Enhancing the antihepatitis B virus immune response by adefovir dipivoxil and entecavir therapies

Abstract

Chronicity of hepatitis B (CHB) infection is characterized by a weak immune response to the virus. Entecavir (ETV) and adefovir dipivoxil (ADV) are effective in suppressing hepatitis B virus (HBV) replication. However, the underlying immune mechanism in the antiviral response of patients treated with nucleoside or nucleotide analogs is not clearly understood. In this study, regulatory T cells (Tregs) and intracellular cytokines, including IL-2, interferon (IFN)-γ, tumor-necrosis factor (TNF)-α and IL-4, were measured prior to and at 12, 24, 36 and 48 weeks after treatment with ETV or ADV. The cytokines were increased from 24 to 48 weeks after treatment. Higher levels of Th1 cytokines were observed with ETV (n=29) versus ADV (n=28) treatment. By contrast, the numbers of Tregs in both groups were decreased. The altered cytokine profile and cellular component was accompanied by a decrease in HBV DNA levels in both groups, which may contribute to their therapeutic effect in CHB infection. Our findings suggest that the antiviral effect of the drugs may be attributed not only to their direct effect on virus suppression but also to their immunoregulatory capabilities.

Figure 1

Analysis of Tregs and T-cell subsets during antiviral therapy. (a) FACS was performed to assess the populations of Tregs and T-cell subsets in PBL. Data shown are representative of baseline and post-treatment. (b) The effect of ADV and ETV treatments on the ratio of CD4⁺CD25⁺ Foxp3⁺ and CD3⁺CD4⁺ T cells was analyzed. ADV, adefovir dipivoxil; ETV, entecavir; FACS, fluorescence-activated cell sorting; PBMC, peripheral blood lymphocytes; Tregs, regulatory T cells.

Figure 2

Effect of ADV and ETV treatments on cytokine production in patients with positive and negative HBeAg. Cytokine production (a) and T-cell subsets from total lymphocytes (b) were assessed at the time points of treatment as indicated and analyzed according to the initial measure of HBeAg in each patient's serum. HBeAg-positive and -negative are indicated as +ve and −ve, respectively. ADV, adefovir dipivoxil; ETV, entecavir; HBeAg, hepatitis e antigen; IFN, interferon; TNF, tumor-necrosis factor.

Figure 3

Correlation between cytokine production and HBV DNA load in patients treated with ADV and ETV. The mean values of HBV DNA and indicated cytokines in patients treated with ADV (a) and ETV (b) were shown. ADV, adefovir dipivoxil; ETV, entecavir; HBV, hepatitis B virus; IFN, interferon; TNF, tumor-necrosis factor.