Monday Posters (11/14/2005)– HCV Therapy: Phase 3,4 Trials – 8:00AM – 6:30PM
Abstract ID: 62836
Category: JO8: HCV
Therapy: Phase 3, 4 Trials
SHORT-TERM TREATMENT DURATION FOR HCV-2 AND HCV-3 INFECTED PATIENTS WITH CHRONIC HEPATITIS.
A. Andriulli, Division of
Gastroenterology, Hospital CSS, San Giovanni Rotondo, Ital, SAN GIOVANNI
ROTONDO, Italy, O. Dalgard, Aker University Hospital, Oslo, Norway, K. Bjoro,
Rikshospitalet, Oslo, Norway, A. Mangia, Hospital Casa Sollievo Sofferenza,
IRCCS, San Giovanni Rotondo, Italy
Introduction
We have previously shown that 12-14 weeks treatment is
effective in HCV-2 or -3 patients in whom HCV-RNA become undetectable after 4
weeks of therapy (rapid virologic response, RVR).
Aims
To identify predictors of SVR, RVR and relapse following short
treatment.
Patients
Data from two sets of patients (from
Methods
Primary end point was undetectable HCV-RNA 24 weeks after
therapy (SVR). Possible predictors of SVR, RVR and relapse following short
treatment were analyzed by logistic regression models.
Results
SVR was obtained in 313/403 patients (78%). SVR differed
between cases with or without RVR (85% vs 61%, P<.0001), mild or bridging
fibrosis/cirrhosis (83% vs 67%, P=.004), absent/mild or moderate/severe
steatosis (82% vs 71%, P=.011), HCV-2 or -3 (81% vs 73%, P=.05) low or high
viremia (79% vs 76%, P=.5).
RVR, mild fibrosis, and HCV-2 were independent predictors of
SVR.
RVR was obtained in 274/403 (68%) patients, 163/242 (67%)
HCV2, and 111/161 (69%) HCV-3. Patients with RVR had, as compared to those
without RVR, more frequently low grade steatosis (70% vs 63%, P=.43), mild
fibrosis (70% vs 56%, P=.03), and high PegIFN dose (78% vs 64%, P=.005); RVR
was independent of viral load. In a logistic regression model, absence of severe
fibrosis independently predicted RVR. In
RVR patients, SVR was achieved in 85% of both HCV-2 and HCV-3.
Virologic relapse was observed in 27/274 RVR patients, and
was more frequently observed among those with low ALT levels (14% vs 2%,
P=.04), high viremia (13% vs 9%, P=.40), and severe fibrosis (23% vs 8%, P=.82).
Peg-IFN dose, steatosis and genotype were not associated with
risk of relapse. Severe fibrosis and low ALT were independent predictors of
relapse.
SVR was significantly predicted by the RVR status (OR 3.49,
CI 1.73-5.36) and a low fibrotic score (OR2.91, 1.57-5.38), but not by
genotype, baseline viral load, and treatment regimen.
Relapse could be predicted by any of baseline features
evaluated in the present study.
Conclusion
o
In HCV-2 or -3, the HCVRNA status after 4 weeks of therapy
may guide treatment duration, as the majority of rapid responders may safely
receive shorter courses of therapy without compromising SVR.
o
With a short therapy, patients with advanced fibrosis are
less likely to experience both RVR and SVR.
o
In non-RVR patients, 24 weeks of therapy for HCV-2 patients
may be satisfactory, whereas longer courses should be considered for genotype
3.
Abstract ID: 61186
Category: JO8: HCV
Therapy: Phase 3, 4 Trials
Peg-IFN alpha2b and ribavirin in decompensated cirrhotic patients with chronic HCV infection: a controlled study.
A. Iacobellis, Hospital
Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy, L. Accadia,
Hospital Casa Sollievo Sofferenza, San Giovanni Rotondo, Italy, N. Caruso,
Hospital Casa Sollievo Sofferenza, San Giovanni Rotondo, Italy, A. Andriulli,
Division of Gastroenterology, Hospital CSS,, San Giovanni Rotondo, Italy
Objectives:
To evaluate efficacy, safety, and impact on natural history
of PegIFN α -2b (1.0 μ g/kg) and ribavirin (800-1000 mg/daily),
administered for 24 weeks, in type C decompensated cirrhosis.
Patients & Methods:
From Sept 2003 to May 2004, 78 consecutive pts, admitted for
ascites (72%), variceal bleeding (16%), encephalopathy (18%), naïve to therapy,
were offered treatment: 40 pts agreed and those who did not (n=38) served as
controls. Therapy was started when pts were compensated. Treated and control
pts presented, respectively, in Child-Pugh (CP) class A (13% and 5%), B (60%
and 61%) and C (27% and 34%); their respective mean ages were 63 ±9
vs 65 ±7;
HCV-1 was typed in 60% and 79%. The main end point was the effect of therapy on
the natural history, estimated by the Kaplan-Meier method. Undetectable HCV-RNA
24 weeks off therapy (SVR) and safety were secondary end points.
