors were allowed.
Results:
Sample included 45 patients with 27 (60%) prior nonresponders
and 18 (40%) prior relapsers. Nonresponders had an age range of 35-56 years
(mean 49.8 ± 4.2); 17 (63%) males and 10 (37%) females; genotype 1 in 93% and 2
in 7%; race with 15 (56%) White, Black 9 (33%), and 3 (11%) other; biopsy stage
1-2 in 10 (37%) and 3-4 in 17 (63%). Relapsers had an age range of 40-60 years
(mean 49.5 ± 6.0); genotype 1 in 12 (67%), 2/3 in 4 (22%) and 4 in 29 (11%);
race with 12 (67%) White, Black 0 (0%), and 6 (33%) other; biopsy stage 1-2 in
5 (28%) and 3-4 in 13 (72%). Patients currently at ≥12 weeks of treatment
in 22 (81%) of nonresponders and 13 (72%) of relapsers. Discontinuations between
week 4-12 for adverse events have occurred in 2 (7%) nonresponders and 1 (6%)
relapsers. HCV RNA response at 4 weeks in nonresponders vs. relapsers was
undetectable virus in 2 (7%) vs 6 (33%); ≥2 log decrease in 8 (30%) vs 14
(78%); 1 log decrease in 12 (44%) vs. 2 (11%); and <1 log decrease in 3
(11%) vs 1 (6%) with no data in 4 (15%) vs. 1 (6%), respectively. HCV RNA
response at 12 weeks in nonresponders vs. relapsers was undetectable virus in 5
(23%) vs. 9 (69%); ≥2 log decrease in 17 (77%) vs. 13 (100%); and £1 log
decrease in 5 (23%) vs. 0, respectively. Logistic regression for a ³2 log
decrease in HCV RNA at week 4 identified prior response type and genotype as
significant variables (-2 log likelihood 37.0; model Chisquare 16.8, df=2,
p<.001).
Conclusions:
In nonresponders and relapsers to prior PEG IFN plus
ribavirin therapy, the early virologic response rates (³2 log decrease) with
CIFN 15 mcg daily plus weight based ribavirin therapy are 77% and 100%,
respectively. Further investigation of predictive factors of sustained viral
response is needed in the nonresponder and relapser population to guide
selection of appropriate treatment candidates and therapies.
Abstract ID: 66875
Category: JO7: HCV:
Treatment
Influence of Apolipoprotein E genotype on virologic response in HCV type 1-infected patients treated With Peg-IFNa plus Ribavirin
V. Weich, Charité, Campus
Virchow, Berlin, Berlin, Germany, G. Teuber, Klinikum der Johann-W.-Goethe-
Universität, Frankfurt, Germany, C. Sarrazin, Universitätsklinikum des
Saarlandes, Homburg, Germany, H. Klinker, Klinikum der Universität Würzburg,
Würzburg, Germany, P. Buggisch, Universitätsklinik Eppendorf, Hamburg, Germany,
E. Schott, Charité,Campus Virchow, Berlin, Germany, A. Bergk, Charité,Campus
Virchow, Berlin, Germany, H. Witt, Charité, Campus Virchow, Berlin, Germany, T.
Berg, Charité, Campus Virchow, Berlin, Germany
Background:
Lipoproteins have been reported to be involved in the infection
cycle of hepatitis C virus. A protective role of the apolipoprotein E4 (ApoE4)
allele regarding the development of severe liver fibrosis was recently
described in HCV-infected patients. Furthermore, reduced sustained response
rates (SVR) after standard interferon alpha (IFNa) plus ribavirin combination
therapy were found in HCV type 1-infected carriers of the Apo-E4 allele. The
aim of the present study was to assess whether carriage of an Apo-E4 allele
influences viral dynamics as well as SVR rates in a homogeneous group of HCV
type 1-infected patients treated with pegylated IFNa plus ribavirin.
Patients and Methods:
295 treatment-naive patients with histologic proven chronic
HCV type 1 infection (56% male, mean age 44 years) were analyzed. All patients
received 1.5 μg/kg Peg-IFNa-2b plus 800-1400 mg ribavirin/day (according
to body weight). HCV RNA was measured quantitatively and qualitatively at
treatment week 1, 4, 8 ,12, 24 and 48 as well as 24 weeks after stopping
therapy. The Apo-E polymorphism was determined by PCR amplification and melting
curve analysis with FRET probes.
Results:
Neither early viral decline nor the frequency of a complete
virologic on-reatmentresponse (HCV RNA negative by qualitative PCR) at week 4,
12 and 48 were significantly different between carriers or non-carriers of the
Apo-E4 allele (31% vs. 30%, 78% vs. 67%, 75% vs. 72%). A sustained virologic
response (SVR) was achieved in 61% of the Apo-E4 allele positive patients as
compared to 52% of those patients not having an Apo-E4 allele (p=0.4). No
single Apo-E genotype (E2/2, E2/3, E2/4, E3/3, E3/4, E4/4) could be associated
with the dynamics of HCV RNA decline or SVR rates.
Conclusion:
Virologic response rates after combination therapy with
Peg-IFNa-2b plus ribavirin are not influenced by the Apo-E genotype. The
previously postulated disadvantage of treatment response in Apo-E4-allele
carriers after standard combination therapy could not be confirmed. The more
effective antiviral regimen given to our patients (i.e. Peg-IFNa plus
ribavirin) may have overcome the unfavourable genetic background and might be
an explanation for this discrepancy.
This work was supported in part by viRgil Network of
Excellence and Hep-Net-Network
of Competence for Hepatitis.
Abstract ID: 67076
Category: JO7: HCV:
Treatment
Clustering of Poor Prognostic Factors in Heavier Patients with Chronic Hepatitis C (CHC): Baseline Characteristics and Outcomes With Peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin (RBV, COPEGUS®) in Randomized, International, Phase III Trials.
M. G. Swain, University of
Calgary, Calgary, Canada, G. Foster, Queen Mary College, The Royal London
Hospital, London, United Kingdom (Great Britain), S. Hadziyannis, Henry Dunant
Hospital, Athens, Greece, J. Heathcote, University of Toronto, Toronto Western
Hospital, Toronto, Canada, D. Jensen , Rush University Medical Center, Chicago,
IL, S. Lee, Liver Unit, University of Calgary, Calgary, Canada, P. Pockros, The
Scripps Clinic, La Jolla, CA, M. Sulkowski, Johns Hopkins University,
Baltimore, MD, C. TREPO, HOTEL DIEU Hospital, Lyon, France
Sustained virological response (SVR) rates tend to decrease
as body weight increases. This is apparent in a retrospective subanalysis of a
Phase III trial of pegylated interferon alfa-2b (12KD)/RBV where the overall
SVR of 54% increased to 61% when patients who weighed ≥75.5kg were
excluded (Manns et al. 2001). Therefore, in this study, we assessed the complex
relationship between body weight and baseline factors in patients enrolled in
two phase III randomized international studies, and between weight and outcomes
in patients treated with peginterferon alfa-2a (40KD) (PEGASYS®) plus RBV
(COPEGUS®).
Methods:
Data from the two studies were combined (NEJM. 2002;347:975;
Ann Intern Med 2004;140:346). Patients were classified by weight (≤75.5
or >75.5kg) and baseline characteristics of all patients were compared.
Outcomes by weight in patients who were treated for 48 wk with peginterferon
alfa-2a (40KD) plus RBV 1000/1200 mg/d in the two trials were also compared.
Results(table):
At baseline, significantly more patients in the >75.5 kg
group were male, black, had cirrhosis, HCV genotype 1 infection or had acquired
HCV through intravenous drug use (IVDU). Heavier patients also had
significantly higher HCV RNA levels. Overall, SVR rates were significantly
higher in the lighter patients with a body weight of ≤ 75.5 kg vs. >
75.5 kg (Odds ratio 1.87, 95%CI,
1.42-2.45). Similarly, the SVR rate in patients infected with HCV genotype 1
was significantly higher in lighter than heavier patients (or 1.99; 95% CI
1.42-2.80; p=0.00006. The incidence of
serious adverse events (SAEs) was higher in the lighter patients, although
there was generally no difference in withdrawal rates for AEs.
Conclusions:
· Bodyweight has a
complex relationship with a range of baseline characteristics and treatment
outcomes in patients with chronic hepatitis C.
· At baseline, patients
with a heavier bodyweight (>75.5 kg) were significantly more likely to have a
histological diagnosis of cirrhosis, be
infected with HCV genotype 1 and have higher HCV RNA levels than lighter
patients (≤ 75.5 kg). In addition,
heavier patients were more likely than lighter patients to be male, older and
black.
