Abstract ID: 67504

Category: JO7: HCV: Treatment

Interim Analysis of the Safety and Efficacy of Peginterferon Alfa-2a plus Ribavirin in Chronic Hepatitis C Patients Unable to Tolerate or Nonresponsive to Treatment with Peginterferon Alfa-2b plus Ribavirin.

V. K. Rustgi, Georgetown University Medical Center, Fairfax, VA, S. Esposito, North Shore Hospital at Forest Hills, Bayside, NY, B. Freilich, Baptist Medical Center, Kansas City, MO, J. Lopez-Talavera, Roche Laboratories, Nutley, NJ, E. Lentz, Roche Laboratories, Inc, Nutley, NJ, M. L. Shiffman, Virginia Commonwealth University Medical Center, Richmond, VA

Introduction

In clinical studies, patients infected with hepatitis C virus (HCV) who are treated with peginterferon alfa-2a plus ribavirin (PEG-2a/RBV) had a lower incidence of depression and other symptoms, including flu-like symptoms, such as myalgia and pyrexia, than those patients treated with standard interferon (IFN) plus RBV.1 In contrast, patients treated with peginterferon

alfa-2b plus ribavirin (PEG-2b/RBV) had a side-effect profile similar to that of standard IFN plus RBV.2 These findings suggest that patients intolerant of or nonresponsive to treatment with PEG-2b/RBV may be more tolerant of, or more responsive to, treatment with PEG-2a/RBV. This present study describes the efficacy and safety of PEG-2a/RBV in patients who are intolerant of the adverse effects of PEG-2b/RBV or who are nonresponders

to treatment with PEG-2b/RBV.

Methods

Patients infected with HCV genotype 1 who had been treated with PEG-2b/RBV for a maximum of 12 weeks, but were intolerant due to depression, fatigue, flu-like symptoms, or injection-site reactions, or did not achieve an early virologic response (EVR–defined as a 2-log decrease or undetectable HCV RNA after 12 weeks), were treated with PEG-2a/RBV. Per protocol, nonresponders (NRs) and nontolerators (NTs) with detectable HCV RNA after 12 weeks of treatment with PEG-2a/RBV were to be discontinued.

At each visit, depression was evaluated by the Beck Depression Inventory, Version 2 (BDI-II); fatigue was assessed using the Fatigue Severity Scale Visual Analogue Scale (FSS VAS); injection-site reactions were evaluated by a local injection-site reaction questionnaire, and flu-like symptoms by a flu-like symptom questionnaire. HCV RNA was measured at defined intervals by Roche Amplicor® (limit of detection, 60 IU/mL).

Results

· The study enrolled 32 PEG-2b/RBV NRs and 25 PEG-2b/RBV NTs. Baseline characteristics are shown in Table 1.

· Of the 25 NTs who withdrew from PEG-2b/RBV treatment, 19 (76%) withdrew due to fatigue, 3 (12%) due to flu-like symptoms, 2 (8%) due to injection-site reactions, and 1 (4%) due to depression—all prior to PEG-2a/RBV treatment.

· To date, only 4 NRs (12.5%) and 0 NTs have been withdrawn from PEG-2a/RBV treatment due to adverse events or intercurrent illness.

· Only 2 and 4 NTs have required dose adjustments of PEG-2a and RBV, respectively, for adverse events or laboratory abnormalities.

· Currently, about 74% of patients have completed or withdrawn from PEG-2a/RBV treatment.

· Of the 32 PEG-2b/RBV NRs, 4 achieved EVR, with 3 patients having undetectable HCV RNA and 1 having a ≥2-log decrease 12 weeks after being switched to PEG-2a/RBV (Table 2). Three PEG-2b/RBV NRs have remained on treatment with PEG-2a/RBV through Week 48.

· Of the 25 PEG-2b/RBV NTs, 23 achieved undetectable HCV RNA 12 weeks after being switched to PEG-2a/RBV, and 21 of these patients continued on treatment through Week 36.

· In the 23 NTs treated for 24 weeks with PEG-2a/RBV, relative to baseline, BDI-II score declined from 15.20 ± 1.54 (mean ± SE) to 11.26 ± 1.52 (Table 3), FSS VAS score declined from 63.74 ± 4.35 to 56.52 ± 5.98 (Table 4), and the number of patients with injection-site reactions declined from 10 (40%) at baseline to 2 (8%).

