Tuesday Poster Sessions, October 30, 2006
Clinical Trials and Therapeutic Developments
T. Poynard; E. Schiff; R. Terg; R. Moreno Otero; S. Flamm;
W. Schmidt; T. Berg; F. Goncales; J. Heathcote; M. Diago; T. McGarrity; A. Maieron; J. Reichen; H. Tanno; C. Brandao; J. McHutchison; M.
Silva; P. Bedossa; W. Deng; P. Mukhopadhyay;
L. Griffel; M. Burroughs; C. Brass; J. K. Albrecht.
Introduction:
The EPIC3 program includes a large, prospective, controlled
trial designed to assess the safety and efficacy of re-treatment with peginterferon α-2b (PEG) and ribavirin (RBV) of
subjects who have failed previous treatment with any α-interferon plus
ribavirin (I/R), including those that had failed PEG/RBV or peginterferon
alfa-2a/RBV. We have previously reported a surprisingly high SVR in these
patients, especially those with an early viral response.
Aim:
To define early viral response at week 12 as a predictor of
SVR in these patients.
Methods:
HCV NRs or those that had relapsed
after previous treatment with I/R who have significant fibrosis (Metavir F2-F4)
received PEG-Intron 1.5 microgram/kg subcutaneously once weekly plus Rebetol
800-1400 mg/day for up to 48 weeks. All patients had pre-treatment biopsies
scored by a single reviewer using METAVIR criteria. Plasma HCV-RNA was
determined at weeks 12, 24 and 48 of therapy and FU 12 and 24 using a
quantitative Taq-Man assay (SPRI; sensitivity 29
IU/mL). Genotype was determined by sequencing PCR product.
Results:
Of the first 1354 patients treated in the combination therapy
trial, 23% achieved SVR. Of those who attained > 2 log decrease in viral
load at week 12, 37% achieved SVR: 56% of those who were HCV-RNA (-), but only
6% of those who attained a 2 log decrease in HCV-RNA but remained HCV-RNA
positive. Of this latter group, 17% of subjects with very low viral load at
TW12 (<100 IU) achieved SVR compared to 5% of those with residual viral load
of >100-250IU, and 0 in those with HCV-RNA >750.
Conclusions:
SVR is strongly correlated with a negative HCV-RNA or HCV-RNA
near the lower limit of detection at week 12, but is extremely low in those
with HCV-RNA>100 IU/ml. These data suggest that undetectable viral load at
week 12 (<29 IU/ml) best defines a robust EVR that predicts SVR for previous
I/R treatment failures re-treated with PEG-Intron plus WBD ribavirin.
Rate
of SVR based on viral load at TW12
|
HCV-RNA at TW 12 (I.U./mL) |
SVR %
(n/total) |
|
>750 |
0 (0/582) |
|
>500-750 |
4.8 (1/21) |
|
>250-500 |
5.1 (2/39) |
|
>100-250 |
5.1 (2/39) |
|
29-100 |
16.9 (13/77) |
|
Undetectable |
56.1 (281/501) |
A.
Mangia; N. Minerva; V. Carretta;
D. Bacca; G. L. Ricci; F. Vinelli;
R. Cozzolongo; O. Vuturo;
S. Gaetano; F. Spirito; L. Mottola;
D. Petruzzellis; A. Andriulli.
Objectives:
To prospectively compare the efficacy of PEG interferons (IFNs) alpha 2a or 2b and Ribavirin (RBV) when given for the
standard 48 wks or as individualized treatment, for 24, 48 or 72 wks in
accordance with HCVRNA negative by PCR at different time points in naïve pts
with HCV genotype 1. To identify predictive factors of both 1) HCVRNA negative
test at wk 4 (RVR), and 2) sustained virological response (SVR).
Methods:
A total of 645 naïve pts were enrolled and randomly assigned
at 2:1 ratio to a standard 48-wk regimen of PEGIFNs
(alternatively alpha 2b, 1.5 mcg/wk or alpha 2a, 180 mcg/wk) plus ribavirin
(RBV) 1000-1200 mg/daily on the basis of body weight (n= 215, Group B) or to an
individualized treatment based on HCVRNA evaluation at different time points,
with the same PEGIFNs and RBV doses (n= 430, Group
A). When HCV was firstly not detectable (< 50 UI /ml) at wks 4, 8 or 12, pts
in individualized treatment group were treated for 24, 48, 72 wks,
respectively. Pts RNA positive at wk 12 were considered non responders. Primary
end point was SVR (HCVRNA <50 IU/ml ) 24 wks after the end of treatment.
