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Improved Inflammatory Activity With Low-Dose PegIntron (PEG) Maintenance Therapy in Prior Nonresponders With METAVIR Fibrosis Scores (MFS) of F2/F3: Final Results From the EPIC3 Program
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Reported by Jules Levin
EASL Apr 14-18 2010 Vienna Austria
T. Poynard,1 J. Bruix,2 E. Schiff,3 M. Diago,4 T. Berg,5 R. Moreno-Otero,6 L. G. Lyra,7 F. Carrilho,8 L. H. Griffel,9 N. Boparai,10 M. Burroughs,10 C. A. Brass,10 and J. K. Albrecht10
1Service d'Hepato-Gastroenterologie, APHP-UPMC Liver Center, Paris, France; 2Centro de Investigacion Biomédica en Red de Enfermedades Hepaticas y Digestivas, Liver Unit, Hospital Clinic, University of Barcelona, Barcelona, Spain; 3University of Miami School of Medicine,
Miami, Florida, U.S.A.; 4Hospital General Universitario de Valencia, Valencia, Spain; 5Klinik und Poliklinik für Gastroenterologie & Rheumatologie, Sektion Hepatologie, Universitätsklinikum Leipzig, Leipzig, Germany; 6Hospital Universitario de la Princesa and
Centro de Investigacion Biomédica en Red de Enfermedades Hepaticas y Digestivas (Instituto de Salud Carlos III), Madrid, Spain; 7Hospital Sao Rafael, Salvador, Brazil; 8Gastroenterology, University of Sao Paulo School of Medicine, Sao Paulo, Brazil;
9Former employee of Schering-Plough Corporation, now Merck & Co., Inc., Whitehouse Station, New Jersey, U.S.A.; 10Schering-Plough Corporation, now Merck & Co., Inc., Whitehouse Station, New Jersey, U.S.A.
AUTHOR SUMMARY
· In the primary analysis, low-dose PEG-IFN alfa-2b did not significantly improve fibrosis response among patients with METAVIR F2 and F3 compared with the Observed group
· Significantly more patients receiving PEG-IFN alfa-2b had improvement in METAVIR activity score compared with patients in the Observed group
· In the subgroup of patients treated for >2.5 years, both METAVIR fibrosis and activity scores trended toward improvement
- 21% of PEG-IFN alfa-2b recipients and 14% of Observed patients had ≥;1-unit improvement in METAVIR fibrosis score
- 26% of PEG-IFN alfa-2b recipients and 10% of Observed patients had ≥;1-unit improvement in METAVIR activity score
· The possibility that carry-over effects from full-dose PEG-IFN alfa-2b plus weight-based ribavirin may have obscured maintenance therapy treatment effects cannot be excluded
Author Conclusion
· These data suggest that PEG-IFN alfa-2b decreases hepatic inflammation, but impact on METAVIR fibrosis score could not be demonstrated in the 3 years of maintenance therapy that followed ~18 weeks of full-dose PEG-IFN alfa-2b therapy plus weight-based ribavirin. For those patients with HCV with significant hepatic fibrosis who are unable to clear virus, therapies to slow or reverse
the march toward cirrhosis are still needed. It remains undefined whether longer periods of low-dose PEG-IFN alfa-2b therapy would extend the trend toward improvement in fibrosis observed in patients treated for >2.5 years
ABSTRACT
Background: Therapeutic options for patients failing hepatitis C retreatment are limited. EPIC3 includes a prospective trial assessing long-term
PEG 0.5 µg/kg/week maintenance therapy (MT) in patients with F2/F3 MFS previously failing any alfa-interferon plus ribavirin and retreatment
with PEG plus weight-based ribavirin.
Methods: Patients with F2/F3 MFS who failed retreatment were randomized to PEG or observation (OBS) for 36 months. Blinded liver biopsies obtained before retreatment and after MT were evaluated using MFS and activity scores (AS).
Patients were categorized as improved (1-unit decrease in MFS or AS), no change (including missing post-MT biopsy [PEG n=88; OBS n=104]), or worsened.