· At the end of treatment (36 weeks on PEG-2a/RBV) of 18 NTs, relative to baseline, BDI-II score declined from 14.67 ± 1.90 to 8.56 ± 1.39 (Table 3), FSS VAS score declined from 61.44 ± 5.39 to 47.72 ± 6.96 (Table 4), and the number of patients with injection-site reactions declined from 10 (40%) to 1 (4%).

Conclusions

· More than 90% of patients who discontinued treatment because of intolerance to 12 weeks of treatment with PEG-2b/RBV were able to tolerate treatment with PEG-2a/RBV and completed therapy.

· The majority of NTs (23/25) who switched to PEG-2a/RBV achieved undetectable HCV RNA at 12 weeks.

· In addition, 4/32 (12.5%) NRs to PEG-2b/RBV achieved a greater than 2-log decrease or undetectable HCV RNA 12 weeks after being converted to PEG-2a/RBV.

Poster 204

12:30-12:45PM

Abstract ID: 61151

Category: JO5: HCV: Clinical Trials and Therapeutic Developments

A PHASE 2 STUDY OF ALBUFERON IN COMBINATION WITH RIBAVIRIN INNON-RESPONDERS TO PRIOR INTERFERON THERAPY FOR CHRONIC HEPATITIS C.

D. Nelson, University of Florida, Gainesville, FL, V. Rustgi, Georgetown University,

Fairfax, VA, V. Balan, Mayo Clinic, Scottsdale, AZ, J. McHutchison, Duke University,

Durham, NC, G. Davis, Baylor University Medical Center, Dallas, TX, L. Lambiase,

University of Florida, Jacksonville, FL, M. Sulkowski, Johns Hopkins University,

Baltimore, MD, R. Dickson, Mayo Clinic, Jacksonville, FL, M. Fiscella, HGS,

Rockville, MD, R. Yu, HGSI, Rockville, MD, H. Davidson, HGSI, Rockville, MD, P.

Cronin, Human Genome Sciences, Inc., Rockville, MD, W. Freimuth, Human Genome

Sciences, Inc., Rockville, MD, M. Subramanian, Human Genome Sciences, Inc.,

Rockville, MD

Background

Albuferon©is a novel recombinant protein consisting of IFNa genetically fused to human serum albumin. The resulting molecule combines the antiviral properties of IFNa with the prolonged serum half-life of albumin.

Methods: This Phase 2, randomized, dose-ranging study is being conducted in chronic HCV patients (CHC) who were non-responders (NR) to previous treatment with IFNa containing regimens. 71 subjects were enrolled in parallel into 3 Albuferon SC treatment cohorts (900 mg Q2w, 1200 mg Q2w or 1200 mg Q4w) in combination with ribavirin (RBV) 1000-1200 mg/d.

The treatment duration is 48w with 24w follow-up and the primary efficacy end-point is SVR. Following evaluation of 8w of safety data, 22 subjects were enrolled in a 4th treatment cohort of Albuferon 1500 mg Q2w with RBV.

Interim Results:

The majority of subjects enrolled were non-responders to PEG-IFNa+RBV therapy (64.8%) and were infected with genotype 1 HCV (93%). Subject demographics and antiviral response is summarized in the table.

Safety up to week 24

Albuferon in combination with RBV was well tolerated. No subject required dose reduction for the management of non-hematologic adverse events. The most common adverse events were fatigue (86%), headache (70%), myalgia (59%) and nausea (58%). The adverse events were similar across all treatment arms. No subject required discontinuation of Albuferon or ribavirin for hematologic abnormalities.

Antiviral response (up to w24): The antiviral response at w12 and w24 was comparable in the Q2w and Q4w groups. Overall 30% of patients were RNA negative at week 12.

Conclusions

· Albuferon in combination with ribavirin is safe, well tolerated and shows antiviral activity in IFNa non-responders.

· No significant drug accumulation between week 12 and 24

· No significant increase severity of adverse events between week 12 and week 24

· Hemotologic reductions were maximal by week 8 and are well managed with dose reductions.

· Evaluation is ongoing.