· SVR rates with peginterferon
alfa-2a (40KD) (Pegasys) plus ribavirin (Copegus) 1000/1200 mg/day for 48 weeks
were higher in patients with bodyweight of ≤ 75.5 kg vs. > 75.5 kg.
· In patients weighing ≤
75.5 kg, the SVR rate was 67% overall and 59% in patients with genotype 1 infection. This was compared with 52% and 41%,
respectively, in patients weighing > 75.5 kg.
· The clustering of poor
prognostic factors in heavier patients may explain, in part, the lower SVR
rates observed in these patients with all interferon-based treatments.
Abstract ID: 62002
Category: JO7: HCV:
Treatment
Mutations in the HCV-p7 protein and sensitivity to antiviral therapy with amantadine in chronic hepatitis C.
U. Mihm, Klinik für Innere Medizin II, Universitätsklinikum des Saarlandes,
Homburg/Saar, Germany, N. Grigorian, Klinik für Innere Medizin II,
Universitätsklinikum des Saarlandes, Homburg/Saar, Germany, C. Welsch, Klinik
für Innere Medizin II, Universitätsklinikum des Saarlandes, Homburg/Saar,
Germany, E. Herrmann, Fachbereich Mathematik, Technische Universität Darmstadt,
Darmstadt, Germany, B. Kronenberger,
Klinik für Innere Medizin II, Universitätsklinikum des Saarlandes,
Homburg/Saar, Germany, G. Teuber, Medizinische Klinik I, Klinikum der Johann
Wolfgang Goethe-Universität, Frankfurt, Germany, M. von Wagner, Klinik für
Innere Medizin II, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany,
W. P. Hofmann, Klinik für Innere Medizin II, Universitätsklinikum des
Saarlandes, Homburg/Saar, Germany, M. Albrecht, Max-Planck Institut für Informatik,
Saarbrücken, Germany, T. Lengauer, Max-Planck Institut für Informatik,
Saarbrücken, Germany, S. Zeuzem, Klinik für Innere Medizin II,
Universitätsklinikum des Saarlandes, Homburg/Saar, Germany, C. Sarrazin, Klinik
für Innere Medizin II, Universitätsklinikum des Saarlandes, Homburg/Saar,
Germany
Introduction:
Formation of transmembrane ion channels by HCV-p7 and
abrogation of channel function by amantadine was demonstrated in vitro. The
clinical relevance of mutations in the HCV-p7 protein for response to antiviral
therapies with and without amantadine is unknown.
Patients and Methods:
HCV-p7 was sequenced in 67 patients with chronic hepatitis C
genotype 1 infection. Thirty-six (HCV-1a: n=12, HCV-1b: n=24) of 67 patients
received amantadine in addition to an interferon-alfa-based therapy. Helical
wheel modeling for HCV-p7 was performed by in silico analyses.
Results:
In patients with HCV-1b infection (n=42) a higher number of
nonconserved mutations within the complete p7 protein and the transmembrane
helix 2 as well as amino acid substitution L44F were associated with
nonresponse to interferon based therapy independent of administration of
amantadine (p<0.05). In patients with HCV-1b infection and combination
therapy with amantadine amino acid substitution L20F was observed more
frequently in virologic nonresponders compared with end-of treatment and
sustained responders (5/9 vs. 3/15; p=0.099). By in silico modeling amino
acid position 20 was located towards the p7 channel lumen and
mutation L20F might impair amantadine interaction due to changes in size and
shape of the p7 ion channel pore. In patients with HCV-1a infection (n=25) no
significant correlation of p7 mutations with treatment response or amantadine
was found.
Conclusion:
In patients with HCV-1b infection, a higher number of amino
acid mutations within HCV-p7 was associated with virologic nonresponse to
interferon-alfa based therapy. Impaired antiviral activity of amantadine in
patients with HCV-1b infection may be associated with substitution L20F in
HCV-p7 helix 1.
Abstract ID: 64030
Category: JO7: HCV:
Treatment
Predictive factors for histological response to long-term phlebotomy in patients with chronic hepatitis C.
M. Sartori, Azienda
Ospedaliera Maggiore della Carita', Novara, Italy, S. Andorno, Azienda
Ospedaliera Maggiore della Carita', Novara, Italy, S. Colombi, Azienda
Ospedaliera Maggiore della Carita', Novara, Italy, C. Rigamonti, IRCCS Maggiore
Hospital Milan, Gastroenterology Dept., Milan, Italy, R. Boldorini, Department of
Medical Sciences. University of East Piedmont, Novara, Italy, G. B. Contessi,
Hepatology Unit, A.O. Spedali Civili, Brescia, Italy, A. Rossini, Hepatology
Unit, A.O. Spedali Civili, Brescia, Italy
Introduction:
Mild hepatic iron overload is common in patients with chronic
hepatitis C (CHC) and may contribute to liver disease progression. Iron
depletion reduces serum aminotransferase levels in most subjects with CHC and
might improve liver histology in several patients. Our aim was to identify
predictive factors for histological response (HR) to phlebotomy in CHC.
Methods:
Twenty-eight patients with CHC, 15 unsuitable for and 13 non
responder to antiviral therapy (21 men, mean age 57±7 years), underwent iron
depletion (achieving serum ferritin (SF) level < 35 μg/L by 200-450 mL
phlebotomy every two weeks, then maintaining SF level < 70 μg/L by
phlebotomy every 2-4 months). All patients underwent liver biopsy before iron
depletion and after a period of 48±16 months. HR was defined, by two
independent pathologists, as a one point reduction of staging score or, in case
of unchanged staging score, as a two point reduction of grading score
(Knodell). Pre-treatment factors putatively predictive for HR (age, sex, previous
antiviral therapy, serum HCV-RNA level, HCV genotype, aspartate
aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl
transferase (GGT), serum iron, SF, hepatic iron concentration (HIC), stainable
liver iron, grading and staging scores) were evaluated by univariate and
multivariate logistic analysis.
Results:
12/28 patients (43%) achieved HR, as previously defined (5
achieved both staging and grading score reduction). No woman was histological
responder. In an univariate logistic analysis male sex, high pre-treatment
histological grading (P=0.01) and HIC (P=0.04) predicted HR to phlebotomy. In a
multivariate logistic analysis on male patients (females dropped due to
estimability) only pre-treatment HIC (P=0.03; 95% CI=1.001-1.01) predicted HR.
In fact, 12/17 men (71%) with HIC >= 1000 μg/g achieved HR, whereas 4/4
with HIC <1000 μg/g were not responder. HIC decreased in all patients
after phlebotomy (1299±387 vs 447±313 μg/g; P<0.001). Furthermore,
serum ALT decreased in all patients at the end of treatment (130±57 vs 70±39
U/L; P<0.001), AST in 27/28 patients (108±58 vs 64±45 U/L; P<0.001) and
GGT in 22/28 patients (86±59 vs 56±56 U/L ; P=0.004). Finally, 7/28 patients
(25%) achieved persistently normal aminotransferase levels during and at the
end of phlebotomy. No side effects related to moderate iron depletion were
reported.
Conclusions:
Male patients with CHC and HIC >= 1000 μg/g (17,91
μmol/g) are likely to achieve hepatic histological improvement by
long-term phlebotomy. Therefore, iron depletion may be useful in such patients
with CHC in whom antiviral therapy is contraindicated or proved to be
ineffective.
Abstract ID: 64508
Category: JO7: HCV:
Treatment
A significant association of the substitution in position 2209 of NS5A of hepatitis C virus 1b infection and the response to standard, consensus, or pegylated interferon plus ribavirin therapy.
H. Moriguchi, The
University of Tokyo, Tokyo, Japan, T. Uemura, Keio University, Tokyo, Japan, C.
Sato, Tokyo Medical and Dental University, Tokyo, Japan
Background:
The sustained virologic response (SVR) rate in patients with
genotype HCV 1a/b isolates is insufficient (40 -50%) even with standard,
consensus, or pegylated interferon plus ribavirin therapy (combination therapy).
Furthemore, determinants for SVR or non -|response in the combination therapy
for individual patients have not fully been understood despite extensive
investigations with DNA microarray analyses.
Methods:
By using the PubMed data base from 1966 to May 2005, we
analyzed the association between mutations in the nonstructural protein 5A gene
(NS5A gene) and SVR to the combination therapy in the patients with HCV |1b
infection (n=315). We analyzed the data by Spearman -fs rank correlation test
and Mann-|Whitney-fs U test in the univariate analysis. Furthermore, a multiple
logistic regression analysis was used to examine the influence of several
factors on viral response.