Results: PEG (n=270; 46% F2/54% F3) and OBS patients (n=270; 45% F2/55% F3) had similar baseline characteristics: 71% male, mean age 49.5 years, mean weight 75.8 kg, 70% viral load >600,000IU/mL, and 92% genotype 1. A higher percentage of PEG patients had improvement in MFS vs OBS (16% vs 11%; P = .32). Improvement increased in patients completing longer MT (Table). Significantly more PEG patients had improvement in AS vs OBS (20% vs 9%; P < .001). PEG patients with improved AS experienced greater mean ALT decrease from pre-retreatment to end of MT vs OBS (-0.90 x upper limit of normal [ULN] vs -0.36 x ULN). MFS improved by 2 units in 3.3% of PEG and
1.9% of OBS patients; AS improved in 1.5% of PEG and 0% of OBS patients. Safety profile of PEG was similar to previous studies.
Conclusions:
In the primary analysis, long-term PEG MT did not significantly improve MFS among F2 and F3 patients vs OBS. More PEG patients had a decrease in inflammation vs OBS. MFS and AS trended toward increased improvement with treatment duration >2.5 years. Since all subjects participated in the retreatment study, carryover effects from full-dose PEG/RBV may have obscured MT treatment effects. These data suggest PEG decreases hepatic inflammation, but impact on MFS may not be demonstrated with 3 years of MT.
BACKGROUND
· Treatment options are limited for patients with chronic hepatitis C who fail to respond to retreatment with the current standard of care, peginterferon (PEG-IFN) alfa plus ribavirin
- Sustained virologic response (SVR) rates range from 43% among previous relapsers to interferon alfa plus ribavirin to lower than 10% among previous nonresponders to PEG-IFN alfa plus ribavirin who undergo a repeat course of PEG-IFN alfa plus ribavirin1,2
· However, previous studies have shown that PEG-IFN alfa plus ribavirin therapy may have a beneficial effect on liver fibrosis, even in the absence of SVR
- 17% of patients who fail to attain SVR when treated with PEG-IFN alfa-2b plus ribavirin may experience an improvement in fibrosis, and an additional 62% of patients will have stabilization of fibrosis3
· Studies assessing the use of low-dose PEG-IFN alfa for maintenance therapy in patients with chronic hepatitis have enrolled differing patient groups (mainly patients with cirrhosis), utilized different treatment regimens, and yielded conflicting results4-6
Aim
· To assess long-term PEG-IFN alfa-2b 0.5 µg/kg/wk maintenance therapy in patients with F2/F3 METAVIR fibrosis score who previously failed treatment with any interferon alfa plus ribavirin and retreatment with PEG-IFN alfa-2b plus weight-based ribavirin
Patients and Methods
Patients
· The enrolled population consisted of patients with detectable hepatitis C virus (HCV) RNA following a minimum of 12 weeks of therapy with PEG-IFN alfa-2b plus weight-based ribavirin and F2 or F3 METAVIR fibrosis score in the EPIC3 retreatment program
-- To be eligible for retreatment in the EPIC3 program, patients were required to have previously received a minimum of 12 weeks of therapy with any interferon alfa plus ribavirin and failed to attain SVR1
Study Design
· The EPIC3 program included a prospective, randomized, long-term study of maintenance therapy for chronic hepatitis C (Figure 1)
-- Patients were randomized to PEG-IFN alfa-2b (0.5 µg/kg/wk) or observation for 36 months
Figure 1. EPIC3 study design. CHC = chronic hepatitis C; HCV RNA = hepatitis C virus RNA; PEG-IFN = peginterferon; RBV = ribavirin.
Assessments
· Blinded liver biopsies obtained before retreatment and after maintenance therapy were evaluated using METAVIR fibrosis and activity scores
· Patients were categorized as improved (≥;1 unit decrease in METAVIR fibrosis or activity scores), no change, or worsened (≥;1 unit increase in METAVIR fibrosis or activity scores)
Results
· 540 patients were enrolled with METAVIR F2 or F3 scores
--- 270 patients were randomized to receive PEG-IFN alfa-2b
- 270 patients were randomized to Observation
Patients
· Baseline patient demographics and disease characteristics were similar between the PEG-IFN alfa-2b and Observed groups (Table 1)
-- The majority was infected with HCV genotype 1 and had high baseline viral load
Table 1. Patient Characteristics
aIn the Observed group, 1 patient was nontypable and 2 had missing genotype.
PEG-IFN = peginterferon.