Abstract ID: 67080

Category: JO5: HCV: Clinical Trials and Therapeutic Developments

Peginterferon alfa-2b plus ribavirin versus Interferon alfa-2b plus ribavirin for chronic hepatitis C in HIV-coinfected patients.

M. Crespo, Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain, S. Sauleda, Centre de Transfusio i Banc de Teixits, Institut Català de la Salut, Barcelona, Spain, J. I. Esteban, Liver Unit, Hospital Universitari Vall d'Hebron, Barcelona, Spain, A. Juarez, Liver Unit, Hospital Universitari Vall d'Hebron, Barcelona, M. Buti, Liver Unit, Hospital Universitari Vall d'Hebron, Barcelona, Spain, A. Pahissa, Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain, R. Esteban, Liver Unit, Hospital Universitari Vall d'Hebron, Barcelona, Spain, J. Guardia, Liver Unit, Hospital Universitari Vall d'Hebron, Barcelona, Spain

Background and aims

Treatment of chronic HCV in HIV-coinfected patients has been associated with low rates of viral response. Furthermore, severe side effects related to mitochondrial toxicity raised concerns about the safety of ribavirin in combination with nucleoside analogue-containing antiretroviral (ARV) regimens. We have conducted a randomized trial to compare efficacy and safety of standard interferon (IFN) vs peg interferon (Peg-IFN), both in combination with ribavirin (RBV) among HCV HIV coinfected patients

Methods

121 patients with chronic hepatitis C and controlled HIV infection, were randomized to receive IFN Ą-2b (3 MU/tiw) (n=61) or Peg-IFN Ą-2b (1,5

ƒÝg/kg/wk) (n=60) plus RBV (800 mg/d), for 24 (genotypes 2 or 3) or 48 weeks (genotypes 1 or 4). The primary end point was sustained viral response (SVR) (HCV RNA < 50 IU/mL 24 weeks after end of treatment). Viral load was tested at baseline, 4, 8, 12, 24, 48 and 72 weeks and PBMCs were obtained and cryopreserved at the same time points. Safety was assessed clinically and analytically weekly the first month and monthly thereafter Results In intention-to-treat analysis SVR rates were 55% (33 of 60) in the Peg-IFN group and 26% (16 of 61) in the IFN group (p = 0.001). For genotypes 1/4, SVR rates were 46% (18 of 39) vs 18 % (7 of 40) (p = 0.006), and for genotypes 2/3, 71% (15 of 21) vs 43% (9 of 21) (p = 0.06), respectively. Viral dynamics during the first 12 weeks was the most powerful predictor of SVR, irrespective of treatment group. ROC curves of HCV RNA decrease from baseline (ƒ´HCV RNA) identified sensitivity peaks with 100 % NPV for SVR prediction at weeks 4, 8 and 12 (>1, >1.9 and >3 logs, respectively) During the study, 2 patients died, (lactic acidosis and liver failure, one each) and RBV was discontinued in another 4 because of symptomatic hyperlactataemia. In these 6 patients, all receiving two nucleoside analogue-containing ARV therapy, relative quantitation of mitochondrial DNA (mtDNA) in cryopreserved PBMCs showed an average decrease from baseline of 54 %, 4 to 12 weeks after onset (a median of 12 weeks before clinical manifestations)

Conclusions

Peginterferon plus ribavirin can eradicate HCV RNA in over 50 % of coinfected patients with controlled HIV infection, and in more than 70 % of those with HCV genotype 3 with a 24-week schedule. However, combination therapy may precipitate life-threatening mitochondrial toxicity when combined with some nucleoside analogue-containing ARV regimen especially in patients with advanced liver disease.

Abstract ID: 66232

Category: JO7: HCV: Treatment

Sustained Virological Response (SVR) is Durable After Treatment With Peginterferon Alfa-2a (40KD) (PEGASYS®) Alone or in Combination With Ribavirin (COPEGUS®): Results of an Ongoing Long-term Follow-up Study.