Results
3 pts dropped out prematurely for intolerance. Antiviral
therapy was associated with 20 adverse events (4 severe infection with death,
12 mild infections, 2 bleedings, and 2 HCC); during the same span of time, 20
events were registered in controls (4 severe infections with death, 7 mild
infections, 5 bleedings, and 4 HCC). All but one severe infections occurred in
CP class C. SVR rates were achieved in 8/40 pts (20%), including 6/13 HCV-2
(46%) and 2/27 HCV-1 (7%). After 19±1,3 months of follow up, the mean CP score,
as compared to basal value, improved in pts with SVR (8±1,3 vs 7±0,8), was
unchanged in non responders (7,9±1,3 vs 8,2±1,4), and worsened in controls
(8,6±1,5 vs 9,3±1,7). In the 64 surviving pts without OLT, CP score at follow
up, as compared to basal value, decreased by at least 1 point in 6/8 (75%) pts
with SVR, in 4/26 (15%) non-responders and 1/30 (3%) controls; was unchanged in
2 SVR pts (25%), 11 non responders (42%) and 9 controls (30%), and increased by
at least 1 point in 11 nonresponders (42%) and 20 controls (66%) (p=0.001). At
Kaplan-Meier evaluation, the number of decompensated events were significantly
reduced during the follow up in pts with SVR, as compared to both unresponsive
and control pts (Figure).
Conclusions:
In decompensated cirrhotics, combination therapy is poorly tolerated,
and unsafe in CP class C. The obtained SVR rates are encouraging for HCV-2, but
not for HCV-1 pts. In pts with SVR, therapy positively influences natural
history of the disease.
Abstract ID: 65419
Category: JO8: HCV
Therapy: Phase 3, 4 Trials
Sustained Virologic Response Rates from a Randomized Trial of HCV Genotype-1 Subjects Treated with Either Consensus IFN and Ribavirin or Pegylated Interferon alfa-2b and Ribavirin.
M. Sjogren, Walter Reed Army Medical Center, Washington ,
DC, R. Sjogren, Kaiser Permanente Mid Atlantic States, Falls Church, VA, M. F.
Lyons, Tacoma Digestive Diseases Center, Tacoma, WA, M. Ryan, Digestive &
Liver Disease Specialists, Norfolk, VA, J. Santoro, Atlantic Gastroenterology
Associates, Egg Harbor Township, NJ, C. Smith, Minnesota Gastroenterology, St.
Paul, MN, K. R. Reddy, University of Pennsylvania GI Research, Philadelphia,
PA, H. Bonkovsky, University of Connecticut Health Center, Farmington, CT, B.
M. Huntley, Walter Reed Army Medical Center, Washington , DC, L. Ibarra,
InterMune, Inc., Brisbane, CA, S. Faris-Young, Intermune, Inc., Brisbane, CA
Background:
Over 50% of patients treated with genotype-1 chronic HCV
infection fail to achieve a sustained virologic response (SVR). Recent studies
have shown that consensus interferon (CIFN) in combination with ribavirin (RBV)
may be particularly active against genotype-1 HCV infection.
Aim:
Proof of concept study to compare treatment with CIFN/RBV to
pegylated interferon (PEGIFN) and RBV in achieving SVR. This was a prospective
randomized clinical trial where treatment-naïve HCV genotype-1 subjects
received either CIFN 15 mcg TIW and weight-based generic ribavirin (Ribasphere)
(group 1) or PEG-Intron 1.5 mcg/kg/week and weight based ribavirin (Rebetol),
(group 2).
Methods:
59 subjects were enrolled, 30 in group 1 and 29 in group 2.
Treatment lasted 48 weeks if HCV RNA was undetectable at week 24, otherwise
drugs were discontinued. SVR was determined at week 72. Safety laboratory tests
and adverse events (AE) assessments were done monthly. To date all subjects
have completed week 48 and 56 subjects have finished week 72. Results: At
baseline the 2 groups were similar in gender (67% men), age (mean = 44 years),
weight (202 lbs men, 152 lbs women), ethnicity (59% Caucasian, 30% African
American), high viral load (75%, mean levels: 3.8 and 3.6 million IU/mL for
groups 1 and 2) and hemoglobin (mean: 15 g/dL). Cirrhosis was diagnosed in 3
subjects of group 1 and 5 subjects of group 2. The SVR was similar for both
groups: 37% for CIFN/RBV and 35% for PEGIFN/RBV.