Results:
Both groups were well matched for baseline characteristics.
By wk 8, 54% out of 645 patients were HCVRNA-ve.
Overall SVR was 46.2% with the individualized and 44.6% with the standard
treatment (p= 0.55). RVR was achieved in 28% of pts (n= 184) in both groups. Of
these rapid responders 76.5% in group A and in 84.1% in Group B obtained SVR
(p=0.25). RVR was achieved in 29.7% of pts treated with alpha 2b and 27.2% of
those treated with alpha 2a. Relapse rate was 18% among pts treated for 24 wks,
but 10.5% overall in Group A, and 9.5% in Group B. No differences were found on
the rate of relapse between the two IFNs (10.1 vs 10.5%). By univariate
analysis, factors associated with RVR were age ≤45 yrs (p=0.01), HCVRNA
levels lower than 600.000 IU/ml (p= 0.01) and fibrosis score < 3 (0.008).
Factors associated with SVR in the table. The independent predictor of 1)RVR
was fibrosis score <3, p=0.024; OR 1.27, 95% CI 1.03-1.57, 2)SVR was RVR,
p=0.0001, OR 8.6, 95% CI 5.3-13.9.
Conclusions:
In HCV1 pts, once RVR is obtained, a 24 wks course of
treatment is effective as a 48 wks course. Pts with advanced liver damage are
less likely to achieve RVR and to be treated for only 24 wks. RVR is the best
predictor of SVR. The highest likelihood of SVR is achieved by wk 8.
|
|
NR
(N=335) |
SVR(N=273)
|
P value |
|
Age<45 yrs |
87 |
104 |
0.002 |
|
Fibrosis < 3 |
169 |
180 |
0.0001 |
|
RVR |
38 |
143 |
0.0001 |
|
Drop out |
58 |
0 |
0.0001 |
C.
Huang; C. William; H. Chen; C. D. Howell.
Introduction:
There is a need for biomarkers that when measured either before
or during the first month of treatment can accurately predict the outcomes of
HCV therapy. Goal: We conducted a study of global gene expression in the
peripheral blood mononuclear cells (PBMC) of HCV genotype 1 patients during the
first 4 weeks of peginterferon (PEGIFN) plus ribavirin treatment and defined a
minimal set of genes for predicting a SVR and no SVR.
Methods:
Treatment-naïve, HCV genotype 1 patients (n = 24) were
treated with PEGIFN alfa-2a (180 mcg/wk) plus ribavirin (1000-1200 mg per day)
for 48 weeks. PBMC were isolated at baseline (day - 0) before treatment and at
day-28 of therapy. PBMC RNA was amplified one time and hybridized to the Affymetrix GeneChip HG-U133 plus
2.0 array representing 39,000 human genes. Significance Analysis of Microarray (SAM) software was used to identify genes
expressed differentially between day-0 and day-28 and between SVR (undetected
serum HCV RNA > 24 weeks after treatment) and non-SVR patients. Genes were
classified by biological process and ranked using DAVID 2.0. Prediction
Analysis of Microarray (PAM) software was used to
select sets of differentially expressed genes to predict SVR and to determine
the misclassification rate.
Results:
Compared to day 0 (pretreatment
baseline), the expression of 309 genes was increased significantly and the
expression of 668 genes was decreased at day 28 with a false discovery rate of
<1.0 %. A large number of interferon-stimulated genes were increased with
response to pest, pathogen or parasite (p < 0.0001), response to virus (p
< 0.0001), host defense response (p < 0.0001),
inflammatory response (p < 0.001), protein kinase
cascade (p < 0.001), chemotaxis (p < 0.05),
protein modification (p < 0.05), and regulation of NF-kappa B (p < 0.05)
being the most significant biological processes. DNA dependent RNA
transcription, RNA processing, and protein biosynthesis, modification, and
transport (p < 0.001 for each category) were the main processes associated
with the decreased genes. The microarray results were
confirmed by realtime RT-PCR for 10 select genes. PAM
identified differentially expressed gene subsets from 13 to 124 in number that
correctly predicted SVR and no-SVR among with a misclassification (i.e. error)
rate of <10%.
