Lamivudine plus interleukin-12 combination therapy in chronic hepatitis B: Antiviral and immunological activity
AuthorRigopoulou, E. I.; Suri, D.; Chokshi, S.; Mullerova, I.; Rice, S.; Tedder, R. S.; Williams, R.; Naoumov, N. V.
Interleukin-12 (IL-12) is an immunomodulatory cytokine that promotes cellular immunity. Pre-clinical data suggest that IL-12 inhibits hepatitis B virus (HBV) replication by stimulating interferon-gamma (IFN-γ) production. We investigated whether a combination treatment with lamivudine plus recombinant human interleukin-12 (rhIL-12) will result in a greater and prolonged suppression of HBV replication in comparison with lamivudine monotherapy. Fifteen patients with HBeAg-positive chronic hepatitis B were randomized to receive either lamivudine alone for 24 weeks (group 1); combination of lamivudine for 16 weeks and rhIL-12 (200 ng/kg twice weekly), starting 4 weeks after initiation of lamivudine, for 20 weeks (group 2), or the same schedule as for group 2, with lamivudine and a higher dose of rhIL-12 (500 ng/kg, group 3). Serum HBV DNA levels, T-cell proliferation, frequency of virus-specific T-cells, and IFN-γ production were evaluated serially during and 24 weeks posttreatment. Lamivudine plus rhIL-12/500 showed greater antiviral activity than lamivudine monotherapy. However, after stopping lamivudine in groups 2 and 3, serum HBV DNA increased significantly despite continuing rhIL-12 administration. Lamivudine plus rhIL-12 treatment was associated with a greater increase in virus-specific T-cell reactivity, IFN-γ production, and an inverse correlation between the frequency of IFN-γ-producing CD4+ T-cells and viremia. The T-cell proliferative response to HBcAg did not differ between the three groups. In conclusion, the addition of IL-12 to lamivudine enhances T-cell reactivity to HBV and IFN-γ production. However, IL-12 does not abolish HBV replication in HBeAg-positive patients and does not maintain inhibition of HBV replication after lamivudine withdrawal. Copyright © 2005 by the American Association for the Study of Liver Diseases.
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