The week 48 and SVR by viral load were:
ITT Analysis - Undetectable HCV RNA in Subjects Infected
with Genotype-1 HCV
|
|
High Viral Load |
Low Viral Load |
||
|
Groups |
Week 48 |
Week 72 |
Week 48 |
Week 72 |
|
CIFN/RBV |
6/22 (27%) |
6/22 (27%) |
5/8 (63%) |
5/8 (63%) |
|
PEGIFN/RBV |
10/22 (45%) |
5/19 (26%) |
5/7 (71%) |
4/7 (57%) |
No subject dropped hemoglobin to <8.5 g/dL. Neutrophils
dropped to <750/uL in 13% and 24% of groups 1 and 2, respectively (p= 0.29).
Dose modification for one or two drugs were required in 37% and 62% in each of
the 2 groups (p=0.09). AE were flu-like symptoms in 100% and 93%, headache in
63% and 39%, fatigue in 77% and 50%, mood disorders in 67% and 66%. Serious AE
were observed in 6 subjects (3 per group) (cellulitis, severe fatigue,
psychosis, seizure, dehydration, EtOH recidivism, and pyelonephritis).
Conclusion:
CIFN/RBV combination therapy elicited a comparable SVR to PEGIFN/RBV in previously untreated subjects with genotype-1 chronic HCV. There were no relapsers among the CIFN/RBV treated group. The AE profile for CIFN/RBV demonstrated less neutropenia and dose reductions. A larger clinical trial for genotype-1 chronic HCV infection utilizing CIFN and ribavirin is warranted.
Abstract ID: 67537
Category: JO8: HCV
Therapy: Phase 3, 4 Trials
A STUDY ON THE TREATMENT OF CHRONIC HCV HEPATITIS WITH PEGYLATED INTERFERON ALPHA-2a AND RIBAVIRIN IN HAEMODIALYZED PATIENTS WAITING FOR RENAL TRANSPLANT.
m. rendina, university
hospital, bari, Italy, n. m. castellaneta, department of gastroenterology
university of bari italy, bari, Italy, a. castellaneta, gastroenterology university
of bari italy, bari, Italy, f. losito, gastroenterologia universita' bari
italy, bari, Italy, a. schena, nefrologia universita' di bari italy, bari,
Italy, g. stallone, nefrologia universita' bari, bari, f. p. schena, nefrologia
universita' bari, bari, Italy, a. francavilla, gastroenterologia universita'
bari, bari, Italy
Introduction
Hepatitis C virus (HCV) infection is very common among
patients on haemodialysis and in some transplant Centres this condition
represents a contraindication to kidney transplant. As it is well known, IFN
therapy is not recommended after renal transplant due to the increased
incidence of chronic rejection and graft failure. Furthermore, Ribavirin use is
contraindicated for the increased risk of haemolytic anemia and renal
impairment. The beneficial effect of the IFN+Riba therapy in liver transplanted
pts with HCV recurrence, demonstrated that the combined antiviral therapy
doesn’t modify the immunobiologic state of transplanted pts achieving viral
eradication in about 50% of pts when all the genotype are considered.
Aim of the study:
Aim of the study is to determine 1) the efficacious dose of
Ribavirin which doesn’t adversely affect the anemic state of the patients and
2) to test the clinical efficacy of the IFN+Riba therapy accordingly to the
haemathologic state of the patients.
Patients and Methods:
Twenty-five naïve HCV pts on chronic dialysis and in waiting
list for renal transplant were enrolled. In all cases transaminases were mild
elevated. All were positive for HCV-RNA and the mean viral load was
310327±257147 IU/ml. HCV genotype 1b was detected in 50% of pts. Liver
histology revealed a mild disease in all pts (grade1, stage1-2).The time that
pts were on dialysis ranged from 2 to 16 years. All were in treatment with Epo
at the beginning of therapy. The antiviral schedule consisted of Peg-IFN
alpha-2a, 135 μg/week and Riba 200 mg/day for 48 weeks.
Results:
Twenty-one/25 pts completed study treatment. Four pts were
discontinued for non compliance in 2 cases and for inefficacy at week 12 in the
other cases. Therapy was clinically well tolerated. The main expected
biochemical drawbacks was mild to severe anaemia which was controlled in all
cases with reduction in Ribavirin dose (200mg on every other day) and by increasing
EPO. A 1st virological analysis made at week 12, showed: 19 pts (90%) was
HCV-RNA Neg. This results has been maintained until the end of the study. AST
returned normal in all patients. Post-treatment F-Up is ongoing.
Conclusion:
Combined therapy with Peg-IFN+Riba seems a feasible option in
the particular setting of haemodialysis patients waiting for renal transplant.
A careful pt monitoring is recommended as regards the anemic state.
Surprisingly, up to 90% of pts avhieved a viral negativization thus suggesting
that in these pts the sensibility of the virus to antiviral therapy is quite
different in respect to non haemodialyzed pts.
