http://www.natap.org/2005/ddw/ddw_15.htm
Does Retreatment with Interferon Alfacon (Infergen) Plus Interferon Gamma (Actimmune) Benefit Nonresponders to Peginterferon Plus Ribavirin?
The elimination of serum HCV RNA following interferon (IFN)-based therapies displays biphasic kinetics with the first order attributed to the direct antiviral effects of IFN-alfa and the second order attributed to an immune-mediated clearance of infected cells by induction of TH1 cytokines, primarily IFN-gamma.
Patients who have not had >2 log10 reduction in serum HCV RNA by wk 12 have a 97–100% chance of not responding.
The authors say they have demonstrated in prior studies that antiviral effects and TH1 responses are enhanced by combining IFN-gamma and IFN-alfa in in vitro systems.
Given these data, the researchers conducted a retrospective study of nonresponders to PEG IFN-alfa-2 + ribavirin (RBV) who were re-treated with IFN alfacon-1 (Infergen) and IFN-gamma 1b (Actimmune) without ribavirin.
All patients (N = 50) received PEG IFN-alfa-2 and RBV for 12 wk and did not achieve >2 log10 drop in HCV RNA. With no washout, patients were retreated with IFN alfacon-1 15 microgram SQ daily, and IFN-gamma 1b 50 microgram SQ TIW for 48 wk.
Serum HCV RNA was assessed at wk 8, 12, 24, 48 (EOT), and 60 (12 wk post-treatment) to determine virologic response on- and off-treatment and will be assessed at wk 72 to determine SVR.
Results
Virologic responses are shown below (Amplicore qualitative assay, Roche Diagnostics):
|
Week |
8 |
12 |
24 |
48 (EOT) |
60| |
| HCV RNA Negative %(N) |
36% (18/50) |
40% (20/50) |
46% (23/50) |
46% (23/50) |
35% (13/37) |
One patient interrupted therapy due to constitutional symptoms while all others tolerated therapy well. By wk 48, 13 patients (26%) required filgrastim for reductions in ANC to below 0.75 X 109/L. After 12 wk of PEG IFN-alfa-2 and RBV therapy the mean hemoglobin level was 11.6 ± 0.7 g/dL. By wk 8 all of IFN alfacon-1 and IFN-g 1b patients recovered hemoglobin levels to normal with no use of erythopoeitin.
Conclusions
· Retreatment of PEG IFN-alfa-2 + RBV nonresponders with the combination of IFN alfacon-1 and IFN-gamma 1b is well tolerated, and preliminary analysis of post-treatment virologic response suggests that this treatment may be of potential benefit in these difficult-to-treat patients.
· This combination did not interfere with hemoglobin recovery, indicating a differential safety profile with respect to RBV containing regimens.
· Further analysis will assess SVR and a larger dose-finding study of the combination of IFN alfacon-1 and IFN-gammag 1b is ongoing.
05/27/05
Reference
C Leevy, C
Chalmers and L M Blatt. Response Of Chronic Hepatitis C PEG IFN-2 +
Ribavirin Nonresponders To Treatment With IFN Alfacon-1 (15 Mcg) and IFN
Gamma-1b (50 Mcg). Abstract S1537. Digestive Disease Week 2005. May 14-19,
2005. Chicago, IL.
http://www.hivandhepatitis.com/2005icr/ddw2005/docs/hcv_052705_f.html
Interferon Alfacon-1 (Infergen) Alone or in Combination with IFN Gamma-1b (Actimmune) Suppresses Replication of a PEG IFN-Alfa-2b-resistant Hepatitis C Virus Replicon
Treatments for chronic hepatitis C virus (HCV) infection employing pegylated interferon (IFN) alfa 2 plus ribavirin are successful in ~50% of all treated patients, suggesting that HCV may evade the antiviral actions of contemporary IFN therapy and demonstrating a need for more effective therapy application.