Conclusions:
PEGIFN alfa-2a and ribavirin treatment is associated with
significant alterations in PBMC gene expression during the first 28 days. A
change in expression of a limited set of genes at day-28 was able to predict
SVR with greater than 90% accuracy.
M.
Yoneda; K. Fujita; T. Fujisawa; H. Chiba; H. Mawatari; H. Takahashi; A. Goto;
H. Kirikoshi; K. Yonemitsu;
S. Saito; A. Nakajima.
Introduction:
Insulin Resistance (IR) is associated with obesity, type 2 DM
and in particular, the visceral adipose tissue area. However, none of the
epidemiological studies conducted until now have analyzed the relationship
between HCV infection and the risk of IR independent of the influence of
obesity, type 2 DM and heavy alcohol consumption; therefore, the precise
relationship between HCV and IR remains unclear. Elucidation of the
relationship between HCV and IR is of great clinical relevance, because IR
promotes liver fibrosis. In this study, we tested the hypothesis that HCV
infection by itself may promote IR, independent of the influence of the
visceral adipose tissue area, in non-obese, non-diabetic and non-alcoholic
patients with chronic HCV infection.
Material and Methods:
We prospectively evaluated 47 patients with chronic HCV
infection who underwent liver biopsy. Patients with obesity (BMI >25), type
2 DM, and a history of alcohol consumption were excluded from this study. IR
was estimated by calculation of the modified homeostasis model of insulin
resistance (HOMA-IR) index. The abdominal fat distribution in the subjects was
determined by computed tomography (CT).
Results:
Fasting blood glucose levels were within normal range in all
the patients. The results of univariate analysis
revealed a significant correlation between the quantity of HCV RNA and the
HOMA-IR. While a significant correlation between the visceral adipose tissue
area and the HOMA-IR was observed in the 97 control non-diabetic,
non-HCV-infected patients (r= 0.398, p<0.0001. However, to our surprise, no
such significant correlation between the visceral adipose tissue area and the
HOMA-IR (p= 0.04465) was observed in the patients with HCV infection. Multiple
regression analysis with adjustment for age, gender and visceral adipose tissue
area revealed a significant correlation between the HCV-RNA titer
and the HOMA-IR (p= 0.0446).
Conclusion:
Hepatitis C virus directly causes IR in a dose-dependent
manner independently of the visceral adipose tissue area before the onset of
diabetes. This is the first report to demonstrate the direct involvement of HCV
and IR in patients with chronic HCV infection.
S.
Villano; A. Howe; D. Raible;
D. Harper; J. Speth; G. Bichier.
Background:
HCV-796, an oral non-nucleoside inhibitor of hepatitis C virus
(HCV) RNA-dependent RNA polymerase, has demonstrated potent antiviral activity
in vitro and in vivo. In a clinical dose-ranging study, HCV-796 was
administered twice daily for 14 days and demonstrated dose-related antiviral
activity across multiple HCV genotypes, with maximal effects observed at
approximately day 4 of treatment. Mean reductions of HCV RNA at day 4 in the
highest dose groups were 1.4-1.5 log10 below baseline. In all dose groups, the
predominant virologic response pattern demonstrated an initial decline of
plasma HCV RNA levels followed by an increase of viral RNA levels that were not
explained by changes in plasma concentrations of HCV-796.
Methods:
In a randomized, double-blind, placebo-controlled study, 102
treatment-naïve adult patients with HCV (72% genotype 1) received 50, 100, 250,
500, 1000, or 1500 mg oral doses of HCV-796 or placebo given as monotherapy
twice daily (q12h) for 14 days. Samples from baseline, during treatment, and at
the end of treatment were selected for analysis from patients with various
virologic response patterns (no response, initial decline in HCV RNA levels
followed by an increase, and continuous decline). HCV RNA from plasma was
isolated, and full length NS5B was amplified using RT-PCR and then sequenced.