Abstract ID: 61390
Category: JO8: HCV
Therapy: Phase 3, 4 Trials
Fibrosis Stage is not a Predeterminant of Significant Adverse Events in Previous Interferon (IFN)-Ribavirin (Riba) Treatment Failures Receiving PEG-Interferon-alfa 2b/RIBA Weight Based Dosing: Results from the EPIC3 Program.
R. Terg, Hospital Municap
de Gastroenterologia Dr. Bonorino Udaondo, Buenos Aires, Argentina, E. Schiff,
University of Miami School of Medicine, Miami, FL, R. Moreno, Hospital
Universitario de la Princesa, Madrid, Spain, F. Goncales, Hospital das Clinicas
da Unicamp, Campinas, Brazil, S. Flamm, Northwestern Memorial Hospital,
Chicago, IL, M. Diago, Hospital Gernal Universitario de Valencia, Valencia,
Spain, J. Reichen, Institut fuer klinische Pharmakologie, Bern, Switzerland, J.
Heathcote, University Health Network, Toronto, Canada, T. McGarrity, Milton S.
Hershey Medical Center, Hershey, PA, T. Berg, Universitaetsklinikum
Charite-Campus Virchow, Berlin, Germany, H. Tanno, Hospital Provincial del
Centenario, Rosario, Argentina, A. Mattos, Irmandade da Santa Casa de
Misericordia de Porto Alegre, Porto Allegre, Brazil, J. McHutchison, Duke University
Medical Center, Durham, NC, T. Poynard, Hopital Pite-Salpetriere, Paris,
France, P. Bedossa, Service d'Anatomie Pathologique, Hopital Beaujon, Clichy,
France, P. Savino, Schering Plough Research Institute, Kenilworth, NJ, L.
Griffel, Schering Plough Research Institute, Kenilworth, NJ, M. Burroughs,
Schering Plough Research Institute, Kenilworth, NJ, C. Brass, Schering Plough
Research Institute, Kenilworth, NJ, J. Albrecht, Schering Plough Research
Institute, Kenilworth, NJ
Introduction:
The EPIC3 program includes a large, prospective,
controlled trial designed to understand the safety and efficacy of treatment of
subjects who have significant fibrosis (Metavir F2-F4) with PEG-IFN- α 2b
and RIBA weight based dosing (WBD) for 48 weeks in previous treatment failures
to any IFN- α and RIBA therapy. We have previously reported an SVR
of 21% for these patients. AIM: To compare the safety of administering PEG-IFN-
α 2b and RIBA in subjects with moderate and advanced fibrosis.
Methods
Subjects received PEG-IFN- α 2b 1.5 µg/kg subcutaneously
once weekly plus RIBA 800-1400 mg/day WBD for up to 48 weeks. All patients had
pre-treatment liver biopsies scored by a single reviewer using METAVIR criteria.
Adverse events (AE) and safety laboratories (hematology, chemistries) were
assessed at screening and treatment weeks 2, 4, 8, 12, 18, 24, 30, 36, 42 and
48.
Results:
1964 subjects have initiated treatment; 568 F2, 580 F3 and 806 F4. Subjects have completed a median of 133 days of treatment; 33% have completed 48 weeks of treatment. No new or unexpected AE have been reported in this population with moderate-severe fibrosis.
|
METAVIR FIBROSIS SCORE |
DISCONTINUATION FOR ADVERSE EVENTS |
DOSE MODIFICATION FOR ADVERSE EVENTS N (%) |
SERIOUS ADVERSE EVENTS |
|
N (%) |
N (%) |
Any |
N (%) |
|
F2 (568/29) |
31 (5) |
116 (20) |
31 (5) |
|
F3 (580/30) |
47 (8) |
140 (24) |
47 (8) |
|
F4 (806) |
56 (7) |
234 (29) |
56 (7) |
· There was no difference
in the incidence of these events between fibrosis groups.
· The slight increase in
dose modifications (MOD) for F4 subjects represented minimal increases in a
variety of indications, primarily an increase in the frequency of MOD for
thrombocytopenia for F4 subjects (5%) compared to F2 or 3 subjects (1% and <1%,
respectively).
· Fibrosis score did not
predict the incidence and type of serious adverse event.
· 72 patients developed
WHO grade 3 (25-50,000/mL) and 3 patients developed grade 4 (<25,000/mL)
platelet counts.
· Only 14 patients
developed bleeding that was temporally associated with thrombocytopenia.
· Two subjects developed
significant bleeding episodes: one
hematemesis due to Mallory-Weiss tear and one melena. The remainder of the
episodes were not clinically significant.
Summary
· The incidence of common
adverse events and serous adverse events was not impacted by fibrosis stage.
· Discontinuations and
dose modifications due to hematologic and psychiatric events were not common.
· The pattern of adverse
events and serious adverse events was similar to that in other studies.