Researchers evaluated the in vitro biochemical, antiviral response and anti-HCV efficacy imparted by IFN-alfa-2a (Roferon A), PEG IFN-á-2b (PegIntron), consensus IFN (IFN alfacon-1; Infergen) or a combination of IFN alfacon-1 and IFN-gamma 1b in cultured human hepatocytes or hepatoma cells that harbor genetically distinct HCV RNA replicons with differential sensitivity to the antiviral actions of IFN-alfa-2a.
IFNs were applied to cultured cells using relevant dosing based upon the pharmacologic attainable in vivo serum maximum (Cmax) IFN concentration. Gene expression and antiviral properties were measured using protein and RNA quantification assays.
Results
· At Cmax concentrations of each IFN, the researchers found that ISG56 and PKR, interferon stimulated genes (ISGs) with demonstrated antiviral properties, were maximally expressed following IFN alfacon-1 treatment.
· Treatment with IFN-alfa-2a or PEG IFN-alfa-2b resulted in the slower accumulation and an overall lower level of ISG expression.
· While replication of an IFN-alfa-2a-sensitive HCV 1b subgenomic HCV replicon in cultured hepatoma cells was equally suppressed by IFN alfacon-1, IFN-alfa-2a, and PEG IFN-alfa-2b, only IFN alfacon-1 effectively suppressed the replication of an IFN-alfa-2a–resistant HCV replicon variant at relevant Cmax dosing.
· When combined with the therapeutically relevant Cmax dose of IFN-gamma 1b, IFN alfacon-1 induced a unique ISG expression profile marked by the induction of interferon regulatory factor (IRF)-1 and IRF-7, and resulted in further enhancement of antiviral action against the IFN-alfa-2a–resistant HCV replicon.
Based on these findings, the authors conclude, “The application of IFN alfacon-1 alone or in combination with IFN gamma 1b induces a cellular antiviral response distinct from that induced by IFN-alfa-2a or PEG IFN-alfa-2b. This distinction may provide an advantage for the treatment of chronic HCV in infected individuals who do not respond to pegylated interferon alpha-2-containing regimens.”
05/27/05
Reference
A Kaup, C Wang and M. Gale, Jr. Consensus Interferon (IFN
Alfacon-1) Alone or in Combination with IFN Gamma-1b Suppresses Replication
of a PEG IFN-Alpha-2b-resistant Hepatitis C Virus Replicon. Abstract S918.
Digestive Disease Week 2005. May 14-19, 2005. Chicago, IL.
http://www.hivandhepatitis.com/2005icr/ddw2005/docs/hcv_052705_e.html
High Dose Consensus Interferon (Infergen) and Ribavirin Is Effective for Patients with Chronic Hepatitis B Who Have Failed on Peginterferon and Ribavirin
The majority of nonresponder and relapser patients with chronic hepatitis C are unable to achieve a sustained virologic response (SVR) with the combination of PEG-Interferon (PEG-IFN) and ribavirin (RBV), especially those who have genotype 1 and advanced disease.
Consensus interferon (Interferon alfacon-1, CIFN) [Infergen] is a bio-optimized alfa interferon that exhibits increased in-vitro antiviral activity compared to the naturally occurring alfa interferons 2a and 2b.
Improved response rates have been reported with high-dose CIFN therapy and RBV for patients who have failed to respond to PEG-IFN / RBV. The aim of the current study was to evaluate the efficacy and safety of high-dose daily CIFN and RBV in HCV patients who failed therapy with PEG-IFN / RBV.
Patients who had been treated with PEG-IFN/ RBV for HCV but did not obtain a SVR were eligible for treatment if they: 1) tolerated treatment with PEG-IFN/RBV, and 2) had advanced liver disease (bridging fibrosis or cirrhosis).
Patients were given 27 ug of CIFN daily and RBV 400 mg BID during the first four weeks, followed by 18 ug daily and ribavirin 400 mg BID daily for the next eight weeks.
At 12 weeks, CIFN was decreased to 15 ug daily while RBV was increased to 1,000-1,200 mg daily for 36 weeks.
Results
· Twenty nine patients have been enrolled in the study, 76% male with a mean age of 52 years old.
