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Consensus Interferon for Peg-IFN Non Responders
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Reported by Jules Levin
Digestive Disease Week conference
Chicago
May 13-19, 2005
These study results have received quite a bit of attention at this DDW meeting. The effectiveness of Consensus Interferon (Infergen, Alfacon-1) for patients who are non-responders to peginterferon plus ribavirin has been studied for several years & the study results have been promising but have received criticism at previous conferences. At this meeting for the first time researchers have not been criticizing the use of Infergen but have actually been referring to these study results in their talks at this meeting. Infergen for pegIFN non-responders is now in large phase III studies. Several researcher/doctors have discussed the use of Infergen in their practices for PegIFN nonresponders. Infergen for nonresponders is used at a high dose (15 ug daily) and several doctors in talking about its use say it can be difficult to tolerate at this high dose. But they also say that patients who are non-responders often have incentive to start Infergen high-dose therapy & stick with it. In the studies pioneered by Carroll Leevy & reported below, you will note Leevy did not have a time break between switching pegIFN nonresponders at week 12 to Infergen "No washout period". In speaking with Leevy, he told me this was an important aspect of his success in patients staying on Infergen therapy. Since the patients were already used to the pegIFN/RBV side effects, an immediate switch to Infergen without a washout period helped in patient adherence & not discontinuing, and this makes sense.
"Predictive Model and Sustained Virologic Response for PEG IFN-Alfa-2 + Weight-Based Ribavirin Nonresponders Re-Treated with IFN Alfacon-1 + Weight-Based Ribavirin"
Carroll Leevy1, Chris Chalmers2, Lawrence M. Blatt2
1The New Jersey School of Dentistry and Medicine, Newark, NJ
2InterMune, Inc., Brisbane, CA
Author's Summary:
Treatment of chronic HCV with IFN alfacon-1 (15 µg SC) daily plus daily RBV (weight-based dosing) in patients who did not respond to previous therapy with PEG IFN-_-2 + RBV resulted in an SVR rate of 37%
--Only the log10 reduction in HCV RNA from prior PEG IFN-_-2 + RBV therapy was an independent predictor of outcome (P < 0.001). Neither HCV genotype, presence of fibrosis, viral copy number at baseline, nor sex was a significant predictor of SVR
-- Patients who had an SVR to IFN alfacon-1 plus RBV had significantly greater reductions in HCV RNA after 12 weeks of peg- IFN-_-2 plus RBV the mean reduction in HCV RNA after 12 weeks of PEG IFN-_-2 + RBV for patients who achieved SVR to IFN alfacon-1 + RBV was 0.5 ± 0.05 log10 copies/mL
For selected patients who do not respond to 12 weeks of PEG IFN-_-2 + RBV therapy, switching to therapy with IFN alfacon-1 + RBV for 48 weeks
may offer clinical benefit.
--No patients discontinued treatment
--Hematologic toxicities were manageable
Patients chronically infected with hepatitis C virus (HCV) who fail to achieve ≥2 log10 reductions in HCV RNA after 12 weeks of PEG IFN-_-2 plus ribavirin (RBV) therapy have a ≤3% chance of obtaining a sustained virologic response (SVR), and often therapy is halted at that point.
Because all activities of IFN-_ are mediated by the production of IFN-stimulated genes (ISG), lack of response to PEG IFN-_-2 might be attributed to lack of adequate ISG induction. IFN alfacon-1 is a bioengineered, type I IFN that displays 10- to 100-fold higher biological potency and can hyperstimulate
ISG production when compared to naturally occurring IFNs.1 We hypothesized that switching to IFN alfacon-1 in patients who failed to achieve ≥2 log10 reductions in HCV RNA after 12 weeks of PEG IFN-_-2 + RBV therapy might result in increased SVR. In addition, we constructed a stepwise logistic
regression model to determine baseline and post–PEG IFN-_-2 + RBV characteristics that may serve to predict response (SVR) to retreatment with IFN alfacon-1 + RBV. Characteristics examined at baseline and post–PEG IFN-_-2 + RBV included sex, age, body weight, race, HCV genotype, viral load, and liver
histology. Variables that were significantly associated with SVR (P < 0.05) were used to construct a logistic regression model.
INTERFERON ALFACON-1 (Consensus Interferon, Infergen)
Interferon alfacon-1 is a novel, nonnaturally occurring type I consensus interferon. The 166-amino acid sequence of interferon alfacon-1 was derived by scanning the sequences of several nonallelic natural IFN-_ subtypes and assigning the most frequently observed amino acid in each corresponding position, producing a consensus sequence.2
Interferon alfacon-1 can be effective in treating HCV patients who do not respond to monotherapy.3 Specifi c activity of interferon alfacon-1 is up to 3 log10 greater than that of PEG-IFN.2,4,5
Comparison of Specific Antiviral Activity (units/mg) Using Vesicular Stomatitis Virus
STUDY METHODS
We conducted a retrospective review of 137 consecutive patients. All patients previously received 12 weeks of PEG IFN-_-2b (1.5 µg/kg subcutaneously [SC] every week), plus RBV (weight-based dosing, administered orally) and did not
have a ≥2 log10 reduction in HCV RNA. Without a washout period, these patients were switched to daily combination therapy with IFN alfacon-1 15 µg SC and weight-based RBV for 12 weeks, after which they switched to interferon alfacon-1 15 µg SC three times per week (TIW) and daily weightbased
RBV for the remaining 36 weeks.
