Analysis of the ex vivo interferon-alpha response in patients with chronic hepatitis B after initiation of antiviral therapy with adefovir

Background and aims: The currently approved therapeutic regimen for treatment of chronic hepatitis B include interferon-alpha, lamivudine and adefovir. However, only a minority of patients treated with these agents has a long-term sustained response with ‘eradication’ of the virus. Patients with a high viral load in particular only very rarely respond to IFN therapy. We therefore aimed to determine whether PBMC from HBV patients with a high viral load have a suppressed IFN-response and if the response to IFN is modulated by treatment with the nucleotide analogue adefovir. Methods: PBMC were isolated from 28 patients with chronic hepatitis B from whom 25 received de novo therapy with adefovir before and at week 4, 8, 12 and 24 of therapy. The cells were stimulated for 12h with 10, 100 and 1000 U/ml IFN-α2. Total RNA was isolated and analyzed by customized cDNA arrays that cover a large proportion of known interferon-inducible genes. Significant results were checked by quantitative rt-PCR where appropriate. Viral load and clinical parameters were assessed in parallel are correlated with expression data. Results: When baseline responses to IFN were compared no significant differences were detectable between patients with high and low viral loads (cut off: 1×10E07 IU/ml). There was no difference when patients with good and weak antiviral responses were compared (cut off: 2 log drop in viral load at week 12). Overall the IFN response of the majority of ISGs remained stable over the period of the study. Conclusions: The ex vivo IFN response in PBMC of patients with chronic hepatitis B is not influenced by high viral load or antiviral treatment. This may indicate that the reduced clinical response to IFN that is observed in patients with high viral load is specific for target cells (i.e. hepatocytes) of this treatment rather than the effector arm (immune system). Alternatively, it is possible that exogenous HBsAg and/or HBeAg is responsible for the reduced IFN response in patients with a high viral load.

Schlüsselwörter

adefovir - hepatitis B - interferon - therapy