Despite the fact that we have been discovering HBV for more than half a century, finding a treatment for chronic hepatitis B is still a big challenge. Treatments that have been approved for chronic hepatitis B include nucleotide analogs and interferons. Nucleotide analogs are effective in suppressing HBV replication to undetectable levels by inhibiting the viral polymerase, but the virus often returns to the blood after drug withdrawal, primarily because of the presence of an active transcriptional template in HBV covalent closed-loop DNA (cccDNA). Curing HBV therefore requires either the removal of cccDNA or the killing of infected liver cells. We know that interferon has a dual effect by directly inhibiting viral replication and also indirectly increasing the antiviral immune effect. Although a higher rate of sustained remission can be achieved after discontinuation of interferon compared to nucleotide analogs. However, this remission rate is still far from satisfactory. HBV-specific immunity in patients cured of HBV infection is very strong and multifunctional, whereas chronic hepatitis B is characterized by an abnormal innate or acquired antiviral immune function. Multiple mechanisms can explain the abnormal HBV-specific T-cell immune function in patients with chronic hepatitis B, including high concentrations of viral antigens (including HBsAg and HBeAg) and tolerance of the hepatic microenvironment. Previous studies have shown that application of nucleotide analogues can inhibit viral replication and transiently and partially re-establish T-cell antiviral immunity. This supports the hypothesis that long-term exposure to high concentrations of antigens can lead to abnormal T-cell antiviral function. Studies of interferon remission have identified several factors associated with treatment success, including lower amounts of virus in the blood at basal status, lower amounts of viral antigens, and higher concentrations of alanine aminotransferase. Therefore, it is reasonable to assume that the combination of nucleotide analogs and interferon sequential therapy is more effective than either regimen alone. This is because nucleotide analogs reduce viral load, thus enhancing the remission rate with subsequent application of interferon therapy. Interestingly, a clinical trial reported that the application of entecavir-pegylated interferon alpha 2a sequential therapy in HBeAg-positive patients with chronic hepatitis B resulted in higher rates of HBeAg seroconversion and HBsAg conversion. In this study, remission rates were higher in patients with lower HBsAg and HBeAg concentrations with sequential pegylated interferon therapy compared with those with higher HBsAg and HBeAg concentrations at the end of entecavir application therapy.