Summary/Conclusion:
Sequence data of the NS5B gene are available for 58 patients
with HCV genotype 1a.
·
HCV-796
demonstrated initial rapid antiviral activity in treatment-naïve patients with
HCV infection.
·
Subsequent
increases of plasma HCV RNA levels during HCV-796 monotherapy appear to be
associated with selection of viral variants with reduced susceptibility to the
inhibitor.
·
The
major variant expresses a C316Y substitution in NS5B, and remains susceptible
to interferon and ribavirin in vitro.
·
C3164/f/s
replicons results in 10- to 166 fold reduced
susceptibility to inhibition by interferon, ribavirin, and other HCV inhibitors
·
Several
baseline and on-therapy mutations were identified in patients who did not
achieve continued virologic response
·
Analyses
of additional subjects and timepoints are in
progress.
·
Validity
of these mutation need to be confirmed in phase II studies
P.
Kaiser; H. Holger; L. Bissinger;
L. Bettina; B. Sauter; M. Gregor.
Treatment of naive, genotype 1, high viral load chronic
Hepatitis C patients with pegylated interferon and ribavirin (RBV) results in
sustained viral response rates of about 30 –35 %. Recently improved response
rates have been suggested in treatment trials using an extended treatment
duration of 72 weeks. Furthermore, treatment with an bio-optimized interferon,
Consensus interferon (CIFN), has shown higher response rates in
difficult-to-treat patients such as nonresponders and relapsers.
Methods:
The efficacy of CIFN daily dosing + RBV for 48 versus 72
weeks in genotype 1, high viral load patients was evaluated. 120 patients have
been included, average weight of patients was 79 kg. Patients were either
treated with CIFN at 9 ug QD for 48 or 72 weeks both
in combination with weight-based RBV.
All patients had HCV RNA >600 KIU.
Results:
Data show that after the initial 12 weeks a primary response
with a 2-log drop of HCV-RNA (EVR) was observed in 89% and 92% of patients in
the CIFN QD 48 week and 72 week treatment group. The sustained viral response
rates (SVR) were 51 and 68 %, respectively (p<0.05), indicating a
significantly higher relapse rate in patients treated with CIFN for 48 weeks
compared to 72 weeks. No growth factors were used in this study. Three patients
experienced grade III thrombocytopenias, while no
grade IV neutropenias or thrombocytopenias
were observed. The overall tolerability of the CIFN QD regimen was comparable
to PEG IFN standard combination therapy, while the 72 week regimen lead to a
higher rate of injection site reactions and a slightly higher drop out rate of
7% versus 4% (p=n.s.).
Conclusions:
Extended CIFN daily dosing combination therapy for 72 weeks
shows promising response rates in difficult-to-treat patients with genotype 1
and high viral load when compared to a standard treatment period of 48 weeks.
Although a significant proportion of patients also experienced a relapse after
cessation of a 72 week treatment period, the overall sustained response rates
are nevertheless promising showing a SVR in 68% of patients. It is concluded
that extended treatment with CIFN in combination with RBV may be an effective
treatment modality for this difficult-to-treat patient group. In addition, a larger prospective study is
underway to confirm these findings.
P.
Kaiser; L. Bissinger; H. Hass; B. Lutze;
B. Sauter; M. Gregor.
Objective:
Antiviral treatment response in patients with chronic
hepatitis C and liver cirrhosis is considerably lower than in non-cirrhotic
patients and therapy is complicated by high dropout rates, less tolerablity of side effects and high rates of hematological complications.
Pegylated interferons have shown higher response rates than
standard interferons, however, also higher dose-reduction and drop-out rates
due to lower tolerability, especially regarding thrombocytopenia, thus
resulting in an overall only minor benefit. Consensus interferon (CIFN) is an
interferon with a relatively low half-life, but stronger antiviral potency as
shown by high efficacy in nonresponders.
Methods:
The efficacy of CIFN together with ribavirin (RBV) was
evaluated in 114 patients with chronic hepatitis C and cirrhosis Child A and B.
