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 Italy and Norway) were pooled (n= 403); patients had been treated with PegIFN α -2b (1.0, n=281 or 1.5 μ g/kg, n=122) and ribavirin (800-1200 mg) for 12-14 or 24 weeks, depending on negative or positive HCV-RNA at week 4. Patients were <45 yrs (51%), 58% were males, infected with HCV-2 (60 %), 53% had low (<600,000 IU/ml) viremia, 78% had absence of bridgingfibrosis/cirrhosis. and 57% moderate/severe steatosis.

 

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%), nave 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 191,3 months of follow up, the mean CP score, as compared to basal value, improved in pts with SVR (81,3 vs 70,8), was unchanged in non responders (7,91,3 vs 8,21,4), and worsened in controls (8,61,5 vs 9,31,7). 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-nave 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 doesnt 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 doesnt 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 nave 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 310327257147 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 g/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 g/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/L, only 4 (<1%) had a decrease to < 50 x103/L; all were F4. Of those with a baseline count of 100-149 x103/L, 37 (8%) had decreases to < 50 x103/L; 1 F2, 5 F3 and 31 F4. Of those with a baseline level of <99 x103/L 31 (28%) had decreases to <50 x103/L; 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/L, 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, Ullevl University Hospital, Oslo, Norway, K. B. Hellum, Akershus University hospital, Nordbyhagen, Norway, B. Myrvang, Ullevl University Hospital, Oslo, Norway, K. Bjro, 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--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 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, Kenilworth, NJ

 

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.