M. G. Swain, University of Calgary, Calgary, Canada, M. Lai, National Taiwan University Hospital, Taipei, Taiwan, M. L. Shiffman, VCU Medical Center, Richmond, VA, W. G. Cooksley, Royal Brisbane Hospital, Brisbane, Australia, A. Abergel, Hôpital Hotel Dieu, Clermont- Ferrand, France, A. Lin, Hoffmann-La Roche, Inc, Nutley, NJ, E. Connell, Hoffmann-LaRoche Inc., Nutley, NJ, M. Diago , Hospital General Universitario Valencia, Valencia, Spain

SVR is associated with improved health-related quality of life, improved liver histology, and prevention of liver-related death. It has been reported that HCV RNA sequences can be amplified from liver tissue from patients with an SVR; whether this represents intact virus capable of reactivation remains to be determined. Thus durability of SVR is an important question. We report interim results of an ongoing long-term follow-up study.

Methods

Participants in seven randomized, international registrations trials of peginterferon alfa-2a (40KD) monotherapy or peginterferon alfa-2a (40KD)/RBV combination therapy were eligible for the long-term follow-up trial if they were negative for serum HCV RNA (<50IU/mL, COBAS AMPLICOR HCV Test, v2.0) at their final HCV RNA determination in the original study. During follow-up, Serum HCV RNA is determined yearly for five years from the date of last treatment in the original study.

Results (Table):

To date, follow-up is available for 901 patients who achieved an SVR. Of these received peginterferon alfa-2a (40KD) monotherapy and 715 received the combination of peginterferon alfa-2a plus ribavirin. Overall, 894 patients (99.2%) have remained HCV RNA-negative throughout long-term follow-up. HCV RNA has been detected in the serum of seven patients (<1%). All patients who were treated for 48 weeks with peginterferon alfa-2a (40KD) plus standard-dose ribavirin (1000 or 1200 mg/day), all patients with persistently ‘normal’ ALT levels and all HIV/HCV coinfected individuals continue to be HCV RNA-negative.

Conclusions

· An SVR achieved with peginterferon alfa-2a (40KD) (Pegasys), alone or in combination with ribavirin, is durable for up to 5 years after completion of therapy.

· No patient treated for 48 weeks with peginterferon alfa-2a (40KD) plus standard dose of ribavirin (1000 or 1200 mg/day) experienced clinical relapse. Moreover, it appears that there is no difference in the durability of an SVR in patients with persistently ‘normal’ ALT levels or in those with HIV/HCV coinfection.

· Our results demonstrate that SVR, as defined by a commercial HCV RNA assay, is long lasting and the clinical relapse is extremely rare in patients who are ‘cured’ of chronic hepatitis C.

· There is no obvious common risk or treatment factor associated with the detection of HCV RNA during follow-up.

· As yet it has not been determined whether the seven patients who reverted to HCV RNA-positive status during follow-up experienced a relapse of the original infection or were re-infected by another strain of HCV. We are currently seeking permission to sequence the viral strains and distinguish between these alternative.

Abstract ID: 67524

Category: JO7: HCV: Treatment

PEGETRON PROSPECTIVE OPTIMAL WEIGHT-BASED DOSING RESPONSE PROGRAM (POWER): PRELIMINARY RESULTS.

N. Abadir, Schering Canada, Pointe Claire, Canada, P. Marotta, London Health Sciences Centre, London, Canada, S. V. Feinman, Mount Sinai Hospital, Toronto, Canada, L. J. Scully, University of Ottawa, Ottawa , Canada, M. Varenbut, Ontario Addiction Treatment Centres, Richmond Hill, Canada, J. Daiter, Ontario Addiction Treatment Centres, Richmond Hill, Canada, J. D. Farley, University of British Columbia, Vancouver, Canada

Background

The weight-based dosing regimen approved in Canada for peginterferon alfa-2b and ribavirin resulted from analysis of the pivotal study by Manns et al (Lancet. 2001;358:958-965.), and, regardless of patient weight, this treatment regimen has shown high efficacy. The primary objective of the Pegetron® Prospective Optimal Weight-Based Dosing Response Program (POWeR) is to prospectively track the sustained virologic response (SVR) of treatment-naive HCV patients receiving peginterferon alfa-2b and ribavirin (Pegetron®) using a weight-based dosing regimen in a “real-life” healthcare setting.

Methods

Patient selection

· Treatment-naïve patients (n=2,194) with chronic HCV were prospectively enrolled between December 2002 and December 2004, in this open label trial conducted in 160 academic and community clinics across Canada.