All patients had histologically proven cirrhosis, elevated ALT values and were viremic, with 79% having genotype 1. Child A patients were
treated with CIFN 9 ug TIW for 4 weeks, followed by 9
ug QD for another 4 weeks. Continuing treatment
consisted of CIFN 9 ug QD with RBV with a stepwise
increase from 400 mg by 200 mg increments at 4 week intervals for a total of
another 52 weeks. For Child B patients the two lead-in phases with CIFN
monotherapy were extended to 6 weeks each, and the starting dose of RBV was
200mg with an otherwise identical therapy as with Child A patients. Based on
tolerability the dosing of RBV was increased to a weight-based dosing for all
patients.
Results:
At 60 weeks therapy an undetectable HCV-RNA was observed in
76% and 47% of Child A and B patients, respectively, with drop out rates of 13%
and 27%. Sustained response rates showed a 64% and 29% response for Child A and
B, respectively. Due to side effects CIFN had to be dose reduced in 11% and
31%, mainly due to low platelet counts. As growth factors erythropoetin
as well as G-CSF was used. Three patients experienced grade III and one
patients a grade IV thrombocytopenia. Overall tolerability of the CIFN QD
regimen was comparable to a standard therapy with pegylated IFN and RBV, while
CIFN even as QD treatment resulted in a lower rate of thrombocytopenias.
Conclusions:
CIFN as a low ascending and finally daily dosing regimen with
subsequent escalating RBV shows significant response rates in Child A and B
cirrhotic patients. Therapy is also safe, however, a significant portion of
patients was unable to even tolerate lower doses of CIFN or RBV. These data
suggest that for a subgroup of cirrhotic patients even in stage Child B a
combination therapy of CIFN and RBV may lead to viral eradication.
R.
Flisiak; A. Horban; J. Kierkus; J. Stanczak; I. Cielnak; G. P. Stanczak; A. Wiercinska-Drapalo; E. Siwak; J. Higersberger; C. Aeschlimann; P. Grosgurin; V. Nicolas; J. Dumont; H. Porchet;
R. Crabbé; P. Scalfaro.
Background:
In Poland almost 50% of HIV-1 infected patients are HCV co-infected.
Available therapies do not include agents with a dual antiviral activity.
DEBIO-025, a cyclophilin inhibitor, showed strong
anti-viral activity in in vitro and in vivo studies,
both against HIV-1 and HCV. This phase I study aimed to determine the
anti-viral effect, the pharmacokinetic profile and the safety of an oral
therapy with DEBIO-025.
Methods:
Two centers, double blind, placebo controlled, oral dosing,
single arm, phase I study design. Treatment-naïve HIV-1 mono- or HIV/HCV
co-infected subjects received 1200 mg of DEBIO-025 or placebo twice daily
during 15 days (unbalanced randomization). DEBIO-025 blood and plasma levels
were assessed on days 1 and 15. Viral loads were determined with the Abbott Realtime m2000 PCR system (HCV limit of quantification
LOQ=10 IU/mL, HIV-1 LOQ= 25 copies/mL) daily from day -1 to 2, at days 4, 8,
10, 15 of treatment and at 1, 2 and 3 weeks after the last dose.
Results:
23 Caucasian subjects (19 DEBIO-025, 4 placebo) completed the
study. DEBIO-025 was rapidly absorbed with peak plasma levels reached after 2
hours and a terminal half life of 100 hours. The mean maximal decrease in HIV-1
load was 1.0 log10 (±0.1 SE, p<0.001). A pronounced effect on HCV load was
found with a mean maximal decrease of 3.6 log10 (±0.4 SE, p<0.001). All
subjects, except one, showed a HCV reduction of >2 log10 with differences
depending on genotype (GT; Tab). Three subjects had undetectable HCV plasma
levels. Hyperbilirubinaemia was observed in 10
subjects and led to premature treatment discontinuation in 4. No increase of
ALT/AST or γ-GT was observed. A platelet decrease was reported on 3
occasions, but was not associated with signs of bleeding. Abnormal bilirubin
and platelets returned to baseline after end of treatment.
