α-Galactosylceramide in Chronic Hepatitis B Infection: Results from a Randomized Placebo-Controlled Phase I/ II Trial

Background The glycosphingolipid α-galactosylceramide (α-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 α-GalCer as a novel class of treatment for chronic hepatitis B patients. Methods Patients were randomly assigned to 0.1 μg/kg ( n=8), 1 μg/kg ( n=6) or 10 μg/kg ( n=6) α-GalCer or placebo ( n=7) treatment. Results Almost all α-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-α and interleukin-6 levels, and development of fever. Three patients demonstrated a transient decrease in hepatitis B virus (HBV) DNA. Only one α-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 α-GalCer (0.1–10 μg/kg) used as mono-therapy for chronic hepatitis B infection resulted in a strong decrease of NKTs, but did not clearly affect HBV DNA and alanine aminotransferase levels. α-GalCer was poorly tolerated and is unlikely to be suitable as an alternative monotherapy to the current treatment regimen.