· All patients were eligible for treatment with PEG-IFN alfa-2b and RBV (Pegetron®, Schering-Plough Canada) according to criteria listed in the Pegetron Product Monograph.

· At baseline, the following patient characteristics were recorded:

– bodyweight (<50kg, 50–<64kg, 64–<75kg, 75–<85kg, ≥85kg)

– HCV genotype (G1, G2, G3, or other)

– extent of fibrosis determined by liver biopsy (not all patients)

· none to mild (Metavir score 0–1)

· moderate (Metavir score 2)

· severe (Metavir score 3)

· cirrhosis (Metavir score 4).

· All patients received:

– PEG-IFN alfa-2b 1.5µg/kg/week

– RBV 800–1,200mg/day (dependent on bodyweight).

· Patients received treatment for 24 weeks (non-G1) or 48 weeks (G1) based on treatment guidelines and standard of care.

· In this community-based trial, patients were treated, followed and managed per current treatment guidelines, with no study-related intervention beyond collection of data.

Virologic response

· An end-of-treatment (EOT) virologic response was defined as being HCVRNA negative after 24 weeks (non-G1) or 48 weeks (G1) of treatment.

· SVR was defined as being HCV-RNA negative at 24 weeks after the EOT.

· SVR rates were analyzed by baseline bodyweight, fibrosis level and HCV genotype.

· Further to this initial analysis, future reports will analyze data on relapse rate and prognostic indicators.

Results

Baseline demographics

· Baseline demographics of the study population are shown in Table 1.

· Patient distribution by genotype within each weight group was similar, ranging from 48% to 52% for genotype 1 and 46% to 52% for genotypes 2/3.

· Over one-third of patients (36.6%) had severe or cirrhotic fibrosis (Metavir score F3 or F4), with 62.6% of patients having mild to moderate (F0–F2) levels of fibrosis.

Baseline characteristics: (N=2,194)

Weight,kg number %

<50 58 2.6

50–<64 355 16.2

64–<75 490 22.3

75–<85 549 25.0

≥85 742 33.8

Genotype (N=1,506)

G1 876 58.2

G2 242 16.1

G3 350 23.2

Other 38 2.5

Fibrosis level (N=1,240)

F0–F1 375 30.2

F2 410 33.1

F3 249 20.1

F4 206 16.6

· Patient distribution by baseline fibrosis level was similar within the lower weight groups (<50kg and 50kg–<64kg groups: F3/F4 = 25–26%). However, as weight increased, an increasing number of patients had severe or cirrhotic fibrosis (64kg–<75kg group: F3/F4 = 33%; 75kg–85kg and ≥85kg groups: F3/F4 = 38%).

Virologic response

· EOT response rate was 69% (775/1,120)

· Overall SVR rate was 66% (629/952) following weight-based dosing with PEG-IFN alfa-2b and RBV.

· PEG-IFN alfa-2b combined with RBV, administered as a weight-based dosing regimen, provided SVR rates of ≥62% (62.9–68.9%) in all weight groups, with no significant differences in SVR between the different weight groups.

· As expected, a higher percentage of patients with genotypes 2 or 3 achieved an SVR (85% and 78%, respectively) than patients with genotype 1 (52%).

· More patients with a baseline fibrosis level of F0–F1 or F2 achieved an SVR (76% or 68%, respectively) than patients with a severe fibrosis level (F3 or F4; 42% or 41%, respectively).

Conclusions

· Regardless of bodyweight, SVR rates were consistently high in patients treated with a weight-based dosing regimen of PEG-IFN alfa-2b and RBV.

· These findings are particularly encouraging given that this is a “real-life” community study with similar patient distribution by genotype within each weight group and a higher level of fibrosis in the heavier weight groups.

· Preliminary data from this community study indicates that genotype and fibrosis level influence SVR. Other baseline characteristics which were not recorded in this study, such as viral load, may also influence SVR.

o A higher proportion of patients with HCV G2 and G3 achieved an SVR compared with patients with G1

o Patients with mild-to-moderate levels of fibrosis (F0–F2) achieved higher SVR rates than patients with severe fibrosis/cirrhosis (F3–F4) (which was present in over one third of patients with available histology in this study).