· WHO grate 3 and 4 ALT
evaluations were not common. The pattern
of WHO grade ALT values were similar among fibrosis broups.
Conclusions
Retreatment of previous interferon/ribavirin treatment
non-responders with PEG-IFN alfa-2b and ribavirin appears safe for subjects
with advanced disease.
Abstract ID: 61926
Category: JO8: HCV
Therapy: Phase 3, 4 Trials
Interferon (IFN) Induced Thrombocytopenia is Independent of Level of Fibrosis in Patients with Chronic Hepatitis C (CHC): Results from the EPIC3 Program.
E. Schiff, University of
Miami School of Medicine, Miami, FL, R. Terg, Hospital Municap de Gastroenterologia
Dr. Bonorino Udaondo, Buenos Aires, Argentina, R. Moreno, Hospital
Universitario de la Princesa, Madrid, Spain, F. Goncales, Hospital das Clinicas
da Unicamp Cidade Universitaria Zefirino Vaz, Campinas, Brazil, S. Flamm,
Northwestern Memorial Hospital, Chicago, IL, M. Diago, Hospital General
Universitario de Valencia, Valencia, Spain, J. Reichen, Institut fuer klinische
Pharmakologie, Bern, Switzerland, J. Heathcote, University Health Network,
Toronto, Canada, T. McGarrity, Milton S. Hershey Medical Center, Hershey, PA,
T. Berg, Universitaetsklinikum Charite-Campus Virchow, Berlin, Germany, H.
Tanno, Hospital Provincial del Centenario, Rosario, Argentina, A. Mattos,
Irmandade da Santa Casa de Misericordia de Porto Alegre, Porto Allegre, Brazil,
J. McHutchison, Duke University Medical Center, Durham, NC, T. Poynard, Hopital
Pite-Salpetriere, Paris, France, P. Bedossa, Service d'Anatomie Pathologique,
Hopital Beaujon, Clichy, France, P. Savino, Schering-Plough Research Institute,
Kenilworth, NJ, M. Burroughs, Schering-Plough Research Institute, Kenilworth,
NJ, L. H. Griffel, Schering-Plough Research Institute, Kenilworth, NJ, C. A.
Brass, Schering-Plough Research Institute, Kenilworth, NJ, J. K. Albrecht,
Schering- Plough Research Institute, Kenilworth, NJ
Introduction:
The EPIC3 program includes a large, prospective,
controlled trial designed to understand the safety and efficacy of re-treatment
of subjects who have significant fibrosis (Metavir F2-F4) with PEG-IFN α2b
and ribavirin weight based dosing for 48 weeks in previous treatment failures
to any IFN- α and ribavirin therapy. We have
previously reported an SVR of 21% for these subjects.
Aim:
Here we report the effects of PEG-IFN α 2b/ribavirin on
platelet counts in these patients.
Methods:
HCV patients that
did not respond or relapsed after previous treatment with any IFN- α and
ribavirin received PEG-IFN α2b 1.5 µg/kg subcutaneously once weekly plus
ribavirin 800-1400 mg/day weight based dosing for up to 48 weeks. All enrolled
patients had pre-treatment biopsies scored by a single reviewer using METAVIR
criteria. Platelet counts were assessed at screening and at all treatment
visits. We report on the 1964 (568 F2, 580 F3, 806 F4) patients who have been
treated to date.
Results:
Most patients (94%) had decreases in their platelet count
with only 3% having drops greater than 60%. The median decrease was 30%. Less
than 5% of subjects experienced platelet count decreases of more than 60%.
There were no differences in the percentage drop of any level between F2, F3 or
F4 patients. While the median time to nadir platelet count was treatment week
18, 23% of patients reached their nadir at treatment week 36 or later; with 7%
reaching their nadir at week 48.Of patients with a baseline platelet count of
>150x103/µL, only 4 (<1%) had a decrease to < 50 x103/µL; all were F4.
Of those with a baseline count of 100-149 x103/µL, 37 (8%) had decreases to
< 50 x103/µL; 1 F2, 5 F3 and 31 F4. Of those with a baseline level of <99
x103/µL 31 (28%) had decreases to <50 x103/µL; 3 F2, 5 F3 and 23 F4.
Conclusions:
Thrombocytopenia occurs at a similar rate in patients in
patients with CHC undergoing treatment with PEG-IFN α2b and ribavirin
independent of their level of baseline fibrosis. In total, 58/806 (7%) F4
patients reached dose reduction criteria of platelets <50 103/µL, while only
10/580 (2%) F3 patients and 4/568 (<1%) F2 patients reached this level.
These differences are due to the lower baseline values in the F4 subjects, who
were more likely to require dose reductions.