Results:
In the univariate analysis, there was a significant positive
correlation between the number of mutations in the NS5A 2209 -|2248 or the
mutation at position 2209 in the NS5A gene and SVR to the combination therapy
(P< 0.001 and P< 0.001, respectively). Furthermore, these results were
confirmed with the multiple logistic regression analysis (regression
coefficient:0.234, adjusted odds ratio:1.263 [95% CI: 1.056 -|1.511], P=0.011
and regression coefficient:1.871, adjusted odds ratio: 6.494 [95% CI: 1.485
|28.393], P=0.013, respectively). The SVR rate in the combination therapy in
the patients with the mutation at position 2209 in the NS5A gene was 84.2 %
(16/19), while that in those without the mutation was 31.8 % (94/296).
Moreover, even though the patients with HCV-|1b infection had more than three
mutations in the NS5A 2209-|2248, if they hadnot the mutation at position 2209
in the NS5A gene, the SVR rate in the combination therapy for them became
significantly lower than those with the mutation at position 2209 in the NS5A
gene (regression coefficient: -1.669, adjusted odds ratio: 0.188 [95% CI: 0.039
-0.921], P=0.039) using the multiple logistic regression analysis.
Conclusions:
The mutation of specific position 2209 in the NS5A gene plays
an important role in obtaining SVR in the combination therapy for the patients
with HCV-|b infection worldwide. This phenomenon could not be observed in the
recent three published meta-analyses (n=675 1351) on interferon monotherapy.
Abstract ID: 64864
Category: JO7: HCV:
Treatment
PEG-INTERFERON ± RIBAVIRIN IN ADVANCED HCV CIRRHOSIS.
V. Di Marco, V. Calvaruso, D. Ferraro, P.L. Almasio, G. Alaimo, M. Giglio,
S. Peralta, R. Di Stefano, A. Craxì. Gastroenterology
& Hepatology, University of Palermo, Italy
Background:
Treatment of advanced HCV cirrhosis with PEG-IFNs and
ribavirin, either as pre-emptive strategy before OLT or as a way to slow down
the disease progression toward decompensation, has received relatively scarce
attention.
Aim:
To assess effectiveness and tolerability of PEG-IFN ± RBV in
patients with advanced, compensated HCV cirrhosis.
Patients and method:
102 subjects with HCV cirrhosis (Child-Pugh < B7), age
< 70 years, with platelets < 100,000/mm³ and/or F1/F2 gastroesophageal
varices, 76 naives and 35 non-responders to previous alpha-IFN monotherapy,
were randomized to receive 1 mcg/kg/week of PEG-IFN alpha2b as monotherapy (51
pts, mono group) or with RBV 800 mg/day (51 pts, combo group) ) for 52 weeks.
Patients stopped therapy at 26 weeks if HCV-RNA positive.
Results:
Mono and combo groups were comparable for age (mean 56 ± 7.5
years), gender (64% males) body weight (mean 70 ± 11.2 Kg), previous IFN
treatment and HCV-RNA load (mean MT 2.083.366 UI/ml vs CT 1.641.292 IU/ml,
p=ns). By ITT analysis, 12 patients on mono and 21 patients on combo achieved
an end-of treatment (ETR) viral response (23.5% vs 41.1%; p=0.057). After 6
months of follow-up 5 patients on mono and 10 patients on combo maintained a
sustained virological response (SVR: 9.8% vs 19.6%, p=ns). Five out of 9 (55%)
patients with genotypes 2 or 3, 10/88 (11.3%) of patients with genotype 1b, but
none of 5 patients with genotype 4 had a SVR. Ten of 67 naïve patients and 5/35
of those previously treated achieved SVR (14.9% vs 14.2%, p ns). Thirty-four
patients stopped therapy because of AE (20 mono vs 14 combo, p=ns). Causes of
withdrawal were depression/intolerance (15%), leukopenia (10%),
thrombocytopenia (4%), anaemia (3%), ALT flare (1%). One combo patient
decompensated under treatment.
Conclusion:
PEG-IFN obtains profound suppression of HCV viraemia under
treatment in 1/3 of patients with advanced cirrhosis, but SVR is obtained only
by 15% of all patients. SVR was more common for genotypes 2 or 3, and
comparable among naïves and nonresponders to previous monotherapy. A trend
towards an increase in SVR was seen with RBV, but the trial groups were
relatively small and the amount of RBV given probably insufficient. Treatment
withdrawal due to intolerance and haematological toxicity was common, without
life-threatening events.
Abstract ID: 65200
Category: JO7: HCV:
Treatment
PREDICTED OUTCOMES IN PATIENTS WITH PERSISTENTLY ‘NORMAL’ ALT LEVELS AND HCV GENOTYPE 1 TREATED WITH PEGINTERFERON ALFA-2a (40KD) (PEGASYS®) PLUS RIBAVIRIN (RBV, COPEGUS®) 1000/1200 MG/DAY FOR 48 WEEKS.
S. Zeuzem, Saarland
University Hospital, Homburg, Germany, S. Hadziyannis, Henry Dunant Hospital,
Athens, Greece, C. Puoti, Marino Hospital, Rome, Italy, M. Swain, University of
Calgary, Calgary, Canada, T. Berg, Universitatsklinikum Charité, Campus
Virchow-Klinikum, Berlin, Germany, J. Zarski, Hôpital A Michallon, Grenoble,
France, E. Snoeck, Exprimo NV, Lummen, Belgium, K. Jorga, F Hoffmann-La Roche,
Basel, Switzerland, P. Marcellin, Hôpital Beaujon, Clichy, France
Introduction
In patients (pts) with ‘normal’ ALT, peginterferon alfa-2a
(40KD) (PEGASYS®) plus RBV (COPEGUS®) 800 mg/d for 48 wk produced an SVR in 52%
of pts overall and in 40% of genotype 1 pts in a randomized, international
trial (Zeuzem, Gastroenterology 2004). We modeled the probability of SVR and
the incidence of anemia in these same genotype 1 pts if they had been treated
with the currently recommended dosage of RBV (1000/1200 mg/d).
Methods
Baseline and outcome data from ‘normal’ ALT pts were
incorporated into an existing generalized additive model established with data from
elevated ALT pts treated for 48 wks with peginterferon alfa-2a (40KD) plus RBV
1000/1200 mg/day in two trials (Fried,
NEJM 2002; Hadziyannis, Ann Intern Med 2004). The effect of RBV dose/kg and
other prognostic factors for SVR rates and incidence of anemia (Hgb ≤10
g/dL) were analyzed. Simulations were run with the updated GAN models to
predict SVR in genotype 1 normal ALT pts and the incidence of anemia in all
normal ALT pts after treatment with peginterferon alfa-2a (40KD) + RBV
1000/1200 vs 800 mg/day. Model uncertainty was quantified by ‘bootstrapping’.
Results
· Data from 38 HCV
genotype 1-infected patients with persistently ‘normal’ ALT levels were used to
update the SVR model, while data from 206 patients with persistently ‘normal’
ALT levels were used to update the anemia model.
· The GAM analyses showed
that, in patients infected with HCV genotype 1, the following prognostic
factors in order of importance) were retained in the predictive model for an
SVR: baseline HCV RNA level; age;
ribavirin dose per kilogram of bodyweight; baseline ALT quotient; histological
diagnosis (cirrhotic vs. non-cirrhotic); and race (Caucasian vs.
non-Caucasian).
· Prognostic factors
retained in the predictive model for anemia (in order of importance) included
baseline hemoglobin level, ribavirin dose per kilogram of bodyweight, age,
gender, baseline ALT and histological diagnosis.
· Increasing the dose of
ribavirin from 800 to 1000/1200 mg/day was predicted to increase the median
probability of achieving an SVR by 9% in genotype 1 patients with persistently
‘normal’ ALT levels. Moreover, the
predicted SVR rate was similar to the predicted SVR rate in patients with
elevated ALT activity treated with ribavirin 1000/1200 mg/day.
· The incidence of anemia
was predicted to rise when the dose of ribavirin was increased from 800 to
1000/1200 mg/day in patients with persistently ‘normal’ ALT activity (as has
been seen in patients with elevated ALT activity).
· From the model, the
overall incidence of anemia in patients with persistently ‘normal’ ALT levels
was predicted to be approximately double than in patients with elevated ALT.
·
However, further analyses demonstrated that the predicted
differences in the incidence of anemia between patients with persistently
‘normal’ ALT levels were due prelimarily to the higher number of female
patients with persistently ‘normal’ vs. elevated ALT activity (62% vs.