· 94% had genotype 1 and 39% of patients had cirrhosis.19 patients (62%) have achieved an early virologic response (EVR) at 12 weeks.
· Eleven patients (52%) were undetectable at 24 weeks and 6 patients (43%) achieved an End-of-Treatment response.
· 6 patients were dose reduced and 3 patients stopped therapy due to adverse effects.
| HCV RNA VIRAL LOAD |
Week 12
(n=29) |
Week 24
(n=21) |
Week 48 (n=14) |
| > 2 LOG DECREASE | 66 % | ----- | -------- |
| UNDETECTABLE |
34% |
52% |
43% |
The authors conclude, “For HCV patients with advanced histologic disease who
had previously failed therapy with PEG-IFN and RBV, the combination of
high-dose CIFN and RBV is a
well-tolerated and effective option.”
05/23/05
Reference
K D Rothstein
and others. High Dose Consensus Interferon and Ribavirin Is Effective for
Treatment of Chronic Hepatitis C Infection in Patients Who Are Resistant to
Peg-Interferon and Ribavirin. Abstract S1536. Digestive Disease Week 2005.
May 14-18, 2005. Paris, France.
http://www.hivandhepatitis.com/2005icr/ddw2005/docs/hcv_052305_d.html
Efficacy of Daily Consensus Interferon (Infergen) and Ribavirin Compared to Peg-Interferon Alfa2b (PegIntron) and Ribavirin in Treatment-Naive Patients with HCV Genotype 2 or 3
Consensus interferon (CIFN; Infergen) is a synthetic type 1 interferon with enhanced in vitro activity compared to conventional IFN-alfa (IFNa). In the prospective, randomized multicenter PegIntron-Against-Consensus-Trial (PACT), the efficacy and safety of daily CIFN-treatment and ribavirin is compared to peg-IFNa2b [PegIntron] plus ribavirin.
400 patients with chronic HCV infection and serotype-2 or -3 will randomly be assigned to treatment with 9 mcg qd CIFN sc. (group A) or peg-IFNa2b (1,5 mcg/kg body weight once weekly, group B), each in combination with ribavirin (>10,6 mg/kg body weight) for 24 weeks.
Treatment is interrupted for primary non-response, if viral load drops by less than 2 log until week 12 or drops by more than 2 log but remains positive at week 16.
Follow up includes further 24 weeks. Viral response rates are analyzed by the Roche COBAS Amplicor HCV Monitor v2.0 test.
129 patients out of 199 patients enrolled before November 2004 reached at least the end of treatment at week 24 and represent the base of this interim analysis.
Results
¡¤ There were no significant differences in patient baseline characteristics between both treatment groups concerning age, gender, genotype and viral load.
¡¤ The virological response rates analyzed as intent-to-treat are shown in the Table:
|
Group A
|
Group B
|
|||||
|
wk 12 (n=67) |
wk 24 (n=68) |
wk 48 (n=43) |
wk 12 (n=60) |
wk 24 (n=61) |
wk 48 (n=38) |
|
|
PCR neg |
99% |
93% |
95% |
92% |
94% |
95% |
¡¤ Thus, end-of treatment response (ETR) rates as well as sustained virological response (SVR) rates were very high and identical in both treatment groups.
¡¤ This was also true for all subgroup analyses, including analysis according to baseline viral load (< vs. ¡Ý 800.000 IU/ml) gender, body weight (< vs. ¡Ý 75 kg) and age (< vs. ¡Ý 60 yrs).
¡¤ Treatment was rather well tolerated in both treatment groups, as there were no significant differences in the numbers of serious adverse events or preterm treatment discontinuations.
Conclusions
In conclusion, the authors write, ¡°In treatment-naive patients with chronic hepatitis C and serotype-2 or -3 infection, daily treatment with CIFN combined with ribavirin has the same antiviral efficacy and safety profile as weight adjusted peg-IFNa2b. Further analyses will show whether some subgroups might preferentially benefit from one or the other interferon.¡±
05/18/05
Reference
W Bocher
and others. Interim Results From the PACT-Trial: High Antiviral Efficacy Of
Daily Consensus Interferon/ribavirin Compared To Peg-Interferon Alfa2b/ribavirin
in Treatment-Naive Patients With Chronic Hepatitis C and Serotype-2 or -3.
