Lamivudine plus interleukin-12 combination therapy in chronic hepatitis B: antiviral and immunological activity.
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.
Rigopoulou
Eirini I
EI
Institute of Hepatology, Division of Medicine, University College London, London, UK.
Suri
Deepak
D
Chokshi
Shilpa
S
Mullerova
Ivana
I
Rice
Steven
S
Tedder
Richard S
RS
Williams
Roger
R
Naoumov
Nikolai V
NV
D000276:Adjuvants, Immunologic / Q000009:adverse effects / Q000627:therapeutic use*; D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D004279:DNA, Viral / Q000097:blood; D004359:Drug Therapy, Combination; D005260:Female; D006512:Hepatitis B Core Antigens / Q000276:immunology; D006515:Hepatitis B virus / Q000276:immunology; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000009:adverse effects / Q000627:therapeutic use*; D019259:Lamivudine / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D010865:Pilot Projects; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000276:immunology; D014766:Viremia / Q000188:drug therapy; D014779:Virus Replication / Q000187:drug effects
D000276:Adjuvants, Immunologic; D004279:DNA, Viral; D006512:Hepatitis B Core Antigens; D011994:Recombinant Proteins; D018894:Reverse Transcriptase Inhibitors; D018664:Interleukin-12; D019259:Lamivudine; D007371:Interferon-gamma