HCV RNA levels were assessed at baseline and at Weeks 12, 24, 48, and 72 (6 months posttherapy) (Roche, Amplicore, Roche Diagnostics, USA). A logistic regression model was constructed to determine variables that predicted SVR to IFN alfacon-1 + RBV therapy.
BASELINE PATIENT CHARACTERISTICS
N=137
Sex: 57% male
Age: 47.5 yrs
Weight (mean): 78 kg
African American: 32%
Genotypes 1 & 4: 94%
Viral load before PEG-IFN/RBV therapy (mean, SD): 3.2 million copies/ml (+/-)
2.1 million copies/ml)
Viral load before CIFN/RBV therapy (mean, SD): 1.6 million copies/ml (+/- 2.1 million copies/ml)
EFFICACY
Sustained Virologic Response to IFN alfacon-1 + RBV in PEG IFN-_-2 + RBV Therapy
Nonresponders (N = 137)
--37% of previous nonresponders had sustained virologic responses after treatment with IFN alfacon-1 + RBV
Log10 Reduction of HCV RNA After 12
Weeks of Peg IFN-_-2 + RBV Therapy
Although no patient had ≥2 log10 reductions in HCV RNA levels, several did have ≥0.5 to 1.0 log10 and were therefore sensitive to IFN alfacon-1.
Patients who had an SVR to IFN alfacon-1 plus RBV had significantly greater reductions in HCV RNA after 12 weeks of peg- IFN-_-2 plus RBV (P < 0.01, t-test) compared to the nonresponder group.
Log10 Change in HCV RNA After PEG IFN-_-2 + RBV (12 Weeks)
Treatment by Response to IFN Alfacon-1 + RBV Treatment
Patients who had an SVR to IFN alfacon-1 + RBV had significantly greater
reductions in HCV RNA after 12 weeks of PEG IFN-_-2 + RBV (P < 0.01, chi
square) compared with the nonresponder group
SVR was statistically significantly different than NR (nonresponder) but not RR (responder relapser). RR was not significantly different than NR.
PREDICTORS OF OUTCOME
In a multivariate model that assessed the predictive value of viral and
demographic factors and SVR to retreatment with IFN alfacon-1 + RBV,
only the log10 reduction in HCV RNA from prior PEG IFN-_-2 + RBV therapy
was an independent predictor of outcome (P < 0.001). Specifically, the mean
reduction in HCV RNA after 12 weeks of PEG IFN-_-2 + RBV for patients who achieved SVR to IFN alfacon-1 + RBV was 0.5 ± 0.05 log10 copies/mL vs 0.18 ± 0.04 log10 copies/mL for nonresponding patients. Neither HCV genotype, presence of fibrosis, viral copy number at baseline, nor sex was a significant predictor of SVR.
SAFETY
--No patients discontinued treatment
--22 patients (16%) had a reduction in WBC (ANC <0.75 x 109) that
required use of G-CSF
AUTHOR'S CONCLUSIONS
The following conclusions are based on this retrospective analysis of 137 patients chronically infected with HCV who did not respond to 12 weeks of
therapy with PEG IFN-_-2 + RBV, who then switched to 48 weeks of therapy with IFN alfacon-1 + RBV:
--Retreatment of chronically infected HCV patients with IFN alfacon-1 + RBV for 48 weeks was generally well-tolerated
--For selected patients who do not respond to 12 weeks of PEG IFN-_-2 + RBV therapy, switching to therapy with IFN alfacon-1 + RBV for 48 weeks
may offer clinical benefit
--Log10 reductions during prior PEG IFN-_-2 + RBV should be explored further as a predictor of response to therapy with IFN alfacon-1 + RBV
References
1Klein SB, et al. Consensus interferon induces peak mRNA accumulation at lower concentrations than interferon-alpha 2a. J Interferon Res.1993;13:341–347
2Blatt LM, et al. The Biologic Activity and Molecular Characterization of a Novel
Synthetic Interferon-Alpha Species, Consensus Interferon. J Interferon Cytokine
Res 1996;16:489-499.
3Heathcote EJ, et al. Re-treatment of chronic hepatitis C with consensus interferon. Hepatology 1998;27:1136–1143. Erratum in Hepatology 1998;28:599.
4PEGASYS (peginterferon alfa-2a). Complete Product Information. Hoffman La-
Roche, Inc. 2003.
5PEG-Intron (Peginterferon alfa-2b). Product Information. Schering Corporation.
2003.
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