33%). When the gender imbalance was
taken into consideration, there was no significant difference in the incidence
of anemia in patients with persistently ‘normal’ and elevated ALT.
Conclusion
·
Model simulations predict that SVR
rates genotype 1 patients with persistently ‘normal’ ALT activity would be
similar to those in patients elevated ALT activity following 48 weeks’
treatment with peginterferon alfa-2a (40KD) (PEGASYS) plus the standard
approved dose of ribavirin (COPEGUS) (1000/1200 mg/day).
·
The predicted incidence of anemia
in genotype 1 and non-1 patients treated with peginterferon alfa-2a (40KD) plus
ribavirin 1000/1200 mg/day for 48 weeks was also independent of ALT status; for
patients populations with a similar distribution of risk factors, such as
gender and baseline haemoglobin, the risk of developing anemia should be the
same in patients with persistently ‘normal’ and elevated ALT activity.
·
As such, the combination of
peginterferon alfa-1a (40KD) plus the standard approved ribavirin dose of
1000/1200 mg/day for 48 weeks should be used in patients infected with HCV
genotype 1, independent of ALT status at baseline; this is reflected in the labeling for
peginterferon alfa-2a (40KD).
Abstract ID: 66031
Category: JO7: HCV:
Treatment
Efficacy and Cost-effectiveness of 24 Weeks of High-dose Induction Therapy with Consensus Interferon in Chronic Hepatitis C Patients with Genotype 2 Infection.
Y. Iwasaki, Okayama
University Graduate School of Medicine and Dentistry, Okayama Japan, H. Tanaka,
Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan,
H. Ikeda, Okayama University Graduate School of Medicine and Dentistry,
Okayama, Japan, K. Yabushita, Okayama University Graduate School of Medicine
and Dentistry, Okayama, Japan, H. Kobashi, Okayama University Graduate School
of Medicine and Dentistry, Okayama, Japan, K. Takaguchi, Okayama University
Graduate School of Medicine and Dentistry, Okayama, Japan, T. Sakata, Okayama
University Graduate School of Medicine and Dentistry, Okayama, Japan, M. Ando,
Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan,
Y. Araki, Okayama University Graduate School of Medicine and Dentistry,
Okayama, Japan, R. Okamoto, Okayama University Graduate School of Medicine and
Dentistry, Okayama, Japan, M. Kawaguchi, Okayama University Graduate School of
Medicine and Dentistry, Okayama, Japan, M. Ohmoto, Okayama University Graduate
School of Medicine and Dentistry, Okayama, Japan, Y. Makino, Okayama University
Graduate School of Medicine and Dentistry, Okayama, Japan, J. Shimamura,
Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan,
K. Sakaguchi, Okayama University Graduate School of Medicine and Dentistry,
Okayama, Japan, Y. Shiratori, Okayama University Graduate School of Medicine
and Dentistry, Okayama, Japan
Background and Aims:
Several treatment strategies are currently available to
patients with chronic hepatitis C. While these treatments have been compared in
terms of their efficacy, the cost-effectiveness of treatment should be further
considered. We conducted a study to evaluate the efficacy, safety, and
cost-effectiveness of consensus interferon therapy with high-dose induction for
patients with chronic hepatitis C.
Methods:
We consecutively enrolled 104 patients with chronic hepatitis
C; 62 men and 42 women, 38 with genotype 1 and 66 with genotype 2, with a mean age
± SD of 54 ± 12 years old. Patients were scheduled to receive 12 or 18 μg
of consensus interferon daily for two weeks, then three times a week for
twenty-two weeks. Efficacy, safety, and tolerance were assessed. A Markov model
was constructed to evaluate cost-effectiveness simulating the natural history
of patients with chronic hepatitis C. Transition probabilities were drawn from
published data and US vital statistics. All cost data were obtained from
published medical reimbursement data. Simulation and analysis were performed
using TreeAge pro 2004.
Results:
Of 104 patients, a sustained virologic response was achieved
in 66 (63%). Logistic regression analysis revealed that genotype 2 (risk ratio,
95% CI: 8.85, 2.70-29.41), lower hepatitis C virus RNA levels (less than 200
KIU/ml) (12.82, 3.36-47.62), and patient age (6.25, 1.90-20.41) were
independently associated with sustained virologic response. Sustained virologic
response was achieved in 40% (15/38) of genotype 1 patients and 77% (51/66) of
genotype 2 patients (P < 0.001). Discontinuation of therapy was
required in 19 of 104 (18%) patients, and there was a tendency towards a higher
discontinuation rate in older patient (≥55 vs. < 55) (24% (14/58) vs.
11% (5/46), P =0.082). Cost-effectiveness analysis revealed that the treatment
increased life expectancy as assessed by quality-adjusted life years (QALYs)
and it cost less than $17,000/QALY
in patients with genotype 2 infection.
|
|
QALY |
Cost
($)/QALY |
|
Consensus IFN (12 mg) |
14.3 |
16,583 |
|
Consensus IFN (18 mg) |
14.3 |
16,919 |
|
No treatment |
11.8 |
25,765 |
Conclusions:
24-week consensus interferon therapy with high-dose induction
shows high efficacy and is highly cost-effective in chronic hepatitis C patients
with genotype 2 infection.
Abstract ID: 66153
Category: JO7: HCV:
Treatment
Peginterferon a-2b 1 mcg/kg dose plus ribavirin 800-1200mg for 24-48 weeks, according to genotype, in naive patients with chronic hepatitis C: efficacy and cost-effectiveness evaluation.
M. Basso, Dpt Internal
Medicine, University of Genova, Genoa, Italy, A. Grasso, Ospedale San Paolo,
Savona, Italy, G. Percario, Ospedale San Carlo, Genoa, Italy, E. Azzola,
Ospedale Santa Corona, Pietra Ligure, Italy, S. Artioli, Ospedale Civile S.
Andrea, La Spezia, Italy, N. Pelli, Dpt Internal Medicine, University of
Genova, Genoa, Italy, F. Torre, Dpt Internal Medicine, University of Genova,
Genoa, Italy, A. Picciotto, Dpt Internal Medicine, University of Genova, Genoa,
Italy
Background & Aims:
Dose finding study on monotherapy demonstrated no significant
difference in sustained virological response (SVR) rate between peginterferon
alpha-2b 1,5 mcg/kg/week and 1 mcg/kg/week in naive patients with chronic
hepatitis C (Lindsay et al. Hepatology, 2001; 34:395-403). In the attempt to
optimise efficacy and resources, we designed a multi-centre observational
protocol, treating chronic hepatitis C naïve patients with peginterferon
alpha-2b 1 mcg/kg/week and ribavirin 800-1200mg, according to body weight, for
24 weeks in genotype 2 or 3 and for 48 weeks for genotype 1 or 4 infected
patients.
Methods:
148 consecutive, unselected naive patients (M/F: 87/61;
median age: 49 yrs, range 19-67) were enrolled between 12/2001 and 6/2003 in
five regional referring centres in Liguria, Italy. 51.4% had genotype 1/4. None
of the patients had clinical sign of cirrhosis. HCV-RNA was assessed at week 2,
4, 12, end of treatment and at the end of follow up.
Results:
Six patients DO - dropped out (two due to intolerance after
few injections, 4 due to non-compliance with the treatment). 142 patients were
adherent to the protocol and follow-up. No statistically significant
differences were presents between the genotype groups for age, sex, ALT levels.
Overall, we achieve SVR in 59.4% of patients, with a 5.4% of relapse-responders
(RRs) and a 35.2% of non-responders (NRs) (intention to treat). For genotype
1/4 (76 pts, 48 weeks treatment), we had 32.9% SVR, 7.9% RRs, 52.6% NRs and
6.6% DO. For genotype 2/3 (72 pts, 24 weeks treatment), we had 87.5% SVR, 2.8%
RRs, 8.3% NRs and 1.4% DO. Week 2 and 4 HCV-RNA determinations did not prove to
be reliable predictors of SVR. No major side effects or adverse events were
reported. No dose reduction was needed for peginterferon alpha-2b, while a dose
adjustment for anemia was necessary in 5% of the patients.
Conclusions:
· Peginterferon alpha-2b
1 mcg/kg dose plus ribavirin 800-1200mg combination treatment was well
tolerated in our group.
· The overall SVR is comparable
with the published data (54%, Manns et al, Lancet, 2001; 358:958-965).
· Whilst in genotype 1/4
our results are slightly below the best-published results (32.9% vs 42%, Manns
et al; peginterferon alpha-2b 1.5 mcg/kg plus 800mg ribavirin),
· For genotype 2/3 we
obtained identical results (87.5% vs 82%, Manns et al. with a 48 weeks
treatment).
