title: A phase I/II study of recombinant human interleukin-12 in patients with chronic hepatitis B.
abstract: OBJECTIVE
  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 microg/kg b.w., n=15; 0.25 microg/kg b.w., n=15; 0.50 microg/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 microg/kg b.w. (25%) or with 0.25 microg/kg b.w. (13%) compared with those given 0.03 microg/kg b.w. (7%). Moreover, HBeAg became undetectable at the end of follow-up in five of the patients given the 0.25microg/kg (2/15) or the 0.50 microg/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-gamma, IL-10, neopterin and beta2-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.
authors.affiliation: Fundación Jiménez Díaz, Madrid, Spain. vcarreno@uni.fjd.es
authors.forename: V
authors.initials: V
authors.lastname: Carreño
authors.forename: S
authors.initials: S
authors.lastname: Zeuzem
authors.forename: U
authors.initials: U
authors.lastname: Hopf
authors.forename: P
authors.initials: P
authors.lastname: Marcellin
authors.forename: W G
authors.initials: WG
authors.lastname: Cooksley
authors.forename: J
authors.initials: J
authors.lastname: Fevery
authors.forename: M
authors.initials: M
authors.lastname: Diago
authors.forename: R
authors.initials: R
authors.lastname: Reddy
authors.forename: M
authors.initials: M
authors.lastname: Peters
authors.forename: K
authors.initials: K
authors.lastname: Rittweger
authors.forename: A
authors.initials: A
authors.lastname: Rakhit
authors.forename: M
authors.initials: M
authors.lastname: Pardo
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D000293:Adolescent; D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D005260:Female; D019694:Hepatitis B, Chronic / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D007371:Interferon-gamma / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D018664:Interleukin-12 / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D016896:Treatment Outcome; D001613:beta 2-Microglobulin / Q000097:blood
chemical_list: D000276:Adjuvants, Immunologic; D011994:Recombinant Proteins; D001613:beta 2-Microglobulin; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma