TY - JOUR
T1 - Randomized placebo controlled phase I/II trial of alpha-galactosylceramide for the treatment of chronic hepatitis C
AU - Veldt, Bart J
AU - van der Vliet, Hans J J
AU - von Blomberg, B Mary E
AU - van Vlierberghe, Hans
AU - Gerken, Guido
AU - Nishi, Nobusuke
AU - Hayashi, Kunihiko
AU - Scheper, Rik J
AU - de Knegt, Robert J
AU - van den Eertwegh, Alfons J M
AU - Janssen, Harry L A
AU - van Nieuwkerk, Carin M J
PY - 2007/9
Y1 - 2007/9
N2 - BACKGROUND/AIMS: The glycosphingolipid alpha-galactosylceramide has been shown to activate invariant natural killer T cells when presented in the context of CD1d and induces powerful antiviral immune responses via the production of inflammatory cytokines. The aim of this study was to investigate the safety and the antiviral activity of alpha-galactosylceramide as a novel class of treatment for chronic hepatitis C patients.METHODS: International multicenter dose-escalating randomized placebo-controlled phase I/II trial.RESULTS: Forty patients were allocated to a dose of 0.1 microg/kg (n=9), 1 microg/kg (n=9), 10 microg/kg (n=11) or to placebo (n=11). alpha-Galactosylceramide was well tolerated and no patients were withdrawn due to side effects. Although most patients showed a decrease in invariant natural killer T cells after administration, no clinically relevant suppression of viral replication was observed. Only one patient, a previous non-responder to peginterferon and ribavirin with high baseline invariant natural killer T cell levels, showed profound signs of immune activation, accompanied by a transient 1.3 log decrease in HCV-RNA and a concomitant increase in ALT after the first administration.CONCLUSIONS: alpha-Galactosylceramide used as monotherapy for interferon-refractory patients in doses of 0.1-10 microg/kg is safe and it exerts moderate immunomodulatory effects. However, in its current form it has no significant effect on HCV-RNA levels.
AB - BACKGROUND/AIMS: The glycosphingolipid alpha-galactosylceramide has been shown to activate invariant natural killer T cells when presented in the context of CD1d and induces powerful antiviral immune responses via the production of inflammatory cytokines. The aim of this study was to investigate the safety and the antiviral activity of alpha-galactosylceramide as a novel class of treatment for chronic hepatitis C patients.METHODS: International multicenter dose-escalating randomized placebo-controlled phase I/II trial.RESULTS: Forty patients were allocated to a dose of 0.1 microg/kg (n=9), 1 microg/kg (n=9), 10 microg/kg (n=11) or to placebo (n=11). alpha-Galactosylceramide was well tolerated and no patients were withdrawn due to side effects. Although most patients showed a decrease in invariant natural killer T cells after administration, no clinically relevant suppression of viral replication was observed. Only one patient, a previous non-responder to peginterferon and ribavirin with high baseline invariant natural killer T cell levels, showed profound signs of immune activation, accompanied by a transient 1.3 log decrease in HCV-RNA and a concomitant increase in ALT after the first administration.CONCLUSIONS: alpha-Galactosylceramide used as monotherapy for interferon-refractory patients in doses of 0.1-10 microg/kg is safe and it exerts moderate immunomodulatory effects. However, in its current form it has no significant effect on HCV-RNA levels.
KW - Adult
KW - Aged
KW - Alanine Transaminase/blood
KW - Antiviral Agents/administration & dosage
KW - Blood Cells/pathology
KW - Cytokines/blood
KW - Dose-Response Relationship, Drug
KW - Female
KW - Galactosylceramides/administration & dosage
KW - Hepacivirus/genetics
KW - Hepatitis C, Chronic/drug therapy
KW - Humans
KW - Immune System/drug effects
KW - Killer Cells, Natural/pathology
KW - Male
KW - Middle Aged
KW - RNA, Viral/blood
KW - T-Lymphocytes/pathology
KW - Treatment Outcome
KW - Virus Replication/drug effects
U2 - 10.1016/j.jhep.2007.04.018
DO - 10.1016/j.jhep.2007.04.018
M3 - Article
C2 - 17599630
VL - 47
SP - 356
EP - 365
JO - Journal of Hepatology
JF - Journal of Hepatology
SN - 0168-8278
IS - 3
ER -