Abstract ID: 66344
Category: JO8: HCV
Therapy: Phase 3, 4 Trials
Minimal important difference (MID) in vitality score; a new outcome measure in HCV treatment trials.
o. dalgard, Infectious
Disease Department, Ullevål University Hospital, Oslo, Norway, K. B. Hellum,
Akershus University hospital, Nordbyhagen, Norway, B. Myrvang, Ullevål
University Hospital, Oslo, Norway, K. Bjøro, Rikshospitalet, Oslo
Background:
Hepatitis C virus (HCV) infection is associated with
tiredness and decreased vitality . In large treatment trials the mean vitality
score, as measured by the questionnaire short form 36 (SF-36), is significantly
improved in those who obtain a sustained virological response (SVR). However, a
significant change in large trials does not necessarily reflect an important
difference. The aim of this study was to determine the number of patients who
experience an important change (improvement or worsening) in vitality score
after HCV treatment.
Materials and methods:
Pegylated interferon-á-2b and ribavirin was administered to
76 patients with HCV genotype 2 or 3.
SVR was defined as a negative HCV RNA test (Cobas Amplicor HCV monitor test) 6
months after end of treatment. SVR was obtained in 66/76 (87%). The median age
was 36 years (range 20-50), 46/76 (61%) were men and cirrhosis was present in
one (1%). The health related quality of life questionnaire SF-36 was
administered before and 6 months after treatment. From the answers to 4 of the
36 questions in SF-36 a vitality score was calculated. Previous calculations of
the minimal important difference (MID) have consistently found half a standard
deviation (SD) to be a threshold for discriminating differences in psychometric
testing. We therefore chose ½ SD of the calculated vitality score as MID.
Results:
The mean vitality score in the 76 patients before treatment
was 53,2 (SD: 20,7). Thus the MID was set to be 10.4.The mean vitality score
among patients with SVR was 53,8 before treatment and 60,9 after (P=0.01). In
patients without SVR vitality score before and after treatment was 49,5 and
47,0 (P=0.69). An improvement greater than MID was observed in 27/76 (36%)
patients and a worsening greater than MID was seen in 15/76 (20%). Among
patients with SVR 26/66 (40%) experienced an improvement greater than MID as
compared to 1/10 (10%) without SVR (P=0.09). Worsening greater than MID was
observed in 12/66 (18%) with SVR and 3/10 (30%) (P=0.26)without SVR.
Conclusion:
Important improvement in vitality was observed in 40% of
patients with SVR. However, a significant number of patients experienced a
worsening of vitality still present 6 months after end of treatment.
Abstract ID: 72446
Category: JO5: HCV: Clinical Trials and
Therapeutic Developments
Weight-Based Ribavirin Dosing (WBD) Increases Sustained Viral Response (SVR) inPatients With Chronic Hepatitis C (CHC): Final Results of the WIN-R Study, A US Community Based Trial
.
I. M. Jacobson, Weill
Medical College of Cornell University, New York, NY, R. S. Brown, Columbia University
College of Physicians & Surgeons, New York, NY, B. Freilich, Baptist
Medical Center, Kansas City , MO, N. Afdhal, Beth Israel Deaconess Medical
Center, Boston, MA, P. Kwo, Indiana University School of Medicine,
Indianapolis, IN, J. Santoro, Atlantic Gastroenterology Associates, EGG HARBOR
TOWNSHIP, NJ, S. Becker, Austin Gastroenterology, PA, Austin, TX, A. Wakil,
California Pacific Medical Center, San Francisco, CA, D. Pound, INDIANAPOLIS
GASTROENTEROLOGY RSCH, Indianapolis, IN, E. Godofsky, Bach and Godofsky, MD PA,
BRADENTON, FL, R. Strauss, Northwest Georgia Gastroenterology Associates, P.C.,
Marietta, GA, D. Bernstein, NORTH SHORE UNIVERSITY HOSPITAL, MANHASSET, NY, S.
Flamm, Northwestern Memorial Hospital, Chicago, IL, N. Bala, Gastroenterology
Consultants, Houston, TX, V. Araya, ALBERT EINSTEIN MEDICAL CENTER,
Philadelphia, PA, M. Davis, South Florida Center of Gastroenterology, P.A.,
Wellington, FL, H. Monsour, Liver Specialists of Texas, Houston, TX, J.
Vierling, Cedars-Sinai Medical Center, Los Angeles, CA, F. Regenstein, Tulane
University Medical School, New Orleans, LA, V. Balan, Mayo Clinic, Phoenix, AZ,
M. Dragutsky, GI CONSULTANTS OF THE MIDSOUTH, Memphis, TN, M. Epstein,
Digestive Disorders Associates, Annapolis, MD, R. W Herring, Nashville
Gastrointestinal Incorporated, NASHVILLE, TN, R. Rubin, Atlanta
Gastroenterology Assoc, Atlanta, GA, G. Galler, KELSEY-SEUBOLD CLINIC, HOUSTON,
TX, M. Pauly, Kaiser Permanente, SACRAMENTO, CA, L. H. Griffel, Schering-Plough
Research Institute, Kenilworth, NJ, C. A. Brass, Schering-Plough Research
Institute, Kenilworth, NJ, t. S. Group,
Background
The trial of Manns (Lancet 2001) established PEG IFN alfa-2b
1.5 ug/kg/wk plus ribavirin (RBV) as the standard for the treatment of CHC.