SABstract S1531. Digestive Disease Week 2005. May 14-18, 2005.
Chicago, IL.
http://www.hivandhepatitis.com/2005icr/ddw2005/docs/hcv_051805e.html
|
Consensus Interferon for Peg/RBV
Nonresponders |
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| 55th Annual
Meeting of the American association for the Study of Liver Diseases October 29-November 2, 2004 Boston, MA |
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| Reported by Jules Levin Carroll Leevy reported results from a pilot study of high dose Consensus Interferon (IFN alfacon-1) for patients who did not respond to pegIFN plus RBV. In vitro Consensus Interferon appears more potent than IFN a or b. In this study patients started therapy with peg-IFN-a-2 +RBV. Patients who did not achieve >2 log HCV RNA reductions by 12 weeks (nonresponders) received IFN alfacon-1 15 mcg once daily plus weight based RBV for 12 weeks and then received IFNalfacon-1 15 mcg three times per week for 36 weeks (n=137). This was followed by a 24 week followup period. There were 45 African-Americans (27 men, 18 women) and 92 non African-Americans (49 men, 41 females) receiving treatment. Over 90% were genotype 1. Baseline viral load was 6.2 log copies/ml. Doctors in the audience again came to the microphone to say they have tried high dose Consensus IFN but their patients could not tolerate it. Leevy countered by saying that 15% of patients dose reduced or took drug holidays. Growth factor was permitted. Additionally, patients were selected for this study. Only patients who were >80% adherent on PegIFN/RBV were permitted into the study. Also, patients did not wash out but were switched immediately to new interferon therapy, which may have facilitated tolerance. It appears that this therapy is for motivated patients. But Leevy said all patients completed therapy in this study. Large phase III studies are ongoing. RESULTS OVERALL RESPONSES TO THERAPY WEEK 12 on IFNalfacon-1: 23% HCV RNA negative; 60% >2 log HCV RNA reduction WEEK 24 on IFN-alfacon-1: 31% HCV RNA negative; 69% >2 log reduction WEEK 48 on IFN-alfacon-1: 43% HCV RNA negative WEEK 72: 37% SVR N=137 at all time points. HCV RNA NEGATIVE RESPONSES BY ETHNIC GROUP WEEK 12: 13% AAs; 28% non-AAs WEEK 24: 24% AAs; 35% non-AAs WEEK 48: 31% AAs; 48$ non-AAs WEEK 72: 27% SVR AAs; 41% non-AAs SVR (p=0.09) N=137 at all time points. Throughout time on therapy platelet count remained relatively stable. WBC counts had significant decreases. 22 patients (16%) had a reduction in WBC (ANC <0.75 x 109) that required GCSF. Hematocrit declined throughout treatment period. Leevy concluded: Patients who did not achieve an EVR after treatment with peg-IFN + RBV can achieve an SVR after switching to IFN alfacon-1 (15 mcg) +RBV (37%) overall for 48 weeks, Virologic reduction in HCV RNA after 12 weeks of peg-IFN-a-2 + RBV is predictive of SVR to IFN alfacon-1 (15 mcg) + RBV. African-Americans achieved an SVR of 27%, non-African-Americans achieved an SVR of 41%. Leevy said therapy was well tolerated. Further study is ongoing in phase III studies by Intermune. http://www.natap.org/ |
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| Comparison of Black and Nonblack Nonresponders Treated With Interferon alfacon-1 Plus Ribavirin |
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| Leevy II C. Comparison of African American and non African American patient end of treatment response for peginterferon alfa-2 + weight based ribavirin nonresponders retreated with IFN alfacon-1 + weight-based ribavirin. Program and abstracts of the 55th Annual Meeting of the American Association for the Study of Liver Diseases; October 29 - November 2; Boston, Massachusetts. Abstract 172. |