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Consensus Interferon in Peg/RBV Nonresponders
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Reported by Jules Levin
"INTERIM RESULTS OF A PILOT STUDY OF THE COMBINATION OF TYPE 1 (IFN ALFACON-1) AND TYPE 2 (IFN GAMMA-1B) INTERFERONS IN CHRONIC HEPATITIS C PATIENTS WHO HAVE FAILED TO RESPOND TO PEG-INTERFERON ALPHA 2 PLUS RIBAVIRIN"
study authors: Carroll B Leevy, G. Ramaraju, Chris P Chalmers, Lawrence M Blatt
Two studies were presented today in the Hepatitis oral session at DDW 2004 using Infergen (consensus interferon) plus ribavirin in treating nonresponders to pegylated interferon plus ribavirin. The two studies reported good results for these nonresponders to PEG/RBV but there was an air of disbelief by researchers and thought leaders at this conference. The reported positive results were vigorously challenged both in the session and after the session. A number of doctors I've spoken with who have used Infergen report it is very difficult to tolerate at the dose of 15 mcg. In the first study from Leevy he reports no drop-outs from 32 studied patients. Both of these studies are phase II and 2 phase III studies are ongoing so it is best to wait for the results of these studies. In addition, in the first study from Leevy he used actimune in combination with Infergen but at the 2003 DDW a preliminary study examining actimune did not find any benefit. Also, recently the FDA called Intermune, the manufacturer of Infergen, on the carpet for claims they've made about actimune.
We initiated a pilot study of consensus interferon plus RBV in 32 Null Responders to pegylated IFN alpha 2 + ribavirin. 32 patients were retreated with IFN alfacon-1, 15 mcg SQ daily, and IFN gamma-1b (actimune) 50 mcg SQ TIW for 48 weeks.
All patients had previously received PEG IFN alpha 2b (PegIntron) and ribavirin for 12 weeks, and did not have at least a 2- log10 drop in HCV RNA (Null Responders). Following the initiation of combination therapy with IFN-alfacon-1 and IFN-gamma 1b, serum HCV RNA was assessed at week 12 to determine EVR and will be assessed at weeks 24, 48 and 72 to determine viral kinetics and sustained virologic responses. Patients were monitored for constitutional symptoms and bloods were collected for serum chemistries and hematological evaluations.
The authors reported that the combination of consensus interferon plus RBV was well tolerated in this study. All 32 patients had a reduction from baseline in serum ALT and by week 12, all patients had ALT values that were below the upper limit of normal. There were 4 patients supported by Filgrastim for reductions in ANC. No reductions in hemoglobin were observed. Reductions in ANC were well controlled (neutrophils or white blood cell count) with GCSF (Filgrastim) (25%) and hemoglobin levels returned to normal during treatment. 47% of these patients, who failed PegIntron + RBV were HCV RNA negative by week 24. Another point to consider is that relapse rates can be high after 48 weeks treatment in previous nonresponders. In the Jacobson study where prior IFN/RBV nonresponders were retreated with PegIntron/RBV the relapse rate was 50%. Patients in this Leevy study will be treated for a total of 48 weeks and assessed for SVR. Further study in a larger patient population is now being initiated.
The second study presented at the Hepatitis oral session.
"Successful Retreatment of peginterferon Nonresponder Patients with Chronic Hepatitis C with High Dose Consensus Interferon Induction Therapy"
Steve Kaiser (University Hospital of Tuebingen, Germany) reported results from this study at DDW 2004. Kaiser previously reported results using high dose induction CIFN plus RBV in treatment naives: 74% SVR (CIFN 27/18/9 ug plus RBV), 71% SVR (18/9 ug plus RBV) in genotype 1 low viral load; 48% SVR (CIFN 27/18/9 ug plus RBV) and 42% (CIFN 18/9 ug plus RBV) in genotype 1 low viral load.
Other studies of retreatment with PEG/RBV for IFN/RBV nonresponders found 6-12% SVR.
Previously Kaiser reported week 72 results using CIFN 27/18/9 ug once daily plus RBV 1000/1200 mg—43% SVR; using CIFN 18/9 ug once daily dosing plus RBV 1000/1200 mg—37% SVR. A lot better than the 10% seen in other studies using PEG/RBV retreatment for IFN/RBV nonresponders.
In the current study reported by Kaiser he reported these patients were previous nonresponders toPegIntron/RBV and had good adherence. Patients were 74-85% men; 46-49 yrs old; 93% genotype 1; 70% >850,000 IU HCV RNA; Ishak Fibrosis Stage (mean): 3.79-3.57; 28% had cirrhosis.
60 patients were randomized in open-label fashion to one of two high dose induction CIFN regimens: (1) CIFN 27 ug once daily for 4 weeks followed by CIFN 18 ug once daily for 12 weeks+ RBV 11 mg/kg BW followed by CIFN 9 ug once daily+ RBV 11 mg/kg BW for 32-72 weeks, or (2) CIFN 9 ug QD for 4 weeks, CIFN 9 ug QD + RBV 11 mg/kg BW for 12 wks, followed by CIFN 9 ug QD + RBV 11 mg/kg BW for 32-72 weeks.
RESULTS
Week 24: 47% HCV RNA negative with high-dose; 40% HCV RNA negative with low dose.
ETR: 50% with high dose; 43% with low dose.
SVR: 27% with high dose; 23% with low dose.
ADVERSE EVENTS
Discontinuations: 3% in low dose group; 10% in nhigh dose group.
Dose reductions: 10% lo dose; 23% high dose.
SAE: 1 in high dose (seizure).
AE:
Myalgia: 88% low dose; 95% high dose
Fatigue: 87% & 97%
Headache: 82% & 88%
ALT to 10 x ULN: 45% & 55% (transient)
Mood changes: 55% & 45%
LABORATORY SIDE EFFECTS: HEMATOLOGICAL PARAMETERS
Neutrophil count (grade 4) (<500): 0 in low dose, n=30; 2 in high dose, n=30)
Anemia (grade 3/4): 0 in both groups
Thrombocytopenis (grade 3/4): 0 in low dose; 1 in high dose).
No growth factors were used.
The authors concluded CIFN was well tolerated. Rates of adverse events and serious adverse events were comparable to standard combination therapy (observers did not believe this as doctors report high dose CIFN is hard to tolerate). Grade 3/4 neutropenia and thrombocytopenia not sifnificantly higher than with standard combination therapy (3%). Discontinuation and dose reductionrates not higher than standard combination therapy. 23-27% of patients are HCV RNA negative under CIFN + RBV combination therapy at week 72 (SR). CIFN as daily therapy with RBV is a promising approach for PEG/RBV nonresponders. Further study in larger patioent population is warranted: two studies ongoing in US & Germany.
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