Safety:
·
Hyperbilirubinaemia in 10 subjects
·
A
total of 4 patients discontinued treatment prematurely for this reason
·
Bilirubin
levels returned to normal after cessation of treatment
·
This
was not observed in doses up to 1200mg od for 10 days
·
Decreased
plates in 2 patients but was not associated with signs of increased bleeding
and patients’ platelets returned to normal.
Conclusions:
DEBIO-025 administered for 15 days showed a dual anti-viral
effect in HIV-1 and HCV co-infected treatment naïve subjects and appears to be
a very promising compound with a new and unique mode of action. Despite good
clinical tolerance, the observation of hyperbilirubinaemia
and platelet decrease requires further investigation.
J.
H. Lewis; S. F. Zweig; R. Belder.
Introduction:
The use of HMG-CoA reductase inhibitors (statins) is
generally not recommended in pts with chronic liver disease (CLD), although
retrospective analyses of statins indicate their safe
use in patients’ with elevated ALT (due mostly to NAFLD) and a recent
prospective, randomized ,placebo-controlled trial demonstrated the safety and
efficacy of pravastatin in hypercholesterolemic
subjects with various CLD [Gastroenterology 2006;130(4 suppl
2):A65 abstract #446].
Aim:
We performed a subgroup analysis of subjects with CHCV from
our 36-week study of Prava 80mg/day conducted in 320 hypercholesterolemic pts with various well-compensated CLDs (about 25% with CHCV and two-thirds having NAFLD). No statisically signifcant
differences were observed between Prava or placebo
recipients at any time point in terms of the primary safety endpoint of a
doubling of ALT from either a normal or elevated baseline for the cohort as a
whole. We did, however, observe a numerically lower number of subjects with ALT
events in the Prava group, and sought to correlate
this potential beneficial effect with the reduction in lipids that was also
seen.
Results:
Changes in mean ALT values were analyzed in 38 and 43 CHCV
pts randomized to Prava and placebo respectively and
correlated with the percentage change in total cholesterol (TC), LDL, and
triglycerides (TGs) over the 36 wks of the trial.
Using a 2 sample t-test, we observed a modest reduction in ALT values at nearly
all time points over the 36 wk trial among the Prava
recipients (ranging up to a 6% decrease from baseline), while ALT values on
placebo tended to increase (as much as 33%). At several time points, the
comparative difference in the change in ALT approached statistical significance
(e.g. p=0.0637). These reductions in ALT on Prava
appeared to correlate with the highly statistically significant reductions in
lipids seen on Prava compared to placebo (p
<0.0001).
Summary:
Pravastatin Efficacy in HCV
·
Pravastatin 80 mg daily statistically lowered total cholesterol and LDL-C
at week 12 compared with placebo in subjects with chronic hepatitis C
·
Mean
lipid values at other time points (weeks 4,8,24 and 36) also showed similar
statistical significance favoring pravastatin.
Pravastatin Safety in HCV
·
ALT
events were not statistically different between pravastatin
and placebo recipients at any time during the 36 week study in patients
underlying compensated chronic hepatitis C.
·
However,
the incidence of ALT events was lower at all time points compared to placebo in
hepatitis C patients (possible treatment effect?).
·
No
difference in serious AEs or discontinuations due to AEs between the groups.
Conclusions:
This subgroup analysis of our larger prospective, randomized,
double-blind, placeo-controlled trial demonstrates
the efficacy and safety of high-dose Prava in hypercholesterolemic subjects with CHCV. In addition to the
significant reduction of TC, LDL and TGs, there was
also a trend toward a significant numerical reduction in ALT values on Prava compared to placebo for the patients with CHCV. While
the mechanism for the ALT reduction is uncertain, the results warrant further
study relative to the interrelationship between hepatitis C and serum lipids.
R.
Brown; I. Jacobson; A. Nezam; B. Freilich;
M. Pauly; F. Regenstein; S. Flamm;
P. Kwo; S. Becker; L. Griffel;
C. Brass.
Aim:
Patients with G2/3 hepatitis C virus (HCV) have high SVR
rates to PEG-IFN alfa-2b + RBV and require shorter duration of treatment. G3
patients with a baseline high viral load (HVL) have lower response rates and
higher relapse rates than G2 patients (Table), but predictors of relapse are
not known. The purpose of this analysis was to determine the predictors of
relapse to PEG-IFN alfa-2b + RBV in patients with HCV G3.
