Aerosol Liposomal IL-2 Combined with Interferon+Ribavirin in Patients Who Previously Failed Interferon+Ribavirin
     Nizar N Zein, Rosa Ten, John Gross Jr, Rolland Dickson, John Poterucha, Laurie Czaplewski, Claudia Zein, Peter Anderson, Jacksonville, FL, Rochester, MN.

The investigators of this study proposed to use aerolized liposomal IL-2 to help interferon+ribavirin non-responders improve response with retreatment and IL-2. As background for their premise, they talked about how viral eradication after treatment in HCV patients correlates with cytotoxic T-cell (CTL) proliferative responses (Missale et al Hepatology 1997). They suggested that IL-2 enhances T-cell proliferation and may potentially contribute to viral clearance after interferon therapy. But I don’t think this study demonstrates benefit.

As well, they said treatment of HCV patients with free IL-2 monotherapy (aldesleukin, Chiron Co. Emeryville, CA) was somwhat disappointing (Pardo M et al, Hepatology 1997). They said free IL-2 has also substantial systemic toxicity and narrow therapeutic index. Actually, several studies I’m familiar with show mixed results. Some show IL-2 may contribute to improved ALT and HCV-RNA response from IFN/RBV therapy, while other studies show no improvement.

Aerolized liposomal IL-2 (aIL-2) is a special formulation of IL-2 that is prepared locally at Mayo Clinic under GMP condition. Preparation of aIL-2 involves encapsulation of free IL-2 into liposomes and aerolized delivery as nebulizers.

The advantages of aIL-2 as explained by the presenters are:

--the halflife is much longer: 15 hours compared to 6 minutes for free IL-2

--lower toxicity than free IL-2

--better distribution of IL-2 to immune centers including liver and spleen

The authors said this has been shown in animal models (Khanna C et al J Pharma Pharmacolo 1997; Anderson PM et al J Immunotherapy).

The aim of the study is to evaluate the safety and efficacy of triple therapy (aIL-2, interferon alpha-2b, and ribavirin) in chronic HCV patients who failed previous therapy with IFN and RBV.

The study was designed as a single-arm, non-blinded pilot study to enroll 30 patients who failed previous IFN/RBV treatment given for at least 12 weeks duration. At entry patients had to have: elevated ALT, detectable HCV-RNA by PCR, and compatible liver histology.

Patients received IFN 3 MIU 3x/wk + RBV 1000-1200 mg per day based on weight. The aerolized IL-2 was dosed at 1 million IU twice daily for 7 days every other week (one week on & one week off). Patients received 24 weeks of triple therapy. If they were PCR positive they stopped therapy. If they were PCR negative they continued for 24 additional weeks.

Here are baseline characteristics for the first 16 patients completing the study:

Mean age: 46

Females: 3/16 (19%)

Caucasians: 15/16 (94%)

Genotype 1 14/16 (87%)

Relapsers: 4/16 (25%) and 12/16 were previous nonresponders

Median HCV-RNA (bDNA- Meq/ml): 13.2 (range: 0.22->120)

Stage 3/4 fibrosis: 3/16 (19%)

RESULTS:

--5/16 (31%) of patients had SVR

--of these 5 patients with sustained virologic response 4 (4/4) were relapsers and 1 (1/12) was a nonresponder

--significant decline in HCV-RNA was noted in all patients

HISTOLOGY

--11/16 of patients had a liver biopsy at the end of therapy

--4/11 (36%) had Ž 1 point decline in fibrosis score

--3 of these 4 patients with decreased fibrosis score were among virologic nonresponders after the triple therapySafety and Tolerability