A phase I/II study of recombinant human interleukin-12 in patients with chronic hepatitis C.
Interleukin-12 (IL-12) plays a central role in mounting an effective cellular immune response directed towards elimination of intracellular pathogens. The present open-label, multicenter, dose-escalation phase I/II study was designed to assess tolerability, pharmacokinetics, pharmacodynamics, and efficacy of subcutaneously administered recombinant human interleukin-12 (rHuIL-12) in the treatment of chronic hepatitis C. Sixty patients (42 men, 18 women, aged 24-60) were treated with 0.03 microgram/kg (n = 16), 0.1 microgram/kg (n = 14), 0.25 microgram/kg (n = 15), or 0.5 microgram/kg rHuIL-12 (n = 15) for 10 consecutive weeks. rHuIL-12 was generally well tolerated, with 2 patients (3.3%) being withdrawn from treatment for adverse events. Treatment was associated with temporary decreases in neutrophils and lymphocyte counts and with elevations in serum transaminases and bilirubin. Serum IL-12 levels observed were higher at 0.5 microgram/kg compared with 0.25 microgram/kg doses, suggesting a dose-related increase in systemic exposure of IL-12. Measurable levels of interferon gamma (IFN-gamma) were also observed at the highest dose of 0.5 microgram/kg. At the end of treatment hepatitis C virus (HCV) RNA was detectable in all patients. A more than 50% decrease in pretreatment HCV RNA levels was observed in 3 of 16 patients of the 0.03-microgram/kg dose group, in 3 of 14 of the 0.10-microgram/kg dose group, in 6 of 15 of the 0.25-microgram/kg dose group, and in 8 of 15 patients of the 0.5-microgram/kg dose group. Although in several cases serum alanine transaminase (ALT) levels decreased either during or after treatment, ALT normalization was observed in only 4 patients at the end of treatment and in 5 patients at the end of follow-up. Significant anti-rHuIL-12 antibody titers were not detectable in any patient. In conclusion, antiviral activity of rHuIL-12 in patients with chronic hepatitis C does not appear advantageous in comparison with other currently available treatments.
Zeuzem
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Medizinische Klinik II, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt, Germany. Zeuzem@em.uni-frankfurt.de
Hopf
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Carreno
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Diago
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Shiffman
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Grüne
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Dudley
F J
FJ
Rakhit
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Rittweger
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Yap
S H
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Koff
R S
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Thomas
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D000293:Adolescent; D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D000906:Antibodies / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D019698:Hepatitis C, Chronic / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D007371:Interferon-gamma / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D018664:Interleukin-12 / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D019798:Neopterin / Q000097:blood; D012367:RNA, Viral / Q000097:blood; D011994:Recombinant Proteins / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014766:Viremia / Q000188:drug therapy; D001613:beta 2-Microglobulin / Q000378:metabolism
D000906:Antibodies; D012367:RNA, Viral; D011994:Recombinant Proteins; D001613:beta 2-Microglobulin; D016753:Interleukin-10; D018664:Interleukin-12; D019798:Neopterin; D007371:Interferon-gamma; D000410:Alanine Transaminase