Methods:
In the WIN-R trial, which was a multicenter,
randomized, open-label, investigator-initiated trial in 225 US sites,
treatment-naïve HCV patients with compensated liver disease were randomized to
receive PEG-IFN alfa-2b 1.5μg/kg/wk + fixed dosing (FD; 800mg/d) or
weight-based dosing (WBD; 800 mg/d, <65kg, 1000mg/d, 65–85kg; 1200mg/d,
>85–105kg; 1400mg/d, >105–125kg) of RBV for 24 or 48 wks. HCV RNA was
assessed by PCR (Taqman/SPRI, LLQ 29IU/mL) at wks 0,
24, 48 and 72. The primary endpoint was SVR (HCV RNA negative at wk 72) in
patients ≥65kg. Multivariate regression analyses were used to analyze
predictors of relapse.
Results:
G2/3 patients (n=1829) were enrolled and randomized to WBD
(24 wks n=317, 48 wks n=602) or FD (24 wks n=322, 48 weeks n=588). With WBD and
24 wks of therapy, SVR rates were higher and relapse lower with G2 than G3
patients (SVR: 72% vs 63% and relapse: 5% vs 11%). Relapse rates were highest among G3 HVL patients
treated for 24 weeks (16%). Univariate analyses
revealed G3 (vs G2), viral load (high vs low) and duration of treatment (24 vs
48 weeks) were associated with higher relapse rates in Caucasians. African
Americans had a lower relapse rate and no difference between G2 and G3.
Multivariate analyses controlling for the above, race, and steatosis revealed
only G2 vs G3 as a predictor of relapse. G3 HVL
patients had similar relapse rates with WBD/48 wks of therapy than with FD/24
wks therapy.
Summary:
·
Overall,
G2 patients experienced higher SVR rate3s and lower relapse rates than G3
patients.
·
Relapse
rates were highest among G3 high viral load patients treated fro 24 weeks.
·
Multivariate
analysis revealed G3 patients (versus) G2 patients as the only predictor of
relapse.
·
Similar
to G2 patients, when controlling for viral load, G3 patients do no appear to
benefit from longer duration of therapy or WBD ribavirin.
Conclusions:
|
|
SVR, % |
Relapse
Rate, % |
|
|
WBD vs FD |
WBD vs FD |
|
G2 patients |
72/68 vs
71/62 |
6/3 vs
6/66 |
|
LVL (24/48 wks) |
71/66 vs
73/66 |
6/5 vs
6/7 |
|
HVL (24/48 wks) |
69/59 vs
74/58 |
7/2 vs
8/6 |
|
G3 patients |
63/54 vs
57/49 |
10/11 vs
10/13 |
|
LVL (24/48 wks) |
65/56 vs
61/51 |
6/9 vs
7/16 |
|
HVL (24/48 wks) |
70/52 vs
53/55 |
18/16 vs
14/7 |
I.
Jacobson ; P. Pockros; Y. Benhamou;
R. Esteban-Mur; Y. Lurie; R. Flisiak;
N. Afdhal; Y. Kim; Y. Xu;
B. Murphy.
Introduction:
A recent Phase 3 trial examining the efficacy and safety of
fixed-dose taribavirin when combined with PEG IFN alfa 2b vs
weight base dosed ribavirin (RBV) plus PEG IFN alfa 2b revealed that the
taribavirin treated pts exhibited a significantly lower anemia rate (5% vs 24%;p<0.001) but failed to meet the non-inferiority
criterion when analyzed for efficacy (38% vs 52%).
Taribavirin is a liver-targeting pro-drug of RBV and is converted to the active
moiety by the enzyme adenosine deaminase. Since the
current standard of care in the management of HCV is to weight base drug
exposure of RBV, this post-hoc analysis looked at the impact on efficacy and
the development of anemia (hemoglobin<10g/dL) of drug exposure based on
weight(mg/kg).
Methods:
This Phase 3 study randomized 970 pts in a 2:1 ratio into a fixed dose taribavirin arm vs a weight base dosed RBV arm, stratifying pts on the basis of genotype, baseline viral load, and weight. In thi