Interleukin-12 Does Not Halt HBV Replication in HBeAg Positive Patients and Does Not Inhibit HBV Replication after Withdrawal of Lamivudine

Hepatitis B virus (HBV) is a noncytopathic DNA virus, which can cause acute, self-limited hepatitis or chronic hepatitis, cirrhosis, and/or hepatocellular carcinoma.[1] The diversity of clinical outcomes after exposure to HBV is determined primarily by the host immune response.

Interleukin-12 (IL-12) is a proinflammatory cytokine, produced by activated phagocytic cells (monocytes/macrophages) and dendritic cells, that plays a central role in stimulating cell-mediated immunity. [2,3]

IL-12 stimulates natural killer cells and T-lymphocytes to produce interferon IFN-gamma (IFN-gamma), promotes T-helper 1 responses, and enhances CD8+ cytotoxic T-cell activity. These unique properties of IL-12 indicate that it might have an important role in achieving sustained control of HBV replication.

Researchers at the University College London, London, UK conducted a pilot study to investigate in patients with chronic hepatitis B whether a combination treatment with lamivudine (Epivir-HBV) plus recombinant human interleukin-12 (rhIL-12) will result in a greater antiviral effect and prolonged suppression of HBV replication in comparison with lamivudine monotherapy [4].

In addition, by monitoring longitudinally the HBV-specific T-cell reactivity, the study aimed to determine whether IL-12-stimulated T-cell responsiveness to HBV can maintain the control of viral replication after stopping the antiviral agent.

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 post-treatment.

Results

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,” write the authors, “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.”

Discussion

This study demonstrates that administration of rhIL-12 in patients with chronic hepatitis B stimulates Th1 cell reactivity to HBV, increases the frequency of virus-specific CD4+ T-cells, and enhances IFN-gamma production.

However, unlike in HBV transgenic mice, where hepatic HBV DNA and viremia were abolished after only three injections of rIL-12, [5] in patients with chronic hepatitis B, continued rhIL-12 administration, after stopping lamivudine, was not able to maintain suppression of HBV replication, according to the authors.

“In our study, rhIL-12 was added to lamivudine, which increased significantly the on-treatment antiviral effect. Similarly, pegylated interferon-alfa plus lamivudine showed a greater antiviral effect than monotherapy, but this was not sustained after stopping treatment.”

The researchers employed a dose and duration of rhIL-12 therapy that were greater than in pilot monotherapy trials, and they caution “A further dose increase is unlikely to be tolerated. A trial with rhIL-12 (500 ng/kg twice weekly) in chronic hepatitis C was terminated prematurely because of poor tolerance and treatment-related severe adverse events.”

Finally, the authors conclude, “The failure of lamivudine plus rhIL-12 to achieve sustained improvement suggests that combination therapy with an antiviral drug and immunomodulatory cytokine is unlikely to establish sustained resolution of HBV replication.”

Institute of Hepatology, Division of Medicine, University College London, London, UK, and Department of Virology, Windeyer Institute, University College London, London, UK.

Primary Source

E Rigopoulou, D Suri, S Chokshi and others. Lamivudine plus interleukin-12 combination therapy in chronic hepatitis B: Antiviral and immunological activity. Hepatology 42(5): 1028-1036. November 2005.

References

1.      Ganem D, Prince AM. Hepatitis B virus infection: natural history and clinical consequences. N Engl J Med 2004; 350: 1118-1129.

2.      Gately MK, Renzetti LM, Magram J, Stern AS, Adorini L, Gubler U, et al. The interleukin-12/interleukin-12-receptor system: role in normal and pathologic immune responses. Annu Rev Immunol 1998; 16: 495-521.

3.      Trinchieri G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol 2003; 3: 133-146.

4.      Rigopoulou, EI, Suri D, Chokshi s, et al. Lamivudine plus interleukin-12 combination therapy in chronic hepatitis B: Antiviral and immunological activity. Hepatology 2005: 42: 1028-1036.

5.      Cavanaugh VJ, Guidotti LG, Chisari FV. Interleukin-12 inhibits hepatitis B virus replication in transgenic mice. J Virol 1997; 71: 3236-3243.

11/02/05