Lamivudine plus interleukin-12 combination therapy in chronic hepatitis B: antiviral and immunological activity.

Abstract

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-gamma) 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-gamma 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-gamma production, and an inverse correlation between the frequency of IFN-gamma-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-gamma production. However, IL-12 does not abolish HBV replication in HBeAg-positive patients and does not maintain inhibition of HBV replication after lamivudine withdrawal.

• Authors: Eirini I Rigopoulou, Deepak Suri, Shilpa Chokshi, Ivana Mullerova, Steven Rice, Richard S Tedder, Roger Williams, Nikolai V Naoumov
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 42 Issue 5 Pg. 1028-36 (Nov 2005) ISSN: 0270-9139 [Print] United States
• PMID: 16250037 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Adjuvants, Immunologic
• DNA, Viral
• Hepatitis B Core Antigens
• Recombinant Proteins
• Reverse Transcriptase Inhibitors
• Interleukin-12
• Lamivudine
• Interferon-gamma

Topics

• Adjuvants, Immunologic (adverse effects, therapeutic use)
• Adult
• CD4-Positive T-Lymphocytes (pathology)
• DNA, Viral (blood)
• Drug Therapy, Combination
• Female
• Hepatitis B Core Antigens (immunology)
• Hepatitis B virus (immunology)
• Hepatitis B, Chronic (drug therapy, genetics)
• Humans
• Interferon-gamma (biosynthesis)
• Interleukin-12 (adverse effects, therapeutic use)
• Lamivudine (adverse effects, therapeutic use)
• Male
• Pilot Projects
• Recombinant Proteins (adverse effects, therapeutic use)
• Reverse Transcriptase Inhibitors (adverse effects, therapeutic use)
• T-Lymphocytes (immunology)
• Viremia (drug therapy)
• Virus Replication (drug effects)