· Our results suggest
that this combination therapy for 24 weeks can be considered the best option in
genotype 2/3 infected patients. With the same SVR ratio, we obtained to reduce
significantly length of treatment and side effects, and to halve the costs.
Clearly, genotypes 1/4 need more aggressive schedules.
Abstract
ID: 66704
Category: JO7: HCV:
Treatment
Reliability and Validity of the Beck Depression Inventory (BDI-II) in a Chronic Hepatitis C Population Undergoing PEG IFN plus Ribavirin Therapy
C. D. Levine, Liver
Institute at Methodist Dallas, Dallas, TX, K. Sellman, John Peter Smith
Hospital, Fort Worth, TX, R. Ghalib, Liver Institute at Methodist Dallas, Dallas,
TX
Purpose:
To determine the reliability and validity of the Beck
Depression Inventory (BDI-II) in the chronic HCV population undergoing
treatment with PEG IFN and ribavirin.
Methods:
The BDI-II is a self-report tool for depression with demonstrated
reliability and validity in the normal and depressed populations. It was given
to 182 subjects prior to office visits before beginning treatment, during
treatment, and following completion of treatment. During interferon plus
ribavirin therapy, subjects with signs of depression, anxiety or irritability
were treated aggressively with antidepressants and referred for psychiatric
evaluation as indicated.
Sample:
A total of 788 useable BDI-II tools were obtained with 119
(15%) prior to treatment, 586 (74%) during treatment, and 83 (11%) after
treatment was discontinued. Age range was 18 to 74 (mean 48 ±7.4 yr) with 71
females (39%) and 111 males (61%). Ethnicity represented were Asian (9, 4.9%),
Black (29, 15.9%), White (124, 68.1%), Hispanic (18, 9.9%), and Middle Eastern
(2, 0.1%). BDI-II scores were slightly higher in the females vs. males prior to
and during treatment. Scores returned to near baseline after treatment was
discontinued. Most subjects were in the mild category of depression prior to (94%),
during (72%) and after therapy (95%); however, 28% developed moderate or severe
depression during therapy.
Results:
Factor analysis was used to determine construct validity in
the HCV population. Principle component factor analysis with varimax rotation
revealed 2 distinct factors (eigenvalues above .35) consistent with constructs
identified in the depressed population. Factor 1 measured loss of pleasure,
interest, and energy; indecisiveness; irritability; concentration difficulties;
tiredness; and agitation. This factor represents the somatic affective
dimension of depression. Factor 2 measured sadness, past failure, guilt
feelings, self-dislike, self-criticalness, and worthlessness. Factor 2 reflects
a cognitive dimension of self-reported depression. Variance explained by the
two factors was 57.8%. Cronbach’s alpha levels above 0.8 demonstrate internal
consistency reliability of the instrument. In this population the BDI had a
Cronbach’s alpha of .911.
Conclusion:
BDI-II is an internally consistent and valid tool in
measuring depression in the HCV patients during therapy. It is useful tool in
identifying the presence and ongoing monitoring of changes in severity of
depression during interferon plus ribavirin therapy.
Abstract ID: 66921
Category: JO7: HCV:
Treatment
Efficacy of Daily Consensus Interferon and Ribavirin Compared to PEG-Interferon á-2b and Ribavirin in Non-Responders with chronic Hepatitis C.
M. M. Dollinger,
Martin-Luther-University Halle-Wittenberg, Halle, Germany, Y. Dridi,
Martin-Luther-University Halle-Wittenberg, Halle, Germany, J. Lesske,
Martin-Luther-University Halle-Wittenberg, Halle, Germany, S. Behl,
Martin-Luther-University Halle-Wittenberg, Halle, Germany, W. E. Fleig,
Martin-Luther-University Halle-Wittenberg, Halle, Germany
Consensus interferon is a synthetic type 1 interferon with
enhanced in vitro efficacy compared to conventional interferon-α, but its
use is limited by the acceptance of patients to tolerate the daily injections
and the potential side-effects.
Objective:
To assess the efficacy, tolerability and safety of consensus
interferon (CIFN) daily versus pegylated IFN a-2b (PEG-IFN) once weekly in
combination with ribavirin (RBV) for HCV non-responders to previous combination
treatment with IFN and RBV in a prospective, randomised, multicentre trial.
Patients/Methods:
40 patients with histologically proven chronic Hepatitis C,
positive HCVRNA, elevated transaminases and previous non-response to treatment
with combination therapy with IFN and RBV were randomised to 18 mcg/D CIFN for
6 weeks followed by 9 mcg/D CIFN for 42 weeks (CIFN + RBV: 18 patients) or 1.5
mcg/kg body weight of PEG-Interferon α-2b once a week for 48 weeks
(PEG-IFN + RBV: 22 patients), each in combination with RBV (> 10.6 mg/kg body
weight daily). There were no statistical differences between the two groups
regarding sex, age, weight, or presence of cirrhosis, all patients had the HCV
genotype 1b.
Results:
Based on an intent-to-treat analysis, the early response rate
(ER, 24 weeks of treatment), the end-of-treatment response rate (ETR, 52 weeks
of treatment) and the sustained response rate (SR, 6 months after treatment)
are reported in Table 1. No significant difference was detected between the two
groups.
There was no clinically significant difference in the
incidence of adverse events between the two groups. However, there was a
significant higher number of patients withdrawing within the first 6 months
from CIFN + RBV than from PEG-IFN because of subjective side-effects (6/18 vs.
1/22, p<0.05, Figure 1). In contrast, the treatment was terminated because
of primary non-response after 6 months in 8/22 patients treated with PEG-IFN +
RBV versus only 2/18 patients treated with CIFN + RBV (p<0.05).
Figure 1: Patients on treatment
Conclusions:
Based on an intent-to-treat analysis, daily CIFN combined
with ribavirin has the same antiviral efficacy and safety profile for the
treatment of non-responders with chronic Hepatitis C as weight adjusted
peg-IFNa2b. The daily regimen of CIFN is however less well tolerated by
patients, a potential higher efficacy can therefore not be established in
studies, and will be difficult or impossible to achieve outside of studies.
The study was supported by
a grant of Yamanouchi and essex-pharma, Germany
Abstract ID: 66971
Category: JO7: HCV:
Treatment
Sequential Treatment with Ribavirin and Low-Dose Pegylated (PEG) Interferon alfa 2b in Chronic Hepatitis C Patients with Normal ALT: A Pilot Study.
S. Schulte, Department of Gastroenterology,
University of Cologne, Cologne, U. Toex, Department of Gastroenterology,
University of Cologne, Cologne, Germany, J. Mertens, Department of
Gastroenterology, University of Cologne, Cologne, Germany, I. Scheller,
Department of Gastroenterology, University of Cologne, Cologne, Germany, N.
Jaspers, Department of Gastroenterology, University of Cologne, Cologne,
Germany, T. Goeser, Department of Gastroenterology, University of Cologne,
Cologne, Germany, H. Steffen, Department of Gastroenterology, University of
Cologne, Cologne, Germany
Objectives:
Patients with chronic hepatitis C and normal ALT show similar
response rates after PEG-interferon ribavirin combination therapy compared to
patients with elevated ALT. A ribavirin monotherapy prior to the PEG-interferon
ribavirin combination therapy may be advantageous because of immune-modulating
effects of ribivirin. The aim of this pilot study was, therefore, to evaluate a
sequential therapy with ribavirin monotherapy followed by combination of low-dose
PEG interferon alpha 2b and ribavirin in hepatitis C patients with normal ALT.
Methods:
20 HCV RNA positive patients (17 genotype 1 and 3 genotype 2
or 3) with histologically confirmed chronic viral hepatitis and normal ALT and
AST for at least 6 months received ribavirin 1000 or 1200 mg/d for 4 weeks
followed by 4 weeks combination therapy with PEG-interferon alpha 2b 100
μg/week and ribavirin followed by low-dose PEG-interferon (50
μg/week) plus ribavirin for 20 (non-responder) or 44 (responder) weeks.
Follow up was 24 weeks.
Results:
At the end of therapy, 13 patients had become HCV-RNA
negative, and 3 out of these had a relapse during follow up. Sustained
virological response (SVR) was seen in 10 (50%), 7 (47%), and 3 (100%) patients
for all genotypes, genotype 1, and genotype 2 or 3, resp. 5 patients were
non-responders and 2 dropped out prematurely.
Conclusion:
Patients with chronic HCV infection and normal ALT treated
with ribavirin monotherapy followed by a combination of low dose PEG-interferon
alpha 2b and ribavirin have response rates similar to standard treatment.
