A phase I/II study of recombinant human interleukin-12 in patients with chronic hepatitis B

Vicente Carreño*, Stefan Zeuzem, Uwe Hopf, Patrick Marcellin, W. Graham E. Cooksley, Johan Fevery, Moisés Diago, Rajender Reddy, Marion Peters, Karen Rittweger, Ashok Rakhit, Margarita Pardo

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

90 Scopus citations

Abstract

Background/Aims: Interleukin-12 (IL-12) may be active against hepatitis B virus (HBV). The objective of the study was to assess the tolerability, activity, pharmacokinetics, and pharmacodynamics of three dose levels (0.03 μg/kg b.w., n = 15; 0.25 μg/kg b.w. n=15; 0.50 μg/kg b.w., n=16) of recombinant human (rHU) IL-12 given s.c. once a week for 12 consecutive weeks. Methods: Forty-six patients with chronic hepatitis B, HBV DNA positivity and aminotransferase elevation were included in a multicenter prospective randomized phase I/II study. Results: Compared with the baseline, HBV DNA levels had decreased significantly at the end of rHuIL-12 treatment and after the 12-week follow-up period (p<0.001). The response to rHuIL-12 treatment was dose-dependent: At the end of the study HBV DNA clearance was greater in patients treated with 0.50 μg/kg b.w. (25%) or with 0.25 μg/kg b.w. (7%). Moreover, HBeAg became undetectable at the end of follow-up in five of the patients given the 0.25 μg/kg (2/15) or the 0.50 μg/kg (3/16) dose. The drug pharmacology showed that IL-12 had an estimated half-life of 30 h with levels remaining detectable for more than 48 h after rHuIL-12 administration. The serum levels of IL-12, interferon-γ, IL-10, neopterin and β2-microglobulin as well as the area under the curve (AUC) were rHuIL-12 dose-related. Side effects were observed more frequently with higher doses, including moderate decreases in lymphocyte and neutrophil counts; three patients withdrew prematurely from treatment. The local reaction observed at the injection site was unrelated to the drug dose. Only one patient showed detectable antibody levels to rHuIL-12 without clinical impact. Conclusions: Treatment with rHuIL-12 at the doses investigated is safe and tolerable, and appears to be active against HBV in patients with chronic hepatitis B.

Original languageEnglish (US)
Pages (from-to)317-324
Number of pages8
JournalJournal of Hepatology
Volume32
Issue number2
DOIs
StatePublished - Feb 2000

Funding

This study was supported by a grant from F. Hoffmann-La Roche, AG, Basel, Switzerland.

Keywords

  • Chronic hepatitis B
  • Hepatitis B virus e antibody
  • Hepatitis B virus e antigen
  • IL-12 pharmacodynamics
  • IL-12 pharmacokinetics
  • Interleukin (IL)-12 therapeutic use

ASJC Scopus subject areas

  • Hepatology

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