Nucleoside analogs are one of the most important drugs used against the hepatitis B virus. They have the advantage of suppressing the virus faster and improving the disease, as well as being convenient to take and easily accepted by patients. However, nucleoside analogs also have the outstanding disadvantage that they have a high relapse rate when discontinued and require long-term medication. Some patients even have the experience of recurrent relapse, which is imaginatively called “good up but not good down”. How to break the nucleoside relapse nightmare? Achieving clinical cure is undoubtedly the best way. Authoritative guidelines have clearly pointed out that the ideal endpoint of chronic hepatitis B treatment is to achieve HBsAg (surface antigen) clearance, that is, clinical cure. The results of numerous studies confirm that patients who achieve this endpoint have a low risk of cirrhosis and liver cancer and long-term disease remission. The second is the achievement of durable HBeAg (e antigen) serological conversion, such that efficacy can also contribute to long-term disease remission, achieve safe drug discontinuation, and also induce HBsAg clearance. However, the mechanism of action of nucleoside analogues is mainly direct antiviral, and although virological suppression can be achieved relatively quickly, both the HBeAg serological conversion rate and the HBsAg clearance rate obtained by treatment are low, and the HBeAg serological conversion rate of various nucleoside (acid) analogues treated for 2-5 years does not exceed 30%, and the HBsAg clearance rate is close to the natural clearance rate. For patients treated with nucleoside analogs, other drugs need to be found to help achieve safe discontinuation. Compared to nucleoside analogs, interferon therapy achieves higher HBeAg serological conversion and HBsAg clearance rates. This is mainly because pegylated interferon (long-acting interferon) not only has certain antiviral effects like nucleosides, but also helps the host achieve immune control of hepatitis B virus through immunomodulation, and can achieve long-lasting HBeAg serological conversion and even HBsAg clearance rates. It is based on this characteristic that pegylated interferon is able to achieve true successful treatment of slow hepatitis B – clinical cure – with a limited course of therapy, ultimately making it possible for some populations to reach safe discontinuation of the drug. The results of a large clinical study (the OSST study) have shown that patients treated with nucleoside analogs with pegylated interferon alpha-2a have a nearly 2-fold increased chance of achieving HBeAg serologic conversion within 1 year compared to continued nucleoside analog therapy. Especially for patients with cleared HBeAg and low HBsAg levels, the chance of achieving HBsAg clearance can reach 25%. In conclusion, nucleoside therapy is “good on but not good off”. If you have already received nucleoside therapy, you can try to shorten the treatment course with pegylated interferon if your disease is stable, especially when the quantitative level of HBsAg is low, and try to achieve HBeAg serological conversion or even HBsAg clearance.