Further studies should be done to evaluate this protocol with potentially less
side effects and expenses.
Abstract ID: 67504
Category: JO7: HCV:
Treatment
Interim Analysis of the Safety and Efficacy of Peginterferon Alfa-2a plus Ribavirin in Chronic Hepatitis C Patients Unable to Tolerate or Nonresponsive to Treatment with Peginterferon Alfa-2b plus Ribavirin.
V. K. Rustgi, Georgetown
University Medical Center, Fairfax, VA, S. Esposito, North Shore Hospital at
Forest Hills, Bayside, NY, B. Freilich, Baptist Medical Center, Kansas City,
MO, J. Lopez-Talavera, Roche Laboratories, Nutley, NJ, E. Lentz, Roche
Laboratories, Inc, Nutley, NJ, M. L. Shiffman, Virginia Commonwealth University
Medical Center, Richmond, VA
Introduction:
Phase III clinical trials have shown that hepatitis C virus
(HCV)-infected patients treated with peginterferon alfa-2a plus ribavirin
(PEG-2a/RBV) have a lower incidence of depression and flu-like symptoms than
patients treated with standard interferon (IFN) plus RBV. In contrast, patients
treated with peginterferon alfa-2b plus RBV (PEG-2b/RBV) have a side effect
profile similar to those treated with IFN plus RBV. We have therefore tested
the efficacy and safety of PEG-2a/RBV in patients intolerant (NT) of side
effects or non-responders (NR) to treatment with PEG-2b/RBV.
Methods:
Patients infected with HCV genotype 1 treated with PEG-2b/RBV
for a maximum of 12 weeks who were intolerant due to depression, fatigue,
flu-like symptoms, or injection site reactions, or did not achieve early
virologic response (EVR), defined as a 2-log decrease or undetectable HCV RNA
after 12 weeks, were treated with PEG-2a/RBV. NTs and NRs with detectable HCV
RNA after 12 weeks of treatment with PEG-2a/RBV were discontinued. Depression,
fatigue, injection site reactions, and flu-like symptoms were evaluated by the
Beck Depression Inventory, v2 (BDI-II), Fatigue Severity Scale (FSS), and Local
Injection Site Reaction and Flu-like Symptom Questionnaires. HCV RNA was
measured by Roche Amplicor (limit of detection, 60 IU/mL).
Results:
Table. Baseline characteristics at start and EVR at week 12
of PEG-2a/RBV treatment
|
Characteristic |
Males |
Blacks |
Cirrhotics |
Weight |
HCV RNA |
EVR n/N |
On treatment |
|
|
n (%) |
n (%) |
n (%) |
kg* |
log IU/mL* |
(%) |
after 12 weeks, n (%)** |
|
NRs (N=32) |
17 (53) |
13 (41) |
9 (28) |
85.1 +3.8 |
5.29 + 0.19 |
4/29 (13.8) |
4 (12.5) |
|
NTs (N=25) |
18 (72) |
1 (4) |
1 (4) |
81.5 +3.7 |
2.99 + 0.12 |
23/24(95.8) |
22 (88) |
* Mean + SE
**through at least week 24
Only 4 of the NRs (12.5%) and none of the NTs were withdrawn due
to adverse events or intercurrent illness. Only 2 and 4 NTs required dose
adjustments of PEG-2a and RBV, respectively, for adverse events or laboratory
abnormalities. In 21 NTs remaining on treatment at 24 weeks, relative to
baseline, BDI-II score declined from 15.00 +1.48 (mean + SE) to 10.45 + 1.44,
FSS visual analogue scale (VAS) score declined from 62.19 + 4.42 to 53.19 +
6.03, and the number of patients with injection site reaction declined from 10
(40%) at baseline to 2 (8%) at Week 24.
Conclusion:
Over 90% of patients intolerant of PEG-2b/RBV are tolerant of
PEG-2a/RBV, allowing them to achieve EVR. In addition, 14% of patients
unresponsive to PEG-2b/RBV have achieved EVR when converted to PEG-2a/RBV.
Thus, based on a 12-week interim analysis, patients non-responsive or
intolerant to treatment with PEG-2b/RBV can be successfully rescued with
PEG-2a/RBV.
Abstract ID: 67879
Category: JO7: HCV:
Treatment
Eligibility for treatment of hepatitis C virus infection among young injection drug users in three US cities.
H. Hagan, NDRI, New York,
NY, J. Campbell, Public Health Seattle and King County, Seattle, WA, R.
Garfein, University of California San Diego School of Medicine, San Diego, CA,
M. Latka, New York Academy of Medicine, New York, NY, S. Strathdee, University
of California San Diego School of Medicine,, San Diego, CA, D. Thomas, Johns
Hopkins University, Baltimore, MD, E. Golub, Johns Hopkins University,
Baltimore, MD
Background:
Although recent studies have demonstrated feasibility and
effectiveness of interferon with ribavirin as treatment for hepatitis C virus
(HCV) infection in injection drug users (IDUs), treatment access has been low
relative to other patients. We studied factors considered in determining
treatment eligibility according to the 2002 NIH Consensus Guidelines for
Management of HCV.
Methods:
Eligible subjects included HCV-antibody positive IDUs in
Baltimore, New York and Seattle aged 18-35 who injected illicit drugs during
the prior 6 months. We estimated the proportion of HCV-RNA positive young IDUs
who may be considered ineligible for HCV-treatment according to measures of
depression (Beck’s Depression Inventory (BDI) score >19), problem drinking
(Alcohol Use Disorders Identification Test (AUDIT) score >8), and recent
drug injection (last 30 days).
Results:
Of 404 HCV-RNA positive subjects, 45% had BDI scores >19
and 37% scored >8 on AUDIT; 89% had injected drugs at least once in the past
30 days. When both problem alcohol use and depression were considered together,
63% of subjects may be ineligible for treatment of HCV infection; when recent
drug injection is also considered, 95% may be ineligible. African-Americans
were somewhat less likely than other patients to be ineligible for HCV
treatment when alcohol, depression and recent drug injection were considered
together. However, there were no differences between men and women in the
proportion having any of these contraindications to HCV treatment.
Discussion:
Applying multiple exclusion criteria may virtually eliminate
access to treatment of HCV infection in IDUs. Particularly because younger
patients are more likely to respond to treatment of HCV infection, screening
for treatment eligibility should be limited to those factors demonstrated to be
associated with reduced treatment success, such as excess alcohol use.
Abstract ID: 67941
Category: JO7: HCV:
Treatment
Direct Costs of Medical Care for Treating Hepatitis C Patients in a Veterans Affairs Medical Center.
T. Adeniyi, Minneapolis VA
Medical Center, Minneapolis , MN, Y. C. Jonk,
Minneapolis VA Medical
Center, Minneapolis, MN, A. Knott Johnson, Minneapolis VA
Medical Center,
Minneapolis, MN, E. Dieperink, Minneapolis VA Medical Center,
Minneapolis, MN, S. Ho,
Minneapolis VA Medical Center, Minneapolis, MN
OBJECTIVES:
To identify the utilization and total direct cost of medical
care, including outpatient and pharmaceutical care services associated with
treatment and follow-up of Hepatitis C (HCV) patients. Our secondary objective is
to determine the cost per patient cured.
METHODS:
99 patients with a positive HCV enzyme-linked immunoassay
test conducted at the Minneapolis VA Medical Center in calendar years 2000 –
2001 and subsequently treated with pharmacotherapy were included in the study.
This study takes the intent-to-treat perspective. Outpatient utilization and
pharmacy data were extracted from VA administrative databases. Cost data for
outpatient care were extracted from the Health Economics Resource Center’s
outpatient average cost database. Cost data for the prescriptions medication
were derived from the Veterans Health Information Systems and Technology
Architecture database. Of the four strains of Hepatitis C, genotype 1 is the
most prevalent and difficult to treat. Genotype 1 requires 48 weeks of therapy
while genotypes 2-4 (non-genotype 1) require 24 weeks of therapy. Irrespective
of genotype, prior to 2001, combination therapies consisted of interferon alfa
2B and ribavirin (IR). During 2001 interferon alfa 2B was replaced with
peginterferon creating a new combination-therapy (PR). Thus, patients were
transitioning from interferon alfa 2B to peginterferon and received all three
antiviral medications during the course of their treatment (IPR).
