Chronic hepatitis B is a difficult disease to treat, but it is not insurmountable. With the advancement of medical technology, we have been able to effectively inhibit viral replication, and some patients have been able to achieve a durable response after stopping the drug. Among the current antiviral therapeutic drugs, long-acting interferon has both antiviral and immunomodulatory effects, and can achieve a high HBeAg seroconversion rate and a long-lasting response after stopping the drug. The results of the study showed that long-acting interferon (pegylated interferon alpha-2a) treatment of HBeAg-positive chronic hepatitis B patients, also known as “triple positive”, achieved a seroconversion rate of more than 60% of HBeAg at 24 weeks after discontinuation of the drug. Once HBeAg seroconversion is achieved, the efficacy of long-acting interferon therapy is long-lasting and can induce surface antigen (HBsAg) clearance. Who are the lucky ones who can achieve a sustained response after stopping treatment with long-acting interferon therapy? In order to achieve good results, attention should be paid to the efforts before, during and after treatment. Before treatment, it is necessary to grasp the appropriate timing of treatment. First of all, it should be clear that the patient has entered the immune-clearance period suitable for antiviral therapy, because the patient’s immune function is playing an immune-clearance role, and if antiviral therapy is given at this time, a combination of both inside and outside will be able to achieve twice the effect with half the effort. In addition, patients who are in the immune-clearance phase and have strong immune function, i.e., low HBV DNA levels and high aminotransferase (ALT) levels, are more effective with long-acting interferon. Treatment should be actively monitored and the regimen adjusted based on treatment response to maximize the efficacy of the drug. Studies have confirmed that changes in HBsAg quantification during treatment with pegylated interferon alpha-2a predict HBeAg serologic conversion after discontinuation of the drug. The more HBsAg decreases at 24 weeks of treatment, the higher the rate of future HBeAg serologic conversion. So how many patients fall into this lucky category? The results of the study showed that more than 80% of patients with HBsAg quantification below 20,000 IU/ml at 24 weeks of treatment, and six months after the end of their treatment, nearly half of them will experience HBeAg serologic conversion. End-of-treatment evaluation and consolidation therapy are necessary. Long-acting interferon is a limited-course treatment, routinely given for 48 weeks. If HBeAg seroconversion has been achieved at 48 weeks, especially in people with low quantitative HBsAg levels, the rate of sustained response after discontinuation is high, and for those who meet this criterion the drug can be discontinued after consolidation therapy (usually six months). Long-acting interferon is the preferred treatment option for patients with “triple III” to achieve a durable response after discontinuation of the drug, but the treatment is not a one-step process, and choosing a reasonable therapeutic drug at the right time, carefully monitoring the treatment, and adjusting the treatment program at the right time are the keys to success.