· Mean treatment duration was approximately 2.3 years among patients receiving PEG-IFN alfa-2b and 2.4 years among those in the Observed group
· For the 348 patients with pre-retreatment and end-of-treatment liver biopsies, the mean duration between the biopsies was 3.6 years in the PEG-IFN alfa-2b group and 3.9 years in the Observed group
Fibrosis Response
· Fibrosis score response was not significantly different between the PEG-IFN alfa-2b and the Observed groups
- 16% (44/270) of patients receiving PEG-IFN alfa-2b and 11% (29/270) of those in the Observed group achieved a ≥;1-unit improvement in METAVIR fibrosis score (Figure 2)
- 60% (162/270) of patients in the PEG-IFN alfa-2b group and 65% (176/270) of those in the Observed group had no change in METAVIR fibrosis score at the end of treatment
·· 192 patients had missing post-maintenance therapy biopsy (PEG-IFN alfa-2b, n = 88; observation, n = 104) and were classified as having "no change" in METAVIR fibrosis score or activity score
--- 24% (64/270) of patients in the PEG-IFN alfa-2b group and 24% (65/270) of those in the Observed group had worsened METAVIR fibrosis score at the end of treatment
Figure 2. Improvement in METAVIR fibrosis score. MFS = METAVIR fibrosis score; PEG-IFN = peginterferon
· I n the subgroup of patients treated for >2.5 years, 21% (39/186) of PEG-IFN alfa-2b recipients and 14% (28/197) of Observed patients had ≥;1-unit improvement in METAVIR fibrosis score (Figure 3)
Figure 3. Change in fibrosis score according to treatment duration. MFS = METAVIR fibrosis score; PEG-IFN = peginterferon.
· METAVIR fibrosis score improved by ≥;2 units in 3% (9/270) of patients receiving PEG-IFN alfa-2b and 2% (5/270) of Observed patients
Activity Response
· Significantly more patients receiving PEG-IFN alfa-2b (20%, 54/270) had improvement in METAVIR activity score compared with patients
in the Observed group (9%, 23/270, P < .001) (Figure 4)
- 72% (195/270) of patients in the PEG-IFN alfa-2b group and 77% (209/270) of those in the Observed group had no change in METAVIR activity score at the end of treatment
- 8% (21/270) of patients in the PEG-IFN alfa-2b group and 14% (38/270) of those in the Observed group had worsened METAVIR activity score at the end of treatment
Figure 4. Improvement in METAVIR activity score. AS = activity score; PEG-IFN = peginterferon
· In the subgroup of patients treated for >2.5 years, 26% (49/186) of PEG-IFN alfa-2b recipients and 10% (20/197) of Observed patients had ≥;1-unit improvement in METAVIR activity score (Figure 5)
Figure 5. Change in activity score according to treatment duration. AS = activity score; PEG-IFN = peginterferon
Activity Scores and Alanine Aminotransferase Levels
· In patients with improved or no change in activity score, mean alanine aminotransferase (ALT) levels at end of treatment were lower in the PEG-IFN alfa-2b group compared with the Observed group (Figure 6)
Figure 6. Alanine aminotransferase (ALT) levels (x upper limit of normal) at end of treatment
· Patients receiving PEG-IFN alfa-2b with improved METAVIR activity scores experienced greater mean ALT decreases from pre-retreatment to end of maintenance therapy vs Observed patients (-0.90 x upper limit of normal [ULN] vs -0.36 x ULN)
Safety
· The safety profile of PEG-IFN alfa-2b was similar to that seen in previous studies
- 20% (53/270) of patients in the PEG-IFN alfa-2b group and 11% (31/270) of patients in the Observed group had serious adverse
events (SAEs)
·· The most common SAEs were chest pain (1% [3/270]) in the PEG-IFN alfa-2b group and depression (1% [3/270]) in the Observed group
References
1. Poynard T et al. Gastroenterology. 2009;136(5):1618-1628.
2. Jensen DM et al. Ann Intern Med. 2009;150(8):528-540.
3. Poynard T et al. Gastroenterology. 2002;122(5):1303-1313.
4. Bruix J et al. Presented at: 44th Annual Meeting of the European Association for the Study of the Liver; April 22-26, 2009; Copenhagen, Denmark.
5. Di Bisceglie AM et al. N Engl J Med. 2008;359(23):2429-2441.
6. Afdhal N et al. J Hepatol. 2008;48:S4.
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