RESULTS:
The data show that on average genotype 1 patients treated
with IR (n=28), IPR (n=19), and PR (n=24) therapy, received 438.4, 796.5, and
223.5 days of antiviral medication treatment at a cost of $8,232 and $16,536
and $10,786 respectively. Non genotype 1 patients treated with IR (n=20), IPR
(n=5), and PR (n=3) therapy received an average of 226.8, 690.4 and 141.7 days
of antiviral medication treatment at a cost of $6,866, $12,695 and $9,237
respectively. Genotype 1 patients treated with IR, IPR, and PR therapy and
followed for a year and a half to determine cure rates averaged 16.3, 19.2, and
6.4 Hepatitis C related clinic visits at a cost of $1,594, $1,812 and $636
respectively. Non-genotype 1 patients treated with IR, IPR, and PR averaged
12.3, 9.0 and 5.3 Hepatitis C related clinic visits at a cost of $1,184, $863
and $511 respectively.
CONCLUSIONS:
Largely due to treatment patterns, the cost of treating
genotype 1 patients is more substantial than the cost of treating non-genotype
1 patients. The IPR group of patients is higher largely due to patients being
non-responders and switching therapies, extending the length of treatment.
Abstract ID: 67976
Category: JO7: HCV:
Treatment
Pegylated interferons (PEG-IFNs) do not present viral rebound after short-term administration of consensus interferon (CIFN) to IFN-naive patients (pts) with chronic hepatites C (CHC), genotype 1.
L. C. Da Silva, University
of Sao Paulo School of Medicine, Sao Paulo, Brazil, J. R. Pinho, University of
Sao Paulo School of Medicine, Sao Paulo, Brazil, S. K. Ono-Nita, University of
Sao Paulo School of Medicine, Sao Paulo, Brazil, C. L. Madruga, University of
Sao Paulo School of Medicine, Sao Paulo, Brazil, I. M. Mello, University of Sao
Paulo School of Medicine, Sao Paulo, Brazil, F. J. Carrilho, University of Sao
Paulo School of Medicine, Sao Paulo, Brazil
Introduction:
It is well known that genotype 1 and high viral load (>
800,000 U or > 5.9 log) are very important viral factors predictive of a
poor response to combined therapy with PEG-IFN and ribavirin (RBV). According
to three large trials, the rate of sustained response in such patients is below
50%. In an attempt to increase this rate through an improvement of early viral
kinetics, a high dose of CIFN was given for two days just before starting a
PEG-IFN.
Material and Methods:
Six consecutive CHC pts were given a 2-days induction
treatment with 15mcg of CIFN every 12 hs. After 12 hs one of the PEG-IFN (3 pts
with PEG-IFN-alpha-2a and 3 with PEG-IFN- alpha-2b) was administrated followed
by one week dosing. Serum specimens were collected after pretreatment, 48hs, 2,
4, 8 and 12 weeks and submitted to a quantitative (Amplicor/Monitor, Roche,
limit of detection (LD) 600 IU) or qualitative Amplicor/Monitor, Roche, LD 50
IU) when necessary. Results of viral load (VL) in induction group (Group B)
were compared to those found in another group of patients also treated with
PEG-IFN plus RBV but without induction treatment (Group A).
Results:
In the induction treatment groups, the following mean VL were
observed: pre-treatment = 5.9 log, 48hs = 3.2 log, week 2 = 4.3 log, week 4 =
3.8 log, week 8 = 2.7 and week 12 = 2.3. A statistic analyses showed a
significant difference between pre and 48hs (p < 0.0001) and between 48hs
and week2 (p = 0.043). A comparison between the induction and non-induction
group showed no difference among pre, week 2, 4, 8 and 12.
Discussion and conclusions:
Attempt to improve viral kinetics through a decrease of VL in
phase 1 after a high-dose of CIFN did not change the viral patterns when
compared to pts without induction treatment.
Abstract ID: 62985
Category: JO7: HCV:
Treatment
Peginterferon Alfa-2a and Ribavirin in African American and Caucasian Patients with Chronic Hepatitis C, Genotype 1.
H. S. Conjeevaram, UNIVERSITY
OF MICHIGAN, Ann Arbor, MI, M. W. Fried, University of North Carolina, Chapell
Hill, NC, L. J. Jeffers, VA Medical Center, Miami, FL, N. Terrault, UCSF, San
Francisco, CA, T. E. Wiley-Lucas, Rush University Medical Center, Chicago, IL,
N. Afdhal, Beth Israel Deaconess Medical Center, Boston, MA, R. S. Brown Jr,
New York Presbyterian-Columbia Presbyterian Center, New York, NY, S. H. Belle,
University of Pittsburgh, Pittsburgh, PA, P. R. Robuck, NIDDK, NIH, Bethesda,
MD, C. D. Howell, University of Maryland, Baltimore, MD
Background/Aims:
Compared to Caucasian Americans (CA), African Americans (AA)
with chronic hepatitis C virus (HCV) infection are less likely to respond to
interferon-based antiviral therapy. The biological bases for this racial difference
in response are not known. Virahep-C is a prospective, multi-center clinical
study, designed to compare the effects of peginterferon and ribavirin therapy
between AA and CA pts and determine predictive factors for non-response to
treatment.
Methods:
196 AA and 205 CA treatment-naïve pts with genotype 1
infection were treated with peginterferon alfa-2a (180 μg/wk) and
ribavirin (1000-1200 mg/day). Pts who were HCV RNA negative at wk 24 were
treated for an additional 24 wks and followed thereafter for evidence of SVR.
Pts who were HCV RNA positive at wk 24 were considered nonresponders, and
therapy stopped.
Results:
Baseline features were similar among AA and CA including age,
gender, histologic severity but AA had higher average BMI, higher rates of
diabetes and hypertension, and lower mean ALT, neutrophil, and hemoglobin
levels (p< .001 for all). AA were also more likely to have HCV subtype 1b
than CA (46% vs. 28%, p=.0004) and less likely to have 1a (47% vs. 58%, p=.04)
but HCV RNA levels were similar. Virological response rates are shown below,
representing final data on 94% of pts. Complete results are expected by October
2005.
Breakthrough responses between wk 24 and wk 48 occurred in
14% AA and 6% CA (p=.03). Relapse rates following treatment were similar
between AA and CA (34% vs. 27%, p=.30). Frequencies of serious adverse events,
dose reductions/discontinuations were similar among AA and CA. Multiple
logistic regression analyses demonstrated that CA race was independently
associated with a higher SVR rate compared to AA [OR 3.40 (95% CI 2.07-5.61)].
Other factors independently associated with lower SVR included male sex, higher
baseline HCV RNA level, higher Ishak fibrosis score and compliance (<
80/80/80); none of these accounted for racial differences in response.
Summary/Conclusions:
In pts with HCV genotype 1 infection, AA have significantly
lower rate of virological response to peginterferon and ribavirin therapy than
CA. The differences in response are evident soon after starting therapy and
persist. Analyses of other clinical, viral, immunological, and genetic
differences between responders and non-responders in this cohort are ongoing.
Abstract ID: 61115
Category: JO7: HCV:
Treatment
HEPATITIS C VIRUS PERSISTS AND REPLICATES IN THE LIVER OF THE MAJORITY OF SUSTAINED RESPONDER PATIENTS TO ANTIVIRAL TREATMENT.
V. Carreño, Fundación para el Estudio de las Hepatitis Virales, Madrid,
Spain, I. Castillo, Fundación para el Estudio de las Hepatitis Virales, Madrid,
Spain, E. Rodríguez-Iñigo, Fundación para el Estudio de las Hepatitis Virales,
Madrid, Spain, López-Alcorocho,
Fundación para el Estudio de las Hepatitis Virales, Madrid, Spain, J.
Bartolomé, Fundación para el Estudio de las Hepatitis Virales, Madrid, Spain,
J. Quiroga, Fundación para el Estudio de las Hepatitis Virales, Madrid, Spain,
M. Pardo, Fundación para el Estudio de las Hepatitis Virales, Madrid, Spain
Recently it was demonstrated the presence of HCV-RNA in the
liver of 3/11 (27%) sustained responders to antiviral therapy (serum HCV-RNA
negative and persistently normal ALT levels), but HCV replication was not found
in liver cells (1). We studied 20 patients (17 genotype 1 and the other 3 with
genotype 2, 3 and 4) with a histological chronic hepatitis C who responded to
antiviral therapy (pegylated or recombinant IFN ± ribavirin) with normalization
of liver function tests and clearance of serum HCV-RNA and who remained so for
42.7±31.2 months after treatment. HCV-RNA-positive and negative strands were
tested by strand-specific real-time RT-PCR and by in situ hybridization in the
post-treatment liver biopsies obtained 35.3±35.0 months (range:8- 117 months)
after the end of therapy. HCV-RNA strands were also studied in PBMC of the 20
patients. HCV-specific CD4+ and CD8+ T-cell responses were assessed by standard
lymphoproliferative assays and HCV-tetramer analysis respectively. HCVRNA-
positive strand was found in 19/20 (95%) liver biopsies (mean ± SEM:
1.9´105 ± 5.4´104 copies/mg total RNA).