Logistic regression analysis demonstrated a relationship between RBV dose in
mg/kg and sustained virological response (SVR).
Aim
To compare prospectively the
efficacy and safety of ribavirin administered as a flat dose 800 mg/day (FD)
versus ribavirin 800-1400 mg/day (weight based dose) in combination with PEG
IFN alfa-2b 1.5 ug/kg/week in the treatment of CHC.
Methods
Patients in a community setting
with CHC were randomized to PEG IFN alfa-2b 1.5 ug/kg once weekly plus
ribavirin 800 mg/day or ribavirin based on body weight:
·
< 65 kg – 800 mg/day,
·
65 to <85 kg - 1000mg/day,
·
85 to < 105 kg - 1200 mg/day, and
·
105-125 kg - 1400 mg/day.
Treatment was 48 weeks for patients
with HCV Genotype 1 while patients with Genotype 2 or 3 were randomized to 24 or
48 weeks. Follow-up for all patients was 24 weeks. HCV RNA was determined by
PCR (Taqman/SPRI, sensitivity 29 IU/ml) at weeks 24, 48 and 72. Dose reduction
of ribavirin was required for hemoglobin (Hgb) < 10 gm/dl and
discontinuation for Hgb <8.5.
Results
225 sites enrolled 4,913 patients
(2,444 received flat dose and 2,469 received weight base dosing) who received
at least one dose of drug, resulting in the largest HCV therapeutic trial to
date.
Intent-to-treat analysis showed a
significant improvement (p=0.02) in SVR with weight based dose (44%) compared
to flat dose (41%). Relapse rate was lower with weight based dose (15%) vs.
flat dose (19%).
Results of per protocol analysis (patients >65kg) are detailed in
table.
|
Ribavirin Mg/day |
Sustained Virological Response/
Number of Patients |
||
|
Overall |
Genotype 1 |
Genotype 1 High Viral Load |
|
|
800-1400 WBD |
44%
(939/2,121) |
34%
(448/1,313) |
32%
(247/779) |
|
800 FD |
41%
(853/1,313) |
29%
(377/1,305) |
27%
(196/725) |
|
p value |
0.01 |
0.004 |
0.047 |
Weight base
dose (WBD); Flat dose (FD)
Genoypte 2 and 3 SVR
48 week therapy did not improve SVR
in Genotype 2/3 patients; weight based dose 24 vs. 48 weeks 68% vs. 60%, and
flat dose 24 vs. 48 weeks, 65% vs. 58%, respectively.
Serious adverse events were similar
(11%) in both arms. Hgb <11 gm/dL occurred in 32% flat dose patients vs. 46%
of weight based dose patients, but were comparable in all four weight base dose
subgroups.
13.1% (164/1,256) of the weight
base dose group and 13.7% (163/1,193) of the flat dose group who were
responders at the end of treatment were lost to follow-up were counted as
treatment failures under a strict intent-to-treat (ITT) analysis.
Although there was a higher rate of
anemia (hemoglobin <10 gm/dl) in the weight-based dosing group and more dose
reductions (29% vs. 23%), no difference was seen in the rate of occurrence of
serious adverse events between the two groups (12% vs. 11%) and there were
similar rates of discontinuations for the adverse events (15% vs. 14%).
Conclusions
·
Weight based dosing of RBV results
in significantly greater SVR than flat dose especially in the difficult to
treat Genotype 1 (34% vs. 29%).
·
24 weeks of treatment is as
effective as 48 weeks in patients with HCV-Genotype 2 or 3.
·
Weight based RBV dosing results in
higher rates of dose reduction for anemia but not higher rates of
discontinuation.
· 1,400 mg ribavirin appears to be a safe dose for patients >105 kg.
Abstract ID: 61926
Category: JO8: HCV Therapy: Phase 3, 4 Trials
Interferon (IFN) Induced Thrombocytopenia is Independent of Level of Fibrosis in Patients with Chronic Hepatitis C (CHC): Results from the EPIC3 Program.
E. Schiff, University
of Miami School of Medicine, Miami, FL, R. Terg, Hospital Municap de
Gastroenterologia Dr. Bonorino Udaondo, Buenos Aires, Argentina, R. Moreno,
Hospital Universitario de la Princesa, Madrid, Spain, F. Goncales, Hospital das
Clinicas da Unicamp Cidade Universitaria Zefirino Vaz, Campinas, Brazil, S.
