title: Alpha-galactosylceramide in chronic hepatitis B infection: results from a randomized placebo-controlled Phase I/II trial.
abstract: BACKGROUND
  The glycosphingolipid alpha-galactosylceramide (alpha-GalCer) is known to stimulate invariant natural killer T-cells (iNKTs) and is able to induce powerful antiviral immune responses. The present dose-escalating randomized placebo-controlled Phase I/II trial aimed to investigate antiviral activity and safety of alpha-GalCer as a novel class of treatment for chronic hepatitis B patients.
  
  
  METHODS
  Patients were randomly assigned to 0.1 microg/kg (n=8), 1 microg/kg (n=6) or 10 microg/kg (n=6) alpha-GalCer or placebo (n=7) treatment.
  
  
  RESULTS
  Almost all alpha-GalCer-treated patients showed a rapid and strong decrease in natural killer T-cell (NKT) numbers. Patients with high baseline NKT numbers showed immune activation, including natural killer cell activation, increased serum tumour necrosis factor-alpha and interleukin-6 levels, and development of fever. Three patients demonstrated a transient decrease in hepatitis B virus (HBV) DNA. Only one alpha-GalCer-treated patient had a sustained decrease in HBV DNA at the end of follow-up. Four patients discontinued therapy because of fever shortly after drug administration. No significant side effects were observed.
  
  
  CONCLUSIONS
  alpha-GalCer (0.1-10 microg/kg) used as monotherapy for chronic hepatitis B infection resulted in a strong decrease of NKTs, but did not clearly affect HBV DNA and alanine aminotransferase levels. alpha-GalCer was poorly tolerated and is unlikely to be suitable as an alternative monotherapy to the current treatment regimen.
authors.affiliation: Department of Gastroenterology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Woltman
authors.forename: Martijn J
authors.initials: MJ
authors.lastname: Ter Borg
authors.forename: Rekha S
authors.initials: RS
authors.lastname: Binda
authors.forename: Dave
authors.initials: D
authors.lastname: Sprengers
authors.forename: B Mary E
authors.initials: BM
authors.lastname: von Blomberg
authors.forename: Rik J
authors.initials: RJ
authors.lastname: Scheper
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Hayashi
authors.forename: Nobusuke
authors.initials: N
authors.lastname: Nishi
authors.forename: André
authors.initials: A
authors.lastname: Boonstra
authors.forename: Renate
authors.initials: R
authors.lastname: van der Molen
authors.forename: Harry L A
authors.initials: HL
authors.lastname: Janssen
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use*; D003713:Dendritic Cells; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005699:Galactosylceramides / Q000008:administration & dosage / Q000627:therapeutic use*; D006521:Hepatitis, Chronic / Q000188:drug therapy*; D006801:Humans; D007694:Killer Cells, Natural; D008297:Male; D008875:Middle Aged; D013601:T-Lymphocytes; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D005699:Galactosylceramides; C493154:alpha-galactosylceramide