"Triple Anti-HCV Drug Therapy for Nonresponders to Peginterferon/Ribavirin: Interferon Gamma (Actimmune) + Ribavirin + Pegasys or Infergen: A Pilot Study"

"Triple Anti-HCV Drug Therapy for Nonresponders to Peginterferon/Ribavirin: Interferon Gamma (Actimmune) + Ribavirin + Pegasys or Infergen: A Pilot Study"

Reported by Jules Levin

Vijayan Balan and researchers in the Division of Transplant Medicine at Mayo Clinic in Scottsdale, AZ, and Larry Blatt from Intermune reported these study results in poster S914 at DDW May 2005.

There is a need for therapy for HCV-positive patients who have been previously treated with an interferon-based therapy who did not achieve a Sustained Viral Response (SVR). This small pilot study from Balan examines if HCV+ individuals who previously failed (nonresponders & relapsers) prior treatment with peginterferon plus ribavirin could respond well to triple therapy:

This is an ongoing, open-label, single center pilot study. 15 patients are assigned to each study group on a randomized basis:

Group A: Interferon alfacon-1 15 mcg once daily + IFN-gamma 1b 100 ug three times per week, plus RBV weigh-based.

Group B: peginterferon alpfa-2a 180 ug once weekly + IFN-gamma 100 ug three times weekly + ribavirin.

Ribavirin was weight-based dosed at 13 mg/kg with a maximum of 1400mg/day. Ribavirin was administered orally in divided doses, twice daily.

Growth factors such as erythropoietin (EPO) and G-CSF were used when necessary.

These preliminary results from a small pilot study find that both triple drug regimens show similar results after 24 weeks therapy: 2/5 (40%) receiving Pegasys/RBV/IFN-gamma, and 2/6 (33%) receiving Infergen/RBV/IFN-gamma had <50 copies IU/mL, were PCR negative. (note: The Leevy pilot studies of high dose Infergen plus either RBV or IFN-gamma showed 35% SVR rates). The tolerability & safety profile appeared similar & expected results were observed, I don’t think anything out of the ordinary was reported. These results are based on a small number of patients & as the authors say the results are good enough to warrant further study.

The aims of the study are to examine (1) safety & tolerability of this triple regimen, and the percent of patients with early viral response (EVR) at week 12 & 24 of triple therapy. Non-responders to pegIFN/RBV were randomized in this open-label study to receive the triple therapy or Pegasys+IFN-gamma+ribavirin.

A number of clinical studies have found that interferon afacon-1, also known as Infergen or Consensus Interferon, in high doses can achieve an SVR for nonresponders to previous therapy with peginterferon plus ribavirin. Phase III large studies are now examing the efficacy of Consensus Interferon. The main question surrounding the use of daily high dose Consensus is the tolerability, as many researchers feel the side effects are difficult to tolerate. At this DDW meeting and recent conferences results from pilot studies presented showed nonresponders to pegIFN+RBV achieved an SVR with high dose Infergen plus RBV/ At this DDW, researchers reported Carroll Leevy reported 34% SVR rates in a small pilot study (n=50) for PegIFN/RBV nonresponders who received Infergen (daily 15 ug) and IFN Gamma-1b (50 ug 3x/week). You can read the NATAP report of this study:

http://www.natap.org/2005/ddw/ddw_15.htm

RESULTS

(followed by study details)

VIROLOGIC RESULTS

Patients had a significant reduction in HCV RNA; 3 log+ reductions by week 24--

Mean Baseline Values (IU/ml):

--Baseline: 5.83

--Week 4: 4.40

--Week 12: 3.61

--Week 24: 2.71

P<0.05

VIROLOGIC RESPONSE with TRIPLE THERAPY BASED on FIRST 20 PATIENTS

12 weeks 24 weeks

>2 log Neg PCR >2 log Neg PCR

drop <50 IU/ml drop <50 IU/ml

--Overall 9/20 5/20 7/11 4/11

45% 25% 64% 36%

--Pegasys+ 6/10 3/10 3/5 2/5

IFNy1b+RBV 60% 30% 60% 40%

--CIFN/gamma/ 4/10 2/10 4/6 2/6

RBV 40% 20% 67% 33%

--The authors concluded the 3-drug therapy with IFNa+IFN-gamma-1b+RBV has acceptable tolerability.

--based on interim data, the antiviral activity of 3-drug therapy for non-responders appears promising as a significant percent of study patients have a >2 log drop in HCV RNA by week 12.

--further studies in larger cohorts are warranted.

CURRENT ENROLLMENT

26 patients (target enrollment is 30), 16 males, 10 females, genotype 1; pegIFN+RBV failures:

--cirrhotic: 12/26 (46%)

--nonresponders: 21/26 (80%)

--relapsers 5/26 (20%)

--mean duration of prior therapy: 49 weeks

--both 3-drug regimens were tolerated.

ADVERSE EFFECTS

Common adverse effects were mild-to-moderate & include: injection site erythema, fatigue, arthralgia, pyrexia (fever), myalgia, depression, & sleep disturbance. Neutropenia (ANC <750) occurred in 40% of the first 10 patients treated. 2 SAEa reported to date (1 death from suicide at week 40 on treatment; 1 hospitalization for shortness of breath at week 6 of therapy).

Adverse Events Based on Type of Therapy Based on the First 24 Patients

Infergen/gamma/RBV Pegasys/RBV/gamma

11 total patients 13 patients

Hematologic

--anemia (<10 g/dl) 4 36% 2 62%

--neutropenia

(<0.750x10(9)/L) 6 55% 6 46%

--thrombocytopenia

(<50x10(9)/L) 4 36% 0 0%

Lab Abnormalities

--hyperuricemia 2 18% 1 8%

--hypogammaglubulinemia 1 9% 0 0

--lipidemia 1 9% 1 8%

--NPN increased 0 0% 1 8%

--prolonged bleeding

(reported by patient) 0 0% 1 8%

Arthralgia 9 82% 11 85%

Back pain 1 9% 2 15%

Muscle cramps 2 18% 1 8%

Myalgia 9 82% 10 77%

Headache 7 64% 9 69%

Dizziness 1 9% 3 23%

Restless leg syndrome 0 0% 1 8%

Depression 5 45% 8 62%

Emotional lability 1 9% 2 15%

Insomnia 8 73% 6 46%

Irritability/anxiety 6 55% 7 54%

Lipido decreased 1 9% 0 0%

Injection Site Reactions 11 100% 11 85%

Cardiac

--hypertension 1 9% 0 0%

--pedal anemia 3 30% 2 15%

Endocrine disorders

-hypoglycemic 1 9% 0 0%

Flu-like symptoms/signs

--fatigue 10 91% 12 92%

--pain 0 0 1 8%

--pyrexia 10 91% 7 54%

--rigors 10 91% 8 62%

Gastrointestinal

--abnominal pain 3 30% 3 23%

--bleeding hemorrhoids 1 9% 1 8%

--constipation 1 9% 4 31%

--diarrhea 5 45% 6 46%

--dry mouth/

mucous membranes 2 18% 6 46%

--dyspepsia 1 9% 2 15%

--mouth sores 2 18% 5 38%

--nausea/vomiting 4 36% 7 54%

--pharyngitis 0 0% 1 8%

STUDY SUBJECTS

The target population was 30 adult patients with chronic hepatitis C virus infection with genotype 1, who are viremic, previously treated and failed combination peginterferon-a & ribavirin. Patients must have previously failed at least 12 weeks of treatment with pegIFN+RBV (either Pegasys or PegIntron) without significant safety or tolerability issues.

STUDY DESIGN

A sample size of 15 patients has at least a 95% chance of including a serious adverse event if the population incidence is at least 20%. If no serious adverse event were observed in a sample of 15 patients, we would have 95% confidence that the population incidence is less than 20%. Likewise, a sample of 15 patients has at least a 95% chance of including a patient with a sustained virologic response if the population response is at least 20%.

Duration of treatment : 48 weeks with 24 weeks followup.

Medications were not mixed in the same syringe or injected at the same site. The patient administered the first dose of the interferons on day 0 at the Clinic under the direction of the study staff.

Clinical evaluations included Beck Depression inventory-II & baseline ocular exams for all patients with diabetes or hypertension

Key inclusion criteria for patients: hemoglobin >10 gm/dL; WBC >3,000/mm3; neutrophil count >1,000/mm3; platelets >50,000/mm3; prothrombin time <3 seconds prolonged compared to control, or equivalent INR; serum creatinine <2.0 mg/dL; hemoglobin A1C <8.5% for diabetic patients (whether on medication and/or diet controlled); thyroid stimulating hoemone (TSH) within normal limits (patients requiring medication to maintain TSH levels in the normal range are eligible if all other inclusion criteria are met); serum hepatitis B surface antifen (HBsAg) negative; sexcually active patients must practice acceptable methods (e.g., barrier method) of contraception during the treatment period & for 6 months after discontinuation of therapy (due to potential for birth defects from using RBV).

Key Exclusion Cirteria: patients with evidence of advanced liver disease such as history or presence of uncontrolled ascites, bleeding varices, and/or encephalopathy; pre-existing uncontrolled psychiatric condition, especially severe depression, or a history of severe psychiatric disorder; active substance abuse, such as alcohol (>20 gr/day), i.m., i.v., inhaled or per os. Recreational drugs; if the patient has a history of substance abuse, to be considered for study they must have abstained for at least 6 months; patients with clinically significant retinal abnormalities; patients with ECG showing significant abnormalities; poorly controlled diabetes; chronic pulmonary disease; uncontrolled immunologically mediated disease.