Relationship of Treg/Th17 balance with HBeAg change in HBeAg-positive chronic hepatitis B patients receiving telbivudine antiviral treatment: A longitudinal observational study

Abstract

Telbivudine (LdT) is an orally L-nucleoside with potent and specific antihepatitis B virus (HBV) activity. The higher rate of hepatitis B e antigen (HBeAg) seroconversion of LdT treatment than other anti-HBV agents suggests a potential immunomodulatory effect. The aim of the study was to investigate the changes of regulatory T cell (Treg)/interleukin (IL)-17-producing CD4+T helper (Th17) balance during LdT treatment and to discuss the relationship of Treg/Th17 balance with HBeAg change in HBeAg-positive chronic hepatitis B (CHB) patients receiving LdT antiviral treatment. Twenty-seven HBeAg-positive CHB patients received LdT for 24 weeks and the percentages of Tregs and cells (Th17 cells) in peripheral blood as well as the serum TGF-β1 and IL-17 levels in these patients were longitudinally analyzed. We found that the frequencies of Tregs and Th17 cells in peripheral blood as well as the serum TGF-β1 and IL-17 levels increased significantly in CHB patients compared with healthy controls. During the LdT treatment, the Tregs frequency and TGF-β1 level tended to decrease, and Th17 cells frequency and IL-17 level showed a reverse "V"-type change. The frequency of Tregs and the ratio of Treg/Th17 were significantly lower in the HBeAg loss group than those in the HBeAg no-loss group at the baseline. More important, the Tregs frequency and TGF-β1 level were both positively correlated with HBeAg level during the LdT treatment for 24 weeks. Our data suggest that the lower Tregs frequency and Treg/Th17 ratio at the baseline of LdT treatment, the more likely to get the HBeAg loss. HBeAg negative can be predicted using changes in Tregs frequency and TGF-β1 level during LdT treatment in CHB patients. Maybe we could provide the immunology marker for exploring the mechanism of the higher HBeAg seroconversion rate of LdT therapy.

Figure 1

The change of clinical parameters of chronic hepatitis B patients undergoing telbivudine therapy. (A–C) The change of virological parameters during the treatment; (D) The change of serum alanine aminotransferase (ALT) level during the treatment. The hepatitis B virus DNA load, hepatitis B surface and hepatitis B e antigen levels, and ALT level at 4-week were significantly lower than those at the baseline (P < .001). Data were presented as mean ± SD in (A and D), data were presented as median with range in (B and C). ALT = alanine aminotransferase, DNA = deoxyribonucleic acid, HBeAg = hepatitis B e antigen, HBsAg = hepatitis B surface, HBV = hepatitis B virus.

Figure 2

Change in the frequencies of regulatory T cells and interleukin (IL)-17-producing CD4+T helper cells and levels of TGF-β1 and IL-17 during telbivudine treatment. (A) ^∗∗P < .01, ^∗∗∗P < .001, compared with the baseline. ^&P < .001, compared between week 24 and 12. (B) ^∗∗∗P < .001, compared with the baseline; ^#P < .01, compared between week 24 and healthy controls (HCs). (C) ^∗P < .05, ^∗∗∗P < .001, compared with the baseline; ^&P < .001, compared between week 24 and 12; ^#P < .05, compared between week 24 and HCs. (D) ^∗∗∗P < .001, compared with the baseline; ^&P < .001, compared between week 24 and 12; ^#P < .05, compared between week 24 and HCs. (E) ^∗P < .05, ^∗∗∗P < .001, compared with the baseline; ^#P < .05, compared between week 24 and HCs. (F) ^∗∗∗P < .001, compared with the baseline. ^∗P < .05, compared between week 24 and 12. ns: no statistical significance. Data were presented as mean ± SD.

Figure 3

Correlation between the regulatory T cell (Treg)/interleukin (IL)-17-producing CD4+T helper (Th17) balance and hepatitis B e antigen (HBeAg) level. (A–D) The Tregs frequency, TGF-β1 level, the ratio of Tregs/Th17, the ratio of TGF-β1/IL-17, and HBeAg level at various time points of treatment (baseline and weeks 4, 8, 12, 16, 20, and 24) are indicated on the plots by diamonds. Error bars indicate standard error of mean.