Flamm, Northwestern Memorial Hospital, Chicago, IL, M. Diago, Hospital General
Universitario de Valencia, Valencia, Spain, J. Reichen, Institut fuer klinische
Pharmakologie, Bern, Switzerland, J. Heathcote, University Health Network,
Toronto, Canada, T. McGarrity, Milton S. Hershey Medical Center, Hershey, PA,
T. Berg, Universitaetsklinikum Charite-Campus Virchow, Berlin, Germany, H.
Tanno, Hospital Provincial del Centenario, Rosario, Argentina, A. Mattos,
Irmandade da Santa Casa de Misericordia de Porto Alegre, Porto Allegre, Brazil,
J. McHutchison, Duke University Medical Center, Durham, NC, T. Poynard, Hopital
Pite-Salpetriere, Paris, France, P. Bedossa, Service d'Anatomie Pathologique,
Hopital Beaujon, Clichy, France, P. Savino, Schering-Plough Research Institute,
Kenilworth, NJ, M. Burroughs, Schering-Plough Research Institute, Kenilworth,
NJ, L. H. Griffel, Schering-Plough Research Institute, Kenilworth, NJ, C. A.
Brass, Schering-Plough Research Institute, Kenilworth, NJ, J. K. Albrecht,
Schering-Plough Research Institute, Kenilworth, NJ
Introduction
The EPIC3 program includes a large, prospective, controlled
trial designed to understand the safety and efficacy of re-treatment of
subjects who have significant fibrosis (Metavir F2-F4) with PEG-IFN a2b and
ribavirin weight based dosing for 48 weeks in previous treatment failures to
any IFN-a and ribavirin therapy. We have previously reported an SVR of 21% for
these subjects.
Aim
Here we report the effects of PEG-IFN a2b/ribavirin on
platelet counts in these patients.
Methods
HCV + patients that did not respond or relapsed after
previous treatment with any IFN-a and ribavirin received PEG-IFN a2b 1.5 mg/kg
subcutaneously once weekly plus ribavirin 800-1400 mg/day weight based dosing
for up to 48 weeks. All enrolled patients had pre-treatment biopsies scored by
a single reviewer using METAVIR criteria.
Platelet counts were assessed at screening and at all
treatment visits. We report on the 1964 (568 F2, 580 F3, 806 F4) patients who
have been treated to date.
Results
Most patients (94%) had decreases in their platelet count
with only 3% having drops greater than 60%. The median decrease was 30%. Less
than 5% of subjects experienced platelet count decreases of more than 60%.
There were no differences in the percentage drop of any level between F2, F3 or
F4 patients. While the median time to nadir platelet count was treatment week
18, 23% of patients reached their nadir at treatment week 36 or later; with 7%
reaching their nadir at week 48.Of patients with a baseline platelet count of
>150x103/mL, only 4 (<1%) had a decrease to < 50 x103/mL; all were F4.
Of those with a baseline count of 100-149 x103/mL, 37 (8%) had decreases to
< 50 x103/mL; 1 F2, 5 F3 and 31 F4. Of those with a baseline level of <99
x103/mL 31 (28%) had decreases to <50 x103/mL; 3 F2, 5 F3 and 23 F4.
Table: Changes in platelet count
over the study durations, by fibrosis level
|
|
Metavir
fibrosis score |
|||
|
|
F2 (n=568) |
F3 (n=580) |
F4 (n=806) |
ALL (n=1964) |
|
Platelet count |
|
|
|
|
|
Mean Baseline PLT Ct x103/mL |
210 |
189 |
158 |
182 |
|
Mean Minimum PLT Ct x103/mL |
150 |
136 |
108 |
12 |
|
Mean Decrease % |
28% |
28% |
31% |
30% |
|
n (%) Baseline PLT ct <100 x103/mL |
4 (<1%) |
19 (3%) |
86 (11%) |
110 (6%) |
|
n (%) PLT Decrease to <50 x103/mL |
4 (<1%) |
10 (2%) |
58 (7%) |
72 (4%) |
Conclusions
· Thrombocytopenia occurs
at a similar rate in patients in patients with CHC undergoing treatment with PEG-IFN
a2b and ribavirin independent of their level of baseline fibrosis among patients with F2, F3, and F4.
· Only, 3.7% patients had
PEG-IFN alfa-2b dose-reduciton criteria of platelets <50 x 103/ml,
with another <1% developing levels <253/mL . The greatest risk of developing platelet
levels under <50 x 103/mL was in those with a baseline platelet
count <100 x 103/mL.
· Patients with chronic
hepatitis C and significant fibrosis can be safelty treated with PEG-IFN
afla-2b plus ribavirin without undue concern regarding development of
thrombocytopenia.