The HCV-RNA-negative strand was detected in 15/19 (79%) liver samples with
HCV-RNA-positive strand (7.3´104 ± 3.1´104 copies/mg total RNA). The presence
of HCV-RNA-positive and negative strands was confirmed in all cases by in situ
hybridization. With respect to PBMC, 13/20 (65%) had HCV-RNA (9.5´105 ± 6.9´105
copies/mg total RNA). In addition, HCV-RNA-negative strand was detected in 12/13
(92%) of PBMC with HCV-RNA (1.6´105 ± 5.5´104 copies/mg total RNA). HCV-RNA was
amplified from the liver of 4 patients with primers of the core region. PCR
products were cloned and 4 clones from each patient were sequenced.
Phylogenetic analysis showed higher genetic distances among patients than
within patients, indicating that there was no cross-contamination among samples.
Regarding cellular responses, 9/15 patients had a positive HCV-specific
proliferative T-cell response. Moreover, NS3 tetramer-specific CD8+ T-cells
positive for at least one epitope were detected in HLA-A2+ subjects. Finally,
liver necroinflammation remained in the post-treatment liver biopsy of 15
patients and fibrosis was present in 7, although liver damage improved in all
but 2 cases. In conclusion, HCV persists and replicates in the liver and PBMC
of the majority of the patients with chronic hepatitis C after a sustained
response to treatment, although they maintain HCV-specific cellular responses.
As these responders have not cleared HCV infection and may maintain
histological damage, they should be followed for years in spite of apparently
clinical resolution of the disease.
(1) Hepatology 2005;41:106-14
Abstract ID: 65969
Category: JO7: HCV:
Treatment
Rapid Virological Response at Week 4 (RVR) of Peginterferon alfa-2a (40KD) (PEGASYS®) plus Ribavirin (RBV, COPEGUS®) Treatment Predicts Sustained Virological Response (SVR) after 24 Weeks in Genotype 1 Patients.
D. Jensen, Rush University
Medical Center, Chicago, IL, T. Morgan, VA Long Beach Healthcare System, Long
Beach, CA, P. Marcellin, Hopital Beaujon, Clichy, France, P. Pockros, The
Scripps Clinic, La Jolla, CA, R. Reddy, Hospital of the University of
Pennsylvania, Philadelphia, S. Hadziyannis, Henry Dunant Hospital, Athens,
Greece, P. Ferenci, MedicalUniversity of Vienna, Internal Medicine IV, Vienna,
Austria, B. Willems, Universite de Montreal, Montreal, Canada
Introduction
SVR rates were significantly higher in genotype (GT) 1
patients (pts) treated for 48 wks with peginterferon alfa-2a (40KD) (PEGASYS®)
+ RBV (COPEGUS®) 1000/1200mg/d than for 24 wks and/or with a lower RBV dose
(800 mg/d) [52% vs 29–42%; Hadziyannis. Ann Intern Med 2004]. However, 78 of
219 (36%) GT1 pts randomized to peginterferon alfa-2a (40KD)/RBV for 24 wks
achieved an SVR. Data was analyzed from this trial to identify factors that
might predict which GT1 pts are likely to achieve an SVR after 24 wks of
treatment.
Methods
Pts with chronic hepatitis C were randomized to 24 or 48 wks
of peginterferon alfa-2a (40KD) + standard (1000/1200mg/d) or low dose RBV
(800mg/d). SVR = HCV RNA <50IU/mL after 24wks of untreated follow-up. RVR =
HCV RNA <50IU/mL after 4 wks. We used stepwise multiple regression analysis
(MLR) to identify baseline factors predictive of SVR in GT1 pts treated for 24
or 48 wks with standard dose RBV.
Results
Data from 729 GT1 pts with week 4 results were analyzed of
whom /729 patients had an RVR. Pts with an RVR had both higher end-of-treatment
(EOT) and SVR rates than pts without an RVR (Figure). Pts with an RVR had lower
relapse rates between EOT and follow-up, regardless of treatment duration or
RBV dose. In contrast, relapse rates decreased with increasing duration of
treatment and RBV dose in pts without an RVR. RVR was more likely in pts with a
baseline HCV RNA level < 200,000 IU/mL (49 patients), < 200,000—600,000 IU/mL
(26 patients) and > 600,000 IU/mL (9 patients)
Conclusion
This retrospective analysis
of a large, randomized, phase III trial including 729 genotype 1 patients shows
that:
·
Approximately
20% of patients with HCV genotype 1 infection achieved undetectable HCV RNA
levels by qualitative PCR (i.e. an RVR) at week 4 of treatment with
peginterferon alfa-2a (40KD) (Pegasys) plus ribavirin (Copegus).
·
Overall,
89% of patients with an RVR treated for only 24 weeks achieved an SVR. Moreover, patients with an RVR treated for 48
weeks did not obtain a better SVR rate.
·
The
SVR rate in patients without an RVR (44%) was obtained following treatment with
peginterferon alfa-2a (40KD) plus ribavirin at the recommended dose (1000/1200
mg/day) for the recommended duration (48 weeks).
·
A
lower baseline HCV RNA level was the only significant and independent factor
associated with SVR.
·
An
RVR at week 4 of treatment is the single best predictive factor for an SVR.
·
The
use of RVR status to guide treatment duration in genotype 1 patients is
appealing and should ideally be confirmed by prospective studies.
Abstract ID: 62020
Effect of Sertraline on Pruritus in Cholestatic Liver Disease: a Randomized Double Blind Placebo Controlled Crossover Study.
M. J. Mayo, University
of Texas Southwestern at Dallas, Dallas, TX, I. Handem,
University of Texas
Southwestern Medical Center at Dallas, Dallas, TX, S. Saldana,
University of Texa
Southwestern Medical Center, Dallas, TX, H. Jacobe, University of
Texas Southwestern
Medical Center, Dallas, TX, Y. Getachew,
Southwestern Medical
Center, Dallas, TX, A. J. Rush, University of Texas Southwestern
Medical Center,
Background
Pruritus (severe itching) is frequently the most debilitating
symptom of cholestatic liver diseases. Moreover, existing therapies are often
not effective. Recent reports have suggested that serotonin reuptake inhibitors
can improve pruritus, but all have been small, retrospective case series. The
present study was designed to investigate the safety and efficacy of sertraline
as a first-line treatment for cholestatic pruritus.
Methods
18 subjects with chronic pruritus due to liver disease were
studied, including patients with primary biliary cirrhosis, primary sclerosing
cholangitis, chronic hepatitis C cirrhosis, and post-necrotic cirrhosis.
Subjects were not allowed to take any other medication that might affect
pruritus during the study, other than the study drug. In the first part of the
study, subjects underwent an open-label dose escalation to determine the best
dose of
sertraline that would optimize efficacy and tolerability.
After a washout period, subjects were then randomized to either sertraline or
placebo in a double blind fashion and treated for 6 weeks. After a second
washout, they were crossed over to the other therapy for 6 weeks. Subjects made
daily entries into a diary using a 0-10 visual analog scale to quantify their
pruritus. At each study visit, a detailed assessment of pruritus was
documented, including distribution, timing, degree of
disability, and physical evidence of
scratching. Depression inventories were also followed.
Results
The optimum dose was 100 mg for most subjects. One subject
suffered unbearable dizziness with sertraline (12.5 mg) and withdrew from the
study. All other subjects tolerated sertraline without difficulty, although
higher doses were sometimes associated with drowsiness or diarrhea.
In the open-label portion of the study, pruritus improved a
mean of -67% (range -36%to -97%). Improvement in pruritus with sertraline
occurred in both depressed and nondepressed individuals.
In the controlled portion of the study, itch scores improved
in patients taking sertraline (mean -30%, range -10% to -80%), whereas they
worsened in
patients taking placebo (mean +24%, range +70% to -1%). The
difference between the groups was statistically significant (p=.008). Changes
in itch distribution, degree of disability, and physical evidence of scratching
paralleled changes in the visual analog itch score.
Conclusion
· Sertraline treatment
significantly improves pruritus due to chronic liver disease and is well
tolerated.
· These findings imply
that serotonergic pathways are important in the perception of itch and warrant
further investigation.
Although few patients in the study had clinical depression at
entry, "successful treatment of depression was not required for treatment
of pruritus," Dr. Mayo said.