Decline in intrahepatic cccDNA and increase in immune cell reactivity after 12 weeks of antiviral treatment were associated with HBeAg loss

Viral load reduction facilitates recovery of antiviral T-cell responses. Dynamic alterations in intrahepatic viraemia clearance and immune cell reactivity during the early phase of nucleoside analogue (NA) therapy and the impact of these changes on HBeAg seroconversion are unknown. Fifteen HBeAg-positive chronic hepatitis B (CHB) patients were treated with adefovir dipivoxil. T-cell reactivity to HBV core and surface antigens were tested using ELISPOT assay from baseline to week 48 post-treatment (at 4-week intervals). Before and at week 12 of treatment, paired liver biopsies were analysed for intrahepatic HBV-DNA and cccDNA via real-time fluorescent PCR. In situ detection of CD4(+) , CD8(+) T cells and NK cells was analysed by immunohistochemistry. With viral load reduction, HBV-specific IFN-γ-producing CD4(+) T cells in patients with HBeAg loss were greatly enhanced and reached the highest level at week 12, with further increase observed between week 36 and week 48. After 12 weeks of treatment, total intrahepatic HBV-DNA and cccDNA had significantly decreased; however, there was no difference in the viral loads or extent of reduction between patients with and without HBeAg loss. Paralleling reduction in viral load, intrahepatic CD8(+) T lymphocytes increased in patients with HBeAg loss compared with baseline values. Only one patient without HBeAg loss exhibited similar results. Increased immune cells were observed in certain patients along with reduced hepatic viral loads during the second phase of HBV-DNA decline, which could promote the recovery of antiviral immunity and facilitate HBeAg loss.